Future therapy of portal hypertension in liver cirrhosis - a guess

Abstract

In patients with chronic liver disease, portal hypertension is driven by progressive fibrosis and intrahepatic vasoconstriction. Interruption of the initiating and perpetuating etiology-mostly leading to necroinflammation-is possible for several underlying causes, such as autoimmune hepatitis, hepatitis B virus (HBV) infection, and most recently hepatitis C virus (HCV) infection. Thus, in the long run, lifestyle-related liver damage due to chronic alcoholism or morbid obesity will remain the main factor leading to portal hypertension. Both causes are probably more easily countered by socioeconomic measures than by individual approaches. If chronic liver injury supporting fibrogenesis and portal hypertension cannot be interrupted, a wide variety of tools are available to modulate and reduce intrahepatic resistance and therewith portal hypertension. Many of these have been evaluated in animal models. Also, some well-established drugs, which are used in humans for other indications (for example, statins), are promising if applied early and concomitantly to standard therapy. In the future, more individually tailored strategies must also be considered in line with the spectrum of portal hypertensive complications and risk factors defined by high-throughput analysis of the patient's genome, transcriptome, metabolome, or microbiome.

Figure 1.. Pathophysiology and targets of portal hypertension

Viruses, alcohol (or other toxins), obesity, lipids, bacterial components, and other factors induce liver damage and inflammation (often via activation of local and recruited macrophages). This process leads to activation of hepatic stellate cells and proliferation of myofibroblasts. Their fibrogenetic and contractile properties are the main causes of increases in intrahepatic resistance and portal venous congestion inducing portal hypertension. This results in splanchnic vasodilation and an increase in portal tributary blood flow via different mechanisms, which aggravate portal hypertension. Initiators of this cascade may reach the liver via the systemic circulation or may be derived from the gut. The best method to counter portal hypertension is the interruption of the initiating events, whether by eradication of hepatotropic viruses, abstinence from alcohol, or weight reduction. If this fails, there are several strategies to modify and influence intrahepatic inflammation or activation (or both) of hepatic stellate cells, including stimuli coming from the gut and the visceral adipose tissue.