Relationship Between HCC and Gastrointestinal Hemorrhage: Potential Effects of Statins
Portal hypertension commonly occurs in patients with HCC in whom it may precede the development of clinically detectable disease. Gastrointestinal bleeding occurs as the initial manifestation of HCC in 4% of cases and accounts for 15% of mortality in untreated HCC. A recent prospective study has reported portal hypertension to be an independent predictor of HCC development, hepatic venous pressure gradient (HVPG) > 10 mmHg at baseline being associated with a sixfold increase of HCC risk during a 4-year follow-up. Although the mechanistic reasons for such a finding are unclear, both structural and functional changes are likely to be involved. From a pathological point of view capillarization of sinusoids and formation of fibrous septa could all be linked to neoangiogenesis, which might precede the development of HCC. From a physiopathological perspective, intrahepatic shunts, unbalanced ratio of vasoactive substances such as endothelin-1 and nitrates/nitrites and hepatic endothelial dysfunction could well play a role in portal hypertension associated with HCC.[73–75]
It is reported that with currently available treatments as few as 35–40% of the patients achieve target reductions in portal pressure (more than 20% from baseline values or to less than 12 mmHg), which supports the plea for improved treatment schedules. In particular, statins are not included in the presently available strategy for the chemoprevention of either primary or recurrent gastrointestinal bleeding and in clinical practice cirrhotic patients are offered either beta blockers or submitted to rubber band ligation. Physiopathological evidence, however, suggests that statins might in future be used to lower portal hypertension associated with cirrhosis.
Zafra et al. were first in reporting that the administration of simvastatin resulted in decreased hepatic resistance in cirrhotic patients via increased hepatosplanchnic output of nitric oxide products. These authors observed in 13 cirrhotic patients that acute simvastatin administration increased the hepatic blood flow and decreased hepatic sinusoidal resistance without altering HPVG. Such changes were associated with increased nitric oxide product levels in hepatic venous (but not in peripheral) blood. Accordingly, systemic hemodynamics were not modified. In the same study, postprandial portal pressure was evaluated in 17 patients randomized to receive placebo or 40 mg simvastatin 12 h and 1 h before the study. Pretreatment with simvastatin significantly attenuated the postprandial increase in HPVG. Hepatic blood flow increased similarly in the two groups. Hepatic nitric oxide products increased in the simvastatin group but not in the placebo group. The same group of researchers provided further evidence for a beneficial activity of statins in cirrhotic patients in a double-blind clinical trial. Abraldes et al. randomized 59 cirrhotic patients with portal hypertension, defined by HVPG ≥ 12 mm Hg, to either simvastatin (20 mg/day for 1 month increased to 40 mg/day at day 15) or placebo. The authors were able to demonstrate that treatment with simvastatin significantly decreased HVPG irrespective of whether patients were receiving beta-adrenergic blockers or not and that treatment was not only free of adverse effects but also associated with surrogate evidence of improved liver perfusion and function. The mechanisms underlying the pharmacological effects of statins on cirrhotic portal hypertension are being increasingly elucidated. Simvastatin selectively increases nitric oxide availability in the cirrhotic liver circulation through increased eNOS expression, Akt-dependent eNOS phosphorylation and cyclic guanosine monophosphate (cGMP) liver content. These effects are mediated in part by increased hepatic levels of the transcription factor Kruppel-like factor 2 (KLF2), the endothelium inducing the expression of a variety of vasoprotector genes/proteins and its vasoprotective target genes, eNOS and thrombomodulin.
Usually studies on portal hypertension are conducted on cirrhotic patients and the presence of HCC is a criterion for exclusion. Therefore, it is unlikely that studies might be conducted specifically in HCC patients and the unproven assumption is that these patients have a response rate similar to that observed in those with cirrhosis. Importantly, future evaluation of statins is needed to use clinical (e.g. effective prevention of bleeding) as opposed to physiopathological end points before these drugs may be allowed to enter the clinical arena.
J Gastroenterol Hepatol. 2012;27(11):1654-1664. © 2012 Blackwell Publishing