Urinary growth hormone (U-GH) excretion and serum insulin-like growth factor 1 (IGF-1) in patients with alcoholic cirrhosis

doi:10.1016/S0168-8278(05)80211-9

Journal of Hepatology

Volume 17, Issue 3, 1993, Pages 315-320

https://doi.org/10.1016/S0168-8278(05)80211-9 Get rights and content

Basal serum growth hormone (GH) levels are elevated and insulin-like growth factor 1 (IGF-1) concentrations in serum are suppressed in patients with chronic liver disease. The aim of this study was to measure the urinary GH (U-GH) excretion and IGF-1 concentrations in patients with cirrhosis and to correlate these both to clinical and biochemical characteristics and survival rate. Urinary GH excretion, IGF-1, and other biochemical parameters were measured in 36 patients with alcoholic cirrhosis, while in the control group of 34 healthy individuals only U-GH excretion was measured. U-GH excretion was significantly higher in patients than in the healthy controls (p < 0.00001), and increased with deteriorating liver function assessed by modified Child-Turcotte score (p < 0.01). The highest U-GH excretions were found in patients with hepatic encephalopathy (p < 0.003). IGF-1 levels were reduced in cirrhosis and correlated with liver function (p < 0.001). Serum IGF-1 concentrations below 3.1 nmol/l were associated with a poor prognosis (p < 0.004). The elevated U-GH in patients with alcoholic cirrhosis may reflect high serum levels of GH due to increased pituitary secretion or decreased hepatic degradation of GH. In addition, the IGF-1 levels reflect the degree of hepatic insufficiency and, thus, seem to provide new prognostic information.

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Results of discriminant analysis showing validity, sensitivity, and specificity of clinical parameters differentiating patients with compensated cirrhosis from those with decompensated and blunted IGF-1 from non-blunted IGF-1 response are shown in Tables 3 and 5, respectively. Although the relationship of low serum IGF-1 levels to hepatic dysfunction has been previously described [30–32], whether decreases in serum IGF-1 are due primarily to hepatocellular dysfunction, malnutrition, and/or porto systemic shunting remains controversial. The independent and strong correlation between stimulated IGF-1 levels and MELD and CP scores, albumin and INR, together with the poor correlations that existed with malnutrition and portal hypertension support hepatic dysfunction as the explanation of the previous findings.
Previous studies reported decreased serum IGF-1 levels in cirrhosis. We aimed to correlate GH-stimulated IGF-1 responses with both MELD and Child-Pugh scores and determine the impact of portal hypertension and nutrition on IGF-1 responses.
Fifty-three patients (56 ± 2 yrs) with cirrhosis were enrolled. Serum IGF-1 levels were measured by RIA before and 24 h after a single injection of GH (0.06 mg/kg).
Compared to controls, basal IGF-1 levels were significantly decreased in patients with cirrhosis (17.3 ± 6.3 vs 13.6 ± 5.1, P < 0.001). Increments in IGF-1 levels were significantly lower in cirrhotic patients (controls: 133% vs 49% in MELD score <10, 38% in MELD score 11–18, and 13% in MELD score 19–24, p < 0.001). 37% of patients had blunted IGF-1 responses. Increments in IGF-1 levels correlated with albumin (r = 0.6), portal congestive index (r = 0.4), and MAMC (r = 0.25). By multivariate analysis, only CP (OR 5.7) and MELD scores (OR 4.5) accurately differentiated between blunted or non-blunted IGF-1 responses and not portal hypertension (OR 0.9) or malnutrition (OR 1.35).
Cirrhosis is associated with low IGF-1 levels and an attenuated response to exogenous GH. These findings correlate better with the extent of hepatic dysfunction rather than the presence of portal hypertension or malnutrition.
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The liver plays a central role in insulin-like growth factor (IGF) homeostasis providing the majority of circulating IGF-I and some of its binding proteins (IGFBPs). In liver cirrhosis the IGF axis is severely disturbed, and these alterations are associated with reduced IGF-I, IGFBP-3 but elevated IGFBP-1 serum levels.
By Northern blotting and in situ hybridization (ISH), hepatic expression of IGF-I and of IGFBP was studied in a rat model of liver cirrhosis induced by thioacetamide.
ISH revealed a homogeneous distribution of IGFBP-1, IGFBP-4 and IGF-I mRNA over hepatic parenchyma in normal and cirrhotic liver. Fibrous septa of cirrhotic liver were IGFBP-1 mRNA negative, whereas IGFBP-4 and IGF-I transcripts were detected in single cells. In normal liver, IGFBP-3 mRNA was distributed within nonparenchymal cells of the hepatic lobule and in the wall of the portal vein. In cirrhotic liver, IGFBP-3 transcripts were abundant in mesenchymal cells of fibrous tissue. IGFBP-3 mRNA expression was also prominent in cells at the septal–nodular interface most likely representing monocyte infiltration. IGFBP-3 mRNA expression was reduced in nonparenchymal liver cells located more distantly from the septal–nodular interface in the cirrhotic nodule that correlated with reduced IGFBP-3 mRNA expression observed in Kupffer cells (KC) and sinusoidal endothelial cells (SEC) isolated from macronodular cirrhotic livers.
Cirrhosis is accompanied by an altered spatial expression of IGFBP-3 in liver tissue, which is characterized by decreased levels of IGFBP-3 mRNA in KC and SEC, but elevated IGFBP-3 expression in myofibroblast-like cells and inflammatory infiltrate.
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Role of Growth Hormone Resistance and Impaired Insulin-like Growth Factor-I Bioavailability in the Pathogenesis of Cirrhosis and Its Complications
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Growth hormone (GH) and insulin-like growth factor-I (IGF-I) are ubiquitous and potent growth factors that play central roles in cellular proliferation and differentiation, somatic growth, and the regulation of body composition in adult life. Stress, disease, and organ failure may lead to a state of acquired GH resistance that has deleterious effects on whole body homeostasis. Liver is the central organ of the endocrine GH:IGF:IGF-binding protein (BP) axis, and the development of cirrhosis has been associated with profound changes in this axis, which result in significant impairment of IGF-I bioavailability to its tissue receptors. This chapter reviews the reported changes in the GH:IGF:IGF-BP axis in cirrhosis and their relationships to the pathogenesis of cirrhosis and the complications that influence the significant morbidity and mortality of this disease state. IGF-I is an anabolic peptide that is vital to cell proliferation and differentiation in virtually every organ. It stimulates cellular differentiation and proliferation; is an essential cofactor for the progression through the cell cycle from phase G to S; is a dominant regulator of somatic growth before puberty; and, after epiphyseal closure, plays an important role in the maintenance of body composition. The biologic role of IGF-II remains uncertain, although roles in fetal development and in tumor development have been defined. In addition to their functions as endocrine growth factors, IGFs are thought to exert growth-promoting effects at the local tissue level through paracrine and autocrine mechanisms.
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Regular PaperUrinary growth hormone (U-GH) excretion and serum insulin-like growth factor 1 (IGF-1) in patients with alcoholic cirrhosis

Adv Clin Chem

Metabolism

Am J Med Sci

Clin Chim Acta

Metabolism

Am J Med

Regulation of and defects in expression of growth hormone genes

Growth hormone and its disorders

The differential regulation by glucagon and growth hormone of insulin-like growth factor (IGF)-1 and IGF binding proteins in cultured rat hepatocytes

Endocrinology

Growth factors

The somatomedins: biological actions and physiological control mechanisms

Mode of action of pituitary growth hormone on target cells

Annu Rev Physiol

Short-term metabolic effects of recombinant human insulin-like growth factor 1 in healthy adults

N Engl J Med

Metabolic actions of insulin-like growth factor-1 in cultured hepatocytes from adult rats

Hepatology

Human growth hormone and somatomedin C suppress the spontaneous release of growth hormone in unanesthetized rats

Endocrinology

Actions of insulin-like growth factors

Annu Res Physiol

Reduced serum somatomedin activity in patients with chronic liver disease

Clin Sci Mol Med

Radioimmunoassay of serum IGF-I and IGF-II in patients with chronic liver diseases and hepatocellular carcinoma with or without hypoglycemia

J Lab Clin Med

Serum somatomedin activity measured as sulfation factor in peripheral, hepatic and renal veins of patients with alcoholic cirrhosis

Acta Endocrinol

Regular Paper
Urinary growth hormone (U-GH) excretion and serum insulin-like growth factor 1 (IGF-1) in patients with alcoholic cirrhosis