The microscopic human liver architecture is arranged in lobules with cords of liver cells radiated to a central vein. The portal tract consists of a triad containing a portal vein branch, a hepatic arteriole, and a bile duct[1]. Thus, the liver lobule is quantitatively formed by hepatocytes and cholangiocytes. In addition to these two primary epithelial cell populations the liver hosts SEC, Kupffer cells, and HSC, see Figure 1[21-23].

Open in New Tab   Full Size Figure   Download Figure

Figure 1 Fibrogenesis after liver injury. Hepatic stellate cells are activated into myofibroblasts that deposit scar matrix in the Space of Disse.

The hepatocytes accounts for approximately 80% of the total liver cell mass[24]. The hepatocytes have essential physiological functions, such as regulation of carbohydrate and lipid metabolism, clearance and inactivation of drugs, ethanol, toxins and various hormones and vasoactive substances. A very important function of the hepatocytes is the synthesis of plasma proteins, including albumin, C-reactive protein, fibrinogen, complement, and coagulation factors. In patients with acute and chronic liver injury hepatocyte apoptosis plays a major role for the impaired metabolic function[25]. When the liver is exposed for toxic substances such as drugs, alcohol, and hepatitis B or C virus, fibrogenesis increases and initiates the cirrhotic process with development of regeneration nodules with impairment of hepatocyte function[26,27]. The impaired metabolic function results in compromised degradation of various vasoactive substances, which is particularly important for the understanding of the systemic and splanchnic haemodynamic changes[28]. Atrial natriuretic peptide is cleared in the liver with extraction ratios of 22%-75%[29]. The hepatic extraction of glucagon has been determined by infusion studies and ranges 10%-20% and hepatic extraction ratios of adrenaline and noradrenaline are very high and ranges 63% to 67%[28]. Renin, angiotensin II, substance P, vasopressin, and aldosterone are other important other bioactive substances with haemodynamic implications that are degraded in the liver[28].

Kupffer cells are liver macrophages and constitute 80% of all tissue macrophages of the reticuloendothelial system on the body and about 15% of the liver cells[24]. The Kupffer cells are important for the immune function of the liver and act as antigen presenting cells of bacteria, endotoxins, liopolysaccharide (LPS) and other antigens together with natural killer (NK) cells[30,31]. In addition, the Kupffer cells play an important role in the expression of proinflammatory cytokines such as tumour necrosis factor-α (TNF-α), interleukin-1 (IL-1) and IL-6[32]. Furthermore, they play important roles in clearance of endotoxins, and in the defence of microbial infections and contribute to the production of the vasodilator nitric oxide[33].

HSC are located in the space of Disse and they are in close contact with hepatocytes and SEC, Figure 1. They are rich of vitamin A, which relates to their function as hepatic storage of retinyl esters[34]. The HSCs are furthermore actively involved in fibrogenesis and metabolism. They are involved in matrix degradation and tissue inhibitor of metalloproteinase-1 (TIMP-1) has been shown to be a survival factor for HSC, and inhibition of the actions of TIMP-1 may be a target for antifibrogenic treatment[35,36]. HSC has important contractile properties with relation to the development of portal hypertension[37]. Thus, vasoactive agents, such as endothelin-1 (ET-1), angiotensin-2, and trombin induces contraction[35,37]. From this point of view the contraction of HSC constitutes a reversible and dynamic component of the increase in the hepatic flow and regulation of the portal pressure[3]. This function is intimately associated with a counter regulation by nitric oxide and carbon monoxide, which induce relaxation of HSC and thereby ultimately reduces portal pressure[35,36]. The SECs possess highly specialised physiological functions as they serve as a source of several bioactive substances[38]. The cells are involved in regulation and production of proinflammatory cytokines and haemodynamically important vasoactive peptides and substances, including nitric oxide, ETs, prostanoids, and prostaglandins[39,40].

It can be concluded, that various cell types of the liver are deeply involved in the haemodynamic changes and extrahepatic complications. Thus, impaired hepatocyte degradation of vasoactive substances, production of vasodilators in the HSC and SEC, and impaired immune and clearance function of Kuppfer cells inducing production of proinflammatory cytokines and substances are of importance for the development of portal hypertension and directly involved in the pathophysiology of extrahepatic hemodynamic complications. Increased portal pressure leads to portosystemic shunts, and thereby increases the amount of vasodilators and other compounds that bypass the liver metabolism and degradation.

The histological hallmark of chronic liver failure is development and perpetuation of fibrosis in the liver. Sustained fibrogenesis leads to cirrhosis, which is characterized by distortion of the liver parenchyma and reduction of vascular architecture. The fibrogenetic process is like a wound-healing response to injuries and a balance between formation and degradation of fibrotic tissue[35]. This process can be activated by injuries caused by for example viral hepatitis, alcohol intake, and autoimmune disorders. These stimuli primarily activate HSC into myofibroblasts-like cells with contractile, proliferative, and fibrogenic capacities and it is the primary cell type responsible for deposition of extracellular matrix in the liver[34]. The HSCs are located in the subendothelial space between the hepatocytes, Kupffer cells, and SECs so they mutually interact through numerous cellular processes extending across the space of Disse, see Figure 1[37]. Paracrine and autocrine activation of HSCs by tumour growth factor-β1, which is considered the most potent fibrogenic cytokine, initiates the fibrotic process in the liver[35]. In addition, the HSCs cover various physiological functions, including activation of the immune response, secretion of cytokines, and angiogenesis[34]. The activation of the HSC into myofibroblasts consists of an initiation phase and a perpetuation, followed by a resolution phase. Resolution of fibrosis refers to sequences of events such as apoptosis, senescence, or quiescence[27]. The inflammatory response plays an important role in fibrogenesis since inflammation always precedes fibrosis and immune activation induces fibrosis by bacterial LPSs[41]. Kupffer cells also activate HSC by increased NF-κB activity and secretion of pro-inflammatory cytokines, including TNF-α and monocyte chemoattractant protein[22,42]. Finally, NK cells have an anti-fibrotic effect by killing activated HSC. The contractile HSC contributes to the regulation of the sinusoidal blood flow and to angiogenesis in the cirrhotic liver[37]. Thereby, the HSCs contribute to regulate intrahepatic blood flow and portal pressure. Together with SECs that excert a paracrine effect through nitric oxide synthesis, the HSC represent an important dynamic component of the sinusoidal haemodynamic resistance in cirrhosis.

It can be concluded that the HSCs are the major fibrogenetic cells type in the injured liver and its numerous functions have disclosed important targets for effective antifibrotic therapies[36,43].

The splanchnic blood flow increases normally after a meal[47]. The mechanisms are largely unknown but splanchnic blood vessels are richly innervated by sympathetic nerves from the prevertebral sympathetic ganglia and an increase in sympathetic nervous outflow is partly responsible for the initial increase in cardiac output together with mediators such as glucose and long-chain fatty acids[48]. The extrinsic neural control of intestinal blood flow is predominantly through sympathetic vasoconstriction mediated by alfa adrenoceptors. Sympathetic activity reduces intestinal blood flow by increasing the vascular resistance of the arterioles and veins, and this is among the major effects on beta-blocking agents on hepatic blood flow and portal pressure[4,14,49].

In normal conditions, the vascular compliance of the liver is sufficient to maintain pressure homeostasis, but in cirrhotic patients with increased systemic vascular compliance and reduced hepatic and portal compliance, the portal pressure and degree of porto-systemic shunting increases and thereby the risk of bleeding from oesophageal varices[4,50,51]. This risk is further increased following a meal that augment the hepatic inflow[52]. Inversely, changes in splanchnic haemodynamics may affect function of other organs and the existence of a hepatorenal reflex has been debated for years. Experimental and clinical studies have provided support for a direct link between the liver and the kidneys[53,54]. In human cirrhosis, reduced renal blood flow following an increase in portal pressure and a concurrent increase in renal venous ET-1 suport this assumption[55,56]. There are now both clinical and experimental evidence of a hepatic blood flow-dependent hepatorenal reflex and this is a primary pathophysiological mechanism for renal dysfunction in liver disease[57]. This reflex is activated by adenosine in the space of Mall and is regulated by hepatic blood flow[54] (Figure 2).

Open in New Tab   Full Size Figure   Download Figure

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].

The liver receives blood from both the hepatic artery and the portal vein. From a homeostatic point of view this is unique, since it secures a constant blood flow to the liver through a hepatic arterial buffer system[58]. According to the hepatic arterial buffer hypothesis a reduction in portal blood flow will cause a local accumulation of adenosine not washed away from the space of Mall surrounding the hepatic arterial resistance vessels and this will lead to local vasodilatation[54,59]. The metabolic homeostatic mechanisms maintain constant oxygen delivery, whereas the myogenic homeostatic mechanisms maintain a constant intravascular pressure[60].

A number of hormones with vasoactive effects such as gastrin, vasoactive intestinal polypeptide, cholecystokinin, secretin, and glucagon are implicated in the fine-tuning of the splanchnic haemodynamics of the liver[11,61]. As previously mentioned, SECs and HSCs are intimately involved in the regulation of the sinusoidal blood flow and potent vasodilators such as nitric oxide, ET-1, and tromboxan-A2 play a role in the vasodilation/vasoconstriction balance and the dynamic component of the increase in portal pressure in cirrhosis[40,62-65].

In conclusion, several homeostatic mechanism are involved in maintaining blood flow and metabolism in the normal liver. During development of cirrhosis and portal hypertension these mechanisms may not be adequate to meet the requirements of the body and liver failure, metabolic insufficiency, and portal hypertension may develop.

In patients with cirrhotic cardiomyopathy, cardiac failure may become manifest only under conditions of haemodynamic stress. Thus, the left ventricular end-diastolic pressure increases after exercise, but the expected increases in cardiac stroke index and left ventricular ejection fraction (LVEF) are absent or subnormal, which indicates an inadequate response of the ventricular reserve to a rise in filling pressure[130]. A vasoconstrictor-induced increase of 30% in the left ventricular afterload results in a doubling in pulmonary capillary wedged-pressure, with no change in cardiac output[131]. This response may be useful in diagnosing cirrhotic cardiomyopathy. A similar pattern is seen after insertion of TIPS, but the raised cardiac pressures tend to normalise with time[132,133]. Some of these patients (12%) may develop manifest cardiac failure in association with the TIPS insertion[134]. A failure to increase cardiac output, despite increased ventricular filling pressure, indicates that normalisation of the afterload impairs cardiac performance and unmasks left ventricular dysfunction[131].

LVEF reflects systolic function, even though it is very much influenced by preload and afterload. It has been reported to be normal at rest in some studies and reduced in one study of a subgroup of patients with ascites[130,131,135]. After exercise, LVEF increases less in cirrhotic patients than in controls[130,136,137]. The reduced functional capacity may be attributed to a combination of blunted heart rate response to exercise, reduced myocardial reserve, and profound skeletal muscle wasting with impaired oxygen extraction[138,139]. By modern techniques like tissue-Doppler and speckle tracking echocardiography, it is possible also to detect systolic and diastolic dysfunction at rest[140,141] .

The clinical significance of diastolic dysfunction and its importance in cirrhotic cardiomyopathy has been questioned, as overt cardiac failure is not a prominent feature of cirrhosis. However, there are several reports of unexpected death from heart failure following liver transplantation, surgical portocaval shunts, and TIPS[134,142]. These procedures involve a rapid increase in cardiac preload. In a less compliant heart, the diastolic dysfunction could be enough to cause pulmonary oedema and heart failure. This is consistent with the findings of an increase in pulmonary artery pressure, pre-load, and diastolic dysfunction after TIPS[132]. Diastolic dysfunction affecting left ventricular filling may progress to systolic dysfunction[123,143]. The pathological basis of the increased stiffness of the left ventricle seems to be cardiac hypertrophy, patchy fibrosis, and subendothelial oedema[131,136,144]. Decreased E/A ratio and delayed early diastolic transmitral filling with prolonged deceleration and isovolumetric relaxation times indicate diastolic dysfunction on the Doppler echocardiogram and corresponding characteristics on the tissue-Doppler and speckle tracking echocardiography[131,140,141,145].

In cirrhotic patients, the Q-T interval is prolonged and significantly related to the severity of the liver disease, portal hypertension, portosystemic shunts, elevated brain type natriuretic peptide (BNP) and pro-BNP, elevated plasma noradrenaline, decreased heart rate variability, and reduced survival[122,124,146-149]. The prolongation of the Q-T interval is partly reversible after liver transplantation and beta-blocker treatment[146,150]. Recently, it has been documented that gastrointestinal bleeding further prolongs the Q-T interval in cirrhosis and independently predicts bleeding-induced mortality[151]. The prolonged Q-T interval in cirrhosis should be considered an element in the cirrhotic cardiomyopathy and may be of potential use in the stratification and identification of patients at risk[149,152].

Taken together, cirrhotic cardiomyopathy encompasses impaired contractility and diastolic relaxation, and electrophysiological abnormalities in particular prolonged Q-T interval. Independent of aetiology of cirrhosis, systolic dysfunction can be diagnosed at rest by for example tissue-Doppler imaging or demasked by physical or pharmacological stress. Diastolic dysfunction can be detected by echocardiography or tissue-Doppler imaging. Cirrhotic cardiomyopathy may aggravate complications such as gastro-intestinal bleeding and development of the HRS. Liver transplantation may revert the cardiac dysfunction but surgery and TIPS insertion may also aggravate the condition.

A condition with reduced diffusing capacity, abnormal ventilation/perfusion ratio and intrapulmonary vascular dilatations, and low arterial oxygen saturation in association with liver disease and absence of cardiopulmonary disease is termed HPS[153-156]. Arterial deoxygenation is reflected by a widened alveolar-arterial oxygen gradient (P_A-aO₂)[88,157]. The frequency of HPS in patients with cirrhosis is variably reported from 5%-50% according to the type of population with respect to aetiology, geography, etc [154,156,158-160]. The pathophysiological hallmark of HPS, is dilatations of capillaries near the alveolar areas, see Figure 5. Fallon et al[153] have recently reported increased pulmonary vascular endothelial nitric oxide synthase (NOS) and increased production of cholangiocyte ET-1 and increased expression of ET-B receptors[161,162]. Recently, pulmonary angiogenesis have been implemented in the development of this complicated pathophysiology[163].

Open in New Tab   Full Size Figure   Download Figure

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.

From a practical point of view HPS is defined by arterial hypoxaemia [PaO₂ < 70 mmHg (or 9.3 kPa)], an age-adjusted increase in P_A-aO₂ > 15 mmHg (or 2.0 kPa) and presence of intrapulmonary vasodilatations[154,162]. A large proportion of patients with HPS present with insidious onset of dyspnea, plathypnea (upon standing), orthodeoxia, clubbing, and cyanosis[164]. The diagnosis requires arterial blood gas measurements and calculation of P_A-aO₂, Contrast-enhanced echocardiography (CEE) is today considered the most sensitive test and method of choice in the diagnosis HPS[156], but also injection of macroaggregated albumin with estimated the extra-pulmonary shunt fraction > 6% indicates presence of HPS[165]. Currently, the following criteria for HPS are: (1) Presence of liver disease; (2) P_A-aO₂≥ 15 mmHg (2.0 kPa); and (3) a positive CEE (Table 4).

At present there is no effective medical therapy for HPS. Insertion of TIPS has been reported to be successful, but it may result in increased pulmonary pressures and is therefore not recommended[166,167]. Since HPS is reversible after liver transplantation, it has become an indication for urgent liver transplantation and the long-term outcome after LT in HPS is increasingly favorable[168,169].

PoPH is defined as a mean pulmonary artery pressure > 25 mmHg and pulmonary vascular resistance >240 dyn•s•cm^-5, and normal left atrial pressure (< 15 mmHg), see Table 4[154,170,171]. The histological appearance of pulmonary vessels is similar to that seen in primary pulmonary artery hypertension, and includes smooth muscle proliferation, hypertrophy, and fibrosis[154]. Various pathophysiological aspects seem to be involved in the development of portopulmonary hypertension, including vasoproliferation, genetics, and inflammation with increased pulmonary phagocytosis[154]. Of particular interest is the activation of potent local vasoconstrictor systems, like serotonin and the ET system. ET-1 is produced in the pulmonary endothelium and binding to ET_A and ET_B receptors on the pulmonary smooth muscle cells leads to vasoconstriction[172-175]. Symptoms are typically progressive and include fatigue, chest discomfort, exertional dyspnoea, oedema, and syncope[175,176]. The median survival in patients with PoPH is considered low, about six months[177] and lower than in patients with idiopathic pulmonary hypertension[171]. The diagnosis can be based on radiological, echocardiographic, lung functional, and haemodynamic findings. Pulmonary function tests often show reduced lung volumes, diffusing capacity, and forced vital capacities and widened P_A-aO₂[178]. For purposes of screening, Doppler-echocardiography can be used to estimate pulmonary pressures and right ventricular systolic pressure. Right ventricular systolic pressure thresholds from > 30 to > 50 mmHg as cutt-off limits are still discussed[156,179].

Different medical treatments that modify the circulation have been applied. These include prostacyclin analogs such as epoprosterol[180], ET receptor antagonists such as bosentan[180,181], and phosphodiesterase-5 inhibitors such as sildenafil[182]. The effects of these drugs are however modest. TIPS and liver transplantation are not treatment options of choice in these patients sice a mean pulmonary artery pressure > 35 mmHg is associated with increased mortality following liver transplantation[168,183,184].

In conclusion, a considerable number of cirrhotic patients present with changes in pulmonary vascular resistance, impaired ventilation, and hypoxaemia as part of HPS or PoPH. Although, the prevalence varies, the circulatory and neuroendocrine derangements seem to play important roles in the clinical aggravation, hepatopulmonary dysfunction, and circulatory reactivity of these entities. Therefore these pathophysiological aspects should be taken into account in the clinical management of the patient with cirrhosis and pulmonary dysfunction.

Acute renal failure is estimated to occur in approximately 20% of hospitalized patients with cirrhosis[185]. Several attempts have been made to achieve agreement on a more precise definition of AKI. AKI has been defined as an increase in serum creatinine ≥ 133 μmol/L (≥ 1.5 mg/dL) or an increase > 50%, but initiatives from the Acute Kidney Injury Network and others have defined AKI as an absolute increase in serum creatinine > 26.4 μmol/L (≥ 0.3 mg/dL) (or a 50% increase over 48 h)[186]. Differential diagnosis of AKI in cirrhosis is difficult as it ranges from pre-renal AKI (45%), intra-renal AKI including acute tubular necrosis and glomerulonephritis (32%), HRS (23%), and seldom post-renal AKI (< 1%).

Approximately 20% of the cirrhotic patients with ascites who are resistant to diuretics, progress to HRS[187]. HRS denotes a functional prerenal failure that is unresponsive to volume expansion in patients with chronic liver disease and ascites without significant morphological changes in renal histology, and with a largely normal tubular function (Table 5)[78,188]. The prognosis of patients with a full-blown HRS is poor ranging from days to weeks and liver transplantation is the only radical treatment for the HRS[187,189]. Two types of HRS have been defined depending on the rapidness and the extent of the renal failure[78,190,191]. Type-1 HRS is an acute form with a rapid decrease in renal function and renal failure as an independent predictive factor; type-2 HRS is a chronic form with a more stable renal dysfunction[191,192].

The major elements in the development of HRS are the diseased liver, the circulatory dysfunction with vasodilatation and lowering of the arterial blood pressure, the abnormal systemic neuro-humoral regulation with activation of the sympathetic nervous system which alters renal autoregulation, a cardiac dysfunction due to cirrhotic cardiomyopathy with a pre-terminal decline in cardiac output[40,193,194]. These aspects are summarised in Figure 6.

Open in New Tab   Full Size Figure   Download Figure

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.

Low systemic vascular resistance, central hypovolaemia, reduced baroreflex sensitivity, and abnormal renal autoregulation play a pivotal role in the circulatory dysfunction[111,193,195]. In patients with increased sympathetic nervous activity, the autoregulation curve may be shifted towards the right side[193]. Because of this, even minor reductions in arterial blood pressure may be harmful to renal perfusion. Thus, the renal blood flow decreases with the advancement of the clinical stage of liver dysfunction[196] and in these patients low arterial pressure relates to survival[11,85,197]. Cirrhotic cardiomyopathy has been described as a condition with impaired contractile responsiveness to stress and altered diastolic relaxation[123]. With the progression of the disease, the reduction in the systemic vascular resistance becomes so severe that the hyperdynamic cirrhotic heart is unable further to increase the high cardiac output, which leads to an underfilling of the central vascular bed and effective central hypovolaemia[111,188,198]. There is now evidence from several studies of a relation between the terminal decline in cardiac output and the progression of the disease, development of HRS, and survival[115,116]. We have therefore recently hypothesized a cardiorenal interaction in patients with advanced cirrhosis and renal dysfunction that refers to a condition where cardiac dysfunction in cirrhosis is a major determinant of the course of patients who develop HRS[199] (Figure 7).

Open in New Tab   Full Size Figure   Download Figure

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.

Bacterial translocation from the gut plays a significant role for spontaneous infections and the circulatory dysfunction characterised by aggravation of vasodilatation elicited by an inflammatory response with the production of proinflammatory cytokines such as TNF-α and IL-6 as a “cytokine storm”[72]. SBP is frequent in patients with cirrhosis and is an important risk factor for the development of circulatory dysfunction and HRS (Figure 3)[71,77,78].

The future in terms of therapy will probably attack different aspects in the pathophysiological process. A multi-target strategy should seek efficiently to counteract the arterial vasodilatation, central hypovolaemia, and arterial hypotension by administration of potent vasoconstrictors such as terlipressin combined with human serum albumin. Development of orally long-acting systemic vasoconstrictors should be encouraged. All patients with HRS including those who respond to terlipressin and albumin should be properly prioritized on the waiting list for liver transplantation.