Gastrointestinal and Liver Issues in Heart Failure
Abstract
Heart failure affects ≈23 million people worldwide and continues to have a high mortality despite advancements in modern pharmacotherapy and device therapy. HF is a complex clinical syndrome that can result in the impairment of endocrine, hematologic, musculoskeletal, renal, respiratory, peripheral vascular, hepatic, and gastrointestinal systems. Although gastrointestinal involvement and hepatic involvement are common in HF and are associated with increased morbidity and mortality, their bidirectional association with HF progression remains poorly fathomed. The current understanding of multiple mechanisms, including proinflammatory cytokine milieu, hormonal imbalance, and anabolic/catabolic imbalance, has been used to explain the relationship between the gut and HF and has been the basis for many novel therapeutic strategies. However, the failure of these novel therapies such as anti–tumor necrosis factor-α has resulted in further complexity. In this review, we describe the involvement of the gastrointestinal and liver systems within the HF syndrome, their pathophysiological mechanisms, and their clinical consequences.
Introduction
Heart failure (HF) is a systemic disorder caused by the inability of the heart to accommodate the venous return and to maintain sufficient cardiac output to meet the body’s metabolic needs.1 These hemodynamic perturbations result in a state of systemic inflammation with well-described and well-studied consequences in a variety of other organ systems, including the renal, cerebral, musculoskeletal, and immune systems. In contrast, the gastrointestinal and hepatic systems have received less attention, although gastrointestinal symptoms are common. With increasing clinical efforts to resuscitate the advanced HF patient, a greater appreciation and a better understanding of the gastrointestinal and hepatic manifestations of HF are needed.2,3
With some notable exceptions, gastrointestinal and hepatic involvement in heart disease has historically received little attention from cardiologists.4 Mechanisms of gastrointestinal and hepatic dysfunction remain poorly understood despite the common presence of gastrointestinal-related symptoms and the increased morbidity and mortality associated with their presence. The specific involvement of the gastrointestinal system in HF results in a bidirectional relationship that has been called the cardiointestinal syndrome.5 For example, the systemic volume overload characteristic of HF is generally accompanied by concomitant gut edema, which can lead to bacterial translocation into the systemic circulation. Consequent monocyte activation and excessive cytokine release result in systemic inflammation, increased symptoms, and disease progression.6
In this review, we describe the current state of understanding of the gastrointestinal and hepatic systems in HF. Although nutritional status is also relevant in this discussion, we refer the reader to other excellent reviews of nutritional aspects of chronic disease.7,8
The Gut in HF
Gastrointestinal System as a Venous Reservoir
Studies of implantable hemodynamic monitors to manage HF patients document that acute decompensated HF was not associated with weight gain in 33% to 46% of patients. Moreover, pulmonary artery pressures were noted to rise days to weeks before acute decompensated HF hospitalization in the absence of weight gain.9–11 This phenomenon has been attributed to shifts between total extracellular fluid volume and effective circulating volume. The venous system contains up to 70% of the total blood volume. The compliance of the splanchnic veins is much higher than that of the peripheral venous system, and hence they act as a relatively greater venous reservoir. The splanchnic veins have a large number of α-1 and α-2 receptors and therefore are responsive to the sympathetic nervous system.12 In HF, the amplified sympathetic nervous system activation leads to a decrease in the capacitance of splanchnic veins and a shift of fluid out of the splanchnic veins, thereby increasing the effective circulating volume. This shift increases the preload without increasing total body volume and exaggerates the hemodynamic effects of sodium and water retention (Figure 1).14 These splanchnic hemodynamic changes may also be responsible for the abdominal discomfort, nausea, constipation, and diarrhea common in advanced HF.
Figure 1. Gastrointestinal system as a venous reservoir. Adapted from Fallick et al.13
Cardiointestinal Syndrome
Common gastrointestinal manifestations of HF include anorexia, early satiety, and abdominal pain; in patients with advanced HF, ascites, protein-losing enteropathy (PLE), and cachexia may be present. Historically, these symptoms have been attributed to poor abdominal organ perfusion or edema and have not been considered operational in the pathophysiology of HF. However, the gut is a large immunologic organ and may contribute to the proinflammatory cytokine milieu of HF (Figure 2). The failing heart is associated with systemic immune activation, and levels of proinflammatory cytokines predict HF survival.15,16 However, the direct pathological link between the two has yet to be clearly elucidated.17
Figure 2. Pathophysiology of cardiointestinal syndrome.
The intestine serves as an important immunologic barrier and represents the largest mass of lymphoid tissue in the body, containing >106 lymphocytes per 1 g tissue.18 More than 60% of the total immunoglobulin produced daily is secreted in the gastrointestinal tract.19 There is increasing evidence that altered gut morphology and function, for example, increased gut permeability, in HF can alter this immunologic barrier and play an important role in the chronic inflammatory process.
Increased gut permeability in HF appears to be a consequence of gut edema and gastrointestinal hypoperfusion. Neibauher et al20 compared HF patients with recent-onset peripheral edema with stable nonedematous patients with HF and healthy volunteers. Bowel edema was not measured directly, and peripheral edema was used as an indirect reliable marker of bowel edema. They observed significantly higher concentrations of endotoxins (lipopolysaccharide /liposomal binding protein ratio) in patients with edematous HF compared with nonedematous patients with HF. Patients with presumed gut edema had bacterial or lipopolysaccharide translocation to the systemic circulation. Once in the circulation, it is surmised that lipopolysaccharide binds to lipid-binding protein, producing a complex that interacts with CD14 and Toll-like signaling receptors, initiating increased cytokine production. Also in this study, patients with edematous HF had significantly higher plasma concentrations of C-reactive protein, tumor necrosis factor (TNF)-α, soluble TNF receptor-1 and -2, interleukin-6, and soluble CD14 than the other 2 groups. Importantly, the study demonstrated normalization of endotoxins levels (lipopolysaccharide) in edematous HF patients after intensive diuresis.20 Although this study suggests that gut edema incites a proinflammatory response in HF, it may be confounded by the level of illness of the patients with edematous HF (eg, the edematous patients had greater baseline hyponatremia and abnormal renal function and uric acid levels) compared with the nonedematous patients. Other investigators have found similar observations.21,22 Tang et al23 showed that elevated fasting plasma levels of trimethylamine-N-oxide in HF, a downstream metabolite of gut microbiota, was associated with a 3.4-fold increased risk for mortality, indicating that alteration in microbial composition in the gut could potentially lead to progression of the disease. However, these observations may be epiphenomenon, and causality has not been established. Intestinal mucosal ischemia also may lead to increased gut permeability and bacterial translocation. Using intragastric Pco2 as marker of splanchnic hypoperfusion, Krack et al24 demonstrated elevated levels of intragastric Pco2 and inflammatory markers in patients with congestive HF patients low-level and peak exercise.
These findings suggest a potential role for bacterial decontamination of the gut in patients with HF. A randomized trial of probiotics in patients with HF is testing this hypothesis and assessing their effect on inflammatory markers and clinical progression of disease.25
Cardiac Cachexia
Cardiac cachexia has been described as a catabolic state characterized by unintentional and nonedematous weight loss of >7.5% of premorbid body weight over 6 months.26 The prevalence of cardiac cachexia in HF cohorts has been reported to be as high as 45%.27 Cardiac cachexia is associated with poor survival independently of functional capacity, left ventricular systolic function, or peak oxygen consumption. The annual mortality in cachectic HF patients may be as high as 20% to 30%.28
Anker and coworkers29 have suggested that cachexia in HF is driven by an increase in the factors that promote protein and fat tissue degradation. While showing an upregulation of hormonal factors (norepinephrine, epinephrine, TNFα and cortisol levels) that promote catabolism, they also demonstrated an inadequate anabolic response (eg, reduced dehydroepiandrosterone, insulin, and testosterone levels), signifying an anabolic/catabolic imbalance in cachectic HF patients. Anorexia, early satiety, and poor gastrointestinal absorption of foods and nutrients in HF may further exacerbate this anabolic/catabolic imbalance.7,8
The relationship between cardiac cachexia and gastrointestinal function may also be partially mediated through endocrine pathways. Ghrelin, a growth hormone–releasing peptide, is secreted from stomach and circulates in the bloodstream.30 Ghrelin is the endogenous ligand for the growth hormone secretagog receptor and stimulates growth hormone secretion. Growth hormone and insulin-like growth factor are anabolic hormones; elevated serum growth hormone levels with normal or low insulin-like growth factor-1 levels have been described in HF patients with cachexia.31 Growth hormone secretagog receptor has been detected in heart and blood vessels, in addition to the hypothalamus and pituitary.
Ghrelin is an appetite stimulatory peptide, and its levels are increased by fasting and decreased by feeding. Nagaya et al32 measured circulating ghrelin levels in 74 patients with HF; plasma ghrelin levels did not differ between HF patients and control subjects. However, plasma ghrelin levels were higher in cachectic HF patients compared with noncachectic patients and correlated negatively with body mass index. This observation suggests that increased circulating ghrelin levels may be a compensatory response to an anabolic/catabolic imbalance in HF patients with cachexia. Small studies have demonstrated that administration of ghrelin induces weight gain by decreasing fat use and increasing carbohydrate use through a growth hormone–independent mechanism. In animal models, intravenous administration of ghrelin has been shown to decrease systemic vascular resistance and to increase cardiac output.33
Increased intestinal permeability and translocation of endotoxin in HF may be an important stimulus for release of TNF, another mediator of cardiac cachexia. Despite encouraging preliminary experiences with the TNFα antagonist etanercept in HF,34 the experience with etanercept in rheumatoid arthritis led to the current warning that HF may be precipitated or worsened by this drug. Other approaches to block TNFα have also not been successful. In the Anti-TNFα Therapy Against Congestive Heart Failure (ATTACH) trial, infliximab, a chimeric monoclonal antibody to TNFα, increased HF hospitalizations.35 A singular reason for the failure of the anti-TNF is unlikely. Some have surmised that TNFα production is an epiphenomenon in HF and not complicit in the disease progression. However, a signal for harm was noted in these trials, suggesting that perhaps TNFα toxicity may be have been enhanced. Antibody binding may have increased the circulating time of TNFα or even produced a rebound effect, resulting in even higher levels of TNFα. Alternatively, TNFα may be adaptive; evidence also suggests that TNFα may promote vascular nitric oxide production, attenuate stress-induced apoptosis, and decrease the toxicity of prolonged sympathetic activation. These alternative explanations could explain the increased rates of HF hospitalization in those receiving high doses of infliximab.36,37
To summarize, the pathophysiology of cardiac cachexia is complex, and multiple mechanisms (Figure 3) are likely operational. Although chronic inflammation plays an important role, the gastrointestinal system is likely central to its pathophysiology in that anorexia, malnutrition, and malabsorption interact with hormonal disturbances such as ghrelin excretion and other imbalances of anabolic, as well as catabolic systems.
Figure 3. Pathophysiology of cardiac cachexia.
Protein-Losing Enteropathy
Hypoalbuminemia/hypoproteinemia is a common condition in patients with HF and is an independent predictor of poor prognosis.38 It is most often related to malnutrition, inflammation, and cachexia, but other causal factors include hemodilution, liver dysfunction, proteinuria, and PLE.
PLE, a condition characterized by gastrointestinal loss of proteins, is often underappreciated in HF. The pathophysiology of HF-related PLE is related to gut edema and rupture of intestinal lacteals from elevated central venous pressures.39 Increased gut epithelial permeability subsequently leads to protein leakage into the gut lumen. PLE has also been described in other cardiac conditions associated with elevated right-sided filling pressures, including constrictive pericarditis, tricuspid regurgitation, and congenital heart disease.40 Although PLE in HF is a consequence of elevated right-sided filling pressures, it can in turn increase pulmonary capillary wedge pressures as a result of low colloid oncotic pressure.41 Small studies have shown that coadministration of albumin with diuretics in refractory diuretic-resistant edema confers modest clinical benefit, a finding that warrants confirmation with large, prospective studies.42
The first step in the evaluation of patients with hypoproteinemia is to exclude other common causes like malnutrition or liver and renal disease. The most commonly used and reliable method to determine enteric protein loss is to determine the clearance of α-1 antitrypsin (A1AT) from plasma. A1AT is a protein synthesized in the liver that is resistant to proteolysis or degradation in the gut, thereby allowing its intact elimination and detection in feces. The measurement of A1AT clearance requires both blood and stool samples. Elevated A1AT clearance suggests excessive gastrointestinal protein loss distal to pylorus. Patients with PLE generally have A1AT clearance values >50 mL/24 h (normal, <27 mL/24 h). The positive predictive value of the test has been found to be 97.7%, and the negative predictive value is 75%.43,44 Technetium 99m–labeled human serum albumin scintigraphy can also identify protein loss in the gut, but its use is limited to research.45
The cornerstone of treatment for PLE in HF involves treating the underlying disease. Davidson et al46 demonstrated reversal of PLE after pericardial stripping in a small case series of patients with constrictive pericarditis. There are also reports of reversal of PLE with orthotopic heart transplantation.47
Alteration in the Pharmacokinetics and Pharmacodynamics of HF Drugs as a Result of Gastrointestinal Issues
Gut involvement in HF not only causes worsening of symptoms and clinical progression but also potentially complicates HF treatment by decreasing intestinal absorption of HF drugs. Several mechanisms are attributed to cardiointestinal syndrome that are implicated in the decreased permeability of drugs from gut lumen to intestinal epithelial cells to portal circulation in HF.48 Such mechanisms include edematous changes in the intestinal wall, increased thickness of the bowel tissues as a result of collagen deposition, and intestinal damage from chronic hypoperfusion.22,49 The proinflammatory cytokine milieu can also alter the expression of various drug-metabolizing enzymes and transporters.50,51
Drugs are transported from intestinal lumen to epithelial cells through either transcellular or paracellular tight junctions. Evidence suggests that the integrity of paracellular tight junctions to carbohydrates may be damaged in patients with HF.22,48 Although most HF drugs are lipophilic and transported via the transcellular junctions, intestinal transport of certain hydrophilic HF drugs such as lisinopril is via paracellular tight junctions, which may be impaired in HF.48,52 Gut edema may also alter the rate of absorption of certain drugs such as loop diuretics.53 However, this effect appears to be variable even within the same drug class. For instance, the rate of absorption of oral furosemide is delayed in the presence of gut edema, but this phenomenon is not observed with torsemide and bumetanide.54
Involvement of the Liver in HF
Chronic HF can result in a congestive hepatopathy, which is related to a chronically congested liver and generally is not directly related to alterations in cardiac output. Congestive hepatopathy is the most common cause of liver dysfunction in HF, more common than reduced cardiac output. In HF, elevated central venous pressure is transmitted to the sinusoidal bed without any significant attenuation owing to a lack of hepatic venous valves. Sinusoids are small endothelium-lined capillaries in the liver that have open pores, which greatly increase the permeability of the liver.55 Elevated venous pressures can hence cause sinusoidal congestion, resulting in peri-sinusoidal edema, which decreases oxygen diffusion to the hepatocytes. Sinusoidal congestion can also cause exudation of protein-rich fluid into the space of Disse. Excess fluid in the space of Disse is usually drained into hepatic lymphatics, but when the lymph formation exceeds the capacity of the lymphatics, high-protein fluid may ooze from the surface of the liver and drain into the peritoneal cavity. This phenomenon causes high-protein-concentration ascites (typically >2.5 g/dL) and distinguishes cardiac ascites from other types. The relatively high concentration of protein in patients with cardiac ascites could be caused by the relatively modest elevations of portal pressure in patients with cardiac ascites compared with liver cirrhosis or lower protein levels in patients with intrinsic cirrhosis (caused by more compromised synthetic function) than patients with cardiac ascites.56 Persistent congestion over years can further compromise oxygen supply, leading to fibrosis. Fibrosis is a wound-healing response to chronic liver injury and can result in cirrhosis if left untreated.57 Chronic intrahepatic venous stasis can also predispose to intrahepatic thrombi, which can accelerate fibrosis and eventually lead to cirrhosis.58 The various patterns of liver involvement in HF are mentioned in Table 1.
| Condition | Pathophysiology | LFTs | Other Testing | Reversible? |
|---|---|---|---|---|
| Congestive hepatopathy | Right-sided heart volume overload | Modest increase | Rarely required | Yes |
| Hepatic fibrosis | Prolonged congestion (usually years) with wound-healing response | Modest increase | HVPGLiver biopsyLiver-spleen scan | Maybe |
| Hepatic cirrhosis | End-stage fibrosis with liver synthetic dysfunction and portal hypertension | Modest increase | HVPGLiver biopsyLiver- spleen scan | No |
| Ischemic hepatitis | Acute hypotension and more likely with decrease in cardiac output and concomitant congestion | Dramatic elevation | Rarely required | Usually |
Clinical Manifestations
Most reports of the hepatic complications of HF date back to an era before heart transplantation and mechanical circulatory support. However, involvement of the liver in HF is a contemporary independent predictor of poor prognosis.59 In patients with HF with preserved ejection fraction, right ventricular dysfunction is common and may develop from contractile impairment and afterload mismatch from pulmonary hypertension, which can lead to liver dysfunction.60 Progression to liver cirrhosis can in turn lead to intrinsic changes in myocardial structure and function, often described as cirrhotic cardiomyopathy, indicating a vicious cycle of a cause-effect relationship.61
The most common symptom of hepatic involvement of HF is abdominal discomfort, often localized to the right upper quadrant. In the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial, 8% of hospitalized HF patients had abdominal discomfort as their chief complaint. Nausea, early satiety, and weight loss may also be present. Physical examination findings include hepatic enlargement, ascites, jaundice, and signs of portal hypertension. In a large case series of 175 patients in acute and chronic HF, hepatomegaly was present in 90% to 95%, ascites in 17% to 25%, and splenomegaly in 7% to 20%.62
However, liver dysfunction in HF is usually asymptomatic and generally discovered on routine biochemical testing. Hepatic laboratory abnormalities most commonly demonstrate cholestasis, are related to elevations in right atrial pressure and severe tricuspid regurgitation, and correlate with increased serum natriuretic peptide levels. Chronic passive congestion can also impair hepatic synthetic function, leading to prolonged prothrombin time and hypoalbuminemia. Allen et al63 reviewed liver function tests of 2679 patients with symptomatic chronic HF from the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity Program (CHARM) study and found that the most common liver function test abnormalities were low albumin (18.3%), elevated alkaline phosphatase (14.0%), and elevated total bilirubin (13.0%). Alanine aminotransferase and aspartate aminotransferase were less commonly abnormal in these patients. Allen et al also noticed that in the CHARM study elevated total bilirubin was one of the strongest independent predictors of poor prognosis. The outcome of patients with congestive hepatopathy is directly related to the severity of the underlying heart disease. Effective treatment of HF can even reverse early histological changes of passive hepatic congestion.64
Ischemic hepatitis refers to diffuse hepatic injury from a sudden drop in cardiac output or perfusion pressure and may be more likely in the presence of hepatic congestion. Seeto et al65 noted that patients with traumatic hemorrhagic shock did not develop ischemic hepatitis. In contrast, those patients who developed ischemic hepatitis had high filling pressures in addition to low cardiac output. These findings indicate that ischemic hepatitis is more likely a consequence of both hepatic congestion and a low cardiac output.66
From a laboratory perspective, ischemic hepatitis is characterized by rapid increases in serum aminotransferases and lactate dehydrogenase, often to dramatic levels. The aminotransferases peak ≈1 to 3 days after the hemodynamic insult and can rise to 250 times the upper limit of normal. These laboratory values usually return to normal within 7 to 10 days in the absence of any further hemodynamic insult. Serum bilirubin levels rarely rise to >4 times the upper limit of normal, and serum alkaline phosphatase is usually within 2 times the upper limit of normal.67 Ischemic hepatitis generally has a benign and self-limited course, but under rare circumstances, fulminant hepatic failure can occur.68 Management involves restoration of cardiac output and blood pressure while reducing central venous pressure because there is no specific therapy for ischemic hepatitis.
Assessment of Hepatic Status in HF
In advanced HF, the degree of hepatic dysfunction should be quantified because cardiac surgery outcomes are poor in patients with cirrhosis; mortality in Child class C cirrhosis exceeds 50%. Laboratory abnormalities suggestive of synthetic dysfunction are particularly worrisome and should be aggressively investigated.69,70 Evidence for portal hypertension by noninvasive means, for example, liver-spleen scans or abdominal ultrasound, suggests advanced liver disease but lacks sensitivity for significant hepatic dysfunction, for example, fibrosis. Transjugular intrahepatic liver biopsy can be performed safely in patients with advanced HF. Histological fibrosis is common and may affect the decision to proceed with advanced therapies71 (Figure 4). Hepatic venous pressure measurement can be performed along with transjugular liver biopsy and is currently the method of choice for measurement of portal venous pressure. Normal portal pressure ranges from 7 to 12 mm Hg, and the pressure gradient between portal and hepatic veins ranges from 1 to 4 mm Hg. Wedged hepatic venous pressure has been found to closely correlate with the portal pressure.72,73 A catheter is introduced through the jugular vein to the hepatic vein and is advanced until it can go no farther. The pressure measurements are then taken in the free and wedged positions. The difference between the wedge and free pressures gives the hepatic venous pressure gradient (HVPG), which is the pressure difference between the portal and inferior vena cava pressures. The sensitivity and specificity of HVPG >6 mm Hg for predicting stage 1 compensative liver cirrhosis are 78% and 81%, respectively.74 Myers et al75 measured HVPG in 83 patients with cardiac hepatopathy and noticed that HVPG was normal in 81% of these patients. The HVPG therefore allows the clinician to evaluate the cause of ascites when present in HF. If the HVPG is low, then ascites is likely attributable to passive hepatic congestion without cirrhosis from elevated right-sided pressures. If the HVPG is >6 mm Hg with an elevated inferior vena cava pressure, cirrhosis and concomitant portal hypertension are likely present.
Figure 4. Assessment of patients with cardiac cirrhosis being considered for advanced heart failure therapies. ALT indicates alanine transaminase; AST, aspartate transaminase; CABG, coronary artery bypass surgery; PT, prothrombin time; TR, tricuspid regurgitation; and VAD, ventricular assist device. Adapted from Gelow et al.71
The Model for End Stage Liver Disease (MELD) score has also been used in a similar fashion to risk stratify patients with advanced HF and to predict outcomes of HF patients undergoing left ventricular assist device implantations and heart transplantations. Kim et al76 used the MELD score and its modifications, MELD-Na (includes serum sodium) and MELD-X1 (excludes international normalized ratio in patients who are receiving oral anticoagulation), to assess their usefulness as a prognostic tool in ambulatory HF patients with evidence of liver dysfunction. In patients who were not receiving anticoagulation, the MELD and MELD-Na scores were good predictors of death, heart transplantation, or left ventricular assist device implantation at 1 year.
Outcomes When Hepatic Dysfunction Complicates HF
While preexisting severe liver dysfunction is associated with poor outcomes after left ventricular assist device implantation, patients with mild liver function test derangement improve their liver function.77 A retrospective analysis (baseline liver function tests: mean gamma glutamyl transpeptidase, 165 U/L; mean alkaline phosphatase, 121 U/L; mean bilirubin, 2 mg/dL; mean lactate dehydrogenase, 338 U/L; mean aspartate transaminase, 39 U/L; and mean alanine transaminase, 29 U/L) demonstrated improvements in gamma glutamyl transpeptidase, alkaline phosphatase, and bilirubin levels within 3 months, whereas transaminases and lactate dehydrogenase took 12 months to normalize after heart transplantation. This difference in time course was probably related to the shift of fluid from the intrathoracic compartment to the systemic circulation, contributing to an increase in effective circulating volume and thereby increasing blood flow to the liver. Of note, patients with severe liver disease were excluded from these studies.78 High postoperative mortality and morbidity were observed in patients with established cirrhosis who underwent advanced HF therapies. Improved risk stratification and selection of patients with liver function test abnormalities are critical for optimal outcomes after left ventricular assist device implantation and heart transplantation.
Alteration in the Pharmacokinetics and Pharmacodynamics of HF Drugs as a Result of Cardiac Cirrhosis
Liver dysfunction in HF may alter the pharmacokinetics and pharmacodynamics of HF drugs. In general, hydrophilic β-blockers are excreted unchanged by the kidneys, and lipophilic β-blockers are largely metabolized by the liver (Table 2).79Figure 5 shows the route of elimination of various β-blockers used in HF. The majority of angiotensin-converting enzyme inhibitors (except fosinopril) are excreted by the kidneys; hence, drug toxicity is not a major concern in patients with liver dysfunction. However, some angiotensin-converting enzyme inhibitors (eg, enalapril, ramipril) are prodrugs that must be converted to an active metabolite in the liver by esterification.81 However, there are few clinical data on the use of such angiotensin-converting enzyme inhibitors in patients with HF complicated by liver disease. The use of aldosterone antagonists82 has been well established in patients with liver cirrhosis, although there is a limited evidence base of their use when there is concomitant HF. Ivabradine, an If current inhibitor recently approved by US Food and Drug Administration for the management of HF with reduced ejection fraction, is contraindicated in patients with severe hepatic insufficiency.83 The commonly used HF drugs that have hepatic clearance are listed in Table 2.
| Drugs | Clearance |
|---|---|
| β-Blockers | |
| Carvedilol | Liver |
| Metoprolol succinate | Liver |
| Bisoprolol | Liver, kidney |
| Nebivolol | Liver, kidney |
| Angiotensin-converting enzyme inhibitors | |
| Trandolapril | Liver, kidney |
| Fosinopril | Liver, kidney |
| Angiotensin receptor blockers | |
| Losartan | Predominantly liver (90%) |
| Candesartan | Liver, kidney |
Figure 5. Route of elimination of β-blockers used in heart failure. Adapted with permission from Opie and Gersh.80 Copyright © 2013, Elsevier. Authorization for this adaptation has been obtained both from the owner of the copyright in the original work and from the owner of copyright in the translation or adaptation
Conclusions
There is convincing evidence that involvement of the gastrointestinal system and liver in HF is independently associated with poor outcome. Recognizing the clinical and pathophysiological importance of gastrointestinal symptoms should be part of the routine evaluation of HF. When possible, gastrointestinal function should be optimized in HF through improved hemodynamics and guideline-directed HF management. Other therapeutic modalities directed at gastrointestinal and hepatic function in HF such as alterations of gut flora, nutritional supplements, and ghrelin in cardiac cachexia remain to be further explored. As advanced therapeutic options grow for patients with end-stage HF, a thorough understanding of the impact of gastrointestinal and liver complications of HF is increasingly important.
Disclosures
None.
Footnotes
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