Cardiac Manifestations

Cardiac disturbances occur in children with liver disease because of altered physiology, congenital heart defects, and toxic side effects. A hyperdynamic circulation secondary to vasodilation characterizes the altered cardiac physiology from liver disease, with a compensatory increase in cardiac output (CO). Vasodilation is central to the hyperdynamic circulation that accompanies portal hypertension. It likely occurs because of the presence of vasoactive mediators. These mediators or gut-derived “humoral factors” (e.g., nitric oxide [NO], tumor necrosis factor α, endocannabinoids) enter the systemic circulation through portosystemic collaterals and bypass hepatic detoxification.¹⁴ Shunting also occurs at the level of the skin and the lungs. Mixed venous saturation increases in children with liver disease because of poor tissue oxygen extraction. Arterial-venous oxygen difference is reduced because of the combination of decreased oxygen consumption and hypoxia from arterial-venous shunting.

Cardiomyopathy associated with portal hypertension is well described in adults but is not well characterized in children with liver disease. However, children with liver disease can develop a cardiomyopathy for other reasons. Inborn errors of metabolism and other syndromes are associated with cardiomyopathies and cardiac anomalies. Some of the inborn errors include Wilson disease, oxalosis, glycogen storage disease type III, and Gaucher disease.¹⁵ Tacrolimus and cyclosporine A have also been associated with hypertrophic cardiomyopathy in animal studies and in pediatric liver transplant recipients.^16,17,18 Echocardiographic assessment of cardiac function is generally well preserved in children receiving tacrolimus, but there may be evidence of subtle cardiovascular changes, which predispose a small percentage of children to develop hypertrophic cardiomyopathy.¹⁹

Other diseases that may lead to liver failure are associated with congenital heart disease. For example, children with Alagille disease may have pulmonary stenosis, coarctation, tetralogy of Fallot, atrial and ventricular septal defect.

QT prolongation has also been described in adults with alcoholic liver disease and may be associated with sudden cardiac death.²⁰ A decrease in K⁺ currents observed in rat cardiomyocytes with cirrhosis may provide a possible mechanism for the QT prolongation. Children with liver failure have also been shown to have an increase in QT interval (QTc greater than 450 msec in 18% of children with liver disease), possibly increasing the risk of ventricular arrhythmias, however, there is no evidence of an increased dispersion of repolarization (see Chapter 14). These changes appear to be transient and reversible after liver transplantation.²¹ Nonselective β-adrenergic blockade has also been shown to reduce the QT prolongation, but it is unclear if this reduces the risk of arrhythmias or improves survival.²² Although previous data suggested that prolonged QT did not predict decreased survival,²³ more recent evidence suggests that the presence of a prolonged QT was associated with an increased PELD score and portal hypertension. Children with chronic liver disease and prolonged QT may be at increased risk of mortality while waiting for a transplant.²⁴

Pulmonary Manifestations

The hallmarks of the pulmonary manifestations of liver disease are hypoxia and pulmonary hypertension. Hypoxia is secondary to hepatopulmonary syndrome (HPS) and ventilation/perfusion () mismatch from atelectasis caused by tense ascites, hepatosplenomegaly, and/or pleural effusions. HPS is characterized by hypoxia from intrapulmonary arteriovenous shunting and intrapulmonary vascular dilatation.²⁵ The diagnosis is predicated on either arterial hypoxia (Pao₂ less than 70 mm Hg in room air) or an increased alveolar-arterial gradient of more than 20 mm Hg in the setting of pulmonary vascular dilatation. Intrapulmonary vascular dilatation can best be demonstrated on echocardiography or lung perfusion scan with macroaggregated albumin.²⁶ HPS occurs in 15% to 20% of adults and in 0.5% to 20% of infants and children with cirrhosis²⁷ as young as 6 months of age. It appears to be more prevalent in children with biliary atresia and polysplenia syndrome.^28,29

Treatment for hypoxia is long-term supplemental oxygen; definitive treatment is liver transplantation. In a case series of seven children with HPS who were successfully transplanted, all recovered postoperatively with their hypoxia resolving within an average of 24 weeks.³⁰

Portopulmonary hypertension (PPH) is defined by the World Health Organization as pulmonary artery hypertension (pulmonary systolic pressure of 25 mm Hg or greater) in the setting of a normal pulmonary capillary wedge pressure and portal hypertension.³¹ The incidence of PPH is 0.2% to 0.7% in adults with cirrhosis but increase to 3% to 9% in adults presenting for liver transplantation.³² The incidence in children is unknown, with accounts limited to case reports and one case series. Signs and symptoms on presentation are new heart murmurs, dyspnea, and syncope. Echocardiography can successfully identify pulmonary hypertension in pediatric and adult patients with PPH³³; the severity of PPH predicts mortality. In a retrospective review, mild PPH did not increase mortality; however, those children who underwent liver transplantation with moderate PPH (pulmonary artery pressure [PAP] is 35 to 45 mm Hg) had a 50% mortality rate and those with severe PPH (PAP greater than 50 mm Hg) had a 100% mortality rate.³⁴

There are no definitive guidelines for the management of children with PPH. Early identification is essential, and this may be accomplished with echocardiography. If PPH appears likely, cardiac catheterization should be performed to confirm the diagnosis, measure pulmonary artery pressures, and assess the response to NO and epoprostenol. Children who respond to medical management may be candidates for liver transplantation.³⁵ Otherwise, severe PPH is generally a contraindication for liver transplantation because of the increased risk of mortality.

Neurologic Manifestations

Hepatic encephalopathy (HE) is a significant neurologic complication that is classified as either acute (seen in fulminant hepatic failure) or chronic (seen in chronic cirrhosis or chronic portal hypertension). The classification of the severity of acute and chronic HE is similar and is shown in Table 29-1. The pathophysiology is not entirely known, but cerebral edema appears to be a feature of both acute and chronic HE. Cerebral edema is more severe in acute HE and can result in increased intracranial pressure. Ammonia is repeatedly implicated in the pathogenesis of HE and may participate in the process by causing astrocyte swelling and low-grade cerebral edema.^36,37 The two major sources of ammonia in humans are catabolism of endogenous protein and gastrointestinal absorption. Bacterial breakdown of nitrogen-containing products in the gut results in ammonia formation, which is then absorbed in the portal circulation. Factors that increase blood ammonia concentrations can exacerbate the signs and symptoms of HE. These typically include increased catabolism from infection, increased gut absorption from high-protein diets, constipation, and gastrointestinal bleeding. Other neurotoxins that have been implicated in the exacerbation of HE include endogenous production of benzodiazepines, hyponatremia, and inflammatory cytokines; these may all share the final common pathway of increasing cerebral edema.

TABLE 29-1 West Haven Staging Classification of the Severity of Acute and Chronic Hepatic Encephalopathy

Management of HE should begin with assessing the child’s ability to manage their airway. Children with grade 3 (somnolence to semi-stupor, responsive to verbal stimuli but confused) and 4 (coma, unresponsive to verbal or noxious stimuli) HE may require tracheal intubation to protect the airway and to provide adequate oxygenation and ventilation. Otherwise, management typically focuses on reducing gastrointestinal production and absorption of ammonia. Lactulose is often prescribed to create an osmotic gastrointestinal diuresis and to acidify the lumen of the gut to trap ammonia and minimize absorption. Antibiotics (e.g., neomycin and metronidazole) kill the gastrointestinal bacteria that are involved in metabolizing nitrogen products to ammonia. Other medications include sodium benzoate, which combines in the liver with ammoniagenic amino acids, like glycine, to facilitate their excretion.³⁸ Ornithine aspartate may also provide a substrate to the liver for enhancing urea cycle and glutamine synthesis, and reduce ammonia levels. Flumazenil may reduce the symptoms of HE by inhibiting endogenous benzodiazepines and γ-aminobutyric acid, although 0.01 mg/kg in children with fulminant hepatic failure failed to correct the HE.³⁸

Children with fulminant hepatic failure can have increased intracranial pressure (ICP), which is the major cause of mortality and may be a contraindication for liver transplantation. Intracranial hypertension occurs in 38% to 81% of adult patients with fulminant hepatic failure³⁹ and is often monitored in those with fulminant hepatic failure (grade 3 to 4 HE). The risk of intracranial hemorrhage secondary to coagulopathy can be reduced by replacing clotting factors and platelets, and by placing an epidural rather than a subdural monitor.⁴⁰ Management strategies for children with increased ICP should focus on maintaining cerebral perfusion pressure above 60 mm Hg, and ICP at less than 20 mm Hg. Management strategies often include tracheal intubation and ventilation with the head in midline position and slightly elevated to 30 degrees to facilitate venous drainage. Ventilation is adjusted to achieve a Paco₂ of 30 to 35 mm Hg with minimal positive end-expiratory pressure (PEEP). Medical management to reduce ICP includes administering barbiturates or propofol to minimize stimulation and to directly reduce ICP.⁴¹ Mannitol can be administered if ICP remains increased. Hypothermia has also been described, and in a small trial with 14 patients with fulminant hepatic failure, ICP was reduced by maintaining core body temperature at 32° C to 33° C.⁴² Orthotopic liver transplantation is the definitive treatment for children with acute or chronic HE.

Hematologic Manifestations

There are several hematologic alterations associated with liver disease. Anemia is common because of a combination of gastrointestinal bleeding, poor nutrition, and decreased erythropoietin production from renal failure. Portal hypertension can result in splenomegaly, which causes platelet sequestration and thrombocytopenia. All of the coagulation factors (except factor VIII) are synthesized in the liver. As synthetic functions decline, coagulation factor production diminishes. The reduction in bile salt also decreases the absorption of fat-soluble vitamins (A, D, E, K) and contributes to the deficiency of factors II, VII, IX, and X. The result is an increase in prothrombin time (PT) and partial thromboplastin time (PTT). Children with acute or fulminant hepatic failure can present with a hematologic profile similar to disseminated intravascular coagulation.

Renal Manifestations

Renal failure is common in children with acute and chronic liver disease and its cause is multifactorial. Renal failure can be classified as prerenal azotemia, acute tubular necrosis (ATN), or hepatorenal syndrome (HRS). Prerenal azotemia from hypovolemia is a common cause for renal failure and occurs secondary to diuretic therapy, gastrointestinal bleeding, splanchnic pooling, and sepsis. ATN occurs because of decreased central blood volume secondary to central splanchnic pooling, and decreased prostaglandin synthesis. HRS is characterized by renal failure in the setting of liver failure and portal hypertension. The incidence in adults with chronic liver disease is approximately 10% to 15%; in children the incidence is even less, at approximately 5%. The reduced incidence in children may reflect the lack of definitive criteria for diagnosis of HRS in children.⁴³ HRS occurs secondary to intense renal vasoconstriction from activation of the renin-angiotensin, arginine vasopressin, and sympathetic nervous systems. This activation is a homeostatic response to the profound splanchnic vasodilation that occurs with portal hypertension.⁴⁴ HRS presents similarly to prerenal azotemia (increased creatinine, decreased urine sodium [U_Na less than 10 mM, Fe_Na less than 1%]), but is differentiated from azotemia by its lack of response to a fluid challenge. HRS has been classified based on the rate of progression of renal failure into types 1 and 2: type 1, which has a worse prognosis, is characterized by a rapid progression of renal failure with a 100% increase in creatinine in less than 2 weeks. It usually occurs in patients with acute liver failure. In type 2, renal failure progresses over weeks to months, and usually occurs in patients with chronic liver disease. Regardless of the type, prognosis is poor in children with HRS, with a mortality of 80% to 95%.⁴⁵ The definitive treatment for HRS is liver transplantation, because the renal failure is reversible if the liver is replaced.⁴⁶

The primary goal in the management of patients with liver disease and renal failure is to exclude treatable and reversible causes, such as nephrotoxins (NSAIDs), hypovolemia (diuretics, gastrointestinal bleeding), and sepsis. All nephrotoxins should be stopped and children should be given a fluid challenge, ideally with a colloid solution. If sepsis is suspected patients should be extensively cultured and antibiotics that are not nephrotoxic administered.

Pretransplant renal function predicts mortality in adult patients undergoing transjugular intrahepatic shunt and liver transplantation, and serum creatinine is used in the MELD score. Preexisting renal failure is also a major determinant of survival after liver transplantation in adults. Efforts to improve renal function pretransplant may improve posttransplantation outcome.⁴⁷ At this time it is not clear that serum creatinine is a predictor of mortality in children with liver disease.⁴⁸ Before transplantation, type 1 HRS can be managed with vasoconstrictors (vasopressin analogs, norepinephrine), although there are limited data on their use in children. Critically ill children may require continuous renal replacement therapy (continuous venovenous hemofiltration or hemodiafiltration) as a bridge to transplantation.

Metabolic Manifestations