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).
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.
1. Vollmar B, Menger MD. The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. Physiol Rev
2. Kavoliuniene A, Vaitiekiene A, Cesnaite G. Congestive hepatopathy and hypoxic hepatitis in heart failure: a cardiologist's point of view. Int J Cardiol
3. Vollmar B, Conzen PF, Kerner T, et al Blood flow and tissue oxygen pressures of liver and pancreas in rats: effects of volatile anesthetics and of hemorrhage. Anesth Analg
4. Rappaport AM. Hepatic blood flow: morphologic aspects and physiologic regulation. Int Rev Physiol
5. Campbell KM. Systemic disease and the liver. In: Frederick J, Suchy, William F, eds. Liver Disease in Children
. Fourth ed. New York: Cambridge University Press; 2014:695–6.
6. Fuhrmann V, Jager B, Zubkova A, et al Hypoxic hepatitis—epidemiology, pathophysiology and clinical management. Wien Klin Wochenschr
7. Ford RM, Book W, Spivey JR. Liver disease related to the heart. Transpl Rev
8. Naschitz JE, Slobodin G, Lewis RJ, et al Heart diseases affecting the liver and liver diseases affecting the heart. Am Heart J
9. Giallourakis CC, Rosenberg PM, Friedman LS. The liver in heart failure. Clin Liver Dis
10. Shah SC SD. Cardiac hepatopathy: a review of liver dysfunction in heart failure. Liver Res Open J
11. Alvarez AM, Mukherjee D. Liver abnormalities in cardiac diseases and heart failure. Int J Angiol
12. Louie CY, Pham MX, Daugherty TJ, et al 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
13. Simonetto DA, Yang HY, Yin M, et al Chronic passive venous congestion drives hepatic fibrogenesis via sinusoidal thrombosis and mechanical forces. Hepatology
14. Myers RP, Cerini R, Sayegh R, et al Cardiac hepatopathy: clinical, hemodynamic, and histologic characteristics and correlations. Hepatology
15. Luna A, Meister HP, Szanto PB. Esophageal varices in the absence of cirrhosis, Incidence and characteristics in congestive heart failure and neoplasm of the liver. Am J Clin Pathol
16. Ho SS, Brown R, Fitzgibbon B. Hepatocellular carcinoma with cardiac cirrhosis. Med J Aus
17. Saliba T, Dorkhom S, O’Reilly EM, et al Hepatocellular carcinoma in two patients with cardiac cirrhosis. Eur J Gastroenterol Hepatol
18. McMurray JJ, Adamopoulos S, Anker SD, et al ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: the Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail
19. Frazier OH, Rose EA, Oz MC, et al Multicenter clinical evaluation of the HeartMate vented electric left ventricular assist system in patients awaiting heart transplantation. J Thorac Cardiovasc Surg
20. Crespo-Leiro MG, Robles O, Paniagua MJ, et al Reversal of cardiac cirrhosis following orthotopic heart transplantation. Am J Transplant
21. Careddu L, Zanfi C, Pantaleo A, et al Combined heart-liver transplantation: a single-center experience. Transp Int
22. Reich HJ, Awad M, Ruzza A, et al Combined heart and liver transplantation: the Cedars-Sinai Experience. Transp Proc
23. Ofei SY, Gariepy C, Hanje J, et al Liver fibrosis in adults with Fontan palliation: do common screening studies predict disease severity? Int J Cardiol
24. Schwartz MC, Sullivan L, Cohen MS, et al Hepatic pathology may develop before the Fontan operation in children with functional single ventricle: an autopsy study. J Thorac Cardiovasc Surg
25. Kiesewetter CH, Sheron N, Vettukattill JJ, et al Hepatic changes in the failing Fontan circulation. Heart
26. Schwartz MC, Sullivan LM, Glatz AC, et al Portal and sinusoidal fibrosis are common on liver biopsy after Fontan surgery. Pediatr Cardiol
27. Friedrich-Rust M, Koch C, Rentzsch A, et al Noninvasive assessment of liver fibrosis in patients with Fontan circulation using transient elastography and biochemical fibrosis markers. J Thorac Cardiovasc Surg
28. Lindsay I, Johnson J, Everitt MD, et al Impact of liver disease after the Fontan operation. Am J Cardiol
29. Furukawa T, Akimoto K, Ohtsuki M, et al Non-invasive assessment of liver fibrosis in patients after the Fontan operation. Pediatr Int
30. Ginde S, Hohenwalter MD, Foley WD, et al Noninvasive assessment of liver fibrosis in adult patients following the Fontan procedure. Congen Heart Dis
31. Poterucha JT, Johnson JN, Qureshi MY, et al Magnetic resonance elastography: a novel technique for the detection of hepatic fibrosis and hepatocellular carcinoma after the Fontan operation. Mayo Clin Proc
32. Greenway SC, Crossland DS, Hudson M, et al Fontan-associated liver disease: implications for heart transplantation. J Heart Lung Transplant
33. Shim da J, Yi CK, Kim YM. Passive hepatic congestion: findings of two-dimensional, Doppler and acoustic radiation force impulse imaging. Eur Society of Radiology
2012; [Epub ahead of print].
34. Agnoletti G, Ferraro G, Bordese R, et al Fontan circulation causes early, severe liver damage. Should we offer patients a tailored strategy? Int J Cardiol
35. Ghaferi AA, Hutchins GM. Progression of liver pathology in patients undergoing the Fontan procedure: chronic passive congestion, cardiac cirrhosis, hepatic adenoma, and hepatocellular carcinoma. J Thorac Cardiovasc Surg
36. Wu FM, Jonas MM, Opotowsky AR, et al Portal and centrilobular hepatic fibrosis in Fontan circulation and clinical outcomes. J Heart Lung Transplant
37. Atluri P, Gaffey A, Howard J, et al Combined heart and liver transplantation can be safely performed with excellent short- and long-term results. Ann Thorac Surg
38. Raichlin E, Daly RC, Rosen CB, et al Combined heart and liver transplantation: a single-center experience. Transplantation
39. Hill AL, Maeda K, Bonham CA, et al Pediatric combined heart-liver transplantation performed en bloc: a single-center experience. Pediatr Transplant
40. Vallabhajosyula P, Komlo C, Wallen TJ, et al Combined heart-liver transplant in a situs-ambiguous patient with failed Fontan physiology. J Thorac Cardiovasc Surg
41. Hollander SA, Reinhartz O, Maeda K, et al Intermediate-term outcomes after combined heart-liver transplantation in children with a univentricular heart. J Heart Lung Transplant
42. Bradley E, Hendrickson B, Daniels C. Fontan liver disease: review of an emerging epidemic and management options. Curr Treat Options Cardiovasc Med