Extrahepatic complications to cirrhosis and portal hypertension: haemodynamic and homeostatic aspects

Abstract

In addition to complications relating to the liver, patients with cirrhosis and portal hypertension develop extrahepatic functional disturbances of multiple organ systems. This can be considered a multiple organ failure that involves the heart, lungs, kidneys, the immune systems, and other organ systems. Progressive fibrosis of the liver and subsequent metabolic impairment leads to a systemic and splanchnic arteriolar vasodilatation. This affects both the haemodynamic and functional homeostasis of many organs and largely determines the course of the disease. With the progression of the disease, the circulation becomes hyperdynamic with cardiac, pulmonary as well as renal consequences for dysfunction and reduced survival. Infections and a changed cardiac function known as cirrhotic cardiomyopathy may be involved in further aggravation of other complications such as renal failure precipitating the hepatorenal syndrome. Patients with end-stage liver disease and related complications as for example the hepatopulmonary syndrome can only radically be treated by liver transplantation. As a bridge to this treatment, knowledge on the mechanisms of the pathophysiology of complications is essential for the choice of vasoactive drugs, antibiotics, drugs with specific effects on fibrogenesis and inflammation, and drugs that target specific receptors.

Keywords: Ascites; Bacterial translocation; Cirrhotic cardiomyopathy; Fibrogenesis; Hepatopulmonary syndrome; Hepatorenal syndrome; Infections; Inflammation; Portopulmonary hypertension; Splanchnic haemodynamics; Systemic circulation.

Figure 1

Fibrogenesis after liver injury. Hepatic stellate cells are activated into myofibroblasts that deposit scar matrix in the Space of Disse.

Figure 2

Space of Mall is a small space of fluid surrounding a hepatic arteriole, a portal venule and a bile ductule. Adenosine is secreted into the space of Mall. A reduction in portal blood flow increases adenosine levels and leads to hepatic arteriolar vasodilataion and activation of sensory nerves after[54].

Figure 3

Illustration of bacterial translocation from the gastrointestinal lumen through the epithelial layers and capillaries to the lymphalic vessels.

Figure 4

Mechanisms of cirrhotic cardiomyopathy. The figure reviews the most important mechanisms involved in cirrhotic cardiomyopathy: Desensitisation and downregulation of β-adrenergic receptors with decreased content of G-protein (Gαi: inhibitory G protein; Gαs: stimulatory G protein) and following impaired intracellular signalling; alterations in particular in M2 muscarinic receptors; upregulation of cannabinoid 1-receptor stimulation; altered plasma membrane cholesterol/phospholipid ratio; increased inhibitory effects of haemooxygenase (HO), carbon monoxide (CO), nitric oxide (NO), and tumour necrosis factor-α (TNF-α); reduced density of potassium channels; changed function and fluxes through L-type calcium channels; altered ratio and function of collagens and titins. Many post-receptor effects are mediated by adenylcyclase (AC) inhibition or stimulation. PKA: Protein kinase A.

Figure 5

Gas exchange in the normal lung (left) and mechanism of hepatopulmonary syndrome (right). The hepatopulmonary syndrome comprises an increased alveolar-arterial oxygen gradient owing to diffusion limitations and development of intrapulmonary right-to-left shunts leading to arterial hypoxaemia.

Figure 6

Pathophysiological mechanisms in the development of ascites and the hepatorenal syndrome. SNS: Sympathetic nervous system; RAAS: The renin-angiotensin-aldosterone system; AII: Angiotensin II; ET-1: Endothelin-1; NO: Nitric oxide; PGs: Prostaglandins.

Figure 7

Pathophysiological proposal for the background of a cardiorenal syndrome in cirrhosis[194]. CBV: Central blood volume; CO: Cardiac output; GFR: Glomerular filtration rate; HR: Heart rate; HVPG: Hepatic venous pressure gradient; MAP: Mean arterial pressure; RAAS: Renin-angiotensin-aldosterone system; RBF: Renal blood flow; SNS: Sympathetic nervous system; SVR: Systemic vascular resistance.