**3. Effect of GH/IGF-1 on liver function**

The liver is the largest internal organ in humans; in a child it makes up 4.4% of body mass, which is 1.5 times more than in an adult—2.8%. The importance and diversity of liver functions in young children should be noted: it is not only bile production, general metabolism, detoxification, but also, importantly for pediatric liver recipients, the liver works as an immune organ, maintaining overall immune homeostasis of the body (**Figure 2**).

Humoral regulation of liver function is provided by the peculiarity of the hepatic portal system and the diversity of the cellular composition, which are targets for so many hormones and cytokines (**Figure 3**).

The liver forms a unique microenvironment due to its anatomy, in particular the circulatory system consisting of the portal vein, hepatic artery, and liver sinusoid. Portal

#### **Figure 2.**

*Liver functions in children.*

## **Figure 3.**

*Peculiarities of liver structure and cells composition. The hepatic blood supply system consists of the portal vein, the hepatic artery, and the sinusoidal capillary system of the liver, which flows into the central vein. Liver cells with antigen-presenting function: dendritic, Kupffer, stellate, and endothelial. GH – growth hormone, GHR – growth hormone receptor, IGF-1 – insulin-like growth factor 1, IGFR – IGF receptor, TGF-beta1 – transforming growth factor beta 1, sFas/sFasL – soluble Fas/soluble Fas ligand.*

venous blood is rich in dietary antigens and toxins, to which tolerance is developed by a large set of liver cells with antigen-presenting function: dendritic, Kupffer, stellate, and endothelial cells [19–23]. Liver sinusoidal endothelial cells, which, unlike the vascular endothelium, do not have a basement membrane and tight junctions, are capable of blocking proinflammatory CD8+ T cells [24]. The liver is characterized by the generation of autoantigen-specific regulatory T cells, which, through active immunosuppression of type 1 and 2 T helper cells (Th1/2), form a mechanism of autoimmune tolerance [25–27]. It is also assumed that natural killers play a significant role in the immunocompetent properties of the liver; their number in the human liver is up to 10% of all

*Growth Hormone and Insulin-like Growth Factor-1 in Children with Cholestatic Diseases… DOI: http://dx.doi.org/10.5772/intechopen.108301*

lymphocytes [28]. Liver stellate cells are also capable of suppressing immune response, causing apoptosis of activated T cells through expression of costimulatory molecules (CD28/B7) B7-H1 and the production of cytokines—interleukins (IL) 6 and 10, transforming growth factor beta (TGF-β) [29]. Stellate cells induce tolerance through apoptosis of activated T cells via the Fas/Fas ligand system, IL-10 and TGF-β [20].

The GH/IGF-1 axis is the most important regulatory system of the body that controls cell growth and is closely related to liver function [4, 5, 30]. Previously, it was believed that IGF-1 does not directly affect the function of hepatocytes, because in a healthy liver, a small number of IGF-1 receptors are expressed on the surface of hepatocytes. However, further studies have shown that their expression is increased in some liver diseases [30]. In acute viral hepatitis, chronic hepatitis C and B, the expression of IGF-1 receptors on hepatocytes is higher than in a healthy liver. Meanwhile, there are elevated IGF-1 levels, which is believed to accelerate the regeneration of damaged hepatocytes [31].

The antifibrotic effect of IGF-1 is realized both directly through the GH/IGF-1 axis and indirectly through regulation of other profibrogenic factors [32, 33]. Stellate cells play a key role in the development of liver fibrosis: their activation caused by chronic trauma, oxidative stress, and increased levels of inflammatory cytokines and lipopolysaccharides leads to transformation into fibroblasts [34]. It has been shown that IGF-1 is able to inactivate hepatic stellate cells and induce their aging, thus limiting the development of fibrosis [35]. GH and IGF-1 regulate lipid metabolism and influence the development of steatosis, inflammation, and liver fibrosis in a certain way [36]. Thus, reduced IGF-1 production in the liver is not only the result of impaired liver function, but also plays an important role in the development of fibrosis.
