Insulin-like growth factor I (IGF-I) replacement therapy increases albumin concentration in liver cirrhosis: Results of a pilot randomized controlled clinical trial☆
Introduction
Hepatocytes are the main source of circulating insulin-like growth factor-I (IGF-I), a potent anabolic hormone whose secretion is stimulated by growth hormone (GH) [1], [2]. IGF-I circulates bound to 6 different IGF binding proteins (IGFBP-1 to −6), interacts with specific receptors on target tissues (bone, intestine, testis, muscle, etc) and also acts on hypothalamus to suppress GH secretion [3], [4], [5]. The liver is also the major producer of IGFBPs, mainly IGFBP-1 and IGFBP-3. IGFBP-3 sequesters IGF-I in the vascular system, increasing its half-life and providing an IGF-I reservoir. The ratio of total IGF-I/IGFBP-3 is considered as a surrogate index of IGF-I bioavailability [5].
In subjects with liver cirrhosis plasma levels of total IGF-I, free IGF-I and IGFBP-3 are decreased while GH is increased, indicating resistance to GH and reduced hepatic functional reserve [6], [7], [8]. Liver cirrhosis is, therefore, an IGF-I deficiency state, the severity of which correlates with the progression of the liver disease [6], [7], [8], [9], [10]. Indeed, many of the clinical features of advanced cirrhosis such as malnutrition, muscle wasting, loss of bone mass, and hypogonadism could be ascribed to deficient IGF-I anabolic activity. The possible therapeutic use of IGF-I in liver cirrhosis is supported by studies in cirrhotic rats demonstrating that IGF-I replacement therapy (20 μg/kg): (a) increases food intake, nitrogen balance and food efficiency [11]; (b) enhances intestinal absorption of glucose and aminoacids [12]; (c) increases bone density [13]; (d) corrects hypogonadism [14]; (e) diminishes oxidative liver damage [15]; (f) improves liver function [15] and (g) decreases liver fibrogenesis [15].
Based on these premises we decided to perform a small controlled clinical trial to evaluate the effects of IGF-I replacement therapy in patients with liver cirrhosis of non-viral origin. Because of the reported growth-promoting and antiapoptotic properties of IGF-I, in this pilot study we excluded cirrhotic patients with higher risk of cancer development such as those with haemochromatosis or chronic hepatitis B or C virus infection.
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Materials and methods
We designed a randomized, double-blind, placebo controlled pilot study to investigate whether IGF-I replacement therapy could benefit cirrhotic patients. The study was performed in two centers: Clinica Universitaria of Navarra (Spain) and University Hospital Groningen (The Netherlands).
Study design
The patients were randomized to receive human recombinant IGF-I (Chiron Corp., Emeryville, CA, USA) or placebo for 120 days. We used a 1:1 randomization with a block size of 2. The randomization was stratified by investigative site and etiology. The starting dose of IGF-I was 20 μg/kg administered as a single subcutaneous injection within 60 min after breakfast. The dose was selected based on preclinical data showing beneficial effects and absence of hypoglycemia with this dose in cirrhotic rats
Determinations
Serum concentration of total and free IGF-I and IGFBP-3 were determined as previously reported [16]. Muscle mass was measured using CT-scan (SOMATON PLUS 4. Siemens, Forcheim, Germany) [17]. CT of the dominant quadriceps muscle was performed and the midpoint between the great trochanter and lateral joint line of the knee. Slice thickness was 10 mm. The CT scans were evaluated three times and the mean value was recorded. Upper leg muscle strength was measured as peak torque of flexion
Ethics
The study was approved by the Ethic's Committees of University Hospital of Navarra (Spain) and University Hospital Groningen (The Netherlands). Patients entered after written and informed consent was obtained. The study was conducted in accordance with the Declaration of Helsinki (1964), as revised in 1996 and with ICH Harmonised Tripartite Guideline for Good Clinical Practice (GCP) and the Spanish Royal Decree (Real Decreto 561/1993).
Data analysis
Differences between values at day 120 and at day 0 (Δ) were compared between groups. Two-sided exact P-values were calculated using the Mann–Whitney–Wilcoxon test. Correlation coefficients were calculated using Spearman's method. Statistical significance was defined as a P value <0.05. Since alcoholic and primary biliary cirrhosis are pathogenetically different and alcoholic patients constituted the great majority of those included in the study, a second analysis in the subgroup of patients
Results
Between September 2001 and December 2002, 30 consecutive patients were assessed for eligilibility. Of these, seven did not meet the inclusion criteria and three refused to participate. Twenty patients were randomized to receive placebo (nine patients) or IGF-I (eleven patients). Fifteen patients were included in Pamplona and five in Groningen. Neither dropouts nor exclusions occurred in the placebo group. In the treatment arm, one patient was lost to follow up because he underwent liver
Discussion
Since IGF-I displays potent anabolic activities and its levels decrease markedly in liver cirrhosis, we tested the concept that IGF-I supplementation might benefit cirrhotic patients. Because the present study was the first trial administering IGF-I to patients with cirrhosis, entry criteria were stringent and the dose of IGF-I was low in order to minimize potential side effects. Because IGF-I has been associated with development of certain type of tumors such as colorectal, breast and prostate
Conflict of interest
B. Scharschmidt is Vice President of Chiron Corp. and C Yoshizawa is Director of Biostatistics of Chiron Corp. The rest of the authors have no conflict of interest.
Acknowledgements
We thank Dr J. Salvador, Dr G. Frühbeck and Ms Neus Vila (Department of Endocrinology), Dr J. Pueyo (Department of Radiology), Dr J. Boan and Dr J. Richter (Department of Nuclear Medicine) from the Clinica Universitaria de Navarra and Dr J.P.K. Halbertsma (Department of Physiotherapy) from the University Hospital of Groningen for advice and technical contribution to the study. Kirsten Nyborg and Karen Mathiassen for excellent technical assistance and M. Eugenia Cornet, PhD and M. Mar Municio,
References (29)
- et al.
Insulin-like growth factors I and II. Peptide, messenger ribonucleic acid and gene structures, serum, and tissue concentrations
Endocr Rev
(1989) Insulin-like growth factors
Cell Biol Int
(1995)- et al.
Insulin-like growth factors and their binding proteins: biological actions
Endocr Rev
(1995) - et al.
Insulin, insulin-like growth factor-I (IGF-I), IGF binding proteins, their biologic interactions, and colorectal cancer
J Natl Cancer Inst
(2002) Insulin-like growth factors
N Engl J Med
(1997)- et al.
Insulin-like growth factor-I serum concentrations and patterns of insulin-like growth factor binding proteins in patients with chronic liver disease
J Hepatol
(1996) - et al.
Insulin-like growth factor I: a good indicator of functional hepatocellular capacity in alcoholic liver cirrhosis
J Endocrinol Invest
(1991) - et al.
Growth hormone-stimulated insulin-like growth factor (IGF) I and IGF-binding protein-3 in liver cirrhosis
J Hepatol
(1997) - et al.
Altered endogenous growth hormone secretory kinetics and diurnal GH-binding protein profiles in adults with chronic liver disease
Clin Endocrinol
(1995) - et al.
Growth hormone therapy in patients with cirrhosis
Gastroenterology
(1997)
Low doses of insulin-like growth factor-I improve nitrogen retention and food efficiency in rats with early cirrhosis
J Hepatol
Impaired intestinal sugar transport in cirrhotic rats. Correction by low doses of insulin-like growth factor I
Gastroenterology
Osteopenia in rats with liver cirrhosis: beneficial effects of IGF-1 treatment
J Hepatol
Insulin-like growth factor-I reverts testicular atrophy in rats with advanced cirrhosis
Hepatology
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The authors who have taken part in this study have declared a relationship with the manufacturers of the drugs involved and they received funding from the drug companies involved to carry out their research.