Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_51_библиотеки_им_акад_М_И_Перельмана
.pdf
This page intentionally left blank
https://t.me/medicina_free
CHAPTER
7
Cardio-hepatology: liver function tests
in heart failure
Atsushi Okada
Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center, Suita, Osaka, Japan
Liver function tests
Various liver function tests (LFT) are widely used to evaluate hepatic or biliary diseases as a part of the rou-
tine laboratory testing. Commonly used LFT include aspartate aminotransferase (AST), alanine aminotransferase
(ALT), alkaline phosphatase (ALP), gamma-glutamyltranspeptidase (GGT), lactate dehydrogenase (LDH), total
bilirubin (T-Bili), direct bilirubin (D-Bili), total protein, albumin, and cholinesterase. Although not specific to
hepatic diseases, platelet counts are also recognized to decrease in advanced hepatic damage. Furthermore,
hepatic fibrosis markers are often used to evaluate hepatic fibrosis in chronic hepatic diseases as a part of liver
function testing, and they include hyaluronic acid, type IV collagen, 7S domain of type IV collagen, procollagen
type III peptide, Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA
1
-M2BP)/Mac-2 binding pro-
tein glycosylation isomer (M2BPGi), etc. (
Table 7.1).
Although most heart failure (HF) patients who have abnormal LFT remain asymptomatic, various LFT have
been reported to be altered in acute or chronic HF patients (
Fig. 7.1). Abnormalities of LFT observed in HF
patients are generally divided into three different types (1) markers of hepatocellular injury or hepatocellular
necrosis, (2) markers reflective of obstructive or cholestatic disease, and (3) markers of impaired hepatic protein
synthesis function.
While the term “cardiohepatic syndrome” is often compared to the cardiorenal syndrome as a similar end-
organ damage observed in HF patients, there is no easily available marker in cardiohepatic syndrome to evaluate
the “excreted” substrate from the liver, as is available in cardiorenal syndrome to evaluate the urine.
Blood supply of the liver and its anatomy
As one of the major end-organ in the systemic circulation, the liver has a complex blood flow compared to
other organs. The liver is supplied by two systems of blood flow, which is by (1) hepatic artery, a branch of the
celiac trunk from the descending abdominal aorta-delivering oxygenated blood flow from the systemic arterial
circulation and (2) portal vein that flows deoxygenated blood flow-containing nutrients from the small intestines.
The hepatic lobule on two-dimensional (2D) histological view is a hexagonal unit structure organized around
the terminal hepatic venule, a branch of the hepatic vein (
Fig. 7.2A). This vein and the cells surrounding this area
are termed zone 3. The portal tract including the hepatic artery, portal vein, and bile ducts is located at the
apparent corner of the hexagon (zone 1). Sinusoidal cells and structures in the areas between zones 1 and 3 are in
zone 2. The modern three-dimensional (3D) microanatomy schema is the acinar concept (
Fig. 7.2B) [1]. Although
zone 3 is located in the center and zone 1 at the periphery of the lobule on 2D histology slides, understanding
the 3D acinar microcirculatory concept explains the differential vulnerabilities of zonal acinar cells to macro- and
microcirculatory insults such as hypoxia and congestion. Zone 1 portal triad cells receive abundant oxygenated
105
Cardio-Hepatology.
DOI:
https://doi.org/10.1016/B978-0-12-817394-7.00006-1 © 2023 Elsevier Inc. All rights reserved.
https://t.me/medicina_free
blood from the hepatic artery and portal vein branches, are generally the most metabolically active and are most
protected from circulatory insults. Zone 2 cells along the sinusoids enjoy intermediate oxygen delivery. However ,
zone 3 cells surrounding what is essentially a venous drainage vessel have the least oxygen delivery and supply,
and are therefore the most susceptible to circulatory insults, especially acute conditions causing hypoxia/
ischemia.
Generally, the average pressure of the hepatic artery is 80120 mm Hg and the average pressure of the portal
vein is 510 mm Hg, and it is very interesting that these two different blood systems merge in the liver and drain
together in one direction into the central vein, in which the average pressure is generally 512 mm Hg.
Pathophysiology of abnormal liver function tests in heart failure
Conditions associated with decreased cardiac output with impaired organ perfusion and/or hypoxia result in
acute hepatocellular damage and necrosis. As discussed further, this tissue hypoxia especially in zone 2 and zone
3 is believed to cause increased transaminases (AST and ALT) and D-Bili (consequently T-Bili).
TABLE 7.1 Examples of commonly used liver function testing.
Transaminases
Aspartate aminotransferase
Alanine aminotransferase
Hepatobiliary markers
Alkaline phosphatase
Gamma-glutamyltranspeptidase
Lactate dehydrogenase
Total bilirubin
Direct bilirubin
Hepatic protein synthesis
Total protein
Albumin
Cholinesterase
Hepatic fibrosis markers
Hyaluronic acid
Type IV collagen
7S domain of type IV collagen
Wisteria floribunda agglutinin positive Mac-2 binding protein (WFA
1
-M2BP)/ Mac-2 binding protein glycosylation isomer (M2BPGi)
CHF
Normal
Aminotransferases
Bilirubin
Albumin
Alkaline
phosphatase
Normal
Aminotransferases
Bilirubin
Albumin
Alkaline
phosphatase
ADHF
FIGURE 7.1 Distribution of abnormal liver function tests in patients with chronic heart failure and acute decompensated heart failure [70].
(A) Hepatic lobule. (B) Flows in the hepatic lobule. Source: Adopted from Auer J. What does the liver tell us about the failing heart? Eur Heart J.
2013;34:711714.
106 7. Cardio-hepatology: liver function tests in heart failure
II. Hepatobiliary system in heart failure
https://t.me/medicina_free
On the other hand, the bile flows from the hepatocytes in zones 3 and 2 to the larger bile ducts in the portal
tract. Elevated right-sided pressure, or in other words central venous pressure, is known to be transmitted to ele-
vated pressure in the central vein and centrilobular liver sinusoids. The elevated intrahepatic pressure can com-
press any collapsible structure in the lobule, including bile canaliculi and ductules. Thus in the setting of increased
central venous pressure and pressure of the terminal hepatic vein (in other words, congestion of the liver), the bile
flow toward the portal tract may be obstructed and change direction to be reversely drained into the central vein.
This pathophysiology is believed to result in elevated ALP, GGT, and D-Bili (consequently T-bili).
Bilirubin metabolism in the liver
The metabolism of bilirubin in hepatocytes is a little complicated; however, to recognize the metabolism is impor-
tant to understand the abnormalities of T-Bili and D-Bili observed in acute or chronic HF patients. The origin of the
bilirubin is generally produced in extrahepatic sources. Generally, the majority of bilirubin formed in the body is pro-
duced in the bone marrow as the end product of red blood cells (hemoglobin breakdown). The remainder is pro-
duced from other heme-containing proteins found in other tissues such as the liver and muscles. This bilirubin
produced in extrahepatic sources is generally recognized as indirect bilirubin or unconjugated forms of bilirubin.
Indirect bilirubin produced in extrahepatic sources is transported to the liver through the blood flow.
Understanding the bilirubin metabolism in hepatocytes may be useful to understand the bilirubin alternance observed
in HF patients.
Fig. 7.3 shows the bilirubin metabolism in hepatocytes. The bilirubin metabolism in the liver consists
of three main steps: hepatocellular uptake of indirect (unconjugated) bilirubin, glucuronidation to D-Bili (conjugated
bilirubin), and excretion of D-Bili into bile. The first step is known to be a facilitated diffusion and the second step
(glucuronidation) is an enzyme-catalyzed glucuronidation. The third step, excretion of D-Bili into bile canaliculus, is
an adenosine triphosphate-dependent transportation and is known to be the rate-limiting step in this metabolism.
Thus in the case of an acute hepatic injury resulting in impaired energy production in the liver, the excretion
becomes the rate-limiting step, resulting in acute elevation of direct (conjugated) bilirubin. Further, in case of bili-
ary obstruction and increased pressure of the bile canaliculus due to elevated right-sided pressure in HF, the
same step could also be disrupted and consequently cause elevation of D-Bili. Taken together, serum D-Bili eleva-
tion is known to occur in acute hepatocellular damage or hepatic biliary obstruction. Due to this mechanism of
bilirubin elevation, an increase of D-Bili in acute hepatic damage is known to precede the elevation of T-Bili.
Association between abnormal liver function tests and impaired hemodynamics
While blood to the liver is supplied by two different afferent circulating systems, the hepatic artery and the portal
vein, and returned to the venous system in one system, the abnormal LFT observed in HF patients could not be fully
explained by the representative hemodynamic variables, cardiac output, and central venous pressure. However, at least
partly, some of the abnormal LFT observed in HF patients appear to be a surrogate marker for impaired systemic hemo-
dynamics of decreased cardiac output or increased central venous pressure.
(A) (B)
Portal
tract
Terminal
hepatic
venule
central
vein
portal triad
hepatic artery
branch of
portal vein
bile duct
branch of
hepatic
sinusoid
bile
canal
1
2
3
FIGURE 7.2 Anatomy of the hepatic lobule. (CHF, chronic heart failure; ADHF, acute decompensated heart failure.)
107Association between abnormal liver function tests and impaired hemodynamics
II. Hepatobiliary system in heart failure
https://t.me/medicina_free
In order to understand the relationship between systemic hemodynamics and abnormal LFT, physicians
should know the hepatic anatomy and physiology, and the metabolism in hepatocellular cells to understand the
changes of various LFT.
Van Deursen et al. studied 323 HF patients and studied the relationship between liver function abnormalities
and hemodynamic profiles
[2]. They reported that GGT, ALP, T-Bili, D-Bili, AST, ALT, and LDH were predomi-
nantly related to central venous pressure, while AST, ALT, and T-Bili were related to a reduced cardiac index.
Scholfield et al. reported the relationship between abnormal LFT and hemodynamics from pulmonary artery
catheterization from a posthoc analysis of evaluation study of congestive HF and pulmonary artery catheteriza-
tion effectiveness study
[3]. They reported that abnormal AST, T-Bili, and D-Bili were associated with elevated
central venous pressure, as well as T-Bili and D-Bili associated with decreased cardiac index.
Styczynski et al. studied the correlates between abnormal LFT and echocardiographic variables
[4]. In their univari-
ate logistic regression analysis, right ventricular end-diastolic diameter, right atrial area, tricuspid regurgitation, esti-
mated right atrial pressure, tricuspid annular plane systolic excursion, tricuspid lateral annulu s systolic velocity,
portal vein pulsatility index, left ventricular ejection fraction, and cardiac index were significant predictors of elevated
T-Bili. On the other hand, left ventricular end-diastolic diameter indexed to body surface area, right ventricular end-
diastolic diameter, and systolic blood pressure on admission were significant predictors of elevated transaminases. In
a multivariate regression model, only portal vein pulsatility index remained a significant predictor of elevated T-Bili,
and left ventricular end-diastolic diameter indexed to body surface area of elevated transaminases.
The blood supply of the liver is received from two vascular sources, the hepatic artery and the portal vein. As
blood flow from the portal vein carries nutrient-rich blood from the mesenteric and splenic veins and consists
70% of the blood flow of the hepatic blood flow, the abnormal LFT in cardiohepatic syndrome could not always
be explained by the altered systemic hemodynamics measured by cardiac output (cardiac index) and central
venous pressure. However, at least in part, previous studies have reported the relationship between cardiac out-
put (cardiac index) and central venous pressure, and their results are summarized in
Table 7.2 [2,3,5].
Liver function tests and prognosis in heart failure
As abnormal LFT are observed in HF patients, various reports have shown the prognostic significance of LFT
in acute or chronic HF patients in the last decades. Previous reports of relation between abnormal LFT and prog-
nosis in HF patients are summarized in
Table 7.3.
TABLE 7.2 Liver function tests and relationship with impaired hemodynamics in heart failure.
AST ALT T-Bili D-Bili ALP GGT
Increased central venous pressure - - m m mm mm
Decreased cardiac output (index) mm mm m m - -
Enzyme-catalyzed
glucuronidaon
ATP-dependent
Rate liming step
Facilitated
diffusion
Hepatocyte
Unconjugated
bilirubin
Conjugated
Bilirubin
MRP2
UGT1A1
ATP
ADP
OATP1B1
UDP
UDPGA
Sinusoid
Bile canaliculus
FIGURE 7.3 Bilirubin metabolism in hepatocytes. (OATP1B1, organic anion transporter protein 1B1; UDPGA, uridine 5’-diphosphoglucronic
acid; UDP, uridine phophate; UGT1A1, uridine diphosphoglucuronosyltransferase-1A1; MRP2, multidrug resistance protein 2; ATP, Adenosine triphos-
phate; ADP, Adenosine diphosphate).
108 7. Cardio-hepatology: liver function tests in heart failure
II. Hepatobiliary system in heart failure
https://t.me/medicina_free
TABLE 7.3 Liver function test abnormalities and its impact on prognosis in heart failure.
Reference Patient population n Lab Summary of findings
[13] Chronic HF 2679 T-Bili T-Bili was a strong independent predictor for worsening HF, cardiovascular death, and all-cause mortality.
[8] ADHF 2061 Albumin,
T-Bili
Lower baseline albumin and elevated T-Bili were associated with higher rates of all-cause mortality, and in-hospital
decreases in albumin and increases in T-Bili were associated with higher rates of both all-cause mortaliry and
cardiovascular mortality 1 heart failure hospitalization.
[16] ADHF 3224 AST, ALT Patients in the highest quartile of ALT experienced significantly higher rates of all-cause mortality. Elevations of ALT
predict in-hospital mortality independent of known prognostic indicators.
[6] ADHF 189 Albumin, AST, ALT Low albumin and markedly elevated AST and ALT ( . 3 times above the upper normal limit) were associated with
increased mortality during 180-day follow-up.
[17] ADHF 2033 Albumin, AST, ALT Abnormal baseline and discharge LFTs had an unfavorable impact on 180-day mortality.
[22] Chronic HF 1087 GGT, T-Bili GGT and T-Bili are associated with disease severity in chronic heart failure. However, only GGT is independently
associated with adverse outcome.
[54] ADHF 349 Albumin In elderly ADHF patients, serum albumin is associated with in-hospital mortality, even after adjustment for other
known prognostic factors.
[18] ADHF 1134 ALP,
AST, ALT
Of patients with ADHF, 46% presented with altered liver function tests. Abnormal ALP was associated with marked
signs of congestion, elevated right-sided filling pressures, and increased 180-day mortality. Abnormal transaminases
were associated with clinical signs of hypoperfusion and increased 31- and 180-day mortality.
[51] ADHF 294 INR Increased INR is an independent predictor of all-cause mortality in ADHF patients without anticoagulation.
[12] ADHF 556 T-Bili, D-Bili Elevated D-Bili in ADHF was an independent prognostic predictor that was superior to T-Bili.
[20] Chronic HF 998 GGT Increased GGT is an independent predictor of death or heart transplantation.
[19] ADHF 4228 T-Bili,
AST, ALT
Elevated bilirubin was independently associated with worse clinical outcomes. No association with AST or ALT and
outcomes.
[55] Chronic HF 465 Cholinesterase Serum cholinesterase level was an important prognostic factor in CHF.
[9] CHF exacerbation 183 T-Bili Increased T-Bil coincident with cardiac decompensation predicts a worse long-term prognosis of CHF, presumably
through the potential liability to both congestion and tissue hypoperfusion simultaneously when HF deteriorates.
[53] ADHF 438 Alb Hypoalbuminemia is independently associated with increased 1-year mortality in patients with ADHF admitted to
hospital.
[7] ADHF 234 AST, ALT, albumin,
total protein
Baseline ALT and AST were associated with 180-day mortality and worsening HF through day 5. Albumin was
associated with 180-day mortality but not with worsening HF. Total protein was associated with only worsening HF.
[52] NYHA class
III/IV chronic HF
1726 Alb Hypoalbuminemia is associated with significantly increased 1- and 5-year all-cause mortality, progressive HF death,
and increased risk of urgent cardiac transplantation.
[21] Unselected stable HF
patients, with
primarily LV
dysfunction
1032 ALP, GGT AP, T-Bili, and GGT levels are inversely associated with survival. In multivariate analysis, only ALP and GGT
maintained independent predictive capacity for transplant-free survival.
ADHF, acute decompensated heart failure; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CHF, chronic heart failure; D-Bili, direct bilirubin; GGT, gamma-
glutamyltranspeptidase; HF, heart failure; INR, international normalized ratio; LFT, liver function tests; LV, left ventricular; NYHA, New York Heart Association; T-Bili, total bilirubin.
https://t.me/medicina_free
Total and direct bilirubin
While elevated T-Bili is observed in 19%36% of acute decompensated HF patients [3,610], its prognostic
value remains controversial
[3,79,11]. As T-Bili is known to be a nonspecific marker affected by multiple factors
including nonhepatic bilirubin production, D-Bili elevation is known to precede T-Bili elevation in acute liver dis-
eases, leading to the hypothesis that D-Bili may more sensitively reflect hepatic damage compared to T-Bili in
acute HF. Okada et al. reported in their study of 556 acute decompensated HF that the prognostic value of ele-
vated D-Bili was superior to T-Bili
[12].
However, it is important to know that the prognostic value of D-Bili may only be useful in acute HF. In
chronic HF, the candesartan in HF assessment of reduction in mortality and morbidity substudy assessed the
prognostic value of bilirubin levels
[13]. The authors stated that T-Bili and indirect bilirubin were better predic-
tors of outcomes than D-Bili. However, according to the bilirubin metabolism previously discussed, it is reason-
able that D-Bili may lose its superiority in chronic hepatic damage. Another explanation could be the presence of
benign nonhepatic causes of bilirubin elevation including hemolysis or benign inherited hyperbilirubinemia such
as Gilbert’s syndrome, which has a reported incidence of 3%10% in the general population
[14,15].
Transaminases (aspartate aminotransferase and alanine aminotransferase)
Increase in transaminases (AST and ALT) in HF is believed to occur from acute hepatocellular injury or hepa-
tocellular necrosis as a consequence of reduced hepatic perfusion or hypoxia. This is alternatively described as
“ischemic hepatitis,” characterized histologically by severe hepatocellular injury-causing centrilobular (zone 3)
necrosis. Thus increased transaminases are rather more commonly observed in the setting of acute HF than in
chronic HF as they are not generally affected by hepatic congestio n but acute hepatocellular injury. Several stud-
ies have reported the prognostic significance of increased transaminases in acute decompensated HF
[6,7,1619].
Gamma-glutamyltranspeptidase and alkaline phosphatase
GGT and ALP are recognized as markers of cholestasis, are believed to elevate in the context of obstructive
bile flow caused by increased central venous pressure and central vein of the hepatic lobule. Several studies have
investigated the clinical significance of GGT in chronic HF patients. Poelzl et al. reported in their study of 998
chronic HF patients that increased GGT was an independent predictor of death or heart transplantation
[20]. The
same authors also reported that ALP and GGT were associated with survival and independent predictive capac-
ity for transplant-free survival
[21]. Similarly, Ess et al. showed that GGT and T-Bili were associated with disease
severity in chronic HF, however, only GGT was independently associated with the adverse outcome
[22].
Yamazoe et al. reported that serum ALP is a predictor of worsening renal function in acute HF
[23].
Prothrombin time international normalized ratio
Among various observed physiological abnormalities, it has been known for decades that patients with HF are
in a prothrombotic or hypercoagulable state are at increased risk of stroke and venous thromboembolism
[24,25].
The converse situation of coagulopathy and bleeding abnormalities in liver disease is discussed in Chapter 12).
Previous studies have shown that HF leads to activation of coagulation, with increased levels of thrombin forma-
tion markers such as thrombinantithrombin complexes (TAT) and fibrinopeptide A
[2632], as well as activa-
tion of fibrinolysis with significant elevation of D-dimer
[26,28,30]. Recent studies suggest that inflammatory
processes and neuroendocrine activation
[2628,3346] are strongly correlated with activation of the coagulation
cascade.
Decreased concentrations of plasma coagulation factors have been previously reported in patients with severe
chronic HF
[2830], and patients with lower plasma coagulation factors are known to be at increased risk of
adverse events
[47]. Interestingly, activated coagulation and fibrinolysis, decreas ed coagulation factors, and
inflammatory markers are known to be ameliorated by hemodynamic modification by heart transplantation
[28],
left ventricular assist devices
[29,30], or cardiac resynchronization therapy [48], suggesting a reversible relation
between hemostatic derangement and HF severity. However, the mechanism that contributes to decreased coagu-
lation factors in HF is still uncertain.
Prothrombin time international normalized ratio (INR) has been accep ted as a sensitive and reliable marker of
coagulation abnormalities. It is regulated by multiple coagulation factors synthesized in the liver and is widely
110 7. Cardio-hepatology: liver function tests in heart failure
II. Hepatobiliary system in heart failure
https://t.me/medicina_free
used to monitor anticoagulation, to assess hepatic function as in the ChildPugh classification, and to evaluate
coagulation abnormalities such as disseminated intravascular coagulation. Increased INR is associated with poor
clinical outcomes in critically ill patients with hypoxic hepatitis
[49,50].
The prognostic value of INR levels was studied in 294 acute decompensated HF patients with no prior anticoa-
gulation
[51]. Median INR levels on admission were 1.03 (interquartile range 0.971.12) and INR was an inde-
pendent pred ictor of all-cause mortality. Patients in the highest tertile of INR levels (INR $ 1.10) had lower
blood pressur e, lower albumin, higher bilirubin, higher GGT, lower cholinesterase, higher C-reactive protein,
higher TAT, and trends for higher norepinephrine. These results suggest that coagulation abnormalities in HF
may be associated with decreased hepatic protein synth esis, coagulation factor consumption, hepatic congestion,
inflammation, and activated sympathetic activities.
Albumin, cholinesterase, and total protein
Albumin, cholinesterase, and total protein are all recognized as measures of hepatic protein synthesis and are
other markers of hepatic function. Though these markers are considered not to be affected directly by the
impaired hemodynamics; however, are markers of hepatic function reserve. The prognostic significance of
decreased albumin and total protein has been reported both in acute decompensated HF and in chronic HF
[6,7,17,5254]. Cholinesterase is another marker of hepatic protein synthesis, and Sato et al. have reported the
prognostic value of cholinesterase in chronic HF
[55].
Hepatic fibrotic markers in heart failure
Quantification of end-organ damage and predicting its reversibility is an unmet clinical need [5658].
Currently, histopathologic examination by liver biopsy is the gold standard to evaluate the extent of hepatic
fibrosis in patients with advanced HF
[5962], which requires an invasive procedure with a limited success rate
[63]. On the other hand, markers of hepatic fibrosis are widely used to evaluate hepatic damage in patients with
chronic liver disease; however, their clinical impact in chronic HF has only been studied in small observational
studies
[6466].
Nagao et al. recently reported the clinical significance of 7S domain of collagen type IV in HF patients
[67].
They reported that GGT and B-type natriuretic peptides were independently correlated with levels of 7S domain
of collagen type IV. Serum WFA
1
-M2BP or M2BPGi is a novel fibrosis less affected by nonhepatic diseases. And
it has been reported to predict hepatic fibrosis in chronic hepatitis with a higher predictive value compared to
existing markers
[68]. Its value in HF patients have been studied in small study of chronic HF patients with
abnormal LFT [69]; however, there are very limited data regarding hepatic fibrosis markers in HF and further
studies are warranted in this field.
References
[1] Rappaport AM. The microcirculatory hepatic unit. Microvasc Res 1973;6:21228.
[2] van Deursen VM, Damman K, Hillege HL, van Beek AP, van Veldhuisen DJ, Voors AA. Abnormal liver function in relation to hemody-
namic profile in heart failure patients. J Card Fail 2010;16:8490.
[3] Scholfield M, Schabath MB, Guglin M. Longitudinal trends, hemodynamic profiles, and prognostic value of abnormal liver function tests
in patients with acute decompensated heart failure: an analysis of the ESCAPE trial. J Card Fail 2014;20:47684.
[4] Styczynski G, Milewska A, Marczewska M, Sobieraj P, Sobczynska M, Dabrowski M, et al. Echocardiographic correlates of abnormal liver
tests in patients with exacerbation of chronic heart failure. J Am Soc Echocardiogr 2016;29:1329.
[5] Correale M, Tarantino N, Petrucci R, Tricarico L, Laonigro I, Di Biase M, et al. Liver disease and heart failure: Back and forth. Eur J Intern
Med 2018;48:2534.
[6] Biegus J, Zymlinski R, Sokolski M, Nawrocka S, Siwolowski P, Szachniewicz J, et al. Liver function tests in patients with acute heart fail-
ure. Pol Arch Med Wewn 2012;122:4719.
[7] van Deursen VM, Edwards C, Cotter G, Davison BA, Damman K, Teerlink JR, et al. Liver function, in-hospital, and post-discharge clinical
outcome in patients with acute heart failure-results from the relaxin for the treatment of patients with acute heart failure study. J Card
Fail 2014;20:40713.
[8] Ambrosy AP, Vaduganathan M, Huffman MD, Khan S, Kwasny MJ, Fought AJ, et al. investigators Et. Clinical course and predictive value
of liver function tests in patients hospitalized for worsening heart failure with reduced ejection fraction: an analysis of the EVEREST trial.
Eur J Heart Fail 2012;14:30211.
[9] Shinagawa H, Inomata T, Koitabashi T, Nakano H, Takeuchi I, Naruke T, et al. Prognostic significance of increased serum bilirubin levels
coincident with cardiac decompensation in chronic heart failure. Circ J 2008;72:3649.
111References
II. Hepatobiliary system in heart failure
https://t.me/medicina_free
[10] Vyskocilova K, Spinarova L, Spinar J, Mikusova T, Vitovec J, Malek J, et al. Prevalence and clinical significance of liver function abnor-
malities in patients with acute heart failure. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2015;159:42936.
[11] Chintanaboina J, Haner MS, Sethi A, Patel N, Tanyous W, Lalos A, et al. Serum bilirubin as a prognostic marker in patients with acute
decompensated heart failure. Korean J Intern Med 2013;28:3005.
[12] Okada A, Sugano Y, Nagai T, Honda Y, Iwakami N, Nakano H, et al. Usefulness of the direct and/or total bilirubin to predict adverse
outcomes in patients with acute decompensated heart failure. Am J Cardiol 2017;119:203541.
[13] Allen LA, Felker GM, Pocock S, McMurray JJ, Pfeffer MA, Swedberg K, et al. Liver function abnormalities and outcome in patients with
chronic heart failure: data from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) pro-
gram. Eur J Heart Fail 2009;11:1707.
[14] Sieg A, Arab L, Schlierf G, Stiehl A, Kommerell B. Prevalence of Gilbert’s syndrome in Germany. DTSCH Med Wochenschr
1987;112:12068.
[15] Owens D, Evans J. Population studies on Gilbert’s syndrome. J Med Genet 1975;12:1526.
[16] Ambrosy AP, Gheorghiade M, Bubenek S, Vinereanu D, Vaduganathan M, Macarie C, et al. Romanian acute heart failure syndromes
study i. The predictive value of transaminases at admission in patients hospitalized for heart failure: findings from the RO-AHFS regis-
try. Eur Heart J Acute Cardiovasc Care 2013;2:99108.
[17] Biegus J, Hillege HL, Postmus D, Valente MA, Bloomfield DM, Cleland JG, et al. Abnormal liver function tests in acute heart failure: rela-
tionship with clinical characteristics and outcome in the PROTECT study. Eur J Heart Fail 2016;18:8309.
[18] Nikolaou M, Parissis J, Yilmaz MB, Seronde MF, Kivikko M, Laribi S, et al. Liver function abnormalities, clinical profile, and outcome in
acute decompensated heart failure. Eur Heart J 2013;34:7429.
[19] Samsky MD, Dunning A, DeVore AD, Schulte PJ, Starling RC, Tang WH, et al. Liver function tests in patients with acute heart failure
and associated outcomes: insights from ASCEND-HF. Eur J Heart Fail 2016;18:42432.
[20] Poelzl G, Eberl C, Achrainer H, Doerler J, Pachinger O, Frick M, et al. Prevalence and prognostic significance of elevated gamma-
glutamyltransferase in chronic heart failure. Circ Heart Fail 2009;2:294302.
[21] Poelzl G, Ess M, Mussner-Seeber C, Pachinger O, Frick M, Ulmer H. Liver dysfunction in chronic heart failure: prevalence, characteristics
and prognostic significance. Eur J Clin Invest 2012;42:15363.
[22] Ess M, Mussner-Seeber C, Mariacher S, Lorsbach-Koehler A, Pachinger O, Frick M, et al. gamma-Glutamyltransferase rather than total
bilirubin predicts outcome in chronic heart failure. J Card Fail 2011;17:57784.
[23] Yamazoe M, Mizuno A, Nishi Y, Niwa K, Isobe M. Serum alkaline phosphatase as a predictor of worsening renal function in patients
with acute decompensated heart failure. J Cardiol 2016;67:41217.
[24] Lip GY, Gibbs CR. Does heart failure confer a hypercoagulable state? Virchow’s triad revisited. J Am Coll Cardiol 1999;33:14246.
[25] Loh E, Sutton MS, Wun CC, Rouleau JL, Flaker GC, Gottlieb SS, et al. Ventricular dysfunction and the risk of stroke after myocardial
infarction. N Engl J Med 1997;336:2517.
[26] Jafri SM, Ozawa T, Mammen E, Levine TB, Johnson C, Goldstein S. Platelet function, thrombin and fibrinolytic activity in patients with
heart failure. Eur Heart J 1993;14:20512.
[27] Yamamoto K, Ikeda U, Furuhashi K, Irokawa M, Nakayama T, Shimada K. The coagulation system is activated in idiopathic cardiomy-
opathy. J Am Coll Cardiol 1995;25:163440.
[28] Cugno M, Mari D, Meroni PL, Gronda E, Vicari F, Frigerio M, et al. Haemostatic and inflammatory biomarkers in advanced chronic heart
failure: role of oral anticoagulants and successful heart transplantation. Br J Haematol 2004;126:8592.
[29] Wang IW, Kottke-Marchant K, Vargo RL, McCarthy PM. Hemostatic profiles of HeartMate ventricular assist device recipients. ASAIO J
1995;41:M7827.
[30] Kaplon RJ, Gillinov AM, Smedira NG, Kottke-Marchant K, Wang IW, Goormastic M, et al. Vitamin K reduces bleeding in left ventricular
assist device recipients. J Heart Lung Transpl 1999;18:34650.
[31] Jafri SM. Hypercoagulability in heart failure. Semin Thromb Hemost 1997;23:5435.
[32] de Peuter OR, Kok WE, Torp-Pedersen C, Buller HR, Kamphuisen PW. Systolic heart failure: a prothrombotic state. Semin Thromb
Hemost 2009;35:497504.
[33] Sbarouni E, Bradshaw A, Andreotti F, Tuddenham E, Oakley CM, Cleland JG. Relationship between hemostatic abnormalities and neuro-
endocrine activity in heart failure. Am Heart J 1994;127:60712.
[34] Sechi LA, Novello M, Colussi G, Di Fabio A, Chiuch A, Nadalini E, et al. Relationship of plasma renin with a prothrombotic state in
hypertension: relevance for organ damage. Am J Hypertens 2008;21:134753.
[35] Marcucci R, Gori AM, Giannotti F, Baldi M, Verdiani V, Del Pace S, et al. Markers of hypercoagulability and inflammation predict mor-
tality in patients with heart failure. J Thromb Haemost 2006;4:101722.
[36] Anzai T, Yoshikawa T, Kaneko H, Maekawa Y, Iwanaga S, Asakura Y, et al. Association between serum C-reactive protein elevation and
left ventricular thrombus formation after first anterior myocardial infarction. Chest 2004;125:3849.
[37] Chin BS, Conway DS, Chung NA, Blann AD, Gibbs CR, Lip GY. Interleukin-6, tissue factor and von Willebrand factor in acute decom-
pensated heart failure: relationship to treatment and prognosis. Blood Coagul Fibrinolysis 2003;14:51521.
[38] Chin BS, Blann AD, Gibbs CR, Chung NA, Conway DG, Lip GY. Prognostic value of interleukin-6, plasma viscosity, fibrinogen, von
Willebrand factor, tissue factor and vascular endothelial growth factor levels in congestive heart failure. Eur J Clin Invest 2003;33:9418.
[39] Levi M, van der Poll T, Buller HR. Bidirectional relation between inflammation and coagulation. Circulation 2004;109:2698704.
[40] Chong AY, Lip GY. Viewpoint: the prothrombotic state in heart failure: a maladaptive inflammatory response? Eur J Heart Fail 2007;9:1248.
[41] Danenberg HD, Szalai AJ, Swaminathan RV, Peng L, Chen Z, Seifert P, et al. Increased thrombosis after arterial injury in human
C-reactive protein-transgenic mice. Circulation 2003;108:51215.
[42] Devaraj S, Xu DY, Jialal I. C-reactive protein increases plasminogen activator inhibitor-1 expression and activity in human aortic endothe-
lial cells: implications for the metabolic syndrome and atherothrombosis. Circulation 2003;107:398404.
[43] Conway DS, Buggins P, Hughes E, Lip GY. Relationship of interleukin-6 and C-reactive protein to the prothrombotic state in chronic
atrial fibrillation. J Am Coll Cardiol 2004;43:207582.
112 7. Cardio-hepatology: liver function tests in heart failure
II. Hepatobiliary system in heart failure
https://t.me/medicina_free
[44] Davis CJ, Gurbel PA, Gattis WA, Fuzaylov SY, Nair GV, O’Connor CM, et al. Hemostatic abnormalities in patients with congestive heart
failure: diagnostic significance and clinical challenge. Int J Cardiol 2000;75:1521.
[45] Alehagen U, Dahlstrom U, Lindahl TL. Elevated D-dimer level is an independent risk factor for cardiovascular death in out-patients
with symptoms compatible with heart failure. Thromb Haemost 2004;92:12508.
[46] Jug B, Vene N, Salobir BG, Sebestjen M, Sabovic M, Keber I. Prognostic impact of haemostatic derangements in chronic heart failure.
Thromb Haemost 2009;102:31420.
[47] Alehagen U, Dahlstrom U, Lindahl TL. Low plasma concentrations of coagulation factors II, VII and XI indicate increased risk among
elderly with symptoms of heart failure. Blood Coagul Fibrinolysis 2010;21:629.
[48] Marin F, Roldan V, Martinez JG, Hernandez-Madrid A, Hernandez-Romero D, Ortego M, et al. Influence of cardiac resynchronization
therapy on indices of inflammation, the prothrombotic state and tissue remodeling in systolic heart failure: a pilot study. Thromb Res
2011;128:3914.
[49] Fuhrmann V, Kneidinger N, Herkner H, Heinz G, Nikfardjam M, Bojic A, et al. Hypoxic hepatitis: underlying conditions and risk factors
for mortality in critically ill patients. Intensive Care Med 2009;35:1397405.
[50] Raurich JM, Llompart-Pou JA, Ferreruela M, Colomar A, Molina M, Royo C, et al. Hypoxic hepatitis in critically ill patients: incidence,
etiology and risk factors for mortality. J Anesth 2011;25:506.
[51] Okada A, Sugano Y, Nagai T, Takashio S, Honda S, Asaumi Y, et al. Prognostic value of prothrombin time international normalized ratio
in acute decompensated heart failure- a combined marker of hepatic insufficiency and hemostatic abnormality. Circ J 2016;80:91323.
[52] Horwich TB, Kalantar-Zadeh K, MacLellan RW, Fonarow GC. Albumin levels predict survival in patients with systolic heart failure. Am
Heart J 2008;155:8839.
[53] Uthamalingam S, Kandala J, Daley M, Patvardhan E, Capodilupo R, Moore SA, et al. Serum albumin and mortality in acutely decompen-
sated heart failure. Am Heart J 2010;160:114955.
[54] Kinugasa Y, Kato M, Sugihara S, Hirai M, Kotani K, Ishida K, et al. A simple risk score to predict in-hospital death of elderly patients
with acute decompensated heart failurehypoalbuminemia as an additional prognostic factor. Circ J 2009;73:227681.
[55] Sato T, Yamauchi H, Suzuki S, Yoshihisa A, Yamaki T, Sugimoto K, et al. Serum cholinesterase is an important prognostic factor in
chronic heart failure. Heart Vessel 2015;30:20410.
[56] Russell SD, Rogers JG, Milano CA, Dyke DB, Pagani FD, Aranda JM, et al. HeartMate IICI. Renal and hepatic function improve in
advanced heart failure patients during continuous-flow support with the HeartMate II left ventricular assist device. Circulation
2009;120:23527.
[57] Imamura T, Kinugawa K, Shiga T, Kato N, Endo M, Inaba T, et al. How to demonstrate the reversibility of end-organ function before
implantation of left ventricular assist device in INTERMACS profile 2 patients? J Artif Organs 2012;15:3958.
[58] Imamura T, Kinugawa K, Shiga T, Endo M, Kato N, Inaba T, et al. Preoperative levels of bilirubin or creatinine adjusted by age can pre-
dict their reversibility after implantation of left ventricular assist device. Circ J 2013;77:96104.
[59] Gelow JM, Desai AS, Hochberg CP, Glickman JN, Givertz MM, Fang JC. Clinical predictors of hepatic fibrosis in chronic advanced heart
failure. Circ Heart Fail 2010;3:5964.
[60] Demirozu ZT, Hernandez R, Mallidi HR, Singh SK, Radovancevic R, Segura AM, et al. HeartMate II left ventricular assist device implan-
tation in patients with advanced hepatic dysfunction. J Card Surg 2014;29:41923.
[61] Louie CY, Pham MX, Daugherty TJ, Kambham N, Higgins JP. The liver in heart failure: a biopsy and explant series of the histopathologic
and laboratory findings with a particular focus on pre-cardiac transplant evaluation. Mod Pathol 2015;28:93243.
[62] Farr M, Mitchell J, Lippel M, Kato TS, Jin Z, Ippolito P, et al. Combination of liver biopsy with MELD-XI scores for post-transplant out-
come prediction in patients with advanced heart failure and suspected liver dysfunction. J Heart Lung Transpl 2015;34:87382.
[63] Parera A, Banares R, Alvarez R, Casariego J, Carneros JA, Salcedo M, et al. The usefulness of transjugular hepatic biopsy in the evalua-
tion of liver disease in candidates for heart transplantation. Gastroenterol Hepatol 1999;22:6771.
[64] Sato Y, Kataoka K, Matsumori A, Sasayama S, Yamada T, Ito H, et al. Measuring serum aminoterminal type III procollagen peptide, 7S
domain of type IV collagen, and cardiac troponin T in patients with idiopathic dilated cardiomyopathy and secondary cardiomyopathy.
Heart 1997;78:5058.
[65] Masai T, Sawa Y, Ohtake S, Nishida T, Nishimura M, Fukushima N, et al. Hepatic dysfunction after left ventricular mechanical assist in
patients with end-stage heart failure: role of inflammatory response and hepatic microcirculation. Ann Thorac Surg 2002;73:54955.
[66] Li G, Yan QB, Wei LM. Serum concentrations of hyaluronic acid, procollagen type III NH2-terminal peptide, and laminin in patients
with chronic congestive heart failure. Chin Med Sci J 2006;21:1758.
[67] Nagao K, Tamura A, Morimoto T, Shimamura K, Yukawa H, Ito H, et al. Liver fibrogenesis marker, 7S domain of collagen type IV in
patients with acutely decompensated heart failure: Correlates, prognostic value and time course. Int J Cardiol 2017;236:4837.
[68] Kuno A, Ikehara Y, Tanaka Y, Ito K, Matsuda A, Sekiya S, et al. A serum “sweet-doughnut” protein facilitates fibrosis evaluation and
therapy assessment in patients with viral hepatitis. Sci Rep 2013;3:1065.
[69] Okada A, Kanzaki H, Hamatani Y, Takashio S, Takahama H, Amaki M, et al. Increased serum Wisteria floribunda agglutinin positive
Mac-2 binding protein (Mac-2 binding protein glycosylation isomer) in chronic heart failure: a pilot study. Heart Vessel 2018;33:38592.
[70] Auer J. What does the liver tell us about the failing heart? Eur Heart J 2013;34:71114.
113References
II. Hepatobiliary system in heart failure
https://t.me/medicina_free
Соседние файлы в папке Библиотека им академика М.И. Перельмана