TNF-alpha and growth hormone resistance in patients with chronic liver disease.
Liver cirrhosis is characterized by a severe impairment of the growth hormone/insulin-like growth factor-1 (GH-IGF-1) axis, that is, acquired GH resistance. The condition of the GH-IGF-1 axis in the phase of chronic liver disease (CLD) preceding cirrhosis, however, remains uncertain. The origin of GH resistance during CLD is multifactorial, and to date, the liver functional mass is considered to play a major role. Although proinflammatory cytokines, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1beta, were found to be elevated in patients with CLD and were shown to induce a state of GH resistance in other disease models, their involvement in the pathogenesis of GH resistance during CLD has never been investigated. We characterized the GH-IGF-1 axis by analyzing the individual components of the axis (GH, IGF-1, IGF-binding protein-3 [IGFBP-3], acid-labile subunit [ALS]) and the corresponding ratios (GH/IGF-1, GH/IGFBP-3, and GH/ALS) and verified the links with circulating proinflammatory cytokines (TNF-alpha, IL-1beta, and IL-6), in 34 patients with CLD and 12 healthy controls. Evolution of CLD from chronic hepatitis (CH, n = 17) to cirrhosis (CIR, n = 17) was associated with a progressive increase of GH resistance indices (e.g., GH/IGF-1 ratio: controls 0.5 +/- 0.9, CH 15.9 +/- 31.2, p < 0.01 vs. controls; CIR 188.4 +/- 282.7 mU/nmol, p < 0.001 vs. CH and controls), indicating its onset also in the early stages of CLD. The progressive increase in GH resistance indices matched the increase of circulatory TNF-alpha (e.g., TNF-alpha vs. GH/IGF-1, r = 0.54, p < 0.001). A similar trend was found for IL-6 without reaching statistical significance (r = 0.23, p = 0.13). We found undetectable levels of IL-1beta in our sample of patients and controls. We conclude that proinflammatory cytokines play an important role in the pathogenesis of GH resistance in CLD, but TNF-alpha is a major factor. In addition, GH resistance is present in CLD from the early stages. These results could begin new therapeutic lines of attack in the management of CLD.
Picardi
Antonio
A
Laboratory of Internal Medicine and Hepatology, Interdisciplinary Center for Biomedical Research (CIR), University Campus Bio-Medico, Rome, Italy. a.picardi@unicampus.it
Gentilucci
Umberto Vespasiani
UV
Zardi
Enrico Maria
EM
Caccavo
Domenico
D
Petitti
Tommasangelo
T
Manfrini
Silvia
S
Pozzilli
Paolo
P
Afeltra
Antonella
A
D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D004351:Drug Resistance; D005260:Female; D006521:Hepatitis, Chronic / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D019382:Human Growth Hormone / Q000378:metabolism*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D007375:Interleukin-1 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000276:immunology / Q000378:metabolism; D008107:Liver Diseases / Q000209:etiology / Q000276:immunology* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D007375:Interleukin-1; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D019382:Human Growth Hormone; D007334:Insulin-Like Growth Factor I