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• W2030457773 abstract "Hepatic tumors are uncommon in the neonatal period, and of those infantile hepatic hemangioendotheliomas (IHHs) are the most frequently occurring primary hepatic lesions (1). They are divided into 3 main groups—focal, multifocal, and diffuse. Seventy-five percent of the diffuse tumors are associated with hemangiomas in other organs, with almost half presenting with cutaneous hemangiomas (1). Observation is recommended for focal lesions, whereas treatment for multifocal and diffuse IHH, especially if there are signs and symptoms of other organ dysfunction, has included corticosteroids, hepatic artery ligation with or without corticosteroids, hepatic artery embolization, surgical resection, or liver transplantation (1,2). Recently, several groups have reported treatment with oral propranolol as a therapeutic regimen for IHHs (3–8). Although commonly used for cutaneous hemangiomas (9), only 3 studies thus far have used propranolol as a first-line therapy for multifocal or diffuse IHH (4,7,8), demonstrating beneficial outcomes with no or minimal adverse effects. Here we present a case report of diffuse IHH treated with propranolol, and review the literature on using propranolol as a first-line therapy for IHH. A 2-week-old girl was referred to our center for multiple cutaneous and hepatic hemangiomas, otherwise asymptomatic. She was born full-term via repeat cesarean section following a noncomplicated pregnancy and normal prenatal sonograms. The birth weight was 3.37 kg and birth length was 50.2 cm. She was exclusively breast-fed and had no illnesses. The review of systems was negative except as noted above. On physical examination, the patient was an active infant with normal vital signs. Her weight was 3.56 kg (30th percentile), length 50.3 cm (25th percentile), and head circumference 33.8 cm (5th percentile). Skin examination was notable for eleven 2- to 3-mm hemangiomas on the back, chest, arm, and scalp. The cardiac examination was normal, and the abdominal examination was significant for hepatomegaly with the liver edge palpable 3 cm below the right costal margin, an umbilical hernia, but no splenomegaly. Laboratory investigations showed a white blood cell count of 9100 cells/mm3, hemoglobin of 12.5 g/dL, platelet count of 473,000 cells/mm3, total bilirubin of 0.7 mg/dL, albumin of 3.4 g/dL, and serum aminotransferases, γ-glutamyl transferase, alkaline phosphatase, α-fetaprotein, and blood coagulation values were normal. Thyroid function tests revealed a highly elevated thyroid-stimulating hormone (TSH) of 65.10 μIU/mL (0.34–5.6 μIU/mL). Free and total T3 and T4 were within normal limits, but reverse T3 serum level was >200 ng/dL (11–32 ng/dL). The patient had normal urine levels of homovanillic and vanillylmandelic acids. Echocardiography showed mildly dilated ventricles, reflecting volume overload. The MRI of the abdomen demonstrated hepatomegaly with innumerable masses within the liver with low T1 and high T2 signal intensity, largest of which was in the right lobe, measuring 3.0 × 3.1 × 2.9 cm (Fig. 1). Duplex/color Doppler ultrasound evaluation of the abdomen was obtained as a baseline examination for following the lesions (Fig. 2A). It characterized the largest hepatic lesion as a hypervascular hypoechoic mass and demonstrated patent but enlarged hepatic veins and hepatic artery.FIGURE 1: Axial T2 fat-saturated magnetic resonance imaging image of the liver (arrows) at the time of presentation demonstrates innumerable masses within the liver, which demonstrates high T2 signal intensity, with the largest mass measuring up to 3.0 cm in cross-sectional diameter.FIGURE 2: A, Sagittal Duplex/color Doppler ultrasound evaluation of the liver at the time of presentation demonstrated multiple variable-size hypoechoic hypervascular masses throughout the liver, with arrows pointing to the largest lesion. B, Ultrasound evaluation of the liver 1 year later showed significant diminution in the number and size of the lesions with only 1 well-defined small hypoechoic lesion (arrow) within the right hepatic lobe, which measured up to 0.6 cm in cross-sectional diameter.A diagnosis of IHH was made, with diffuse hemangiomatosis and consumptive hypothyroidism. The patient started taking levothyroxine (30 μg · kg−1 · day−1). Propranolol was started at 3 weeks of age at 0.25 mg · kg−1 · day−1 and within 3 days increased to 2 mg · kg−1 · day−1. After 3 months of treatment, significant regression of the cutaneous hemangiomas and decrease in the number and size of the diffuse hepatic lesions were noted. Initially, there was a rapid decrease of the dose requirement of levothyroxine for treatment of hypothyroidism, which had to be changed within 3 to 4 days after starting propranolol and continued to be decreased every 2 to 3 weeks, from 30 to 15 μg · kg−1 · day−1 after 6 weeks, and to 3 μg · kg−1 · day−1 after 5 months of treatment. The patient continued treatment with propranolol at 2 mg · kg−1 · day−1 until 12 months of age, at which time ultrasound imaging of the liver showed avascular hypoechoic lesions with the largest measuring 1.1 × 0.5 × 0.9 cm in the right hepatic lobe. Treatment was discontinued suddenly, and was tolerated well. Follow-up sonography 2 months after discontinuing propranolol revealed a normal size liver, with 1 definitely discernible lesion measuring 0.6 × 0.5 × 0.4 cm, with no evidence of new lesions (Fig. 2B). Thyroid hormone supplementation was continued at 2.5 μg · kg−1 · day−1 dose until 15 months of age. Repeat thyroid functions tests off hormone therapy showed normal TSH levels. No complications occurred during or after discontinuation of therapy. DISCUSSION First-line medical therapy for both cutaneous and solid-organ infantile hemangiomas warranting treatment, both cutaneous and solid organ, has traditionally been corticosteroids, followed by interferon α or vincristine for resistant lesions. Potential serious side effects of these medications are well known. A recent review of management and outcome of hepatic hemangiomas stratified the management of hepatic lesions depending on the extent of their involvement in the liver (10). Due to the higher association of hepatic vascular abnormalities in infants with multiple cutaneous hemangiomas, it is recommended to screen all of the patients younger than 6 months with abdominal ultrasound if 5 or more cutaneous hemangiomas are present (11,12). Patients with multifocal (4–20 lesions) or diffuse (>20 lesions) IHH are screened with echocardiogram and thyroid function tests. There has been variability in the management of these types of IHH, and reported treatments ranging from observation for stable lesions to corticosteroids, hepatic artery ligation, and surgical resection (1). An extensive review on hepatic hemangiomas by Christison-Lagay et al (2) outlined an algorithm for treatment of the various types of IHH; however, recent publications report oral propranolol as a new and possibly first-line treatment option for noncutaneous hemangiomas (Table 1) (3–8).TABLE 1: Characteristics and treatment dose of all of the reported cases of infantile hepatic hemangioendotheliomas managed with propranololPropranolol has been used in infants for various cardiac pathologies, including hypertension, congestive heart failure, supraventricular tachycardias and long QT syndrome, as well as for thyrotoxicosis in up to 8 mg · kg−1 · day−1 doses without any adverse effects (13). Hypotension, bradycardia, and hypoglycemia are well-recognized adverse effects and need to be closely monitored in infants, as important potential risks in this population (14); however, the adverse-effect profile of high-dose corticosteroids, most notably weight gain, hypertension, hyperglycemia, and osteoporosis, of vincristine with constipation and long-lasting peripheral neuropathy, and of interferon α with generalized malaise and transient leucopenia, are well known. In fact, the serendipitous discovery of propranolol as treatment for hemangiomas was in the context of using this drug as treatment for obstructive hypertrophic cardiomyopathy caused by high-dose steroids initially used for the problematic cutaneous hemangioma (15). Propranolol use in cutaneous hemangiomas has also been well established (9). All of the cases noted in Table 1 reported no significant adverse effects from propranolol at the doses used. In the case of our patient, the initiation of therapy was done in an inpatient setting to monitor for the parameters affected by propranolol, including blood pressure, heart rate, and blood glucose concentration, and no adverse effects were noted upon initiation and during the treatment course. The exact pathway by which propranolol acts on hemangiomas is not entirely known, but there are several possible mechanisms that have been identified through both in vitro and in vivo studies, mostly done in cutaneous lesions. These include vasoconstriction via inhibition of β-2 receptors, decrease of 2 important growth factors for hemangiomas, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFDF), via blockade of adrenergic stimulation, arrest of tumor growth by regulation of matrix metalloproteinases 2 and 9, and endothelial cell apoptosis and tumor involution via β-2 antagonism (16). An interesting recent report from Itinteang et al (17) demonstrated the involvement of the renin-angiotensin system in the pathophysiology of proliferating hemangiomas. They showed that proliferating cutaneous tumors from infants contain endothelial progenitor cells, which express angiotensin-converting enzyme and angiotensin II receptor-2, and proliferate in response to angiotensin II. Blocking renin production by a β-blocker thus decreases the proliferative signal for endothelial progenitor cells, leading to the initial steps toward the involution of the tumor (17). IHH, particularly multifocal and diffuse types, may be associated with consumptive hypothyroidism (18). The mechanism is attributed to the elevated levels of type 3 iodothyronine deiodinase, produced by the hepatic hemangioma, as well as decreased degradation of type 3 iodothyronine deiodinase by the liver tissue that has been replaced by the lesions. There is such rapid conversion of active thyroid hormone to reverse T3, the inactive form, that large doses of thyroid hormone replacement are required to keep the patient euthyroid. Reports in the literature of infants and children with consumptive hypothyroidism secondary to hemangioendotheliomas have used doses as high as 94 μg · kg−1 · day−1(19–21). Our patient started taking levothyroxine at 30 μg · kg−1 · day−1, which quickly corrected the TSH levels. The dose of levothyroxine was quickly tapered as the lesions responded to propranolol. Thyroid function tests should be regularly checked in patients with consumptive hypothyroidism, especially in the presence of an effective treatment, for levothyroxine redosing. In summary, we here present a case report of diffuse IHH associated with consumptive hypothyroidism successfully treated with propranolol as a first-line therapy. Improvement in both the hypothyroidism and the size and number of hepatic lesions was notable by 3 months of treatment, with small residual lesions by 12 months of age. Follow-up at 2 months off therapy revealed further decrease of the hepatic lesions. Thyroid hormone therapy was successfully discontinued by 15 months of age." @default.
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• W2030457773 title "Propranolol as a First-line Treatment for Diffuse Infantile Hepatic Hemangioendothelioma" @default.
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