Fibrinogen Synthesis Is Elevated in Fasting Cancer Patients with an Acute Phase Response

Abstract

The unusual amino acid composition of acute phase proteins may be relevant to our understanding of the mechanism of tissue wasting in chronic inflammatory disease. During periods in which demand for amino acids outstrips dietary supply, skeletal muscle protein may be mobilized to meet this demand. An imbalance in the amino acid composition of these proteins may thus be detrimental to the body's nitrogen economy. To address this problem, we have measured the synthetic rate of fibrinogen (perhaps the major acute phase protein) and plasma amino acid profiles in a group of patients with adenocarcinoma of the pancreas and an ongoing inflammatory response (serum C-reactive protein >10 mg/L in the absence of any other obvious infective or inflammatory cause). These were also measured in a control group with no evidence of inflammation. Fibrinogen synthesis was measured after an overnight fast, using a flooding dose of 2H5-phenylalanine. The fractional rate of fibrinogen synthesis was significantly elevated in the cancer group compared with healthy controls [39.3 (20.0-49.9) and 21.9 (13.2-37.7) %/d, respectively; median (range), P < 0.05]. The absolute rate of fibrinogen synthesis was also elevated [84 (33-143) and 26 (15-43) mg/(kg.d), respectively; median (range), P < 0.01]. We calculated that, in cancer patients with anorexia-cachexia (i.e., documented ongoing weight loss in the absence of an obvious cause such as obstruction or malabsorption), aromatic amino acid supply (predominantly tryptophan) most limits fibrinogen synthesis from skeletal muscle reserves. Demand for the nonessential amino acids serine and glycine was elevated. Assuming that tryptophan is limiting, up to 2.6 g muscle protein ( approximately 12 g skeletal muscle tissue) may be wasted to synthesize 1 g fibrinogen. Interpretation of the observation that circulating free tryptophan concentrations were significantly reduced in the cancer patients will have to await flux measurements. The metabolic changes accompanying the inflammatory response suggest that down-regulation of this process may be beneficial.

Serum tryptophan decrease correlates with immune activation and impaired quality of life in colorectal cancer

“…The negative correlation of the serum tryptophan level with IL-2 sRa and sTNF RI was compatible with a Th1 immune response (Mills et al, 1993;Diez-Ruiz et al, 1995) releasing interferon-g to induce tryptophan degradation (Murr et al, 2000). Cachexia studies in pancreatic cancer have suggested (Preston et al, 1998) that a tumour-associated acute phase protein response induces fibrinogen synthesis at the expense of skeletal muscle reserves. The greater aromatic amino acid (mostly tryptophan) content in fibrinogen compared with skeletal muscle proteins, may then result in tryptophan depletion.…”

The relationship between the systemic inflammatory response and survival in patients with transitional cell carcinoma of the urinary bladder

“…For example, interleukin-6, produced by the tumour or infiltrating inflammatory cells, is recognised as a growth promoter in bladder cancer (Okamoto et al, 1997;Andrews et al, 2002). Interleukin-6 also stimulates liver production of acute-phase proteins, such as Creactive protein, which increases the demand for certain amino acids, which, if limited in the diet, must be obtained from the breakdown of skeletal muscle Preston et al, 1998). In this way, the presence and magnitude of a chronic systemic inflammatory response may produce a progressive nutritional and functional decline, ultimately resulting in reduced survival.…”

The relationship between hypoalbuminaemia, tumour volume and the systemic inflammatory response in patients with colorectal liver metastases

“…It may be that the presence of a chronic systemic inflammatory response, with its increased demand for specific amino acids for acute phase protein synthesis, promotes the degradation of available body protein including albumin (Preston et al, 1998;McMillan et al, 2001). Indeed, this relationship between nutritional decline, albumin concentrations and the systemic inflammatory response has recently been exploited to form a new prognostic score in patients with advanced non-small-cell lung cancer (Forrest et al, 2003).…”