What Is Known
- Right-sided heart dysfunction results in passive congestion and poor cardiac output.
- Fontan patients experience congestive hepatopathy.
- More children born with palliative single-ventricle anatomy are surviving into adulthood.
What Is New
- Mouse models demonstrate histologic findings of congestive hepatopathy consistent with human disease.
- Intrahepatic thrombus formation plays a role in fibrosis formation in congestive hepatopathy.
- Liver cirrhosis is being commonly identified in teens and young adults with Fontan circulation.
- Research is ongoing to determine the optimal way to screen individuals with palliative single-ventricle anatomy for liver disease.
The liver receives 25% of total cardiac output in a normal individual and is very sensitive to hemodynamic compromise (1–4). Thirty percent of hepatic blood flow is oxygenated blood under high pressure from the right and left hepatic arteries. The remaining 70% of blood flow is partially deoxygenated blood under low pressure, low resistance from the portal vein (1,2,5). Because of its high flow rate, the liver normally receives >50% of its oxygen requirements from the portal vein. The microvascular tone of the liver is controlled by a complex interaction of relaxing and vasoconstricting factors. Imbalance between these factors results in microcirculatory-associated liver injury. The liver's role in regulating the level of blood nutrients and hormones appears to take precedence over maintaining arterial blood. Unique to the liver, decreased arterial oxygen content is compensated by increasing oxygen extraction with maintenance in blood flow and hepatic clearance, instead of increased arterial blood flow (6). Liver complications of chronic cardiovascular disease are becoming more common in children and young adults with the increased number of patients surviving into adulthood. This article reviews liver disease secondary to chronic cardiac dysfunction and recent research regarding its pathogenesis.
CONGESTIVE HEPATOPATHY AND CARDIAC CIRRHOSIS
Congestive hepatopathy (CH) results from chronic right heart dysfunction with decreased hepatic blood flow, arterial saturation, and increased central venous pressure (CVP) transmitted to hepatic vessels (7,8). Under normal physiologic conditions, blood flows through the sinusoids under low hydrostatic pressure. Elevated CVP leads to chronic passive congestion and increased hydrostatic pressure across the sinusoid leading to dilation, edema, and hemorrhage. When circulatory dysfunction persists, compensatory mechanisms to extract oxygen fail and hypoxic injury to hepatocytes may occur (2,7,9). Grossly, CH results in the classic “nutmeg” appearance of the liver (10) (Fig. 1), with necrosis affecting primarily zone 3 hepatocytes (2,7,8,11). Large histopathologic studies on both autopsy and living patients demonstrate that chronic CH frequently leads to hepatic fibrosis and cirrhosis (cardiac cirrhosis [CC]) (12). Unlike other causes of cirrhosis, CC occurs in the absence of significant inflammation with fibrous septa forming between central veins and sparing portal tracts, known as reverse lobulation (Fig. 2). This pattern is due to damage starting in zone 3 and radiating from the central vein, whereas damage in most primary liver diseases is focused on zone 1. Simonetto et al (13) recently developed a mouse model of CH through partial ligation of the suprahepatic inferior vena cava. Six weeks after surgery, marked increase in hepatic collagen in centrilobular and perisinusoidal distribution was noted, consistent with findings in humans with CH. Also consistent with human CH, the mice had normal transaminases and bilirubin, and no histologic evidence of inflammation. Interestingly, treatment with warfarin after the ligation reduced intrahepatic fibrin, implicating thrombus formation in the production of fibrosis in CH. Fibrin stimulates hepatic stellate cells to form a fibronectin network in vitro and may be the basis for the collagen-based hepatic fibrosis (13). The availability of an animal model will allow for development of new treatment strategies.
Symptoms of CH are vague, including mild right upper quadrant abdominal pain, nausea, vomiting, early satiety, anorexia, malaise, and mild jaundice (2,7). Signs of right heart failure will be present as will be elevated serum markers of cholestasis: alkaline phosphatase, γ-glutamyl transferase (GGT), and very mild increase in total and direct bilirubin (2). Transaminases are normal or mildly elevated. Splenomegaly is unusual in CH and varices are rare (9,14). This is thought to be the result of the general increase in systemic venous pressures reducing the pressure gradient between the portal and venous system that promotes varix formation (14,15). Even with the development of CC, portosystemic shunts are relatively rare in CC compared with other causes of cirrhosis (7,9). Approximately 25% of CH patients develop ascites with higher lactate dehydrogenase levels, higher total protein (>2.5 g/dL), higher serum ascites-albumin gradient (>1.1 g/dL), and higher red blood cell counts than ascites in other forms of liver disease (7–9). Associated complications of CC include hepatocellular carcinoma (HCC), thus warranting regular surveillance (16,17).
Guidelines and expert consensus based on data from adult studies favor the use of loop diuretics in patients with jaundice, hepatic congestion, and ascites but caution against hypotension, dehydration and secondary hepatic ischemia (11,18). Transjugular portosystemic shunts are contraindicated in CC because increased blood from the portal system to the right heart can worsen heart failure. Left ventricular assist devices and cardiac transplantation may be considered in patients who are unresponsive to medical management and can lead to reversal of congestive liver injury (2,10). Frazier et al (19) reported improved cardiac function and low incidence of adverse effects in patients awaiting heart transplant in their study using HeartMate vented electric left ventricular assist system (Thoratec Corporation, Pleasanton, CA). Combined heart and liver transplant (CHLT) may be considered in patients with established cirrhosis, although CC may be reversed with isolated cardiac transplantation as reported in the case study by Crespo-Leiro et al (20). The underlying mechanism is reported to involve imbalance of fibrogenesis and regression of fibrin (20). Reversal of the inciting cause of liver disease has led to regression of cirrhosis and has been observed in animal models (20). Survival rates for CHLT are 83% to 100% at 1 year and 75% to 83% at 5 years (21,22).
CONGENITAL HEART DISEASE: FONTAN-ASSOCIATED LIVER DISEASE
Fontan-associated liver disease (FALD) is a severe complication of single ventricle (SV) physiology after Fontan operation (23) (Fig. 3). SV cardiac disease is congenital with elevated venous pressures that are sustained. The Fontan procedure results in the absence of a subpulmonic pump, so back-pressure on the liver is continuous. Patients develop pulmonary veno-venous collateral that worsens hypoxia (7). These factors appear to lead to more rapid and severe FALD with overt hepatic abnormalities developing in patients by their late teens or early twenties. Schwartz et al (24) reported liver biopsies from 13 children and young adults who had undergone the Fontan procedure. They identified stage 4 (Modified Scheuer) fibrosis in a 14-year-old child (12 years after Fontan) and stage 3 fibrosis in most of the children, the youngest being 8.6 years old (6.9 years after Fontan). Although sinusoidal fibrosis is characteristic of CH, patients with FALD demonstrate a mixed histopathologic pattern of sinusoidal and portal fibrosis. As in CH, inflammation is generally absent. Portal fibrosis may be related to pre-Fontan hepatic injury as it has been reported in children who died within 1 month of the Fontan surgery. FALD affects the liver more homogeneously than CH and CC. Kiesewetter et al (25) hypothesized that exposure of the sinusoids to increased CVP, increased portal venous circulation, and depressed cardiac output, leads to the ideal conditions for hepatocyte hypoxia, congestion, and progression of the fibrotic response. There is a positive correlation between the degree of hepatic fibrosis and time since Fontan surgery, but no clear association exists between the degree of hepatic fibrosis and other demographic, anatomic, surgical, and hemodynamic variables (26). The correlation between fibrosis stage and interval since Fontan has also been described by Friedrich-Rust et al (27), with significant increase in liver fibrosis at 5 years from Fontan.
Patients are usually asymptomatic from their liver disease. Correlation between liver enzyme abnormalities and extent of fibrosis is unreliable (23,28,29). FibroSure (LabCorp, Burlington, NC), a patented biomarker of 6 panel serologic markers (haptoglobin, apolipoprotein A1, bilirubin, GGT, alanine transaminase [ALT], and α-2 macroglobulin) was shown by Ginde et al (30) to be a reliable marker of fibrotic appearing liver on computed tomography (CT) in adult Fontan patients. The length of time since Fontan correlated with elevated FibroSure score (P = 0.05) (30). Magnetic resonance (MR) elastography is useful in detecting hepatic fibrosis, cirrhosis, and HCC in adults as shown by Poterucha et al (31) in their evaluation of 50 patients 21 to 33 years of age. Our institutional retrospective review of adult Fontan patients confirmed hepatic fibrosis or cirrhosis on biopsy but found that noninvasive modalities such as CT, MRI, ultrasound, and FibroSure did not accurately predict the degree of fibrosis (23). MR elastography and ultrasound elastography techniques including transient elastography (TE), shear wave elastography, and acoustic radiation force impulse are being investigated in the population as modalities to noninvasively quantify fibrosis (32). However, passive congestion increases shear wave velocity limiting the usefulness of this test (33). Agnoletti et al (34) recently reviewed the outcomes of 64 patients 1 to 15 years since Fontan and found that liver TE increased rapidly during the first 5 years after Fontan, then relatively stabilized. The overall incidence of established liver cirrhosis was 22% and that of esophageal varices was 0.9% in this cohort. As in CH, patients with FALD are at increased risk of HCC, and the risk increases with time since the Fontan operation. Ghaferi and Hutchins (35) reported 1 patient (24 years of age and 18 years from Fontan) with HCC in their review of 9 autopsy patients. Screening for HCC in FALD patients is recommended (35).
The management implications of FALD are not fully understood. Currently, management centers on regular surveillance for FALD (36). There is no consensus regarding care for FALD, but diagnosis usually prompts evaluation of cardiac systolic function and treatment of hemodynamic abnormalities as appropriate. Individuals with FALD should also be evaluated and treated for complications of liver disease such as varices, coagulopathy, and nutritional deficiencies. CHLT is considered in patients with ascites, hepatic encephalopathy, variceal hemorrhage, or hepatocellular dysfunction resulting in a model for end-stage liver disease score of ≥15. Small studies (N ranging 1–6) have shown good outcomes for CHLT (37–41). With reports that liver fibrosis and even cirrhosis may be reversible following cardiac transplantation, the decision between CHLT and isolated heart transplant is difficult with little data for guidance (32). Greenway et al (32) propose that those with low model for end-stage liver disease score, <12 should be considered for isolated cardiac transplantation and those with more advanced liver disease should be considered for CHLT. Management issues in FALD were recently comprehensively reviewed by Bradley et al (42). Improving knowledge through collaborative efforts will help to improve screening and management efforts.
The spectrum of cardiovascular liver disease is expanding with prolonged survival of children with chronic heart disease. With advancements in the management of congenital heart disease (CHD), ∼85% of children with CHD are surviving into adulthood with ∼1 million adult patients with CHD in the United States (40). Long-term risks and complications warrant comprehensive, integrated care by cardiologists and hepatologists. Prospective studies will establish rate of progression of liver injury and allow for the development of interventions.
The authors thank the following at Nationwide Children's Hospital: Desale Yacob, MD, Division of Gastroenterology, Hepatology and Nutrition for his original artwork and depiction of the Fontan operation; Carol Potter, MD, Division of Gastroenterology, Hepatology and Nutrition, for her review and helpful discussion; Bonita Fung, Division of Pathology for submission of pathology slides.
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