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MEDICAL SCIENCES
Каньовська Л.В., Ляхович О.Д., Антотв А.А., Гайдичук В. С.
Буковинський державний медичний унгверситет DOI: 10.24412/2520-6990-2023-19178-7-10 СЕРЦЕВА НЕДОСТАТН1СТЬ ТА ПЕЧ1НКА: ДЕЯК1 АСПЕКТИ ПАТОГЕНЕЗУ ТА КЛ1Н1КИ ЗА
КОМОРБ1ДНОСТ1
Kaniovska L. V., Liakhovych O.D., Antoniv A.A. Haidychuk V.S.
Bukovinian State Medical University
HEART FAILURE AND THE LIVER: SOME ASPECTS OF PATHOGENESIS AND CLINICAL
FEATURES OF COMORBIDITIES
Анотацш.
Незважаючи наустхи фундаментально! та клжчно!медицини, смерттсть eid серцево-судинних за-хворювань продовжуе займати лiдируючi позицп. Як патофiзiологiчну модель для взаемного обтяження патологИ серцево-судинно! системи та патологи печтки розглядають застшну гепатопатю, яка е основною мiшенню для патогенетично значущих чинниюв хротчно! серцево! недостатностi.
Abstract.
Despite the successes of fundamental and clinical medicine, mortality from cardiovascular diseases continues to occupy a leading position. As a pathophysiological model for the mutual aggravation of the pathology of the cardiovascular system and the pathology of the liver, congestive hepatopathy, which is the main target for patho-genetically significant factors of chronic heart failure, is considered.
Ключовi слова: коморбiднiсть, застiйнi явиша, гепатопатiя, застшна гепатопатiя, серцева недо-статнiсть.
Key words: comorbidity, congestive symptoms, hepatopathy, congestive hepatopathy, heart failure.
Main part. Chronic heart failure (CHF) is the most frequent result of most cardiovascular diseases. According to statistics, the prevalence of CHF among the adult population ranges from 1.5 to 5.5%, increases proportionally with age, and constitutes about 12-15% in the elderly. During progression, characteristic signs are blood circulation disorders and the involvement of a number of organs and systems in the pathological process. Involvement of the liver in the pathological process is a negative prognostic sign since hypoxia, microcirculation disorders, and congestion lead to a whole cascade of pathological changes, which significantly worsens the course of CHF [7]. Today, an urgent problem is the identification of common mechanisms of cardiovascular and concomitant diseases of internal organs to develop a comprehensive and individual approach to treating of comorbid pathology.
Liver disease due to heart failure (HF) is usually called "cardiac hepatopathy" [16]. One of its main forms is congestive hepatopathy (CH), which results from passive venous stasis against the background of chronic heart failure.
The liver is the largest gland of the digestive system, its weight in an adult is 1.3-1.8 kg, it occupies a central place in the regulation and integration of interorgan metabolism and is the "central biochemical la-
boratory of the body" [3]. The liver serves as an intermediate link between the portal and general blood circulation. Since more than 70% of blood enters the liver from v. porta, the rest is from the hepatic artery, all the compounds that are absorbed in the digestive tract (except for of lipids that enter the lymphatic system first) enter the liver, where they undergo a series of transformations and are then transported to organs and tissues with the blood stream. The liver compensates for the supply of nutrients to organs and tissues in the period between meals (during the absorption phase glycogen and fats are synthesized in the liver, and during the post-absorption period glycogenolysis, ectogenesis, etc. occur there). Metabolic products (bilirubin, products of amino acid metabolism) are neutralized in the liver, drugs and toxic substances of exogenous origin are inactivated.
The liver is an organ with active blood circulation, which receives up to 25% of the total cardiac output due to a double blood supply. The hepatic artery delivers well-oxygenated blood and accounts for approximately 25% of total hepatic blood flow, while the remaining 75% is deoxygenated blood supplied by the portal vein [6, 21]. Its robust vascular defense mechanisms make the liver resistant to ischemic damage [9]. The buffering response of the hepatic artery is one mechanism that
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may compensate for up to 60% of the reduction in portal blood flow. It refers to the compensatory regulation of arterial blood flow in the liver caused by any reduction in portal blood flow [2, 5]. The signaling pathway for this response is local, with decreased portal flow leading to increased concentrations of the vasodilator adenosine [14]. In contrast, the portal vein cannot directly control blood flow and depends on cardiac output and the gradient between portal and hepatic venous pressures. The high sinusoidal permeability, which provides oxygen extraction to levels close to 90%, represents a second defense mechanism against hypoxia and prevents any change in hepatic oxygen consumption, despite the reduction of hepatic blood flow to half normal [1].
This significant resistance to ischemic damage contrasts with the lack of protective mechanisms against congestive phenomena. Even though left ventricular dysfunction remains one of the main initiating factors in the formation of chronic heart failure, its progression is not related to the state of pumping function. The resulting stagnation leads to liver damage through several pathogenic mechanisms: 1) shear stress promotes fibrogenesis and sinusoidal ischemia by activating hepatic stellate cells and reducing nitric oxide production by endothelial cells;
2) reduction of the portal and arterial inflow increases liver ischemia. The first is due to a reduced hepatic venous pressure gradient as a result of the transmission of increased central venous pressure to the sinusoidal network, while the second may also be impaired in patients with left-sided HF [13];
3) violation of the diffusion of oxygen and nutrients due to the accumulation of exudate in the space of Disse additionally contributes to fibrogenesis [17];
4) sinusoidal stasis and stagnation contribute to sinusoidal thrombosis, which in turn contributes to liver fibrosis by causing parenchymal death and activation of hepatic stellate cells via protease-activated receptors [5].
The first refers to a hypothesis based on retrospective observations of ex vivo human liver samples from patients with HF. In this autopsy study, Wansless et al. demonstrated sinusoidal thrombi confined to areas of fibrosis, thereby suggesting that intrahepatic thrombosis is involved in the progression of liver fibrosis [8]. The author recently updated his "vascular hypothesis" regarding the pathogenesis of cirrhosis. He postulates that cirrhosis of any etiology is a morphological result of parenchymal death. The definition of the latter was modified to recognize the importance of sinusoidal disruption in the stimulation of fibrogenesis. It is now defined as an area with focal loss of adjacent hepatocytes and adjacent microvascular structures. The new model includes the concept of a "congestive escalator," according to which initial damage usually occurs at the level of sinusoidal endothelial cells and progresses to parenchymal disappearance through a sequence of events that include vascular leakage, transudation into the venous and interstitial walls, ischemia, and hypere-mia" [10].
A recent experimental study provided evidence of a mechanistic link between HF and liver fibrosis
through some of these mechanisms [23]. The main mechanisms of the formation of congestive hepatopathy are the blood overflow of the central veins and the central part of the liver lobules, the development of local hypoxia in them, which leads to the occurrence of dystrophic and atrophic changes, and later - to the necrosis of hepatocytes, collagen synthesis and the development of fibrosis. At the same time, the pressure in the portal vein does not exceed the pressure in the lower and upper vena cava, resulting in portocaval anastomoses developing extremely rarely [25]. The severity and characteristics of liver damage depend on the vessels involved, the severity of venous congestion, and decreased perfusion. The first description of "nutmeg liver" was made by Kiernan and Mallory, who showed central congestion and focal hepatic necrosis associated with impaired blood circulation in the liver [26].
It should be emphasized that, unlike primary liver diseases, in HF, inflammation seems not to play a role in the progression of liver fibrosis. The role of cardi-okines in the pathophysiology of HF remains unclear. These proteins are secreted by the heart for interorgan and intercellular communication. To date, more than 16 cardiokines have been identified, with natriuretic pep-tides (atrial natriuretic factor and B-type natriuretic peptides) being the most well-studied. Increasing evidence suggests that cardiokines are involved in the metabolic relationship between myocardial inflammation in heart failure and peripheral tissue damage in some organs (adipose tissue, tissue, skeletal muscle, spleen, and kidney), but the direct mechanisms that link heart and liver diseases remain incompletely characterized. Experimental evidence suggests that cardiokines enhance lipid uptake and p-oxidation and regulate other genes involved in fatty acid utilization [11]. In the setting of HF, the impact of these metabolic changes on the progression of liver disease and wasting deserves further study.
Clinical manifestations of congestive hepatopathy depend on the rate of increase of HF, i.e., if venous congestion in the liver develops quickly, the clinical manifestations dominate by complaints of sharp pains in the right hypochondrium associated with stretching of the liver capsule, which often simulate acute surgical pathology. If HF develops slowly over several months or years, its manifestations will dominate and mask the symptoms of HF. The latter variant occurs much more often, therefore, in the vast majority of cases, the CH is asymptomatic or asymptomatic [20]. Patients complain of shortness of breath, orthopnea, and cardialgia, practically ignoring the heaviness in the right hypochondrium and the change in skin color of the since jaundice and pain syndrome are not intense. Objective signs of CH (enlarged, dense and sensitive, and sometimes moderately painful during palpation of the liver with a hard and smooth edge) are determined against the background of the expansion of the jugular veins, the appearance of hepatojugular reflux, and symptoms of HF.
A distinctive feature of CH is that the severity of its symptoms varies depending on the state of central hemodynamics and the effectiveness of treatment of the main cause of HF. Adequate therapy of CH leads to a
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rapid decrease in the size of the liver and the elimination of clinical signs of HF [8]. Another characteristic feature of CH is the absence of signs of portal hypertension (varicose dilatation of the veins of the esophagus and stomach, "caput medusae") and the so-called minor signs of cirrhosis (palmar erythema, telangiectasia, "lacquered" tongue) [15]. With a severe or refractory course of HF, the symptoms of CH progress, and cardiac cirrhosis of the liver gradually develops, accompanied by the appearance of ascites and splenomegaly. The liver becomes dense, its edge is sharp, and its size remains constant and does not depend on the effectiveness of HF treatment.
Differentiating cardiac ascites from cirrhotic asci-tes may be difficult when presented with a patient with new-onset ascites since, in both conditions, the serum ascites albumin gradient is >1.1 g/dL resulting from hepatic sinusoidal hypertension [24]. However, cardiac ascites has higher protein levels (>2.5 g/dL) due to preserved hepatic synthetic function and lack of capillari-zation of hepatic sinusoidal endothelial cells [5]. The latter is characterized by a decrease in the permeability of these cells, which appears due to the loss of fenestrae and the development of the basement membrane. These morphological changes prevent the passage of proteins into the space of Disse, and then into the peritoneal fluid, thus explaining the lower concentration of proteins in ascites due to cirrhosis [19]. Other less reliable findings in cardiac ascites are a higher LDH level and a larger number of red blood cells due to leakage of red blood cells into the ascites through the lymphatic tissue resulting from lysis. More recently, measurement of B-type natriuretic peptide (BNP) or its inactive prohormone (N-terminal proBNP) in serum and ascites has been suggested as an adjunct in uncertain cases. Thus, Sheer et al. reported that both serum and ascitic NT-proBNP levels had high sensitivity and specificity in predicting HF as the cause of ascites [18].
Congestive hepatopathy is often characterized by a normal level of liver parameters, a slight (2-3 times) increase in the level of ALT and AST; an increase in the level of y-glutamyltransferase (GHG) is found in 30% of patients with CHF, a moderate decrease in the level of albumin (>25 g/l) - in 30-50%, an increase in the level of total bilirubin - in 70%, a prolongation of prothrombin time - in 80% [16].
Acute ischemic liver damage is characterized by a significant increase in the levels of ALT, AST, LDH (by 10-20 or more times) and prolongation of prothrombin time, which reach their maximum values 1-3 days after the episode of hypotension; hyperbiliru-binemia occurs much less often. After stabilization of the condition, the level of enzymes normalizes within 7-14 days [12]. Ischemic liver damage differs from other forms of acute hepatitis by the ALT/LDH ratio, which is <1.5 [4].
Currently, there are no standards for the treatment of congestive hepatopathy. According to various authors [4,7], the effectiveness of treating such patients is related to the adequate correction of congestive heart failure under the recommendations. It is necessary to carefully monitor the blood pressure level during active
diuretic therapy or the administration of drugs that reduce cardiac output to prevent the development of severe hypotension.
Thus, the liver is actively involved in the patho-genesis of congestive heart failure. Indices of liver function can be used as independent predictors of long-term prognosis in patients with HF. Such patients require constant monitoring of not only indices of liver dysfunction (level of total protein, albumin, blood coagulation) but also indices of cholestasis and activation of cytolysis (level of ALT, AST, LF, GGT, total biliru-bin, and its fractions) to control the liver condition and to assess the long-term prognosis. Timely and adequate specific therapy may have a positive impact not only on the condition of patients but also potentially on their life expectancy. The latter should be proven in appropriate planned studies.
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