Hepatic dysfunction

Over the past 5–10 years, as focus has shifted from short-term survival to long-term survival and quality of life, a number of studies have emerged that describe the impact of the physiology of the Fontan on the liver. By definition, hepatic venous pressure after the Fontan may be three to four times higher than normal, similar to what may be found in adults with congestive heart failure. The implications of this elevated hepatic venous pressure over the long term are not yet well described, but a limited series of autopsy and biopsy studies have shown hepatic congestion, dilated biliary ducts, hepatic fibrosis, and hepatic cirrhosis.Reference Ghaferi and Hutchins^5–Reference Kendall, Stedman and Hacking⁸ Despite the possibility of these findings being mild immediately after the Fontan operation, evidence exists to suggest a correlation in the degree of abnormal hepatic pathology with time from the Fontan, with cardiac output, and with central venous pressure.Reference Ghaferi and Hutchins^5–Reference Camposilvan, Milanesi, Stellin, Pettenazzo, Zancan and D’Antiga⁷

In addition to hepatic congestion and hepatic fibrosis, there are rare reports of hepatic neoplasm late after the Fontan. Hepatocellular carcinoma and hepatic adenomas have both been described and are thought to result from chronic passive hepatic congestion.Reference Saliba, Dorkhom, O’Reilly, Ludwig, Gansukh and Abou-Alfa^9, Reference Babaoglu, Binnetoglu and Aydogan¹⁰ In one published pathological case, the rupture of a hepatic adenoma led to significant loss of blood and ultimately to the demise of the patient. Despite there being no data about the relative risk of neoplastic transformation following the Fontan operation, the case reports certainly indicate that while rare, the risk of neoplasm is most likely higher than in the general population, and may be associated with the duration of hepatic congestion and degree of hepatic fibrosis and cirrhosis.

The risk of hepatic fibrosis, cirrhosis, and hepatic neoplasm suggests a role for routine hepatic screening. Unfortunately, no current screen has shown utility in this population. A number of screens combining serum markers are suggested for inflammatory disease of the liver, though the applicability of these tests to the unique circulation of the Fontan is unknown.Reference Zhou, Gao and Zhao^11–Reference Cales, Oberti and Michalak¹³ Similarly, evaluation of the liver using transient elastography (Fibroscan) is of significant benefit in patients with hepatic dysfunction associated with hepatitis, but may not be an appropriate test in the setting of congestive heart failure or elevated central venous pressures, a condition that is always present following the Fontan.Reference Lebray, Varnous, Charlotte, Varaut, Poynard and Ratziu^14–Reference Millonig, Friedrich and Adolf¹⁶ Without accurate non-invasive tests or tests of serum to evaluate hepatic function and architecture, biopsy of the liver remains the gold standard. Despite the reported mortality with biopsy being low, the potential for morbidity exists,Reference Jarcuska, Janicko, Veseliny and Skladany¹⁷ a potential that might be higher in children who are unwell following palliation for functionally univentricular heart. For now, ultrasonographic assessmentReference Goyal, Jain, Rachapalli, Cochlin and Robinson¹⁸ of the architecture of the liver, or serial magnetic resonance imaging,Reference Huwart, Sempoux and Vicaut¹⁹ may be the most appropriate as baseline testing, with more invasive testing being reserved for those in whom the suspicion of significant abnormalities of the liver is highest.

Unfortunately, even when diagnosed, no direct therapy exists for the elevated hepatic pressure of the Fontan circulation. The elevation is a direct result of the basic physiology following the Fontan operation, and nothing short of a new strategy for treatment of patients with functionally univentricular hearts is likely to have a profound impact. Nevertheless, the potential exists to have at least a modest impact on hepatic pressure through the development of strategies to lower pulmonary arterial pressure. Certainly, the enlargement or creation of a fenestration may allow for a “pop-off” in the setting of elevated pulmonary arterial pressure and is shown to improve systemic delivery of oxygen.Reference Bridges, Lock, Mayer, Burnett and Castaneda²⁰ Newer medical approaches may also have an impact. In particular, the use of medications traditionally used for the treatment of pulmonary hypertension may lower systemic venous pressure by lowering pulmonary vascular resistance.Reference Reinhardt, Uzun and Bhole^21, Reference Giardini, Balducci, Specchia, Gargiulo, Bonvicini and Picchio²² Limited data exist on these medications following the Fontan operation, and no direct measurements exist of their impact on hepatic pressure. Nevertheless, it is certainly reasonable to believe that phosphodiesterase type 5 inhibitors or therapies with prostacyclin that lower pulmonary vascular resistance through their effect on pulmonary vascular resistance may reduce the degree of hepatic congestion.

Abnormalities of coagulation

Abnormalities in the cascade of coagulation remain a vexing problem after the Fontan operation. The precise mechanism by which children are at increased risk for the formation of thrombus after the Fontan is not known and is likely multi-factorial. Certainly, a number of anatomical and physiological risk factors are inherent in the cardiovascular system after the Fontan operation. However, primary abnormalities also exist in the cascade of coagulation following the Fontan that may further impact the risk of thrombosis.

Of the anatomical and physiological differences in the Fontan circuit, those that are likely to play a role in the increased risk of thrombosis include:

• • diminished cardiac output,

• • abnormal patterns of venous flow,

• • prosthetic material used to create the baffle or conduit,

• • the presence of blind pouches with low flow of blood, such as rudimentary ventricles and over-sewn stumps from the pulmonary artery, and

• • in some children, lack of atrioventricular synchrony.

This group of risk factors is characterised by the presence of low-velocity venous flow and the potential exposure of the factors of clotting to prosthetic material.

Despite the possibility of the anatomical and haemodynamic abnormalities after the Fontan being sufficient to explain an increased incidence of thrombus, a number of abnormalities in the coagulation cascade also exist following the Fontan that may add to the thrombotic risk. Interestingly, studies have shown abnormalities in both pro-thrombotic and anti-thrombotic factors of coagulation, making a comprehensive understanding of how factors of coagulation impact on formation of thrombus difficult.Reference Jahangiri, Kreutzer, Zurakowski, Bacha and Jonas^23, Reference Odegard, McGowan and Zurakowski²⁴ Low levels of protein C, protein S, and antithrombin III are described, which would suggest a hypercoagulable state; meanwhile, deficiencies in numerous factors of coagulation, including factors II, V, VII, VIII, and X, have also been described, which would suggest just the opposite. In an attempt to evaluate the total effect of abnormalities of coagulation on the propensity to form a thrombus, a recent study was performed in which thromboelastography was used in an attempt to determine the net effect of the potential alterations.Reference Raffini, Schwed and Zheng²⁵ Surprisingly, in this prospective cross-sectional study, no difference was found between the profiles of coagulation of 25 children following the Fontan operation and 51 age-matched healthy controls.

Whatever the mechanism, the risk of thrombus and thromboembolism following the Fontan operation appears to be significant. In a review at The Children’s Hospital of Philadelphia, Coon showed a prevalence of thrombus of 8.8% in children after the Fontan as diagnosed by surface echocardiography.Reference Coon, Rychik, Novello, Ro, Gaynor and Spray²⁶ Of the patients with thrombi:

• • 48% were located in the Fontan circuit (on the systemic venous side of the baffle/conduit),

• • 44% were found in the pulmonary venous atrium,

• • one patient had thrombus on both sides of the baffle/conduit,

• • two patients had thrombus in their hypoplastic ventricle, and

• • one had thrombus associated with an over-sewn pulmonary arterial stump.

Despite the high prevalence of thrombus, the rate of cerebral vascular accident, while not negligible, was significantly lower. Overall, 15% of those with thrombi had concomitant cerebral vascular events.

Despite the risk of thromboembolic events being important and warranting clear guidelines, no consensus exists on appropriate prophylactic strategies. Protocols for management vary, but typically include aspirin or warfarin, although some patients may be on no anticoagulation at all. The reason for this lack of uniformity is most likely related to the relative rarity of significant thromboembolic events and the lack of prospective studies comparing different regimens of anticoagulation. There are a few retrospective studies comparing strategies, but all have a very low rate of events. However, in these retrospective reviews, there does not appear to be good evidence to suggest that warfarin is a useful therapy for all patients:

• • In a series of 72 patients started on aspirin on post-operative day 1 following the Fontan, Jacobs et alReference Jacobs, Pourmoghadam and Geary²⁷ found no occurrences of thromboembolic events.

• • Mahnke et alReference Kreutzer, Galindez, Bono, De Palma and Laura² reviewed the data from the Children’s Hospital of Pittsburgh. They reviewed the records of 132 patients with a median follow-up of 7.6 years. In their cohort, they found an event rate for significant cerebrovascular accident of 2.3% with no association between anticoagulation strategy and rate of event.Reference Kendall, Stedman and Hacking⁸

On balance, enough evidence exists to suggest that some form of anti-thrombotic therapy is useful following the Fontan. However, there are no prospective data to suggest whether an anticoagulation strategy that targets the function of platelets, or a more robust strategy that targets the cascade of coagulation, should be used. Given the low frequency of events, the absence of a proven benefit of warfarin, the significant risks associated with using warfarin, and the relative safety of aspirin at low doses, we believe that treatment with aspirin is sufficient for prophylaxis against thrombosis, unless other risk factors are present or there is a history of a significant thromboembolic event.

Protein-losing enteropathy

Protein-losing enteropathy is an enigmatic and troubling complication seen after the Fontan operation.Reference Rychik²⁹ The disorder is primarily characterised by the abnormal loss of elements of protein into the lumen of the gut, resulting in hypoproteinaemia and hypoalbuminaemia. Loss of vascular oncotic pressure leads to the seepage of fluid into the interstitial tissues and the development of peripheral oedema, ascites, pleural effusions, and pericardial effusions. The break in integrity of the enteric mucosal barrier affects a number of bodily homeostatic systems:

• • Loss of albumin leads to abnormalities in the metabolism of calcium.

• • Loss of factors of coagulation further upsets an already abnormal cascade of coagulation.

• • Abnormal flow in lymphatics, as a result of lymphatic engorgement, may lead to lymphopaenia and a relative immunodeficient state.

Enteric loss of protein after the Fontan operation can be a slow and indolent process, or it can occur with fairly rapid onset. Diarrhoea is seen when there is marked long-standing hypoproteinaemia and the development of oedema of the wall of the gut with malabsorption; however, diarrhoea is not present in every case of protein-losing enteropathy. Just as many patients complain of constipation and subtle changes in bowel habits, so do those with frank diarrhoea. The most common presenting scenario is a child complaining of shoes feeling tight or clothes not fitting. In young children, peri-orbital oedema upon awakening is common.

Protein-losing enteropathy after the Fontan operation is believed to occur in anywhere from 3% to 10% of patients.Reference Mertens, Hagler, Sauer, Somerville and Gewillig³⁰ As recognition of the disorder has increased, a variety of patterns of manifestation of disease are noted. Some patients manifest the full spectrum of the disorder and remain chronically hypoalbuminaemic unless intervened upon. Then, some patients manifest transient hypoalbuminaemia, commonly 1–2 weeks following a viral syndrome. Within 4–6 weeks, and without intervention, levels of protein in these patients normalise. This phenomenon also suggests that protein-losing enteropathy after the Fontan operation may occur much more frequently than initially thought, as many of these transient periods of mild oedema may go unnoticed by parents, or be ignored by adolescents and young adults.

The diagnosis is made by the presence of low serum levels of protein or albumin in the absence of any other source for loss of protein. Alpha-1-antitrypsin is a protein produced by the liver that remains intact in the circulation. This protein is normally excreted in the stool, and can therefore be used as a marker for abnormal enteric permeability to protein. An increased 24-hour stool clearance of alpha-1-antitrypsin is the “gold standard” assay for diagnosis of protein-losing enteropathy. An increased spot stool concentration of alpha-1-antitrypsin is also diagnostic of protein-losing enteropathy; however, a low concentration does not rule it out.

The underlying pathophysiological mechanism that results in protein-losing enteropathy is still poorly understood. We have postulated it to be due to the confluence of a number of processes:

• • First and foremost is the pervasive circulatory insufficiency of the Fontan circulation.Reference Rychik³¹ To variable degrees, but in essence in all patients with Fontan physiology, cardiac output is diminished and central venous pressure is increased.Reference Gewillig, Brown and Eyskens³² This state is physiologically similar to a state of chronic low-level congestive heart failure. As a result, gastrointestinal perfusion and delivery of oxygen is diminished. In the presence of low cardiac output, compensatory mechanisms will increase and maintain perfusion to vital organs, shunting blood away from the non-vital mesenteric circulation and further limiting delivery of oxygen delivery to the mucosa of the gut. In support of this notion, we and others have shown increased mesenteric vascular impedance in patients with protein-losing enteropathy after the Fontan operation as measured by Doppler echocardiography.Reference Rychik and Gui-Yang^33, Reference Uzun, Wong, Bhole and Stumper³⁴ We found that patients with protein-losing enteropathy have higher mesenteric vascular impedance than those without protein-losing enteropathy after the Fontan. Both of these groups had higher mesenteric vascular impedance than age-matched normal controls.

• • The second mechanistic process that exists in patients with protein-losing enteropathy after the Fontan operation is that of inflammation. Chronic congestive heart failure is an inflammatory disease that results in an increase in inflammatory markers. We showed the presence of increased inflammatory markers such as tumour necrosis factor alpha after the Fontan operation.Reference Ostrow, Freeze and Rychik³⁵ The phenomenon of new onset protein-losing enteropathy, or a flare of symptoms soon after a viral syndrome, supports the role of inflammation in the pathophysiology.Reference Lenz, Hambsch and Schneider³⁶

Experience with response to various treatments supports these two mechanistic concepts as the foundation of the disease. Manoeuvres that increase cardiac output and lower central venous pressure can improve protein-losing enteropathy. Optimising what is a markedly sub-optimal physiology can help alleviate symptoms. Even those who have haemodynamic data that do not suggest a “failing Fontan”, such as a pulmonary arterial pressure less than 15 millimetres of mercury, may benefit from actions that improve cardiac output and increase perfusion of organs and delivery of oxygen. Therapies such as creating atrioventricular synchrony through pacing when it is absentReference Cohen, Rhodes, Wernovsky, Gaynor, Spray and Rychik³⁷ and creation of a fenestrationReference Mertens, Dumoulin and Gewillig^38, Reference Rychik, Rome and Jacobs³⁹ are reported as successful in improving levels of serum protein. Anti-inflammatory therapies, such as administration of unfractionated heparinReference Donnelly, Rosenthal, Castle and Holmes⁴⁰ or systemic steroids,Reference Rychik, Piccoli and Barber⁴¹ are reported to be helpful in a select few. Table 1 lists potential therapies for protein-losing enteropathy by disease severity.

Table 1 Protein losing enteropathy: categories and therapies

CR = controlled release; MCT = medium chain triglyceride

At our centre, we have begun using a combination of controlled release budesonide, started at 9 milligrams per day and sildenafil 20 milligrams per day, in an attempt to control inflammation and to improve haemodynamics.Reference Thacker, Patel, Dodds, Goldberg, Semeao and Rychik⁴² Response, defined as a rise in serum albumin from one category of severity of disease to another, has occurred in most of our patients within 4 months of initiation of this protocol of treatment. Once an appropriate level of serum albumin is achieved, typically greater than 3.0 grams per decilitre, controlled release budesonide can begin to be weaned in a slow manner to a low dose of 3 milligrams per day or every other day. To date, none of our patients who had a successful response were able to wean completely off controlled release budesonide without relapse. Hence, it should be anticipated that low-dose controlled release budesonide will be administered long term to keep the disease in check. A caveat to this approach is that while controlled release budesonide has 90% of first pass hepatic metabolism in those with normal hepatic function, patients with Fontan physiology often have abnormal hepatic function, and thus may be at risk for systemic side effects.

Plastic bronchitis

Plastic bronchitis is a rare complication seen after the Fontan operation in which bronchial casts are formed within the airways with potential for obstruction and asphyxiation.Reference Costello, Steinhorn, McColley, Gerber and Kumar^43, Reference DiCindio, Theroux, Costarino, Cook and O’Reilly⁴⁴ Two distinctive clinicopathological groups are proposed:

• • The cast material may be cellular in nature with inflammatory debris and infiltrate. These types of casts can be seen in patients with severe allergies or asthma.

• • Alternatively, casts may be acellular and composed of mucin and fibrin (Fig 1).

  

  Figure 1 An example of a bronchial cast from a patient with plastic bronchitis.

Plastic bronchitis following the Fontan operation is most commonly of an acellular cast nature; however, a mixed pathological picture is reported in some patients. The bronchial mucosa typically appears oedematous with dilated lymphatics noted upon histology.

The cause of this complication after the Fontan operation is unknown. In a similar manner to protein-losing enteropathy, it is theorised that unique features of the Fontan circulation predispose to dysfunction of membranes and a break in the integrity of the bronchial mucosa, leading to leakage of proteinaceous material into the airway. Unlike the gut, where large amounts of protein can be continuously lost over long periods of time without fear of obstruction in the bowel, in plastic bronchitis, relatively small amounts of protein lost into the airway can accrete and cause significant obstruction if not expectorated. Hence, in protein-losing enteropathy, the dominant clinical manifestation is hypoalbuminaemia and oedema, while in plastic bronchitis, hypoalbuminaemia is not seen and the dominant clinical manifestation is respiratory distress on the basis of obstruction of the airway.

Interventions that improve cardiac output can result in resolution of plastic bronchitis. This finding also suggests a similar pathophysiology to that of protein-losing enteropathy after the Fontan. Pulmonary vasodilating agents may play a role, by improving ventricular filling and increasing stroke volume and cardiac output.Reference Apostolopoulou, Papagiannis and Rammos⁴⁵ Similarly, anti-inflammatory therapy may be beneficial in reducing severity of disease.Reference Onoue, Adachi, Ichida and Miyawaki⁴⁶ Fenestration of the systemic venous pathway has proven effective,Reference Wilson, Russell, Williams and Benson⁴⁷ as has cardiac transplantation. Plastic bronchitis is a more acute disorder than is protein-losing enteropathy, as it can be life-threatening from the point of first presentation. This fact may explain why there are few studies reporting successful chronic medical regimens, as patients either succumb to the disease or receive more aggressive intervention at the outset. Nevertheless, standard care includes maintenance of clearance of the airway through the use of inhaled steroids, albuterol, aggressive pulmonary physiotherapy, and acetylcysteine. Bronchoscopic removal and mechanical clearance of airways can be life-saving.Reference DiCindio, Theroux, Costarino, Cook and O’Reilly^44, Reference Ishman, Book, Conley and Kerschner⁴⁸

An important therapy that has allowed for improvement in clinical symptoms, but does not alter the underlying origin of plastic bronchitis, is the use of aerosolised tissue plasminogen activator.Reference Costello, Steinhorn, McColley, Gerber and Kumar^43, Reference Zaccagni, Kirchner, Brownlee and Bloom^49, Reference Do, Chu, Berdjis and Anas⁵⁰ Administration of aerosolised tissue plasminogen activator will act to dissolve bronchial casts, which either eliminates the cast or improves the ability for expectoration and clearance of the airway. Long-term therapy as an outpatient is feasible while awaiting a more effective therapy such as cardiac transplantationReference Wakeham, Van Bergen, Torero and Akhter⁵¹; however, the agent is very expensive and it has been difficult in the United States of America to convince “third-party payers” to support this strategy.

Future direction

Following the Fontan operation, patients with functionally univentricular hearts have a unique set of long-term challenges. Despite staged palliation resulting in remarkable survival, the possible complications for this group of patients are complex, involve multiple organ systems, and can be life threatening. Identifying the mechanisms associated with each of the rare complications, and developing strategies to treat them, requires the work of many people at many institutions. As long as the Fontan operation continues to be the paradigm for the care of patients with functionally univentricular hearts, we will need to continue to improve our ability to support this circulation. In the long term, a “Fontan pump” or a “Fontan assist device” may usher in a new era of “ventricular replacement”, but while work has started on such devices, they remain many years in the distance.Reference Rodefeld, Coats and Fisher^52, Reference Bhavsar, Kapadia, Chopski and Throckmorton⁵³ In the meantime, continued collaboration between sub-specialists and between institutions will be required to optimise the care for this group of survivors with functionally univentricular hearts.