Have you mastered the pathogenesis of cirrhosis and portal hypertension?

Introduction Portal hypertension (portal hypertension, PH) refers to a group of clinical syndromes caused by the increase in portal system pressure caused by various reasons, which can be defined as: the pressure difference between the portal vein and the inferior vena cava, that is, the portal pressure The portal pressure gradient (PPG) exceeds the upper limit of normal by 5mmHg.

The normal range of PPG is 1-5 mmHg.

In patients with liver cirrhosis, when PPG exceeds the upper limit of normal by 5-10 mmHg, the clinical symptoms are mild or not significant; when PPG exceeds the upper limit of normal by 10 mmHg (such as varicose veins, ascites), patients will have obvious symptoms Clinical manifestations.

The basic pathophysiological characteristics of portal hypertension are that the blood flow of the portal venous system is blocked and/or the blood flow is increased, and the static pressure in the portal vein and its branch vessels is increased with the formation of collateral circulation.

Among all the causes of PH, the first driving force is the increase in portal blood flow resistance, followed by the increase in portal inflow.

The formula can be expressed as: PH=portal vein inflow×outflow resistance Cirrhosis is the most common cause of PH, followed by portal vein thrombosis (PVT).

Among the latter, obstruction of the main portal vein (thrombosis) is the initial cause, so the pathogenesis is more clear.

In contrast, the pathogenesis of PH in cirrhosis is more complicated, so this article reviews the pathogenesis of PH in cirrhosis.

1.
Increased intrahepatic resistance.
In cirrhosis, the increase in intrahepatic resistance is caused by changes in the structure of the liver sinusoids (sinus fibrosis, regenerating nodules) and functional contraction of intrahepatic blood vessels (the reduction of vasodilators produced by sinusoidal endothelial cells).
Lead to) the result of a joint action.

1.
Hepatic vascular structure disorders Chronic liver disease caused by any cause will cause pathological changes of liver sinusoids, which are mainly due to changes in the phenotype and function of hepatic stellate cells (HSC) and sinusoidal endothelial cells (SEC).

Under normal circumstances, HSC participates in the metabolism and storage of vitamin A, as well as the synthesis and degradation of extracellular matrix; after liver injury, HSC is activated, and a large number of them divide and proliferate and migrate to the site of liver injury, and synthesize collagen, fibronectin and proteoglycan Such extracellular matrix will eventually lead to fibrosis of the liver, resulting in changes in the structure of the liver sinusoids.

The SEC is located in the sinusoids and separates the sinusoidal cavity from the perisinusal space.

SEC participates in the material exchange of normal liver cells; in liver cirrhosis, SEC proliferation is active, the cell body swells, extends into the sinus cavity, the cells become thicker, the number of SEC windows decreases or disappears, and the deposition of the basement membrane leads to the capillary endothelium of the liver sinusoids Vascularization.

The capillaryization of the sinusoidal endothelium may play a role in the increase of intrahepatic resistance and the early stage of fibrosis.

2.
Vascular endothelial dysfunction The endothelium-dependent vasodilation function is impaired, which is called vascular endothelial dysfunction.

Under normal circumstances, the vascular endothelial cell layer can sense changes in blood flow and vascular tension, and can release vasodilator factors to inhibit blood flow or vasoconstriction to increase blood pressure.

After liver injury, the production of endothelium-dependent vasodilators such as nitric oxide (NO) is inhibited, and the bioavailability is reduced; while the release of the endothelium-derived contractile factor hydroprost (PGH2)/thromboxane TXA2 increases, which further promotes blood vessels shrink.

3.
Intrahepatic thrombosis Patients with liver cirrhosis are often accompanied by coagulation dysfunction.

The traditional view is that coagulation factor synthesis disorders and thrombocytopenia increase the risk of bleeding, but can also prevent thrombosis.

However, there is currently evidence that patients with liver cirrhosis are accompanied by a reduction in anticoagulant factors, so the above view has been challenged.

In fact, the final result of these changes is a state of hemostasis and rebalance.

However, this rebalance state is not stable, and bleeding or thrombosis may occur under certain conditions.

Some data indicate that there is a close relationship between the prethrombotic state and the exacerbation of liver fibrosis and PH in experimental and clinical models.

In patients with liver cirrhosis, thrombotic obstruction of the intrahepatic veins and sinusoids can lead to intimal fibrosis and venous obstruction, and eventually the adjacent liver cells are lost and replaced by fibrous tissue.

In addition, the formation of thrombosis in the liver sinusoids can activate HSCs through receptors activated by proteases, leading to the deposition of extracellular matrix.

The above-mentioned theory is supported by the research result that "anticoagulation therapy can improve liver fibrosis and PH".

2.
Visceral vasodilatation The increase of intrahepatic vascular resistance leads to an increase in portal venous system pressure, which leads to increased release of vasodilators such as NO from the visceral arteries that drain to the portal vein.
The visceral arteries are significantly expanded, which further increases portal blood flow.

Therefore, visceral arterial vasodilation is a major factor in the progression and deterioration of PH.

Visceral vasodilation also affects the systemic circulation, leading to a decrease in mean arterial pressure and a decrease in effective arterial blood flow.
In turn, it leads to activation of the neurohumoral system, retention of sodium and water, increased cardiac output, and enters a hyperdynamic circulatory state, with further portal pressure.
Increase.

3.
The effect of systemic inflammation or bacterial translocation.
Bacteria or bacterial products entering the systemic circulation from the intestinal lumen are more prominent in decompensated cirrhosis, but they may also occur in the compensatory phase.

It is currently believed that bacterial translocation is both a consequence of PH and a factor that causes PH aggravation.

The products of intestinal bacteria can stimulate the activation of HSC and Kupffer cells, and further promote the occurrence of liver fibrosis.

In addition, bacteria-induced inflammation can lead to the deterioration of the system's hyperdynamic circulatory state and the dysfunction of extraintestinal organs (such as the heart, kidneys, and brain).

Yimaitong compiled from: Laura T, Guadalupe GT, Portal Hypertension Pathogenesis and Diagnosis.
Clin Liver Dis 23 (2019) 573–587.
https://doi.
org/10.
1016/j.
cld.
2019.
07.
007