**5. GH/IGF-1 in pediatric LT**

In pediatric LT, GH and IGF-1 play a significant role in the regulation of growth and body mass, hepatocyte function, and immune system activity [4–6].

Indications for LT in children include ESLD with a life expectancy of less than 1 year, acute liver failure, unresectable liver tumors, and metabolic disease. In 80% of cases, ESLD is caused by congenital anomalies of the biliary tract, such as biliary atresia (BA) and biliary hypoplasia (BH), Alagille syndrome and disease, etc. The incidence of such diseases is about 1 in 10,000–20,000 newborns, atresia is slightly more common in newborn girls than boys. Biliary disorders lead to cholestasis, fibrosis, and cirrhosis, which in turn result in esophageal varices, splenomegaly, hemorrhagic syndrome, esophageal or gastrointestinal bleeding, etc. BA with the inevitable formation of fibrosis and cirrhosis leads to decreased detoxification of metabolites, chronic malnutrition, coagulopathy, growth factor deficiencies, and an excess of proinflammatory cytokines, which together can contribute to delayed physical and psychomotor development. In the absence of early surgical intervention, BA children usually do not live up to one year, dying from liver failure, bleeding, associated pneumonia, cardiovascular disease, and intercurrent infections. With incomplete biliary atresia, some children may live up to 10 years. Therefore, congenital anomalies affecting the biliary tract are a strong indication for LT. LTs performed at Shumakov Center fully cover the needs for this type of care in Russia [50].

The shortage of donor organs for children is compensated by living related donation of liver fragments. As a rule, young children are transplanted with the left lateral lobe of the liver of a living or deceased donor (**Figure 4**).

Transplantation of a liver fragment from a living related donor to children makes it possible to fully satisfy the need for this type of therapy. Improved pretransplantation preparation, patient selection, organ preservation techniques, better immunosuppressive therapy, and post-transplant follow-up techniques have led to outstanding results in this area.

Unlike other solid organs, the liver is an immune-privileged organ, which is due to the peculiarities of development, blood supply, structure, and function of the liver [22, 51, 52]. After LT, incidence of graft rejection is significantly lower than after transplantation of other solid organs, such as the kidney or heart. The best recipient and graft survival rates are observed in pediatric LT from a living related donor. This is due to the peculiarities of immune response development at an early age, the possibility of ensuring greater tissue compatibility, and a shorter graft ischemia time. Pediatric LT from a living related donor is a model of the relationship between the graft and the recipient's body in conditions of minimal risk of rejection and low immunosuppression.

LT has become a standard therapy for children with ESLD, acute or chronic, as well as liver neoplasms and metabolic disorders. According to world statistics, the 5- and 10-year graft survival in children is 85–90% and 77–80%, respectively [53]. *Growth Hormone and Insulin-like Growth Factor-1 in Children with Cholestatic Diseases… DOI: http://dx.doi.org/10.5772/intechopen.108301*

**Figure 4.** *Transplantation of the left lateral liver section in children from an adult living donor.*

The results we achieved at Shumakov Center are fully consistent with global ones. For example, the average 1-year survival rate was 93%, and the 3-year survival rate was up to 90% [50, 54].

#### **5.1 Patients**

The present study included 148 children ≤5 years (60 months) old, selected by random sampling, who underwent liver fragment transplantation at Shumakov Center. The study was approved by the Local Ethics Committee of Shumakov Center (Minutes No.28/1d dated April 15, 2016). All the patients or their guardians gave written informed consent to participate in the study.

The mean age of the recipients was 11 ± 9.8 months (median, 8 months). LT was indicated due to ESLD resulting from various pathologies: biliary atresia (BA, n = 86), Byler disease (n = 15), biliary hypoplasia (BH, n = 14), Alagille syndrome (n = 12), Caroli disease and syndrome (n = 5), and others (n = 16). In the "other" group, we included patients with diseases, which did not exceed three cases, such as autoimmune and fulminant hepatitis, Von Gierke disease, portal vein developmental anomaly, Crigler-Najjar syndrome, Budd-Chiari syndrome, hepatoblastoma, alpha-1 antitrypsin deficiency, and previous liver transplant dysfunction (**Table 1**).

The comparison group consisted of 16 children, 9 boys and 7 girls, practically healthy, examined after treatment of intestinal dysbacteriosis, without other diseases, aged 3–25 (median, 12) months, anthropometric parameters (body height, body mass) were in the range of average population values (25th–75th percentile). The age


#### **Table 1.**

*Baseline patients' characteristics, BA, biliary atresia; BH, biliary hypoplasia.*

and sex of the children included in the study and those of healthy children did not differ (*p* = 0.78 and *p* = 0.84, respectively).

All recipients underwent hepatectomy with preservation of the inferior vena cava, followed by implantation of a liver fragment (left lateral sector) in an orthotopic position. Blood flow characteristics were monitored intraoperatively using ultrasound. Bile duct reconstruction was performed after graft revascularization on the defunctionalized jejunal loop.

### **5.2 Methods**

Patients were examined before and after LT in accordance with the protocol approved at Shumakov Center. Routine examination and treatment of patients before and after LT were carried out in accordance with the clinical guidelines of the Russian Transplant Society and international consensus guidelines.

The required methods were:


Double- and triple-combination immunosuppressive therapies were used at Shumakov Center.

During preparation for donor organ implantation, all recipients received 10 mg of basiliximab. Reintroduction of basiliximab was performed on day 4 after surgery. Immediately before graft reperfusion, methylprednisolone was administered at a dose of 10 mg/kg.

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

Maintenance immunosuppressive therapy included tacrolimus (at 6–8 ng/mL target concentration), glucocorticoids, and mycophenolic acid preparations. Cyclosporin A was administered in a few cases with tacrolimus neurotoxicity. Gradual reduction of methylprednisolone doses to 4–2 mg per day was continued.

Mycophenolic acid preparations were administered as the third component of the therapy in the absence of haplotype compatibility with donors and when a rejection reaction occurred.

In the case of rejection, intravenous pulse therapy was performed with high doses of glucocorticoids (20 mg/kg).

The concentration of biomarkers was studied in plasma or serum obtained from peripheral blood after centrifugation at 1500–2500 g at room temperature. Blood was collected in plastic tubes (BD Vacutainer, Becton Dickinson, USA) without anticoagulant or with sodium citrate as an anticoagulant. Serum and plasma samples were stored at −50°C until analysis.

GH levels were measured by enzyme immunoassay using a reagent kit (DBC, Canada) according to the manufacturer's instructions in blood serum. The optical density of the reaction mixture was measured at 450 nm wavelength using a spectrophotometer. Analytical sensitivity of the method was 0.2 ng/ml. The range of determined concentrations is 0.2–50 ng/ml.

IGF-1 levels were measured by the sandwich immunoassay method using polyclonal sheep antibodies and monoclonal antibodies against IGF-1 in plasma (IDS Ltd. 77 OCTEIA® IGF-1, UK). The analytical sensitivity of the method was 3.1 ng/ml. The range of determined concentrations is 12–627 ng/ml.

#### **5.3 Statistical analysis**

Data are presented as mean and standard deviation (M ± SD), upper and lower limits of the 95% confidence interval for parametric variables, and median and interquartile range from 25th to 75th percentile for nonparametric variables. The data were statistically processed using nonparametric statistics methods: paired Wilcoxon test was calculated to compare dependent samples, and the Mann-Whitney or Kruskal-Wallis U test was used to compare independent variables. Spearman rank correlation coefficient was calculated to evaluate the relationship between quantitative and qualitative ordinal signs. In the case of error probability (*p* < 0.05), the differences were considered statistically significant. The obtained data were processed using Microsoft Office Excel with the IBM SPSS STATISTICS 20 software package for scientific and technical calculations (IBM SPSS Inc., USA).
