ease. When the cause of liver damage is not removed, a chronic infl ammatory reaction devel- ops, which is typically accompanied by the accu- mulation of fi brillar extracellular matrix, nodular regeneration [ 1 ], neoangiogenesis, and the estab- lishment of portal hypertension (PH), i.e., high blood pressure in the portal vein, its branches, and tributaries. While PH increases, the hemody- namic derangement extends beyond the splanch- nic circulation due to a net increase in circulating vasodilating molecules. This increase is second- ary to a systemic and sustained infl ammatory reaction and leads to hyperdynamic circulation.
The latter is characterized by an increased heart rate and cardiac output as well as a decreased systemic vascular resistance with low arterial blood pressure. Infl ammation, altered hemody- namics, and tissue perfusion, together with parenchymal extinction, are also accompanied by a profound metabolic derangement that charac- terizes cirrhosis in its more advanced stages.
Pathophysiology of Cirrhosis and Metabolic Alterations
Portal HypertensionPH is the hemodynamic consequence (and hall- mark) of liver cirrhosis. It is initially caused by two main pathophysiological events. First, colla- gen deposition and nodular regeneration increase intrahepatic vascular resistance by mechanically compressing vessels. Second, a dysregulation of intrahepatic vasoactive molecules dynamically increases the contraction of hepatic myofi bro- blasts around the sinusoids, thus increasing the portal blood pressure.
PH is defi ned by a hepatic venous pressure gra- dient (HVPG) above 5 mmHg. HPVG is the dif- ference between pressure in the portal vein and the intra-abdominal portion of the inferior vena cava. Under normal conditions, substances absorbed by the intestine follow the enterohepatic circulation, fl owing through the portal venous system to be processed by the liver. In cirrhosis, once PH increases beyond 10 mmHg, low-resis- tance vascular sites are used to create alternative circulatory pathways [ 2 ] (e.g., gastroesophageal varices, paraumbilical vein, retroperitoneal venous collaterals, splenorenal shunts) allowing a bypass of the “obstructed” liver. As a conse- quence, there is a reduced hepatic clearance of gut-derived vasodilating agents, such as endoge- nous gastrointestinal hormones (glucagon, vaso- active intestinal peptide, calcitonin gene-related peptide) and intestinal bacterial products [ 3 ].
M. Rosselli • M. Pinzani (*)
Institute for Liver and Digestive Health,
Division of Medicine, University College London, Royal Free Hospital UP3 ,
NW3 2QG London , UK
e-mail: [email protected];
Cirrhosis
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182
In cirrhosis, intestinal transit time is prolonged and the intestinal mucosa is often edematous due to low oncotic pressure (as a consequence of hypoalbuminemia) and increased portal pressure.
In addition, biliary secretion and gut luminal bili- ary content are reduced, so that bile acids no lon- ger exert their antimicrobial effects or contribute to the integrity of intestinal mucosa to a suffi cient extent (see chapter “ Overview ” under the part
“Liver”) [ 4 ]. This can lead to bacterial over- growth and translocation [ 5 ]. The presence of bacterial products in the systemic circulation fur- ther activates the immune system, increasing the infl ammatory response and leading to a functional immune paralysis that characterizes the typical susceptibility of cirrhotic patients to infections [ 6 ]. More specifi cally, endotoxins (such as lipo- polysaccharides, see chapter “ Fever ”) activate infl ammatory cells, which release cytokines (such as tumor necrosis factor α, interleukins 1 and 6) and express specifi c enzymes such as inducible nitric oxide synthase (iNOS) and heme oxygenase (HO) that produce high levels of nitric oxide and carbon monoxide, respectively [ 7 ].
Both of these molecules stimulate soluble gua- nylate cyclase. The resultant cGMP then acti- vates protein kinase G and lowers intracellular Ca 2+ levels in smooth muscle cells (SMCs) thus causing vasodilation. Consequently, the portal pressure increases, whereas the systemic blood pressure decreases (see chapter “ Overview ” under the part “Blood vessels”).
As a compensatory response, the adrenergic system and the renin-angiotensin-aldosterone system (RAAS) are activated (see chapter
“ Overview ” under the part “Kidney”). However, despite high levels of catecholamines and other vasoconstrictors such as angiotensin II, the splanchnic and systemic vasodilation persist due to a vascular hyporesponse to the vasoconstric- tors. Because of increased sodium and water retention (initially driven by RAAS activity), fl uid volume is overall increased but inappropri- ately distributed and pooled in the splanchnic compartment, in the interstitium, and eventually in the peritoneal space (ascites), thus leading to relative hypovolemia (i.e., decrease in blood plasma volume) [ 8 ] (Fig. 1 ). In response, vaso-
pressin (also called antidiuretic hormone, ADH) is secreted with consequent free water reabsorp- tion, further fl uid overload, and dilutional hypo- natremia that characterizes cirrhosis in its more advanced stages [ 9 ]. Moreover, the low vascular resistances, fl uid overload, and high cardiac out- put characterize the hyperdynamic circulatory syndrome of cirrhosis. Hyperdynamic circulation is sustained by the persistent liver-gut infl amma- tory interactions, hyperactivation of neurohor- monal systems, and reduced renal perfusion. The overall effect is a further increase in portal infl ow and portal hypertension, which maintains the vicious cycle [ 10 ].
Reduced Parenchymal Metabolic Function
The progressive decline of functional liver parenchyma is accompanied by reduced albu- min synthesis. Hypoalbuminemia leads to low colloid-osmotic pressure and extravasation of fl uid in the extravascular spaces or intersti- tium. Transport of endogenous (unconjugated bilirubin, transferrin, apoproteins, lipid-soluble hormones) and exogenous molecules (e.g., anti- biotics, diuretics, NSAIDS) in the blood is also impaired. Moreover, albumin is the main extra- cellular source of reduced sulfhydryl groups, and therefore, hypoalbuminemia is accompanied by increased oxidative stress and infl ammation [ 11 ].
In cirrhosis, the lipid profi le is often abnormal due to low synthesis of apoproteins and choles- terol (see chapter “ Hyperlipidemia ”) [ 12 ].
Hepatocytes are responsible for the fi rst hydroxylation of inactive cholecalciferol to cal- cidiol (see chapters “ Overview ” under the part
“Teeth and bones” and “ Osteoporosis ”). During cirrhosis, this step is impaired and vitamin D syn- thesis is reduced together with a low production of vitamin D-binding protein [ 13 ].
Moreover, in severe forms of cholestatic liver disease (i.e., when bile cannot fl ow from the liver to the duodenum), e.g., as a result of primary bili- ary cirrhosis (i.e., an autoimmune disease accom- panied by a progressive destruction of the small bile ducts), vitamin D absorption is also impaired
M. Rosselli and M. Pinzani
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(together with other lipid-soluble vitamins such as A, E, and K). This depletion may severely affect bone metabolism leading to osteopenia (i.e., a con- dition where bone mineral density is reduced) or even osteoporosis (see chapter “ Osteoporosis ”).
Hepatocyte dysfunction is associated with a reduced insulin clearance. Subsequent hyperin- sulinemia may contribute to downregulation of
insulin receptors and may lead to glucose intoler- ance and hepatogenous diabetes [ 14 ]. In contrast, impaired gluconeogenesis or lack of glycogen stores characterizes overt liver failure and can lead to hypoglycemia.
Under physiological conditions, the nitroge- nous products of amino acid catabolism are metabolized by the liver through the urea cycle
NH3 inflow perfusion
NH3
Liver cirrhosis
Portal hypertension
Portal-systemic collaterals
Reduced SVR Bile salts
Bacterial overgrowth Intestinal permeability Bacterial translocation Immune response / paralysis Systemic inflammation
Fluid retention
Splanchnic pooling Systemic
relative hypovolemia Ascites
Neurohormonal response Hyperdynamic circulatory
syndrome
SNS RAAS ADH Shunting of bacterial products
Cytokines
Vasodilators (NO, CO) HPVG > 10 mmHg
Splanchnic inflow Intrahepatic vascular resistance Hepatic
encephalopathy
Muscle wasting
Cardiac output Bacterial products (LPS)
Cytokines Gut vasodilators (CGRP, VIP)
Fig. 1 Pathophysiology of cirrhosis and associated com- plications. Increased splanchnic infl ow and hepatic vascu- lar resistance in cirrhosis lead to portal hypertension.
When the hepatic venous pressure gradient ( HVPG ) rises above 10 mmHg, portal-systemic collaterals reroute infl ammatory cytokines, vasodilators, and gut-derived bacterial products to the systemic circulation. Systemic infl ammation leads to vasodilation and reduced systemic vascular resistance (SVR) triggering a neurohormonal response. Retained fl uid pools in the splanchnic compart- ment causing relative hypovolemia throughout the body maintaining the vicious cycle. Ascites develops, aggravat-
ing bacterial translocation and therefore systemic infl am- mation. Intestinal bacterial overgrowth and reduced transit time increase gut ammonia (NH 3 ) production that is not appropriately metabolized by the liver, skeletal muscle, and kidney. Toxic plasma concentrations of NH 3 can then cross the blood-brain barrier causing hepatic encephalop- athy. NO nitric oxide, CO carbon monoxide, SNS sympa- thetic nervous system, RAAS renin-aldosterone-angiotensin system, ADH antidiuretic hormone (vasopressin), LPS lipopolysaccharide, CGRP calcitonin gene-related pep- tide, VIP vasoactive intestinal peptide
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and glutamine synthesis (see chapter “ Overview ” under the part “Liver”) [ 15 ]. However, in cirrho- sis, nitrogen homoeostasis is disrupted, either because ammonia production exceeds urea cycle capacity (mainly by increased gut bacterial ammoniogenesis) or because the liver is unable to metabolize ammonia due to parenchymal insuffi ciency and portal blood shunting [ 16 ]. The skeletal muscle and kidneys are also regulators of ammonia concentration (by ammonia uptake and excretion). However, during cirrhosis, their com- pensation progressively fails due to muscle wast- ing and renal impairment, and subsequently, the blood-brain barrier is crossed by an excess of ammonia that accumulates within the astrocytes.
The consequent osmotic and infl ammatory dam- age as well as neurotransmission impairment characterize hepatic encephalopathy (HE), one of the most important expressions of metabolic dys- function in acute and chronic liver disease.