Effects of Parenteral Nutrition Without and With Growth Hormone on Growth Hormone/Insulin-Like Growth Factor-1 Axis After Hepatectomy in Hepatocellular Carcinoma With Liver Cirrhosis
By Cao, Jie Luo, Shi-Min; Liang, Lijian; Lai, Jiaming
ABSTRACT. Background: Complex alterations in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis are thought to play an important role in the protein catabolism that complicates major surgical procedures. The aim of this study was to evaluate the potential roles of recombinant human growth hormone (rhGH) therapy after hepatectomy in hepatocellular carcinoma (HCC) with liver cirrhosis, and to investigate whether postoperative administration of rhGH increases the risk of tumor recurrences. Methods: Twenty- four patients with HCC in the setting of cirrhosis who underwent hepatectomy were randomly divided into 2 groups: parenteral nutrition (PN) group (n = 12) and rhGH + parenteral nutrition group (n = 12). Liver function, serum GH, IGF-1, and IGF binding protein- 3 (IGFBP-3) were measured before operation, at postoperative days (POD) 1 and 6. IGF-1 and IGFBP-3 mRNA in liver tissue was measured by reverse transcriptase polymerase chain reaction. Liver Ki67 immunohistochemistry staining was studied. At the same time, 12 patients with cholelithiasis or liver hemangioma who underwent operation were segregated as a normal control. Results: On POD 6, compared with the PN group, serum prealbumin, GH, IGF-1, IGFBP-3, hepatic IGF-1 mRNA, IGFBP-3 mRNA, and liver Ki67 LI were higher in rhGH + PN group. The 6- and 12-month tumor-free survival rates, a median tumor-free survival time, were not different between the PN and rhGH + PN group. Conclusions: rhGH + PN can ameliorate changes in the GH/IGF-1 axis after hepatectomy for HCC in the setting of cirrhosis. (Journal of Parenteral and Enteral Nutrition 31:496-501, 2007) The liver has a role as an endocrine gland in the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis.1 In plasma and extracellular fluids, IGF-1 is complexed to binding proteins (IGFBPs), 6 of which have been identified. In the circulation, IGF- 1 is >90% bound to IGFBPs. IGF binding protein-3 (IGFBP-3) is the major binding-protein. The GH/IGF-1 axis plays a crucial role in the regulation of growth, cellular proliferation and transformation, and apoptosis. Circulating concentrations of IGF-1 might be associated with an increased risk of cancer, whereas IGFBP-3 concentrations could be associated with a decreased cancer risk.2 More than ~60%- 80% of hepatocellular carcinoma (HCC) cases arise in liver cirrhosis. HCC is associated with a higher IGF-1:IGFBP-3 ratio than that found in patients with liver cirrhosis and a similar degree of liver failure.3
The GH/IGF-1 axis is markedly altered in human and experimental liver cirrhosis and in alcohol-induced liver disease. Complex alterations in the GH/IGF-1 axis are thought to play an important role in the protein catabolism that complicates trauma, burns, sepsis, and major surgical procedures. In addition, liver cirrhosis patients with low IGF-1 levels showed a lower long-term survival rate than those with high IGF-1 levels.4 Thus, the deranged protein metabolism due to the altered GH/IGF-1 axis in liver cirrhosis may be related to high morbidity and mortality after surgery.
Postoperative hepatic IGF-1 production may be severely disturbed in patients with liver cirrhosis, and the impaired IGF-1 production contributes to the suppressed postoperative protein metabolism in liver cirrhosis. It may be appropriate to increase serum IGF-1 level in patients with liver cirrhosis to enhance postoperative protein metabolism and improve the postoperative outcome.5 Nutrition energy balance, macronutrient composition of the diet, and physical activity levels seem to be major determinants of IGF-1 bioactivity.6
Considering the negative clinical impact of cancer cachexia, nutrition support has become an extensively investigated field of research. Patenterai nutrition (PN) has been studied as a means of reversing the malnutrition seen in patients with cancer, and potentially decreasing perioperative morbidity and mortality rates. We recently reported that amino acid solution and recombinant human growth hormone (rhGH) can influence the GH/IGF-1 axis in rats with liver cirrhosis. It may be helpful in selecting and evaluating nutrients by measuring the serum IGF-1 and IGFBP-3 level.7 On the other hand, it has also been claimed that rhGH may promote the activation of residual tumor cells and therefore increases the risk of tumor recurrence. The aim of this study was to evaluate the potential roles of rhGH therapy after hepatectomy in HCC with liver cirrhosis and to investigate whether postoperative administration of rhGH increases the risk of tumor recurrences.
TABLE I
Patient characteristics
MATERIALS AND METHODS
Patients
All the patients were from our department who underwent curative resection for HCC with liver cirrhosis between September 2002 and June 2003. Curative resection was denned as complete resection of all macroscopically detectable tumors with histologie tumor clearance (the entire tumor mass was included in the surgical specimen, without exposure of tumor cells on the cut edge). At the time of entry, the inclusion criterion was no evidence of endocrine disease. The study protocol conformed to the ethical guidelines and the patients were enrolled after informed consent was obtained. Twenty-four patients were recruited and, using sealed envelopes, were randomly divided into 2 groups: PN group (n = 12) and rhGH + PN group (n = 12) using sealed envelopes. Between the 2 groups, there were no differences in age, sex, body mass, operative methods, operation time, intraoperative blood loss, and intraoperative blood transfusion (Table I). At the same time, 12 patients with cholelithiasis or hemangioma who underwent operation served as normal controls. None had liver cirrhosis or endocrine disease.
Nutrition Support and rhGH Administration
Nutrition support and rhGH administration were started on the first day after surgery and continued until day 5. PN was initiated through a percutaneously placed subclavian vein catheter threaded into the superior vena cava. The formula provided nonprotein calorie 25 kcal/kg/d. Each patient was provided 250 mL 20% MCT/LCT (medium- chain/long-chain triglycerides) lipid emulsion (Guangzhou Qiaoguang Pharmaceutical Co Ltd, Guangdong, China) and 750 mL 10% aminoplasmal Hepa (Braun Co Ltd, Melsungen, Germany) containing 20 kinds of amino acids, 33.0% branched-chain amino acids, and 15.3 g/L nitrogen. Nonprotein calories were provided 31% as lipid emulsion. The formula provided nitrogen 0.19 g kg/d. The ratio of nonprotein calories to nitrogen was 132:1. The ratio of glucose (g) to insulin was 6:1. Vitamins, trace minerals, and electrolytes were supplied according to the daily requirement. Albumin (ALB) prescriptions were given habitually during this study. This PN was tolerated by all patients without complications, and no patient showed symptoms of sepsis during the treatment period.
Patients in the rhGH + PN group received 10 U rhGH (Saizen; Serono, Geneva, Switzerland) additionally per day subcutaneously.
Collection of Samples
Blood samples were collected from antecubital veins in the morning after an overnight fast before operation in the normal control, PN, and rhGH + PN groups and on postoperative days (POD) 1 and 6 in the PN and rhGH + PN groups. Blood samples were centrifuged at 4[degrees]C and then frozen at -70[degrees]C until assay.
Liver specimens from the control group, PN, and rhGH + PN group, including a core biopsy taken at the time of surgery in the case of the patients with cholelithiasis and part of the surgical specimen in patients with liver hemangioma in the normal control group, HCCs, and adjacent nontumor tissues were excised at the operation, and percutaneous liver biopsies were taken on POD 6 in the PN group and rhGH + PN group, immediately frozen with liquid nitrogen, and stored at -70[degrees]C for analysis of IGF-I mRNA and IGFBP-3 mRNA. Liver biopsy specimens were obtained with Tru-Cut biopsy needles (Bard Inc, Covington, GA). The needle-biopsy specimens ranged in length from 15 to 20 mm. For histologie examination, some liver specimens were fixed in 10% neutrally buffered formaldehyde and embedded in paraffin.
Liver Function Examinations
Liver function, including serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), total bilirubin (TBIL), ALB, and prealbumin, was analyzed by an autoanalyzer.
Radioimmunoassay
Serum GH, IGF-I, and IGFBP-3 levels were measured by radioimmunoassay (RIA), using a kit for GH, IGF-I, and a IGFBP-3 (Diagnostic System Laboratories, Webster, TX).
Reverse Transcriptase Polymerase Chain Reaction (RTPCR)
Total RNA was extracted from frozen liver specimens by the guanidinium isothiocyanate method. Aliquots of total RNA were reverse transcribed using SuperScriptII Reverse Transcriptase and subsequently amplified by PCR using the Taq DNA polymerase. RT-PCR was performed to measure the expression levels of IGF-I mRNA and IGFBP-3 mRNA in liver tissues. The sequences of the primers for IGF- I sense and antisense were 5′-AGCAGTCTTCCAACCCAATTA-3′ (sense) and 5′-CACGGACAGAGCGAGCTG-3′ (antisense), a 355-bp-long fragment was amplified. The sequences of the primers for IGFBP-3 sense and antisense were 5′-ATATGGTCCCTGCCGTAGA-3′ (sense) and 5′- AAATCGAGGCTGTAGCCAG-3′ (antisense), a 345-bp-long fragment was amplified. The sequences of the primers for beta-actin sense and antisense were 5′-ACTCTTCCAGCCTTCCTTCCT-3′ (sense) and 5′- TCACCTTCACCGTTCCAGTTT-3′ (antisense), a 513-bp-long fragment was amplified. The PCR was carried out in 25 mL of reaction mixture containing 0.5 [mu]L cDNA template, 2.5 [mu]L 10 x PCR buffer, 1.5 [mu]L 25 mmol/L MgCl^sub 2^, 0.5 [mu]L 10 mmol/L dNTPs, 0.5 [mu]L 10 [mu]mol/L IGF-1 or IGFBP-3 primers, 0.15 [mu]L 10 [mu]mol/L beta- actin primers, 0.5 [mu]L 5 IU/[mu]L Taq DNA polymerase. The mixture was heated for 5 minutes at 94[degrees]C for initial DNA denaturation, followed by 30 cycles of denaturation (at 94[degrees]C for 45 seconds), annealing (IGF-I at 48[degrees]C for 45 seconds, IGFBP-3 at 55[degrees]C for 45 seconds), polymerization (at 72[degrees]C for 1 minute) and then a final extension of 10 minutes at 72[degrees]C.
PCR reactions were electrophoresed on 1.5% agarose gel, stained with ethidium bromide, and quantitated using the interactive build analysis system. The band intensity of the IGF-I or IGFBP-3 was compared with the band intensity of the beta-actin, and the amount of IGF-I mRNA and IGFBP-3 mRNA was estimated.
Immunohisiochemistry
Main reagent included rabbit polyclonal antibody Ki67 Ab-4 (Neomarkers Corp, Freemont, CA) and PV-6000 PicTure Kits (Zymed Laboratories, Inc; San Francisco, CA). Two-step immunohistochemical staining technique was used. Ki67-positive nuclei were evaluated by means of light microscopy at 400 x magnification. A minimum of 1000 cells was evaluated through a minimum of 200 cells per field in 5 different fields. The Ki67 labeling index (Ki67 LI) is the number (%) of positive cells.
Follow-up Evaluation
After discharge, liver B-model ultrasound and chest x-ray in all patients were examined every 2 months postoperatively and liver CT were examined every 6 months postoperatively within 2 years. Patients without recurrence were not treated with any anticancer drugs during follow-up.
Data Analysis
A database was established by SPSS 10.0 software. Data were expressed as mean +- SD. Comparisons between groups were done with paired and unpaired Student’s t-tests as appropriate. Comparisons across groups were done with ANOVA; when ANOVA showed a significant difference, comparisons between groups were tested with the Bonferroni-Dunn test. Comparisons between percentages were tested with the chi^sup 2^ test. Kaplan-Meier method and log-rank test were used for survival statistics. p < .05 was defined statistically significant.
RESULTS
Surgery Outcome and ALB Infusion Doses Within 5 Days After Operation
There was no surgical mortality in this series. The postoperative hospital stay showed no difference between the PN group and rhGH + PN group (14.7 +- 6.2 days vs 13.5 +- 4.5 days; p > .05). In the PN group, 2 patients had right pleural effusion. In the rhGH + PN group, 1 patient had right pleural effusion; another patient had subcutaneous fat liquefaction. The postoperative complication- related morbidity was not different between the 2 groups (p > .05).
ALB infusion maybe affect surgery outcome. In this study, the ALB infusion doses within 5 days after operation were not different between the PN and rhGH + PN group (57.0 +- 48.8 g vs 52.4 +- 24.4 g; p > .05).
The Changes of Liver Function
Compared with the normal control group, serum AST and ALT of HCC patients with cirrhosis were significantly higher, but serum prealbumin was significantly lower, whereas serum ALP, TBIL, and ALB were not different. Serum AST, ALT, ALP, TBIL, ALB, and prealbumin both on morning of operation and POD 1 were not different between the PN group and rhGH + PN group. Compared with PN group, serum AST, ALT, ALP, TBIL, and ALB on POD 6 in the rhGH + PN group were not different, but serum prealbumin was significantly higher (Table II).
The Changes of Serum GH, IGF-1, and IGFBP-3
In HCC patients with cirrhosis, serum IGF-1 and IGFBP-3 were lower, whereas serum GH was higher than the normal control group. Serum GH, IGF-1, and IGFBP-3 both on morning of operation and POD 1 were not different between the PN group and rhGH + PN group, but serum GH, IGF-1, and IGFBP-3 on POD 6 in the rhGH + PN group were significantly higher compared with the PN group (Table II).
The Changes of Hepatic IGF-1 mRNA, IGFBP-3 mRNA, and Liver Ki67 LI
In HCC patients with cirrhosis, hepatic IGF-1 mRNA and IGFBP-3 mRNA of tumor tissue or adjacent nontumor tissue were lower than the normal control liver tissue, whereas in tumor tissue, hepatic IGFBP- 3 mRNA was lower and hepatic IGF-1 mRNA was higher than in adjacent nontumor tissue. Compared with the PN group, hepatic IGF-I mRNA and IGFBP-3 mRNA on POD 6 were significantly higher in the rhGH + PN group. Liver Ki67 LI in tumor tissue was higher than in adjacent nontumor tissue. Liver Ki67 LI on POD 6 in the rhGH + PN group was higher than in the PN group (Table III).
TABLE II
Comparison of liver function and serum GH, IGF-1, and IGFBP-3
Tumor-free Survival
All patients remain alive. The 6- and 12-month tumor-free survival rates were 71.1% and 46.2%, respectively, with a median tumor-free survival time of 11.2 months in the PN group. The 6- and 12-month tumor-free survival rates were 72.2% and 59.0%, respectively, with a median tumor-free survival time of 11.4 months in the rhGH + PN group. These differences were not significant (p > .05).
DISCUSSION
PN and GH/IGF Axis
The liver has a role as an endocrine gland in the GH/IGF axis and is probably the major source of circulating IGF-1 with GH confirmed as the dominant regulator of IGF-1 gene expression and serum levels in human disease.8 IGF-1 is an important anabolic polypeptide with various effects. IGF-1 synthesis is disturbed in liver cirrhosis and reflects the severity of the clinical stage. Levels of circulating IGF-1 are decreased in such conditions, whereas serum GH is increased; however, there is a reduction in high-affinity GH receptors in the liver parenchyma, which leads to GH resistance in the liver. These alterations are likely to play a role in the metabolic derangements associated with chronic liver disease. Impaired production of IGF-1 in advanced liver disease has been suggested to contribute to malnutrition in cirrhotic patients. It represents a good marker of hepatic function. The etiology of cirrhosis does not seem to influence its levels.9 Serum IGFBP-3 proves to be a better marker for the hepatic synthetic capacity than serum ALB or cholinesterase.10
TABLE III
Comparison of hepatic IGF-1 mRNA, IGFBP-3 mRNA and liver Ki67 LI
IGF-1 is capable of exquisite regulation by nutrients.11 Nutrient restriction in experimental animals and humans results in a marked reduction in the serum concentration of IGF-1.12 Conversely, IGF-1 synthesis is stimulated by refeeding and elevations in GH and amino acids.13 The IGFBP-3 tertiary complex represents a stable reservoir of potential IGF activity. In calorie-restricted rats, the decrease in serum IGFBP-3 is associated with a decrease in hepatic IGFBP-3 mRNA.14
Because liver function is usually impaired in patients with cirrhosis, and because cirrhotic livers are less able to regenerate, it is important to stimulate both the regeneration and function of the remnant cirrhotic liver after hepatectomy. Some studies have shown that nutrition support can improve liver function and survival in a select subgroup of patients with alcoholic liver disease.15-17 Potential areas of further research may include the combination of BCAA (branched-chain amino acids) supplements with other anabolic factors (eg, GH) in managing patients with catabolic disease states.18
In this study, serum AST, ALT, ALP, TBIL, and ALB on POD 6 were not different between the PN group and rhGH + PN group, but serum prealbumin was significantly higher in the rhGH + PN group. Serum ALB, whose long half-life of approximately 20 days makes it a late index of nutrition status, and its exclusive use may delay implementation of appropriate nutrition interventions. Clinically significant changes in ALB can be reliably predicted by earlier changes in serum prealbumin.19 To assess the proliferating cells, we have immunochemically detected Ki-67 nuclear antigen.20 This study showed liver Ki67 LI on POD 6 in the rhGH + PN group was higher than in the PN group. Thus, rhGH can promote liver regeneration, liver function recovery, and liver protein synthesis.
This study showed there was GH resistance in patients with cirrhosis complicated by HCC (PN and rhGH + PN groups) because serum GH was increased, whereas serum IGF-I and IGFBP-3 were lower in comparison with the control group. In addition, serum GH, IGF-I, and IGFBP-3 and hepatic IGF-I mRNA, IGFBP-3 mRNA, and Ki67 LI were significantly higher postoperatively in the rhGH + PN group in comparison with the PN group. It is thus evident that serum IGF-1 and IGFBP-3 recovered more rapidly in the rhGH + PN group. Therefore, a combination of rhGH and PN can ameliorate changes in the GH/IGF-1 axis after hepatectomy for HCC in the setting of liver cirrhosis. This may have implications for liver regeneration in this setting.
rhGH and HCC Recurrence
An important but unresolved question pertaining to intrahepatic recurrence after resection of HCC is the relative importance of intrahepatic metastasis and multicentric occurrence. Metastasis and recurrence of HCC after surgical removal is still common. The frequency of 5-year recurrence after radical resection is 61.5% overall.21 Recurrence, especially early after hepatectomy, is the major cause.22 This is relevant in determining preventive and therapeutic strategies for recurrence. Although all patients in this study underwent curative tumor resection, the potential tumorpromoting effect of GH must be addressed.
The GH/IGF-1 axis plays a crucial role in the regulation of growth, cellular proliferation and transformation, and apoptosis. Circulating concentrations of IGF-I might be associated with an increased risk of cancer, whereas IGFBP-3 concentrations could be associated with a decreased cancer risk.2 This study showed that liver Ki67 L1 in tumor tissue was higher than in adjacent nontumor tissue or in normal liver tissue, and hepatic IGF-I mRNA in tumor tissue was higher than in adjacent nontumor tissue, whereas hepatic IGFBP-3 mRNA in tumor tissue was lower than in adjacent nontumor tissue. On the other hand, hepatic IGF-1 mRNA and IGFBP-3 mRNA in tumor tissue or adjacent nontumor tissue were lower than normal liver tissue. Thus, reduction in IGFBP-3 mRNA in the cirrhotic liver may play an important role in HCC tumorigenesis. IGFBP-3, the product of a tumor suppressor target gene, can modulate cell proliferation and apoptosis by IGF-1-dependent and IGF-1- independent mechanisms.23 No significant increase in somatic cell mutation frequency has been noted with long-term GH therapy.24 In fact, GH supplementation has been shown to inhibit tumor growth in protein-deprived rodents, possibly by indirectly limiting the amino acid substrates available to the tumor.25 However, GH and IGF-1 are both important for cell differentiation and proliferation, and malignant cells require a smaller amount of exogenous growth factor for their proliferation than do normal cells.26 GH has a number of immunomodulatory effects on both lymphocytes and macrophages, enhancing the production of reactive oxygen intermediates and increasing lymphocyte activity.27 Tacke et al28 demonstrated no evidence for an increased risk of tumor recurrence after rhGH treatment for a short period of time after removal of a gastrointestinal adenocarcinoma. Moreover, rhGH attenuated the depression in cellular immunity after surgical stress.29
Concern that the administration of GH after liver resection for HCC might lead to an increase in the risk of tumor recurrence is not supported by our results, which demonstrate no difference in 6- and 12-month tumor-free survival between the rhGH + PN and PN group (p > .05). Therefore, short-term use of rhGH in HCC patients with cirrhosis after operation may be safe.
CONCLUSION
In conclusion, rhGH + PN can ameliorate changes in the GH/IGF-1 axis after hepatectomy for HCC in the setting of liver cirrhosis.
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Jie Cao, MD*; Shi-Min Luo, MD*; Lijian Liang, MD[dagger]; and Jiaming Lai, MD[dagger]
From the * Department of General Surgery, Affiliated Guangzhou First Municipal People’s Hospital, Guangzhou Medical College, Guangzhou, China;
and the [dagger] Department of Hepatobiliaty Surgery, The First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
Received for publication December 2, 2006.
Accepted for publication May 4, 2007.
Correspondence: Jie Cao, MD, Professor, Department of General Surgery, Affiliated Guangzhou First Municipal People’s Hospital, Guangzhou Medical College, 1 Panfu Lu, Guangzhou 510180, Guangdong Province, China. Electronic mail may be sent to ljq77@medmail.com.cn.
Copyright American Society for Parenteral and Enteral Nutrition Nov/ Dec 2007
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