Cardiohepatic Interactions in Heart Failure an Overview
Cardiohepatic Interactions in Heart Failure an Overview
Presentation and Pathophysiology. Acute cardiogenic liver injury (ACLI), historically called "ischemic hepatitis," is often described in patients with HF who have progressed to critical cardiogenic shock, in which cardiac output is no longer sufficient to meet the metabolic demands of hepatic cells. However, review of the literature suggests that an acute change in hepatic blood flow is not the sole incident responsible for the development of ACLI. In a retrospective analysis of patients with clinical and biochemical evidence of ACLI, Seeto et al. found that hypotension alone did not induce acute liver injury. Patients with ACLI were compared with a control group comprising trauma victims who had evidence of prolonged hypotension. No patients in the control group had findings consistent with ACLI. Conversely, nearly all patients with a clinical diagnosis of ACLI had evidence of cardiac disease, with 29 of these 31 subjects demonstrating evidence of elevated right-sided or venous filling pressures. Similarly, Henrion et al. examined ACLI in patients admitted to the coronary intensive care unit with evidence of low cardiac output. Patients with biochemical evidence of cardiogenic injury had significantly higher central venous pressures compared to patients who had low cardiac output but no ACLI.
Several larger studies characterizing the etiology of ACLI have shown that the majority of cases of ACLI are related to acute HF, respiratory failure, and septic shock. However, these same studies have also shown that between 39% and 70% of patients with ACLI have the underlying diagnosis of chronic HF. These findings suggest that ACLI does not result from a single hemodynamic insult, but rather, ACLI is linked to the combination of hepatic congestion from elevated hepatic venous pressure coupled with impaired perfusion (Fig. 1). Venous congestion may ultimately increase the susceptibility of the liver to injury caused by reduced perfusion. The notion that a "second hit" is required for acute liver injury is not captured in the nomenclature commonly used to describe this process, such as "ischemic hepatitis" or "shock liver." Therefore, we believe that "ACLI" is a more accurate diagnostic term, encapsulating the underlying pathophysiological process.
(Enlarge Image)
Figure 1.
Mechanisms Leading to 2 Types of Cardiogenic Liver Injury
Chronic heart failure (HF) leading to chronic passive congestion of the liver leads to a liver function panel consistent with cholestasis. Patients with chronic HF who experience an acute decompensation show evidence of hypoxic hepatitis.
Although the pathophysiological process is not clearly defined, the injury pattern of ACLI represents the release of hepatic proteins in response to tissue hypoxia and cell death. After hemodynamic recovery, symptoms related to the liver injury can present after a latency period of 2 to 24 h. These symptoms may include weakness, apathy, and (in a minority of cases) persistent mental confusion, tremor, hepatic coma, and jaundice. A bleeding diathesis from acquired coagulopathy may also develop due to impaired production of coagulation factors. These abnormalities peak at 1 to 3 days after onset of symptoms and, in patients who survive, return to normal within 5 to 10 days after onset.
Histopathology. The histologic hallmark of ACLI is necrosis surrounding the central vein where oxygenation is poor (zone 3). Depending on the duration of ischemia, a variable degree of architectural collapse around the central veins can occur. Necrosis can extend to the mid-zonal hepatocytes with prolonged ischemia; however, necrosis rarely occurs predominantly in the middle zones (Fig. 2). Although clinical and laboratory diagnostic data are usually sufficient for the diagnosis, a liver biopsy may be useful when it is necessary to clarify the underlying etiology of an acute rise in aminotransferase levels.
(Enlarge Image)
Figure 2.
Photomicrographs
Histology slides showing acute hepatic passive congestion in a patient with heart failure (HF). Changes consistent with acute cardiogenic liver injury: (A) hematoxylin and eosin, original magnification ×4; and (B) hematoxylin and eosin, original magnification ×20. The pattern of hepatocyte loss is consistent with ischemia. The hepatocytes have completely disappeared, leaving only a loose reticular framework. There is no regenerative activity or collagen fibrosis—(C) Masson trichrome stain, original magnification ×10—thereby suggesting a fairly recent event. The presence of mild ductular changes including ductular proliferation, occasional neutrophils associated with ductules, and ductular bile stasis are likely secondary to the ischemic event. (D) Changes consistent with chronic hepatic passive congestion, in a patient with chronic HF (hematoxylin and eosin, original magnification ×10). There is minimal inflammation in the portal areas, and no interface activity is evident. Only 1 focus of canalicular cholestasis is seen. Extensive spidery and dense perivenular fibrosis exists; this extends into the lobule and bridges (stage 3) with other central, and focally, portal areas. (E) Masson trichrome stain (original magnification ×10) highlights the extensive nature of zone 3 (central) fibrosis. Some of the perisinusoidal hepatic plates are atrophic and attenuated.
Biochemical Profile. The typical pattern in laboratory studies consists of a substantial and rapid elevation in aminotransferase and lactate dehydrogenase (LDH) levels to 10 to 20 times normal, typically between 1 and 3 days after hemodynamic insult, and without evidence of another etiology such as cholecystitis or viral hepatitis. With correction of hemodynamics, these levels will return to normal within 7 to 10 days. Early and rapid increase in serum LDH is a distinguishing feature of ACLI, and a ratio of serum alanine aminotransferase (ALT) to LDH <1.5 early in the course of liver injury is characteristic of cardiogenic injury as opposed to other etiologies of hepatitis. Laboratory abnormalities may also include sharp increases in serum ALT and aspartate aminotransferase (AST; typically 10 times normal values), increased serum bilirubin, and prolongation of the prothrombin time. In fact, 2 studies have shown as much as a 50% decrease in prothrombin activity in 79.5% and 84% of ACLI patients, which is thought to be unusual in the case of viral hepatitis.
Although there are few data regarding LFT alterations among patients with acute HF, a recently published analysis of the SURVIVE (Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support) trial helps understand explain how LFTs can be altered in patients presenting with acutely decompensated HF. Baseline LFTs were abnormal in 46% of the 1,134 patients enrolled in the SURVIVE study; of these, 11% had an isolated abnormality in alkaline phosphatase levels, 26% had isolated transaminase abnormalities, and 9% had abnormal alkaline phosphatase and transaminases. Interestingly, abnormal alkaline phosphatase was associated with marked signs of congestion and elevated right-sided filling pressures, as well as increased 180-day mortality. Abnormal transaminases were associated with clinical signs of hypoperfusion and increased 31- and 180-day mortality (Table 1).
Since the original description of the "nutmeg liver," there has been an interest in understanding the biochemical and histological changes associated with transmission of elevated right-sided filling pressures to the hepatic venous system. While the term "congestive hepatopathy" has become synonymous with this clinical syndrome, the incidence of passive congestion, histological changes in the liver, and the impact on physiology and prognosis have not been clearly delineated.
Presentation and Pathophysiology. Patients with chronic passive congestion or congestive hepatopathy from long-standing elevation of right-sided filling pressures may present at various stages along a continuum. In severe cases associated with end-stage biventricular failure, severe tricuspid regurgitation (TR), or restrictive/constrictive cardiomyopathy, affected patients may be indistinguishable from patients with chronic liver disease or cirrhosis. In other HF syndromes, the clinical presentation may be more subtle, with intermittent right upper quadrant discomfort, nausea, early satiety, or anorexia. Symptoms are difficult to distinguish from primary hepatobiliary or gastrointestinal conditions such as cholelithiasis, peptic ulcer disease, or even ischemic colitis. Careful evaluation of the jugular venous pressure provides critical information in the assessment of these symptoms. Importantly, these findings may occur in the absence of overt ascites or lower extremity edema (particularly in younger patients), and a high degree of suspicion should be maintained for HF even in the absence of the typical signs or symptoms.
Hepatopathy secondary to chronic congestive HF is attributed to 3 main processes: increased hepatic venous pressure, decreased hepatic blood flow, and decreased arterial oxygen saturation. Elevated central venous pressures are transmitted through the hepatic veins and into the small hepatic venules. The effect of this transmitted pressure is passive congestion of the liver with resulting elevated hepatic venous pressure, which can impair delivery of oxygen and nutrients to hepatocytes, leading to sinusoidal fenestrae enlargement. Consequently, hepatocyte necrosis and leakage of protein-rich fluid into the space of Disse occurs. Although these histological processes can be subclinical, abdominal symptoms are primarily attributed to stretching of the liver capsule resulting in abdominal discomfort.
Histopathology. Boland and Willius first demonstrated that nearly 50% of patients with severe HF had pathologic changes consistent with chronic passive liver congestion. Atrophy, necrosis, or both were present and most pronounced in the central third of the hepatic lobule. Generally, these findings were most prominent immediately adjacent to the central vein, with decreasing degeneration towards the lobule periphery. Results were later confirmed by the work of Sherlock, which described microscopic sinusoidal engorgement and degeneration. Centrilobular hepatic necrosis was almost always present, with worsening HF resulting in peripheral spread of necrosis and healing of the lesion being associated with decreasing right atrial pressure. Also noted were variable degrees of cholestasis, occasionally with bile thrombi in the canaliculi (Fig. 2).
Biochemical Profiles. Recent studies have attempted to characterize the biochemical profiles observed in peripheral blood associated with cardiogenic liver injury. Kubo et al. examined the incidence of liver disease among 133 patients with chronic systolic HF secondary to dilated cardiomyopathy. Abnormalities in LFTs were common, but generally of small magnitude and primarily limited to patients with a cardiac index <1.5 l/min/m. As cardiac output decreased and intracardiac filling pressures increased, elevations in transaminases, LDH, and total bilirubin were statistically different but did not correlate with hepatomegaly. In a retrospective analysis of patients with more severe HF, LFT abnormalities more characteristic of cholestasis (i.e., increased alkaline phosphatase, gamma-glutamyl transpeptidase [GGT], total bilirubin, and hypoalbuminemia) were noted and correlated with the severity of TR.
The impact of HF on LFT abnormalities in a more contemporary and larger patient cohort was recently described in the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity Program) trial. In addition to the previously described cholestatic LFT pattern associated with chronic stable HF, the investigators observed significantly elevated total bilirubin levels in patients with evidence of volume overload compared with those in patients who were clinically euvolemic. Poelzl et al. also described a cholestatic pattern of LFTs in patients with stable HF and showed a positive correlation between elevations in cholestatic LFTs and disease severity as assessed by the New York Heart Association (NYHA) functional classification. Specifically, total bilirubin, alkaline phosphatase, and GGT independently correlated with signs of right HF, including the presence of jugular venous distention, peripheral edema, and TR. These data, in conjunction with the relationship between LFTs and TR, suggest that elevated right-sided filling pressures may contribute more to LFT elevation in stable HF than reduced cardiac output.
Liver Dysfunction in HF Patients: Presentation, Histology, and Biochemical Profiling in Acute HF
Acute Cardiogenic Liver Injury
Presentation and Pathophysiology. Acute cardiogenic liver injury (ACLI), historically called "ischemic hepatitis," is often described in patients with HF who have progressed to critical cardiogenic shock, in which cardiac output is no longer sufficient to meet the metabolic demands of hepatic cells. However, review of the literature suggests that an acute change in hepatic blood flow is not the sole incident responsible for the development of ACLI. In a retrospective analysis of patients with clinical and biochemical evidence of ACLI, Seeto et al. found that hypotension alone did not induce acute liver injury. Patients with ACLI were compared with a control group comprising trauma victims who had evidence of prolonged hypotension. No patients in the control group had findings consistent with ACLI. Conversely, nearly all patients with a clinical diagnosis of ACLI had evidence of cardiac disease, with 29 of these 31 subjects demonstrating evidence of elevated right-sided or venous filling pressures. Similarly, Henrion et al. examined ACLI in patients admitted to the coronary intensive care unit with evidence of low cardiac output. Patients with biochemical evidence of cardiogenic injury had significantly higher central venous pressures compared to patients who had low cardiac output but no ACLI.
Several larger studies characterizing the etiology of ACLI have shown that the majority of cases of ACLI are related to acute HF, respiratory failure, and septic shock. However, these same studies have also shown that between 39% and 70% of patients with ACLI have the underlying diagnosis of chronic HF. These findings suggest that ACLI does not result from a single hemodynamic insult, but rather, ACLI is linked to the combination of hepatic congestion from elevated hepatic venous pressure coupled with impaired perfusion (Fig. 1). Venous congestion may ultimately increase the susceptibility of the liver to injury caused by reduced perfusion. The notion that a "second hit" is required for acute liver injury is not captured in the nomenclature commonly used to describe this process, such as "ischemic hepatitis" or "shock liver." Therefore, we believe that "ACLI" is a more accurate diagnostic term, encapsulating the underlying pathophysiological process.
(Enlarge Image)
Figure 1.
Mechanisms Leading to 2 Types of Cardiogenic Liver Injury
Chronic heart failure (HF) leading to chronic passive congestion of the liver leads to a liver function panel consistent with cholestasis. Patients with chronic HF who experience an acute decompensation show evidence of hypoxic hepatitis.
Although the pathophysiological process is not clearly defined, the injury pattern of ACLI represents the release of hepatic proteins in response to tissue hypoxia and cell death. After hemodynamic recovery, symptoms related to the liver injury can present after a latency period of 2 to 24 h. These symptoms may include weakness, apathy, and (in a minority of cases) persistent mental confusion, tremor, hepatic coma, and jaundice. A bleeding diathesis from acquired coagulopathy may also develop due to impaired production of coagulation factors. These abnormalities peak at 1 to 3 days after onset of symptoms and, in patients who survive, return to normal within 5 to 10 days after onset.
Histopathology. The histologic hallmark of ACLI is necrosis surrounding the central vein where oxygenation is poor (zone 3). Depending on the duration of ischemia, a variable degree of architectural collapse around the central veins can occur. Necrosis can extend to the mid-zonal hepatocytes with prolonged ischemia; however, necrosis rarely occurs predominantly in the middle zones (Fig. 2). Although clinical and laboratory diagnostic data are usually sufficient for the diagnosis, a liver biopsy may be useful when it is necessary to clarify the underlying etiology of an acute rise in aminotransferase levels.
(Enlarge Image)
Figure 2.
Photomicrographs
Histology slides showing acute hepatic passive congestion in a patient with heart failure (HF). Changes consistent with acute cardiogenic liver injury: (A) hematoxylin and eosin, original magnification ×4; and (B) hematoxylin and eosin, original magnification ×20. The pattern of hepatocyte loss is consistent with ischemia. The hepatocytes have completely disappeared, leaving only a loose reticular framework. There is no regenerative activity or collagen fibrosis—(C) Masson trichrome stain, original magnification ×10—thereby suggesting a fairly recent event. The presence of mild ductular changes including ductular proliferation, occasional neutrophils associated with ductules, and ductular bile stasis are likely secondary to the ischemic event. (D) Changes consistent with chronic hepatic passive congestion, in a patient with chronic HF (hematoxylin and eosin, original magnification ×10). There is minimal inflammation in the portal areas, and no interface activity is evident. Only 1 focus of canalicular cholestasis is seen. Extensive spidery and dense perivenular fibrosis exists; this extends into the lobule and bridges (stage 3) with other central, and focally, portal areas. (E) Masson trichrome stain (original magnification ×10) highlights the extensive nature of zone 3 (central) fibrosis. Some of the perisinusoidal hepatic plates are atrophic and attenuated.
Biochemical Profile. The typical pattern in laboratory studies consists of a substantial and rapid elevation in aminotransferase and lactate dehydrogenase (LDH) levels to 10 to 20 times normal, typically between 1 and 3 days after hemodynamic insult, and without evidence of another etiology such as cholecystitis or viral hepatitis. With correction of hemodynamics, these levels will return to normal within 7 to 10 days. Early and rapid increase in serum LDH is a distinguishing feature of ACLI, and a ratio of serum alanine aminotransferase (ALT) to LDH <1.5 early in the course of liver injury is characteristic of cardiogenic injury as opposed to other etiologies of hepatitis. Laboratory abnormalities may also include sharp increases in serum ALT and aspartate aminotransferase (AST; typically 10 times normal values), increased serum bilirubin, and prolongation of the prothrombin time. In fact, 2 studies have shown as much as a 50% decrease in prothrombin activity in 79.5% and 84% of ACLI patients, which is thought to be unusual in the case of viral hepatitis.
Although there are few data regarding LFT alterations among patients with acute HF, a recently published analysis of the SURVIVE (Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support) trial helps understand explain how LFTs can be altered in patients presenting with acutely decompensated HF. Baseline LFTs were abnormal in 46% of the 1,134 patients enrolled in the SURVIVE study; of these, 11% had an isolated abnormality in alkaline phosphatase levels, 26% had isolated transaminase abnormalities, and 9% had abnormal alkaline phosphatase and transaminases. Interestingly, abnormal alkaline phosphatase was associated with marked signs of congestion and elevated right-sided filling pressures, as well as increased 180-day mortality. Abnormal transaminases were associated with clinical signs of hypoperfusion and increased 31- and 180-day mortality (Table 1).
Chronic Passive Congestion
Since the original description of the "nutmeg liver," there has been an interest in understanding the biochemical and histological changes associated with transmission of elevated right-sided filling pressures to the hepatic venous system. While the term "congestive hepatopathy" has become synonymous with this clinical syndrome, the incidence of passive congestion, histological changes in the liver, and the impact on physiology and prognosis have not been clearly delineated.
Presentation and Pathophysiology. Patients with chronic passive congestion or congestive hepatopathy from long-standing elevation of right-sided filling pressures may present at various stages along a continuum. In severe cases associated with end-stage biventricular failure, severe tricuspid regurgitation (TR), or restrictive/constrictive cardiomyopathy, affected patients may be indistinguishable from patients with chronic liver disease or cirrhosis. In other HF syndromes, the clinical presentation may be more subtle, with intermittent right upper quadrant discomfort, nausea, early satiety, or anorexia. Symptoms are difficult to distinguish from primary hepatobiliary or gastrointestinal conditions such as cholelithiasis, peptic ulcer disease, or even ischemic colitis. Careful evaluation of the jugular venous pressure provides critical information in the assessment of these symptoms. Importantly, these findings may occur in the absence of overt ascites or lower extremity edema (particularly in younger patients), and a high degree of suspicion should be maintained for HF even in the absence of the typical signs or symptoms.
Hepatopathy secondary to chronic congestive HF is attributed to 3 main processes: increased hepatic venous pressure, decreased hepatic blood flow, and decreased arterial oxygen saturation. Elevated central venous pressures are transmitted through the hepatic veins and into the small hepatic venules. The effect of this transmitted pressure is passive congestion of the liver with resulting elevated hepatic venous pressure, which can impair delivery of oxygen and nutrients to hepatocytes, leading to sinusoidal fenestrae enlargement. Consequently, hepatocyte necrosis and leakage of protein-rich fluid into the space of Disse occurs. Although these histological processes can be subclinical, abdominal symptoms are primarily attributed to stretching of the liver capsule resulting in abdominal discomfort.
Histopathology. Boland and Willius first demonstrated that nearly 50% of patients with severe HF had pathologic changes consistent with chronic passive liver congestion. Atrophy, necrosis, or both were present and most pronounced in the central third of the hepatic lobule. Generally, these findings were most prominent immediately adjacent to the central vein, with decreasing degeneration towards the lobule periphery. Results were later confirmed by the work of Sherlock, which described microscopic sinusoidal engorgement and degeneration. Centrilobular hepatic necrosis was almost always present, with worsening HF resulting in peripheral spread of necrosis and healing of the lesion being associated with decreasing right atrial pressure. Also noted were variable degrees of cholestasis, occasionally with bile thrombi in the canaliculi (Fig. 2).
Biochemical Profiles. Recent studies have attempted to characterize the biochemical profiles observed in peripheral blood associated with cardiogenic liver injury. Kubo et al. examined the incidence of liver disease among 133 patients with chronic systolic HF secondary to dilated cardiomyopathy. Abnormalities in LFTs were common, but generally of small magnitude and primarily limited to patients with a cardiac index <1.5 l/min/m. As cardiac output decreased and intracardiac filling pressures increased, elevations in transaminases, LDH, and total bilirubin were statistically different but did not correlate with hepatomegaly. In a retrospective analysis of patients with more severe HF, LFT abnormalities more characteristic of cholestasis (i.e., increased alkaline phosphatase, gamma-glutamyl transpeptidase [GGT], total bilirubin, and hypoalbuminemia) were noted and correlated with the severity of TR.
The impact of HF on LFT abnormalities in a more contemporary and larger patient cohort was recently described in the CHARM (Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity Program) trial. In addition to the previously described cholestatic LFT pattern associated with chronic stable HF, the investigators observed significantly elevated total bilirubin levels in patients with evidence of volume overload compared with those in patients who were clinically euvolemic. Poelzl et al. also described a cholestatic pattern of LFTs in patients with stable HF and showed a positive correlation between elevations in cholestatic LFTs and disease severity as assessed by the New York Heart Association (NYHA) functional classification. Specifically, total bilirubin, alkaline phosphatase, and GGT independently correlated with signs of right HF, including the presence of jugular venous distention, peripheral edema, and TR. These data, in conjunction with the relationship between LFTs and TR, suggest that elevated right-sided filling pressures may contribute more to LFT elevation in stable HF than reduced cardiac output.
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