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Review
. 2022 Feb 11;5(1):pbac006.
doi: 10.1093/pcmedi/pbac006. eCollection 2022 Mar.

Infantile hepatic hemangiomas: looking backwards and forwards

Xue Gong  1 , Yanan Li  1 , Kaiying Yang  1 , Siyuan Chen  2 , Yi Ji  1
Affiliations
Review

Infantile hepatic hemangiomas: looking backwards and forwards

Xue Gong et al. Precis Clin Med. .

Abstract

Infantile hepatic hemangiomas (IHHs) are common benign tumors seen in the liver of infants. IHHs are true infantile hemangiomas (IHs) and have phases of proliferation and involution parallel to those of cutaneous IHs. The definition and classification of IHH are still confusing in the literature. The mechanisms during the pathogenesis of IHH have yet to be discovered. The clinical manifestations of IHH are heterogeneous. Although most IHH lesions are asymptomatic, some lesions can lead to severe complications, such as hypothyroidism, consumptive coagulopathy, and high-output congestive cardiac failure. Consequently, some patients can possibly encounter a fatal clinical condition. The heterogeneity of the lesions and the occurrence of disease-related comorbidities can make the treatment of IHH challenging. Oral propranolol is emerging as an effective systemic approach to IHH with obvious responses in tumor remission and symptom regression. However, the precise clinical characteristics and treatment strategies for patients with severe IHH have not yet been well established. Here, we summarize the epidemiology, pathogenic mechanism, clinical manifestations, diagnosis, and treatment of IHH. Recent updates and future perspectives for IHH will also be elaborated.

Keywords: angiogenesis; consumptive hypothyroidism; endothelial progenitor cells; glycolysis; infantile hepatic hemangioma; screening; treatment; vasculogenesis.

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Figures

Figure 1.
Figure 1.
CHHs are the hepatic equivalent of cutaneous congenital hemangiomas, which arise in utero and are present and fully formed at birth. CHHs may have three distinct growth patterns: rapidly involuting congenital hemangiomas, which rapidly involute in infancy; partially involuting congenital hemangiomas; and noninvoluting congenital hemangiomas, which do not involute., (A) Prenatal T2-weighted MRI at 34 weeks gestational age demonstrates a CHH in the fetus. (B) Postnatal T2-weighted MRI at 5 days of age reveals a large hyperintense lesion in the liver. The lesion continued to involute over time with no treatment. (C) T2-weighted MRI at 2 years of age demonstrates nearly complete involution of the liver lesion.
Figure 2.
Figure 2.
Multiple cutaneous IH with multifocal IHH. (A) Multiple cutaneous IH (IHs) in a 2-month-old female with multifocal IHH. (B) T2-weighted MRI shows multifocal hepatic lesions, which are hyperintense with intervening areas of normal hepatic parenchyma.
Figure 3.
Figure 3.
Diffuse IHH with severe complications. (A) A 1.5-month-old female with massive hepatomegaly, which caused severe respiratory compromise, high output cardiac failure, and abdominal compartment syndrome. (B) T2-weighted MRI shows massive liver involvement of innumerable lesions with near complete displacement of all liver parenchyma.
Figure 4.
Figure 4.
‘Combined’ IHH. A representative T2-weighted MRI of ‘combined’ IHH. The IHHs were innumerable and coalesced, but the lesions did not entirely replace the hepatic parenchyma.
Figure 5.
Figure 5.
Angiogenesis in IH. Angiogenesis plays crucial roles in the development of IH. Angiogenic sprouts emerge from the newly formed vessels in response to proangiogenic cues, such as hypoxia-induced VEGF-A, epidermal growth factor (EGF), fibroblast growth factor (FGF), and HIF-1α. The IH site (hypoxic area) secretes cytokines (e.g. MMP9) that promote EPC homing. After homing, EPCs differentiate into ECs and promote both angiogenic signals and structural support to augment angiogenesis. During sprouting angiogenesis, the VEGF-A and Notch signaling pathways are implicated in the specification of tip and stalk cells in the vascular endothelium. VEGF-A stimulation, acting via VEGFR-2, increases Dll4 on endothelial cells, which in turn activates Notch receptors (e.g. Notch1) on neighbouring endothelial cells. Overexpression of platelet-derived growth factor (PDGF) within the hypoxic tumor site results in increased pericyte recruitment and coverage. (This figure was created by the authors on Biorender, https://biorender.com)
Figure 6.
Figure 6.
Glycolysis promotes angiogenesis in IH. Glycolysis is defined as the conversion of glucose into pyruvate. In the presence of oxygen, glucose is finally converted into lactate, which is known as aerobic glycolysis or the “Warburg effect”. Several advantages exist for tumor endothelial cell reliance on glycolysis, including producing ATP faster, reducing reactive oxygen species production, providing more carbon skeletons for biosynthesis, and more adaptation to a hypoxic environment., Both the PI3K/Akt/mTOR pathway and HIF-1α pathway are involved in the pathogenesis of IH. The PI3K/Akt/mTOR pathway and HIF-1α pathway are key regulators of glycolysis. Upregulated VEGF/VEGFR-2 signaling in HemECs induced an autocrine signaling loop, which resulted in Akt activation. Activation of AKT can stabilize the glucose transporter Glut-1 at the plasma membrane, increasing aerobic glycolysis. Glycolysis promotes endothelial cell competitiveness for the tip position, thus promoting IH angiogenesis (This figure was created by the authors on Biorender, https://biorender.com). Abbreviations: G6P, Glucose-6-phosphatase; F6P, Fructose-6-phosphate; FBP, Fructose-1,6-bisphosphate; G3P, Glyceraldehyde-3-phosphate; 1,3BPG, 1,3-Bisphosphoglycerate; 3PG, 3-Phosphoglycerate; 2PG, 2-Phosphoglycerate; PEP, Phosphoenolpyruvate; Pyr, Pyruvate; Lac, Lactate; GLUT1, Glucose transporter 1; HK2, Hexokinase 2; PFK1, Phosphofructokinase 1; PKM2, Pyruvate kinase M2; LDHA, Lactate Dehydrogenase A; TCA, Tricarboxylic acid.
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References

    1. Hsi Dickie B, Fishman SJ, Azizkhan RG. Hepatic vascular tumors. Semin Pediatr Surg. 2014;23:168–72.. doi: 10.1053/j.sempedsurg.2014.06.018. - DOI - PubMed
    1. Dickie B, Dasgupta R, Nair R, et al. . Spectrum of hepatic hemangiomas: management and outcome. J Pediatr Surg. 2009;44:125–33.. doi: 10.1016/j.jpedsurg.2008.10.021. - DOI - PubMed
    1. Christison-Lagay ER, Burrows PE, Alomari A, et al. . Hepatic hemangiomas: subtype classification and development of a clinical practice algorithm and registry. J Pediatr Surg. 2007;42:62–8.; discussion 67-68. doi: 10.1016/j.jpedsurg.2006.09.041. - DOI - PubMed
    1. Butters CT, Nash M. Infantile Hepatic Hemangiomas. N Engl J Med. 2021;385:e10. doi: 10.1056/NEJMicm1907892. - DOI - PubMed
    1. Kuroda T, Kumagai M, Nosaka S, et al. . Critical infantile hepatic hemangioma: results of a nationwide survey by the Japanese Infantile Hepatic Hemangioma Study Group. J Pediatr Surg. 2011;46:2239–43.. doi: 10.1016/j.jpedsurg.2011.09.007. - DOI - PubMed

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