Rudolph's Pediatrics, 22nd Ed.

CHAPTER 425. End-Stage Liver Disease

Vicky Lee Ng

End-stage liver disease is a term that is applied to chronic liver disease that is associated with minimal liver function or severe complications that may lead to death. Cirrhosis represents a final common histologic pathway for a wide variety of liver diseases, being characterized by diffuse fibrosis and conversion of the normal liver architecture in to structurally abnormal nodules (Fig. 425-1). Often there is a poor correlation between histology and the clinical status of the patient. Some patients with cirrhosis are essentially asymptomatic whereas others have all of the sequelae of chronic liver disease discussed below. In the era of liver transplantation various attempts to measure the severity of chronic liver disease have been applied in order to determine to prioritize organ distribution for liver transplantation such that the sickest patients received organs. The measure now applied in North America is the Model of End-Stage Liver Disease, or MELD score. The MELD score is calculated using laboratory values including the bilirubin, INR and serum creati-nine. The scoring system has been modified for children less than age 12 years (PELD score) such that it uses other measures of chronic disease relevant in children including serum albumin, bilirubin, INR, growth failure (based on gender, height and weight) and age at listing. Calculators to determine the MELD and PELD scores are available at: http://www.unos.org/resources/meldpeldcalculator.asp (accessed March 2, 2010).

FIGURE 425-1. Cirrhosis with architectural alteration resulting from fibrosis and nodular hepatocellular regeneration (Masson trichrome, 2x). (From Fauci AS, Braunwald E, Kasper DL et al (eds). Harrison’s Principles of Internal Medicine. 17th ed. http://www.accessmedicine.com. Copyright © The McGraw-Hill Companies. All rights reserved.)

The major complications of end-stage liver disease include malnutrition, portal hypertension, and its ensuing risk for variceal hemorrhage and ascites, infection, hepatic encephalopathy, and hepatorenal and hepatopulmonary syndrome.1 Early detection with appropriate management may prevent or ameliorate some of these chronic complications.

MALNUTRITION AND SPECIFIC NUTRIENT DEFICITS

A variety of mechanisms may contribute to malnutrition in end-stage liver disease. These include poor dietary intake, malabsorption, increased intestinal protein losses, low protein synthesis, disturbances in substrate utilization, and hypermetabolism. Many of these are not fully understood. Diminished oral intake may be the result of anorexia of chronic disease; gastroesophageal reflux; nausea and early satiety secondary to abdominal distention exacerbated by tense ascites, organomegaly, delayed gastric emptying, small bowel dysmotility and bacterial overgrowth, and altered taste sensation (dysgeusia). Decreased concentrations of intraluminal bile acids and some medications (cholestryamine and antibiotics) predispose the patient to malabsorption of fat and fat-soluble vitamins. Altered protein metabolism and substrate utilization are manifested by hyperammonemia, hypoalbuminemia, reduced clotting factors, and hypoglycemia. Metabolic disturbances consequent to liver disease, such as increased energy expenditure, insulin resistance, and low respiratory quotient (indicating reduced glucose and increased lipid oxygenation), may contribute to malnutrition even in the early stages. Recurrent sepsis is common in patients with end-stage liver disease, and is likely to increase energy expenditure further. Early recognition and timely intervention are essential, given that malnutrition is predictive of complications of end-stage liver disease and mortality.2

Improving nutritional status in children with chronic liver disease is challenging. Tracking linear growth for long-term monitoring is mandatory. Total reliance on body weight may be misleading in children with fluctuating ascites, organomegaly and peripheral edema, with anthropometric assessment (triceps skinfold and midarm circumference) challenged by small patient size and lack of age-appropriate norms. All infants and children will require increased caloric intake, which is usually met in part by increasing their intake to 120% to 180% of their estimated daily caloric requirement. Formulas containing medium-chain triglyceride (MCT) are used to maximize fat absorption in the setting of severe cholestasis, because MCTs do not require bile acid micelles for solubilization and are directly absorbed into the portal circulation. Increased caloric density formula may also increase calorie intake. The goal is to deliver approximately 8 g/kg/day of fat to the child. The usefulness of supplementing enteral feeds with branched chain amino acids remains controversial. Whenever possible, oral feeding is preferred. For those still encountering inadequate growth, supplementation may be necessary, usually via initiation of nasogastric enteral tube feedings, either as a replacement of or supplement to oral feeds. Nocturnal drip feedings appear to be the best tolerated and can allow high caloric intakes without the rise in serum ammonia that might be anticipated with the increased protein intake. However, supplemental enteral feeds do fail in many infants because of volume intolerance resulting from ascites or organomegaly, with emesis, regurgitation, and increased stool output often negating the expected benefits. Parenteral nutrition should be instituted at the first signs of failure of enteral support, and concurrently viewed as an opportunity to more easily address free water, sodium, trace element, and vitamin deficiency requirements. Although central venous catheter sepsis is always a concern, careful training of caregivers can greatly decrease this risk. Early intervention with occupational therapy and speech therapy will help address the development of oral aversion and behavioral feeding problems that occur in infants who receive limited oral intake.

FAT-SOLUBLE VITAMINS

Deficiencies of fat-soluble vitamins and minerals occur in patients with chronic liver disease. Serum levels should be monitored periodically to assess the need for supplementation. Vitamin E deficiency causes mild hemolysis and neuroaxonal dystrophy. Less common manifestations include myopathy, cardiomyopathy, and a pigmented retinopathy. Treatment of vitamin E deficiency is best accomplished with use of D-alpha tocopheryl polyethylene glycol-1000 succinate (TPGS), which enhances absorption by the formation of mixed micelles (infants are treated with 15–25 IU/kg/day). This form of vitamin E may be mixed with other fat-soluble vitamins to enhance their absorption as well. Vitamin E levels are monitored every 2 to 3 months to maintain serum vitamin E:lipid ratio (mg/g) at a level of greater than 0.6 mg/g in infants and 0.8 mg/g in older children.

Vitamin A deficiency is associated with night blindness, xerophthalmia, and increased mortality when patients contract measles. Oral vitamin K supplementation is indicated for those patients with a coagulopathy. If inadequate, then intramuscular or intravenous vitamin K may be required. Measurement of 25-OH vitamin D is best to assess vitamin D sufficiency as levels of 1, 25 OH vitamin D may be normal despite vitamin D deficiency. Vitamin D deficiency is treated with oral vitamin D3 at a dosage of 3 to 10 times the Recommended Daily Allowance (RDA) for age. Water-soluble vitamins and minerals given as a multivitamin preparation are useful.3

PRURITUS

The cause of pruritus in the setting of liver injury is unknown. Current treatment strategies are based on the assumption that one or more unspecified and unknown pruritogens induce itching and that binding or eliminating these agents will alleviate symptoms. Cholestyra-mine, an ion-exchange resin, is thought to bind agents in the gastrointestinal tract that induce itching. Rifampicin inhibits bile acid uptake by the hepatocyte, reduces intracellular bile acid concentrations, and thus may inhibit release of an unidentified pruritogen. Opioid antagonists such as naloxone have been noted to reduce the urge to scratch, suggesting that an increase in opioid tone may be associated with cholestasis and linked to pruritus. Biliary diversion is considered only after these pharmaceutical measures have been found ineffective or not tolerated. Intractable pruritus may be an indication for liver transplantation.

PORTAL HYPERTENSION

Portal hypertension is defined as a portal pressure gradient (portal vein to hepatic vein gradient) of above 10 to 12 mm Hg. In healthy children, the portal pressure gradient rarely exceeds 7 mm Hg. Each of the causes of elevated portal pressure shares the common mechanism of increased resistance to blood flow from the visceral or splanchnic portal circulation to the right atrium. In children, the location of this increased resistance and hence obstruction of portal flow can be at the prehepatic/presinusoidal, intrahepatic/sinusoidal, or postsinusoidal level (Table 425-1).

Table 425-1. Major Causes of Portal Hypertension in Children

Presinusoidal

Arteriovenous fistula

Congenital hepatic fibrosis

Schistosomiasis

Venous obstructions

Portal vein thrombosis

Cavernous transformation of portal vein

Portal vein malformation (congenital)

Splenic vein thrombosis

Intrahepatic

End-stage liver disease secondary to hepatocellular or biliary tract disease

Postsinusoidal portal hypertension

Budd-Chiari syndrome

Chronic congestive heart failure

Constrictive pericarditis

Inferior vena cava obstruction

Hepatic vein thrombosis

Prothrombotic disease

Veno-occlusive disease

Clinical history should include search for possible exposure to viral or toxic pathogens (including herbal remedies), historical events preceding portal vein thrombosis (neonatal dehydration, systemic infection, umbilical catheters, and phlebitis), and family history of inherited metabolic disease or hypercoagulability (factor V mutation; protein C, protein S, and antithrombin III deficiencies; as well as hyperviscosity or polycythemia in infancy).

Physical examination findings suggesting underlying liver disease (ascites, liver size and contour, nutritional status), hypersplenism (spleen size, bruising), or hepatopulmonary syndrome (spider angiomas, clubbing, cyanosis) contribute to diagnostic evaluation and therapeutic planning. Imaging tests to confirm the presence of portal hypertension and define the portal venous anatomy include both noninvasive and invasive considerations, such as ultrasonography with Doppler exam, magnetic resonance angiography or contrast-enhanced computed topography, and ultimately mesenteric angiography. The role of upper gastrointestinal endoscopy and liver biopsy requires consultation with a pediatric hepatologist for assessment of risks versus benefits.4

VARICEAL BLEEDING

The increased splanchnic venous pressures found in patients with cirrhosis results in the engorgement of alternative venous drainage pathways to return blood to the systemic venous system. This occurs at watershed areas where the splanchic and systemic venous systems interdigitate including the esophagus, anus, umbilicus and at various intra-abdominal sites. These engorged veins are at risk for bleeding. Esophageal variceal bleeding is one of the most life-threatening complications seen in pediatric liver disease.5 Once varices develop, the diameter of the varices, or the variceal wall tension, is the main risk factor determining variceal rupture, which is directly related to the portal pressure gradient. Signs and symptoms of variceal bleeding include melena, hematemesis, hematochezia, dizziness, pallor, and weakness. Patients and families must be educated to seek immediate medical attention at the closest emergency room if any of these symptoms or signs is observed.

Emergency therapy for acute variceal bleeding in children is similar to that of adults, with aggressive management beginning with cardiovascular resuscitation and knowledge of the range of pharmacologic, endoscopic, and surgical therapies available.6 Initial management includes cardiovascular stabilization of the child via immediate placement of a large-bore intravenous cannula to allow the rapid delivery of crystalloid or red blood cells. Many children will also have thrombocytopenia secondary to hypersplenism, and platelet transfusions are indicated. Clotting factor supplementation can be considered, with recombinant factor VII, a potential option when large fluid volumes are contraindicated.

Gastric lavage with saline via a nasogastric tube may be helpful in determining the extent and duration of bleeding and to help clear the stomach of blood to allow better visualization of the mucosa at the time of endoscopy. Contraindications to gastric lavage include children in whom the procedure may increase bleeding (intractable coagulopathy) or induce esophageal perforation (recent sclerotherapy with possible esophageal ulcerations). Coincident with resuscitation efforts, the start of a bolus dose of a long-acting analog of somatostatin called octreotide (1–5 ug/kg IV bolus up to 100 ug, followed by the use of continuous intravenous 1–2 ug/kg/hour up to 25 ug/kg/hour infusion) aims to reduce splanchnic blood flow by selective mesenteric vascular smooth muscle constriction, without precipitating systemic vasoconstriction, thereby leading to a decrease in portal venous inflow and a decrease in portal pressure.

Once hemodynamic stability is achieved, proceeding to endoscopic evaluation is helpful to delineate a source of bleeding. Endoscopic variceal band ligation is generally the preferred approach in the scenario of persistent hemorrhage, with greater ease and safety in the setting of a potentially obscured field at time of endoscopy. Sclero-therapy remains the therapy available for those children (generally < 10 kg) who are too small in size to allow for insertion of the band ligation device. In the child who continues to have uncontrollable bleeding, balloon tamponade may be the only method that can stabilize the patient until a more definitive surgical procedure can be undertaken, such as an emergent portosystemic shunt surgery or the transjugular intrahepatic portosystemic shunt (TIPS) procedure. Placement of a Sengstaken-Blakemore tube, designed to balloon tamponade gastroesophageal variceal bleeding, may be helpful, but can be safely left inflated only for 12 to 24 hours, and as such, can be viewed only as a temporizing measure. While practice guidelines exist for acute, recurrent, and prevention of variceal hemorrhages in adults,6similar evidence-based approaches for children with portal hypertension do not yet exist.4

ASCITES

Ascites is the pathologic accumulation of fluid in the peritoneal cavity. In the child with chronic liver disease, the onset of ascites signifies worsening of portal hypertension and hepatic insufficiency.

PATHOPHYSIOLOGY

Ascitic fluid may be noninflammatory, chylous, or inflammatory (Table 425-2). In liver disease, the ascitic fluid is a transudate that develops as a result of an increased portal venous pressure, which results in increased intraluminal pressures in the mesenteric capillaries and a resultant net fluid loss into the peritoneal cavity. When hypoalbuminemia ensues, the decreased colloid osmotic pressure in the capillary potentiates the net fluid losses into the peritoneal cavity. Indeed, the formation of ascites is a continuous process because of the constant replenishment of the intravascular volume as a result of the body’s homeostatic mechanisms with sodium and water retention that occurs in response to the systemic vasodilatation present in end-stage liver disease. This vasodilatation leads to a decrease in “effective” blood volume and to activation of endogenous antinatriuretic and vasoconstrictive systems, specifically the renin-angiotensin-aldosterone system and the sympathetic nervous system, and circulating levels of vasopressin that lead to sodium and water retention.

Table 425-2. Causes of Ascites

Noninflammatory

Heart failure

Hepatic vein thrombosis

Cirrhosis

Portal vein thrombosis

Budd-Chiari syndrome

Veno-occlusive disease

Malignant infiltration of hepatic sinusoids

Cancer

Chylous

Surgical disruption of lymphatic vessels

Congenital lymphangiectasia

Inflammatory

Intestinal perforation

Pancreatitis

Biliary tract perforation

Bacterial peritonitis

DIAGNOSIS

Significant volumes of ascites are easily detected on physical examination. The abdominal flanks bulge with fluid, a fluid level can be percussed, the umbilicus protrudes, and a fluid wave may be detected. In addition, the liver and spleen may become ballotable and, particularly in young children, inguinal hernias and hydroceles may develop. Common findings on a plain film of the abdomen are diffuse abdominal haziness, separation of bowel loops by fluid, and medial displacement of the bowel. More subtle ascites are best assessed by ultrasonography, which can detect small volumes of fluid, as well as differentiating free from loculated ascitic fluid.

Development of ascites is a poor prognostic sign in children with chronic liver disease, and predisposes to spontaneous bacterial peritonitis. For this reason, a diagnostic peritoneal tap is indicated in any child with end-stage liver disease and a non-specific clinical deterioration. A diagnostic paracentesis in which 10 to 20 mL of ascitic fluid is withdrawn can be safely performed even in patients with coagulopathy. Ascitic fluid should be inspected visually, and then sent for cell count, Gram stain and direct inoculation in blood culture media at the bedside, glucose, LDH, triglycerides, albumin, total protein, and amylase. Initiation of treatment with a nonnephrotoxic broad-spectrum antibiotic is warranted following results of a cell count with predominance of neutrophils, pending culture and sensitivity results. An elevated ascitic fluid amylase indicates pancreatic ascites or gut perforation. Ascites fluid in heart failure tends to a high protein concentration. Urine leakage into the peritoneal cavity can be differentiated from ascitic fluid by the high urea concentration.

MANAGEMENT

Given that sodium retention is one of the main mechanisms in the development of ascites, a central goal of therapy is the attainment of a negative sodium balance. Hence, sodium restriction and the promotion of sodium excretion are the cornerstones of ascites management.7 This is achieved by limiting sodium intake to 0.5 g/day or 1 to 2 mEq/kg/day and enhancing urinary sodium excretion with diuretics. Severe water restriction is unnecessary unless there is profound hyponatremia (< 125 mEq/L). The diet required for severe sodium restriction is unpalatable for many patients and may contribute to decrease in intake of more important nutrients. Pharmacologic treatment, if needed, usually is begun with spironolactone at a dose of 3 to 6 mg/kg/day divided two or three times daily. Combination diuretic therapy may be utilized, with the response monitored by measuring urinary sodium.

If refractory ascites develops leading to impaired enteral feedings and diminished respiratory distress, the option of proceeding to large-volume paracentesis should be approached with caution, given complications including cardiovascular decompensation caused by rapid fluid shifts, intraperitoneal infection, and hemorrhage. Surgical reduction of portal pressure by portosystemic shunting poses challenges with both maintenance of long-term patency as well as operative morbidity and mortality in fragile pediatric patients who typically have poor liver function. There is a very little reported experience of the use of transjugular intrahepatic portosystemic shunt (TIPS), a nonsurgical shunt that acts physiologically as a side-to-side porto-caval shunt, in children for the control of ascites. Such children generally benefit more from timely liver transplantation.

SPONTANEOUS BACTERIAL PERITONITIS

Spontaneous bacterial peritonitis (SBP) is defined as bacterial infection of the ascitic fluid that occurs in the absence of a contiguous source of infection such as an intestinal perforation or intra-abdominal abscess. Early diagnosis is a key issue in the management of SBP. An ascites polymorphonuclear (PMN) cell count of greater than 250/mm3 has a sensitivity of 85% and a specificity of 93% for a positive culture. Ascitic fluid must be inoculated directly into blood culture vials to optimize the diagnostic yield. The most frequent organisms isolated in children include gram-negative enteric flora including Escherichia coli and Klebsiella, as well as gram-positive cocci such as Streptococcus pneumoniae and enterococci. Anaerobic infections are very rare. Initial antibiotic therapy should be broad-spectrum until specific culture and sensitivity results are available. Ampicillin and Cefotaxime are good first considerations. Avoiding aminoglycosides is important because many of these children may already have some renal compromise. Given the high rate of recurrence of spontaneous bacterial peritonitis, immunization with the pneumococcal antigen vaccine and initiation of prophylactic trimethoprim-sulfamethoxazole are potentially useful.

HEPATIC ENCEPHALOPATHY

Clinically evident encephalopathy in children with end-stage liver disease appears to be less common compared with adults. However, it is also possible that encephalopathy is underdiag-nosed in children because its more subtle manifestations are difficult to appreciate. Further, there is no specific laboratory test that correlates well with encephalopathy. Irritability and lethargy, two of the most common signs, may be evident in any chronically ill child. Acute changes in mental status in the child with end-stage liver disease should prompt an investigation for occult gastrointestinal bleeding (which increases ammonia production from blood in the intestinal lumen) or an intracranial hemorrhage secondary to coagulopathy. Aggressive diuretic therapy, concurrent infection (including SBP), and placement of a portosystemic shunt may all precipitate the development of encephalopathy. The main principle of management is to decrease gut-derived nitrogen production by restricting dietary protein intake (to 1 g/kg/day during the early phase of encephalopathy), evacuating blood from the gastrointestinal tract, and administering oral lactulose (Older Children and Adolescents. Oral 40 to 90 mL/day in divided doses to produce 2 to 3 soft stools/day. Infants. Oral. 2.5 to 10 mL/day in divided doses to achieve loose stools and a stool pH < 5) or neomycin (50 to 100 mg/kg/day divided into 3–4 doses) to reduce bacterial flora in the bowel. Although oral lactulose is preferred, care must be taken not to induce hypovolemia and electrolyte disturbances from increased stool losses. Oral neomycin has some systemic absorption, which has been associated with ototoxicity; therefore, extended use should be avoided. Hypoglycemia should be corrected, and sufficient nonprotein calories should be administered to prevent catabolism. Correction of fluid and electrolyte imbalance and treatment of infection, hemorrhage, seizures, and respiratory depression should be addressed proactively.

HEPATORENAL SYNDROME

The hepatorenal syndrome (HRS) is defined as functional renal failure in patients with severe liver disease, with clinical evidence of oliguria (< 1 mg/kg/hour of urine output) typically present.8 The diagnosis is supported by a characteristic pattern of urine electrolyte abnormalities: urine sodium of less than 10 mEQ/L, a fractional excretion of sodium of less than 1%, and a urine-to-plasma creatinine ratio of less than 10. Although these findings are not pathognomonic for HRS and, in particular, do not differentiate hypovolemia from HRS, they help to exclude unsuspected acute tubular necrosis (characterized by an increased urine sodium and increased fractional excretion of sodium), as well as other causes of intrinsic renal disease. It is important not to rely solely on serum creatinine as an estimate of the degree of renal impairment, given that children with poor muscle mass may have a normal or even decreased serum creatinine level in the setting of clinically overt renal failure. Other important contributing factors to poor renal function, which must be excluded are the effects of nephrotoxic drugs (particularly aminoglycosides and nonsteroidal anti-inflammatory drugs). Of the childhood diseases that cause chronic liver disease and have associated renal pathology, the most common are hereditary tyrosinemia, Alagille syndrome, and polycystic liver-kidney disease. HRS is best treated by timely liver transplantation, with dialysis potentially being the mainstay of treatment while awaiting organ availability. Complete recovery can be expected.

HEPATOPULMONARY SYNDROME (HPS)

Hepatopulmonary syndrome (HPS) is associated with the triad of hepatic dysfunction, hypoxemia, and intrapulmonary vascular dilatations, characteristically occurring in children with long-standing liver disease and portal hypertension. Progressive hypoxemia, which is exacerbated by the supine position, is commonly seen on evaluation, and does not correct with 100% oxygen, confirming the presence of intrapulmonary shunts contributing to the alveolar perfusion abnormalities. Abnormal extrapulmonary uptake of technetium-99m macroaggregated albumin (MAA) after lung perfusion scanning or the presence of early microbubble perfusion on echocardiography are diagnostic and predictive of morbidity with general anesthesia or liver transplantation.9 Present experience suggests that these abnormalities are reversible following successful liver transplantation.