Increased resistance to portal blood flow is the main pathophysiological mechanisms leading to the development of portal hypertension (PH) in patients either with cirrhosis or in patients with non-cirrhotic portal vein thrombosis (NCPVT). Pathophysiology of PH in cirrhosis has been extensively reviewed and discussed. Briefly, the increase in resistance is mainly located at intrahepatic level and has two main components: one structural and the other dynamic (due to an increase in intrahepatic vascular tone). However, concomitant development of splanchnic and systemic vasodilatation, by increasing portal blood flow, maintains or even aggravates PH despite the formation of porto-collaterals. Various molecules have been proven to promote splanchnic vasodilation and neo-angiogenesis, such as nitric oxide, prostacyclin, vasoactive intestinal peptide, calcitonin-gene related peptide, adrenomedullin, pro-inflammatory cytokines (such as TNF-α and IL-6), bacterial-derived molecules (lipopolysaccharide, LPS) and many other endothelial local factors. Vasodilatation of the splanchnic and, consequently, systemic beds promotes an effective hypovolemia (not enough blood volume to fill the vasodilated vascular bed) that triggers the activation of vasoactive and sympathetic system promoting sodium and water retention in order to expand plasma volume trying to refill the vascular bed. In fact, a progressive activation of the renin/aldosterone (RAS) and arginine/vasopressine (AVP) axis has been demonstrated as PH aggravates, mainly because hypovolemia and plasma hypo-osmolality; furthermore an increased catecholaminergic tone (by both sympathetic nerves and adrenal medulla) was shown to sustain cardiac function and renin production in kidney. Moreover, the stretching of cardiac fibers stimulates the release of brain natriuretic peptide (BNP) as an attempt to reverse sodium and fluid overload and RAS hyperactivation; therefore, BNP elevation could be a marker of hyperdynamic circulation and hormonal activation in PH, besides to represent an expression of heart dysfuncyion. As expansion of plasma volume facilitates the maintenance of an increased portal blood flow, the increase in vasoactive systems further increase intrahepatic vascular tone closing a vicious circle maintaining PH. Once PH is present, porto-systemic collaterals, trying to decompress the portal venous system, develop. Neo-angiogenesis is the cornerstone for porto-collaterals development and, despite its complexity, it is though that increased shear stress due to high pressure and hypoxia could be responsible for secretion of multiple mediators that stimulate endothelial cells, macrophages, monocytes and progenitor cells, especially vascular endothelial growth factors (VEGF-A and VEGF-D) and soluble fms-like tyrosine kinase 1 (sFlt-1) to placental growth factor (PLGF).
In patients with NCPVT (in a healthy liver), the increase resistance to portal blood flow is exerted by the occlusion of the portal venous system by the thrombus. Thrombosis does not require to occlude the entire vessel to produce marked increases in resistance and therefore in PH. Thus, according to Poiseuille’s law, reduction of just 50% of lumen vessel already produces marked increases in the resistance to blood flow. Some preliminary small sample sized studies suggested that patients with NCPVT had a similar systemic vasodilatation than patients with cirrhosis. However, a study including 39 patients with NCPVT and 39 with cirrhosis, matched according to clinical characteristics, showed that despite some patients having hyperdynamic circulation, the mean values of cardiac index (CI) and systemic vascular resistance (SVR) of the two cohorts of patients were within the range of values observed in healthy people. Indeed, this a well described finding in patients with cirrhosis showing that the hyperdynamic circulation appears and progressively aggravates in relation with the severity of PH and of liver dysfunction.
Currently, there is scarce clinical data evaluating whether the vasoactive and neo-angiogenetic systems are activated in patients with NCPVT and if there is a relationship with the presence or absence of systemic/splanchnic vasodilatation. Furthermore, there are very few published researches which show similar prevalence of autonomic neuropathy between cirrhotic patients and NCPVT patients. The autonomic dysfunction, demonstrated by impaired cardiovascular autonomic response, might be proposed as an adjunctive mechanism of hyperdynamic state in patients with portal hypertension without cirrhosis. On the other hand, the potential impact of these potential hemodynamic/neurohumoral alterations in the development of PH related complications in patients with NCPVT is unknown.
The hypothesis of our study is that patients with NCPVT could develop hemodynamic changes and neuro-hormonal alterations similar to those developed in patients with cirrhosis and the presence and severity of these alterations might be associated with survival and the development of complications related to portal hypertension. The study may increase the knowledge of pathophysiological mechanism of the disease.