Liver disease in the survivor with congenital heart disease

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Abbreviations

CHD

congenital heart disease.

The genesis, diagnosis/management, and impact of liver disease in survivors of congenital heart disease (CHD) are diverse in many respects. Liver disease in this population may be a primary part of an underlying genetic disorder (eg, Alagille syndrome); the result of epiphenomena of cardiac disease (ie, transfusion‐associated viral hepatitis); or, most commonly, it may arise as the direct result of cardiac dysfunction (ie, cardiac cirrhosis).1 The management and clinical impact depend on the genesis and may range from medical to surgical options, ultimately including liver and/or heart transplantation. This brief discussion will focus on the type, diagnostic modalities/management, and impact of liver disease that arises as a direct consequence of CHD.

The American Heart Association estimates that congenital heart defects (ranging from mild to severe) occur in nine of 1000 births, with 36,000 affected infants born annually and 1.3 million individuals living with CHD in the United States.1, 2 Causes of the defects are largely unknown, although genetic defects have increasingly been identified, as well as possible environmental factors.2

Hepatic injury from complex CHD results from one or more of three different types of cardiac dysfunction. Cardiac disease may result in hypoxia, hypoperfusion, or congestion of the liver; these injuries may occur in isolation or in combination.1 Hypoxemia is common in children with complex CHD and is generally well tolerated by the liver, especially if perfusion is maintained. Profound cyanosis will likely lead to cardiac intervention, due to the negative impact on other systems, before there is significant hepatic injury; and the diagnosis is generally detected as a result of extrahepatic manifestations. Poor perfusion is perhaps better tolerated in the liver than in other end organs but has greater impact than hypoxia alone. Again, states of poor cardiac output that result in perfusional compromise will generally come to attention because of systemic symptoms that include fatigue, exercise intolerance, or more sensitive end‐organ compromise such as renal insufficiency (with hepatic manifestations noted as incidental increase in serum transaminases and/or bilirubin rather than presenting sign). Poor cardiac output may precipitate a classic acute hepatitis with rise in enzymes, jaundice, and even encephalopathy.

Finally, congestion can cause significant liver injury, but it is often insidious, causing gradual changes over years or decades prior to clinical presentation.3 Performed most commonly for the management of single ventricle syndromes and related CHD, the term Fontan procedure is used for a variety of procedures that divert systemic venous return to the pulmonary artery without an intervening ventricle (Fig. 1; see also imaging in Khanna et al. ⁴).1, 3, 4, 5, 6, 7 The procedure has been performed in increasing numbers since its introduction over 40 years ago, resulting in a growing cohort of pediatric and young adult survivors.1, 3, 5, 6 Fontan circulation produces physiology very likely to cause hepatic congestion, with the paradoxical situation of venous hypertension accompanied by pulmonary arterial hypotension.1, 3 Hepatic venous pressures are often three to four times normal, equivalent to that seen in congestive heart failure in adults but present (without systemic hypoperfusion) over a much longer term. Of particular interest to hepatologists, esophageal varices are uncommon in Fontan physiology because of the absence of pressure gradient from the portal vein to the neo‐right heart/Fontan circuit (both are elevated to a similar degree). Although Fontan physiology has become increasingly recognized as a major cause of congestive hepatopathy, a variety of defects have similar impact, including restrictive right atrial disease (which may follow atrial septal defect repair), as well as tetralogy of Fallot and repair of d‐transposition of the great vessels.7 Again, improved survival has resulted in recognition of late right heart failure, producing similar pathobiology and extracardiac consequences.8 Clinical signs of congestive hepatopathy in the setting of acceptable cardiac output are minimal, with mildly increased international normalized ratio (often obscured by anticoagulation therapy), trivial elevations of transaminases, and low platelet count.3 The cause of the thrombocytopenia is uncertain because splenomegaly/sequestration is not evident. In the absence of proactive screening, congestive liver disease is often undetected until after fibrosis or cirrhosis has been established. Once cirrhosis is established, clinical presentations may include acute decompensation at the time of cardiac surgery, pregnancy, or intercurrent infection—or the development of hepatocellular carcinoma.3, 9 It is desirable to identify individuals with early fibrosis in order to attempt cardiac interventions to alleviate hepatic congestion (eg, pulmonary arterial dilating agents or treatment of pulmonary arterial stenosis), but identification of early stages of fibrosis is difficult. At our center, screening by percutaneous liver biopsy is performed approximately 10 years after completion of Fontan procedure because noninvasive modalities (ie, serologic examination, ultrasound, elastography, etc) lack the sensitivity and specificity to detect early fibrosis. It will be important to compare these and newer modalities with biopsy in future prospective studies. Liver biopsy can be combined with cardiac catheterization in many cases, allowing for an opportunity to measure Fontan pressure and perform interventional procedures when indicated. Follow‐up liver biopsies may be necessary to determine the impact of cardiac interventions, keeping in mind that sampling error and atypical patterns of fibrosis may complicate interpretation.

Older children and young adults with CHD, even if clinically well, should be seen annually at a regional center in anticipation of problems ranging from cardiac and other medical specialties (eg, endocrinologic and immunologic, in addition to gastrointestinal) to obstetric, surgical, and psychosocial.10, 11 Largely unknown is the impact of adult cardiac stressors (ie, obesity and hypertension) in this population.12 Issues related to transition to adult providers and adherence are common, as they are for other young and adult survivors of chronic disease, and these are complicated by the lack of adult cardiology practitioners in CHD—both in cardiology and in cardiac surgery.10

In summary, complex CHD may have significant hepatic consequences through a variety of mechanisms. Cardiologists and hepatologists must collaborate in the evaluation and management of these problems, particularly when liver injury is the direct effect of the cardiac physiology.

Figure 1.

(A) This depicts an anastomosis between the superior vena cava and the right pulmonary artery (bidirectional cavopulmonary shunt). Blood from the inferior vena cava is baffled to the lungs by means of a patch to the pulmonary artery. The main pulmonary artery is ligated to avoid competitive flow from the ventricle. (B) Fontan with an intraatrial conduit (Gore‐Tex) baffling blood from the inferior vena cava through the right atrium to the pulmonary artery. A bidirectional cavopulmonary shunt carries blood from the superior vena cava to the pulmonary artery. (C) Extracardiac fontan. Cavopulmonary extracardiac conduit from the inferior vena cava to right pulmonary artery. The superior vena cava is anastomosed as a bidirectional cavopulmonary anastomosis. IVC, inferior vena cava; PA, pulmonary artery; RA, right atrium; SVC, superior vena cava. Adapted from Arsani et al.¹

Table 1.

Causes of Liver Disease in Patients with CHD

Liver disease associated with underlying disorder:

Alagille syndrome

Syndromic biliary atresia

Trisomy 21

Others

Liver injury due to epiphenomena of treatment:

Transfusion iron overload

Transfusion‐related hepatitis infection

Drug‐induced liver disease

Liver injury as direct result of cardiac disease from any combination of:

Hypoxia/ischemia

Hypoperfusion

Congestion