Successful First‐line Treatment With Propranolol of Multifocal Infantile Hepatic Hemangioma With High‐flow Cardiac Overload

Abstract

Infantile hemangioma is the most common liver tumor in the first year of life. Although spontaneous regression is the rule (1), high-output cardiac failure caused by arterovenous and portovenous shunting may be observed rarely. Current medical treatment consists of high doses of prednisone and interferon and/or vincristine in cases of lack of response (2). In rare situations, more invasive and aggressive measures must be taken, such as selective hepatic arterial embolization and, rarely, liver transplantation (3). Propranolol has been reported to be effective and well tolerated in newborns with severe cutaneous infantile hemangioma (4) and found to have a strong inhibitory effect in several cases of superficial hemangiomas (5). Recently, it was reported to be successful in the treatment of a few infants with hepatic hemangioma (6–9). A girl was the first daughter of unrelated parents. Delivery occurred at the 38th week via caesarean section because of the appearance of maternal itching and elevation of liver enzymes following initiation of treatment with methyldopa for pregnancy-induced hypertension. Delivery was uncomplicated; physical examination at birth revealed a cardiac systolic murmur. Doppler echocardiography suggested the diagnosis of pulmonary valve stenosis, with pulmonary valve annulus of 8 mm and a transvalvular gradient of 25 mmHg. Follow-up echocardiography documented, at age 5 weeks, an increase of pulmonary transvalvular gradient that reached 40 mmHg. The patient was asymptomatic. One week later, several small cutaneous hemangiomas were noted, rapidly increasing in size (maximum diameter 10 mm) and number. An abdominal ultrasound at age 3 months showed multiple isoechogenic nodules involving all of the liver parenchyma. The infant was referred for evaluation, and the clinical examination showed a mildly malnourished baby with 10 small cutaneous hemangiomas of different sizes, some of which had recently appeared. The liver was homogeneously enlarged, and the spleen was not palpable. Ultrasonography showed multiple hypoechoic lesions. An enhanced abdominal magnetic resonance imaging study was performed using a 1.5-T scanner. The liver was enlarged, with regular and smooth margins. The portal venous system and hepatic veins were normally patent, and there were no biliary duct dilatation and no free fluid in the abdomen. The hepatic lesions were hyperintense on T2-weighted (Fig. 1A) and hypointense on T1-weighted (Fig. 1B) images. The arterial phase of the postcontrast T1-weighted images showed intense enhancement with progressive, persistence uptake of contrast on the delayed portal phase (Figs. 1C and D).FIGURE 1: Magnetic resonance investigation following the first ultrasound examination performed before and after the injection of paramagnetic contrast medium. Fat-suppressed T2-weighted (A) and T1-weighted precontrast-enhanced (B) axial images, T1-weighted contrast-enhanced image in arterial phase (C) and venous phase (D) acquired in axial plane show numerous hypervascular hepatic lesions involving the majority of the liver parenchyma.Laboratory tests showed normal total and direct-reacting bilirubin, alanine aminotransferase, and gamma-glutamyltranspeptidase activities, and prothrombin activity. Albumin was 3.10 g/dL and total serum bile acids were 140.5 μmol/L (normal values 0–8 μmol/L). Full blood count showed leukocytes 10.470 μL, hemoglobin 13 g/dL, and platelets 259,000 μL. Cardiologic assessment showed a picture of high-flow cardiac overload with a further increase in transvalvular pulmonary gradient up to 63 mmHg, with an enlargement of all of the cardiac chambers and with mild mitral and tricuspidal insufficiency. The baby girl was fatigued and fed poorly. Treatment with propranolol was begun according to the pediatric cardiologist with close follow-up, and the drug administered at an initial dose of 1 mg · kg−1 · day−1 in 3 divided doses and subsequently increased to 2 mg · kg−1 · day−1. The blood pressure and heart rate were monitored as recommended (4). Lightening of the color and reduction in size of cutaneous lesions was noted within 2 weeks, and the infant progressively improved feeding and behavior. Pulmonary transvalvular gradient reduced to 48, 30, and 20 mmHg after 4 weeks, 3 months, and 6 months of therapy, respectively. Moreover, echocardiographic features of high-flow cardiac overload disappeared since the first control after 4 weeks of therapy. At age 7 months, after 3 months of therapy, a control magnetic resonance of the liver, performed as described above, revealed dramatic reduction of number and size of vascular lesions (Fig. 2). At liver ultrasound at age 15 months, after 12 months of therapy, no clear lesions could be identified and a new magnetic resonance at age 17 months, after 14 months of therapy, demonstrated some residual lesions further reduced in number and size.FIGURE 2: Magnetic resonance control of the liver performed after 3 months of therapy reveals a significant reduction of number and size of multiple hemangiomas. Sequences, scans, and contrast medium are the same as the previous examination: Fat-suppressed T2-weighted (A) and T1-weighted precontrast-enhanced (B) axial images, T1-weighted contrast-enhanced image in arterial phase (C), and venous phase (D). Note the necrosis induced by the treatment inside one of the numerous hemangiomas; the necrosis is well visualized before and after the injection of contrast medium.Propranolol doses were progressively decreased to 1.2 mg · kg−1 · day−1 and no adverse effects of therapy were recorded. At the last visit, at age 17 months, general conditions were excellent, there were 2 small residual cutaneous angiomas, the heart murmur was still present, but the pulmonary transvalvular gradient was stable at 20 mmHg. DISCUSSION Infantile hepatic hemangioma is the most common benign liver tumor presenting in infancy and childhood. Multifocal and diffuse variants are more likely associated with most morbidity and mortality because of high-output cardiac failure, hepatic dysfunction, hypothyroidism, abdominal compartment syndrome, anemia, and consumptive coagulopathy. Although asymptomatic patients usually do not require treatment, in children with significant hemodynamic shunting, adequate high-dose corticosteroids are the first-line treatment. Unfortunately, only 30% to 60% of such cases show a clinical response to steroids (10,11), and a substantial proportion of life-threatening hemangioma is steroid resistant (12). α-Interferon and vincristine are the second-line medical treatments (10,13), but in severe cases, they rarely avoid the need for more aggressive procedures and their safety profile is not optimal. Thus, novel and safe medical treatments that may cause regression of the tumor or alternatively stabilize the picture before spontaneous regression phase may occur are needed. DISCUSSION We report a case of an infant with high-flow cardiac overload related to multifocal liver hemangiomas, first-line treated with propranolol, which showed a dramatic improvement in general conditions, regression of echocardiographic signs of cardiac overload and of hepatic lesions, within 3 months of the beginning of therapy. When this therapy was initiated, no data in the literature were available on the efficacy of propranolol on visceral hemangiomas. The pediatric cardiologist made the decision based on evidence of the efficacy of propranolol in the treatment of severe infantile cutaneous hemangiomas (4). A few reports have appeared concerning the use of propranolol in severe infantile liver hemangioma (6–9). The children were treated with propranolol after several unsuccessful attempts with prednisone, α-interferon, vincristine, and cyclophosphamide. The series described 8 infants from 5 different centers with cutaneous and diffuse or multifocal liver hemangioma. Five of them, with no signs of cardiac failure, received first-line therapy with propranolol, whereas 3, with signs of cardiac failure, received propranolol after unsuccessful attempts with prednisone and/or vincristine. Even when patients included in the series were inhomogeneous and briefly presented, partial or complete resolution of the hepatic lesions was reported in all of the patients. In our patient, mild pulmonary artery stenosis, documented at birth, led us to closely monitor her with echocardiography, and we documented the increase of pulmonary transvalvular gradient in parallel to the rapid development of cutaneous and liver lesions. This allowed us to speculate that this increase was directly related to the increase of cardiac flow through the high-volume vascular shunting inside the hemangiomas. The clinical response to propranolol was prompt and documented by the disappearance of echographic signs of cardiac overload and progressive reduction of pulmonary transvalvular gradient strictly associated with reduction in number and size of cutaneous lesions and liver nodules (Fig. 3). At the end of follow-up, mild pulmonary stenosis subsided, but it was clinically irrelevant because of the resolution of intrahepatic shunting.FIGURE 3: Transvalvular pulmonary valve gradients from birth to 60 weeks of life. Prompt reduction after treatment onset.When the infant was referred to our unit at age 4 months, her hemangiomas were rapidly growing in size and number. Thus, it appears unlikely that clinical amelioration during treatment with propranolol could be attributed to spontaneous involution of the hemangiomas. As previously reported, we did not observe any notable adverse effects of the treatment. In summary, propranolol may be attempted as a first-line treatment of infants with infantile hepatic hemangioma, even in the presence of cardiac symptoms related to high-flow overload, whereas emergency embolization should be reserved for severe, life-threatening, high-output heart failure.