The way to safer liver resection in cirrhotic patients: is Cardiotrophin‐1 the future miracle drug?

The authors of the article ‘Cardiotrophin-1 enhances regeneration of cirrhotic liver remnant after hepatectomy through promotion of angiogenesis and cell proliferation’ address an important question in the treatment of patients with liver cirrhosis. They provide evidence that in a rat model of cirrhosis, Cardiotrophin1 (CT-1) is beneficial after major liver resection (1). Liver cancer is the third most common cause of death from cancer worldwide (2). The majority consists of hepatocellular carcinoma (HCC) and there is increasing incidence of these tumours due to the increasing incidence of hepatitis B (HBV) and hepatitis C (HCV) virus infection. In parallel with the increasing tumour rate, the incidence of liver fibrosis and cirrhosis is increasing as well. A combination of both entities at the same time is a major challenge for the physician. We will probably see an increasing number of patients presenting with HCCs and underlying fibrosis or cirrhosis in the future. The gold standard for the treatment of HCCs is still surgical resection. Other modalities for patients who are not amenable to resection are tumour ablation methods but the only curative approach is still liver transplantation. Because of organ shortage, we cannot offer liver transplantation to all these patients. Therefore, more patients with fibrotic liver tissue will need liver resection because of HCC. This is a challenging situation as fibrosis or even cirrhosis is a major risk factor for surgical outcome after hepatic resection (3). Cirrhosis per se does not limit liver resection but rather the impaired hepatic function of the remnant liver tissue. Therefore, even limited resection in a patient with poor liver function may be detrimental (3). To overcome this dilemma, the functional reserves need to be increased before resection. Several strategies to improve surgical outcome after liver resection have been tested. Ischaemic preconditioning is one of the most commonly applied methods (4, 5). In this setting, the blood supply to the liver is occluded for a short period of approximately 10–15 min, followed by an interval of about the same duration with normal blood flow. After this treatment, a resection with prolonged ischaemia can be performed more safely. During this procedure, a complex interplay of signalling pathways are activated that lead to activation of protective proteins beneficial to liver parenchymal cells. The identification of specific pathways led to a more direct approach by pharmacological targeting individual proteins or protective pathways. Many substances have been proposed as useful activators of protective mechanisms; however, only a few studies have investigated its roles in cirrhotic liver tissue (5–7). One of these putatively protective targets is the CT-1 gp-130 pathway. In the study by Yang and Lau et al., CT-1 is proposed as a new drug to overcome the dilemma of cirrhosis with poor liver function and safer liver resection. In 1995, Pennica et al. discovered that conditioned medium from differentiated embryoid bodies was able to induce a hypertrophic response in neonatal cardiac myocytes. Further screening with a cDNA library from embryoid bodies led to the identification of CT-1 (8). CT-1 was found to be a member of the interleukin-6 family as a result of the high amino acid sequence homology. Besides IL-6 and CT-1, other members of this family are IL-11, oncostatin M (OSM), leukaemia inhibitory factor (LIF) and ciliary neurotrophic factor (CNTF). Based on the cardiac hypertrophy-inducing activity, this protein was subsequently called Cardiotrophin-1. However, CT-1 is also expressed in a number of other tissues including liver, kidney, neuronal tissue and skeletal muscle and also has important roles in these organs. Shortly after its discovery, CT-1 was shown to stimulate rat hepatoma cells and induce an acute phase reaction (9). Mice treated for 2 weeks with CT-1 demonstrated increased liver, spleen and kidney weight, and also enhanced erythroid and myeloid haematopoiesis, suggesting a systemic growth-promoting function of CT-1 that involves most organ systems. (10) Its biological action is mediated through the CT-1 receptor, which consists of three subunits (gp130, LIFR and a third component of about 80 kDa) (10). gp130, which is common to all receptors of the IL-6 family, seems to be the most important component activating the Jak/ STAT3, ERK 1/2 and PI3K-Akt pathway and hence leads to activation of proteins that promote cell survival.