Hepatic Fibrosis to Cirrhosis

Tissue fibrosis describes the encapsulation or replacement of injured tissue by scar-like extracellular matrix and is the perpetuation of the normal wound-healing response. Studies in animal models and histologic findings from both adult and pediatric liver diseases have shown that different mechanisms of hepatic damage may lead to characteristic patterns of fibrosis. A portal-based fibrosis pattern, histologically characterized by the fibrous expansion of portal spaces with extension along the terminal centriacinar portal veins, is seen in most childhood cholestatic disease including, biliary atresia, cystic fibrosis, and congenital hepatic fibrosis. In contrast, chronic viral hepatitis observes a portal–central pattern of fibrosis, while a central–central (vein) form of fibrotic evolution is often reflective of venous outflow obstruction (e.g., cardiac failure). Finally, a mild form of central-based fibrosis, characterized by the deposition of fine collagen fibers (chicken-wire fibrosis) in the sinusoids of the pericentral lobular region is peculiar to metabolic conditions, like nonalcoholic steatohepatitis.

Significant progress has been made in understanding the mechanisms of hepatic fibrosis. The hepatic stellate cell (HSC) is a resident perisinusoidal cell that is the primary source of extracellular matrix (ECM) in liver fibrosis. HSC activation follows a process of initiation , which may be provoked by soluble stimuli (oxidant stress signals, apoptotic bodies, lipopolysaccharides, and paracrine stimuli) and perpetuation , characterized by cellular phenotypic changes including proliferation, contractility, fibrogenesis, altered matrix degradation, chemotaxis, and inflammatory signaling. The net effect of these discrete responses is to maintain the activated phenotype and generate fibrosis. During the course of fibrosis, the ECM is constantly remodeled, leading to deposition of new collagens (predominantly types I) and matrix glycoconjugates (proteoglycan, fibronectin, and hyaluronic acid). Although resorption herein would provide the opportunity to reverse hepatic dysfunction, determinants of progression (disease activity, genetic determinants, and environmental factors) lead to a failure to degrade the increased interstitial or scar matrix, allowing fibrotic septae to become thicker, eventually leading to deleterious effects on cell function via the loss of porosity of sinusoidal endothelia, intrahepatic vascular shunts, and diminished metabolic exchange.

Each of these processes in relation to fibrosis is regulated by a growing number of stimuli and pathways, involving key factors such as, platelet-derived growth factor (PDGF), cytokines, transforming growth factor β1 (TGF-B1), endothelin-1, matrix metalloproteinases (MMPs), and their tissue inhibitors (TIMPs). The development in the understanding of the molecular mechanism of fibrosis has provoked an interest into developing targeted therapy such as cytokine antagonists, MMP inducers, and angiogenesis inhibitors. Noninvasive serologic markers for staging liver fibrosis have also been investigated, although to date, serum biomarkers fail to sufficiently reflect disease severity.

Liver cirrhosis is the advanced stage of liver fibrosis and is the common end point of many different liver diseases. Key morphologic features that characterize cirrhosis include diffuse fibrosis, nodule formation, regeneration, altered lobular architecture, and the establishment of intrahepatic vascular shunts between afferent (portal vein and hepatic artery) and efferent (hepatic vein) liver vasculature.

The pattern of progression to cirrhosis and decompensation is variable. In neonatal extrahepatic biliary atresia, the development of hepatic fibrosis is rapid, with cirrhosis occurring by 8 to 16 weeks of age, whereas in cystic fibrosis (CF)–associated focal biliary cirrhosis, liver function may be normal for many years. The importance of genetic modifiers on outcome and progression of chronic liver diseases is under investigation. Recently, genetic determinants in the form of single-nucleotide polymorphisms (SNPs) within genes that may contribute to stellate cell activation or hepatic injury have been uncovered. Irrespective of the type of injury, the significant architectural distortion in a cirrhotic liver leads to shunting of portal and arterial blood supply into the hepatic outflow (central veins), thereby compromising exchange between hepatic sinusoids and hepatocytes. The corollary of which is (1) impaired hepatocyte function, (2) increased resistance to portal blood flow, that is, portal hypertension, with their relative complications, and (3) the increased risk for the development of hepatocellular carcinoma.

Portal Hypertension

Portal hypertension (PH) develops from the combination of increased portal blood flow and increased portal resistance, and is defined as a portal and hepatic-venous pressure gradient (the portal vein–vena cava pressure gradient) greater than 10 to 12 mm Hg.

Different patterns of fibrosis related to different causes of chronic liver disease may lead to altered patterns in the development of PH. For instance, centrolobular fibrosis, is characterized by early involvement of the centro­lobular vein, leading to sinusoidal PH. Alternatively, fibrosis in a portal-based pattern, is often characterized by late involvement of the centrolobular vein and the development of pre-sinusoidal resistance.

In cirrhosis, the fibrotic and angioarchitectural changes lead to an increase in intrahepatic resistance, followed by an increase in splanchnic blood flow that increases portal pressure, giving rise to a hyperdynamic circulation with increased cardiac and decreased splanchnic arteriolar tone, both of which further increase portal inflow. Intrahepatic resistance is responsible for many of the complications of cirrhosis, such as bleeding esophageal varices, renal dysfunction, encephalopathy, and ascites.

Investigations

Liver Biopsy

The diagnosis of most liver diseases requires histologic confirmation; thus, liver biopsies are a routine procedure in specialist centers. An aspiration technique, using a Menghini needle (or disposable variant), has a complication risk of 1 : 1000 liver biopsies and may be performed under sedation with local anesthesia. In fibrotic or cirrhotic livers, a Tru-Cut needle, which removes a larger core, may be necessary. Transjugular liver biopsies, in which the liver is biopsied through a special catheter passed from the internal jugular vein into the hepatic veins, is now possible for children as small as 6 kg and is the only safe way to perform a biopsy if coagulation times remain abnormal despite support (prothrombin time [PT] more than 5 s prolonged over control value). The complications of this potentially dangerous procedure are much reduced if it is performed in expert hands in specialized units under controlled conditions.

Percutaneous needle liver biopsy interpretation may be difficult because of fragmentation of the specimen or if the specimen is taken from a regenerative nodule, which may look almost normal, although there may be hyperplasia of the hepatocytes or a relative excess of hepatic vein branches.

Specific histologic patterns may be diagnostic, such as a plasma cell or lymphocytic portal infiltrate with piecemeal necrosis and interface hepatitis in autoimmune hepatitis, Mallory’s hyaline and copper deposition in Wilson’s disease, and intracellular periodic acid-Schiff–positive, diastase-resistant inclusions in α ₁ -antitrypsin deficiency.

Diagnosis and Prevention of Progressive Liver Damage

In most circumstances, there is no specific therapy for the liver disease, and general supportive management is required.

Cystic Fibrosis

As long-term survival improves in children with cystic fibrosis (CF), liver disease is recognized in more than 20% of children, with a male preponderance. Liver disease is the third leading cause of death in CF (following pulmonary disease and transplant complications), accounting for 2.5% of overall mortality. Neonatal cholestasis can be the first hepatic manifestation of CF. A sweat test is indicated in any newborns with cholestasis of unknown origin. Children usually present with hepatomegaly and/or splenomegaly. Early diagnosis is difficult, but is based on elevated hepatic transaminases (twice the upper limit of normal); abnormal liver ultrasound (heterogenous echogenicity, nodularity, irregular margins, and splenomegaly); and liver histology with steatosis, chemical cholangitis, focal biliary fibrosis, or cirrhosis.

Management is supportive and involves nutritional therapy, particularly vitamins A, D, and E supplementation and ursodeoxycholic acid (20 to 30 mg/kg/day). Hepatic decompensation is a late feature of CF liver disease, but portal hypertension is common and bleeding esophageal varices may be a serious recurrent problem, which requires standard therapy. Liver transplantation is indicated for children with hepatic decompensation (decreasing serum albumin level, or prolonged coagulation that is unresponsive to vitamin K), severe malnutrition, and portal hypertension unresponsive to medical management. Assessment of pulmonary function is required, because severe lung disease (loss of more than 50% of lung function) may indicate the necessity for a heart, lung, and liver transplantation.

Autoimmune Hepatitis

Autoimmune liver disease is the most common liver disease in older children, particularly in teenaged girls. The clinical presentation is variable and includes both acute and chronic liver failure, but often the presentation is insidious with the discovery of hepatosplenomegaly in a child with a history of recurrent jaundice with lethargy, fatigue, and weight loss.

The diagnosis is confirmed by identifying elevated immunoglobulins, particularly immunoglobulin IgG; reduced levels of complement (C3, C4); nonspecific autoantibodies (type I: anti-nuclear antibody [ANA] and anti-smooth muscle antibody [ASMA]; type II: anti-liver kidney microsomal antibodies [LKM]); liver histology with portal inflammation, bridging fibrosis, and interface hepatitis. Cirrhosis may be present at diagnosis. Therapy includes supportive management and initiating immunosuppression with prednisolone 2 mg/kg and azathioprine (0.5 to 1 mg/kg). Steroids should be limited to a maximum dose of 60 mg as they may exacerbate encephalopathy and induce obesity, which may be persistent in adolescent girls. Second-line drugs such as cyclosporin A, tacrolimus, or mycophenolate mofetil may be required if there is a delayed response or relapse.

Liver transplantation is indicated in about 20% of children who do not respond to immunosuppression, have intolerable side effects, or develop end-stage liver failure with jaundice, malnutrition, ascites, encephalopathy, and coagulopathy despite medical therapy. Failure of medical treatment is more likely when established cirrhosis is present at diagnosis. There is a 25% recurrence posttransplantation and it is important to continue steroid therapy.

Wilson’s Disease

Wilson’s disease may present with acute or chronic liver failure. Biochemical liver function tests indicate chronic liver disease with low albumin (less than 3.5 g/dL or 35 g/L), minimal transaminitis, and a low alkaline phosphatase (less than 200 U/L). The diagnosis is established by detecting a low serum copper (less than 1 mmol/dL or 10 mmol/L); a low serum ceruloplasmin (less than 20 mg/dL or 200 mg/L); excess urine copper (above 1 mmol/24 hours), particularly after penicillamine treatment (20 mg/kg/day); and an elevated hepatic copper (more than 250 mg/g dry weight of liver). Approximately 25% of children may have a normal or borderline ceruloplasmin, as it is an acute-phase protein.

Management is with a low copper diet and trientine (triethylenetetramine) 25 mg/kg/day, in addition to oral zinc. Penicillamine (20 mg/kg/day) is now used less frequently because of the side effects. In asymptomatic children or in those who have minimal hepatic dys­function, the outlook is excellent, although fulminant hepatic failure with hemolysis may occur if treatment is discontinued. Liver transplantation is essential for children who present with subacute or fulminant liver failure and in children with advanced cirrhosis and portal hypertension.

Tyrosinemia Type I

Tyrosinemia type I may present with acute liver failure in infants between 1 and 6 months of age and chronic liver disease in older children. Biochemical liver function tests show an elevated bilirubin, transaminases, alkaline phosphatase, and a reduced albumin. Plasma amino acids indicate an increase in plasma tyrosine, phenylalanine, and methionine with grossly elevated α-fetoprotein levels. Urinary succinylacetone is a pathognomonic but not an invariable finding. The diagnosis is confirmed by measuring fumarylacetoacetase (FAA) activity in fibroblasts or lymphocytes.

Hepatic histology is nonspecific with steatosis, siderosis, and cirrhosis, which may be present in infancy. Hepatocyte dysplasia is associated with a risk of hepatocellular carcinoma.

Initial management is with a phenylalanine- and tyrosine-restricted diet, which may improve overall nutritional status and renal tubular function, but does not affect progression of liver disease. The discovery of 2-(2-nitrotrifluoromethylbenzoyl)-1,3-cyclohexenedione (NTBC) or nitisinone, which prevents the formation of toxic metabolites, has altered the natural history of this disease in childhood. There is rapid reduction of toxic metabolites, normalization of tubular function, prevention of porphyria-like crises, and improvement in both nutritional status and liver function, particularly in those who have acute liver failure. Liver transplantation is now indicated only for the development of acute or chronic liver failure unresponsive to NTBC, or if the diagnosis of hepatocellular carcinoma without extrahepatic disease is proven or there is suspicion of hepatocellular carcinoma (HCC).

Viral Hepatitis

Chronic liver failure due to hepatitis B or C is unusual in childhood. Therapy for hepatitis B is unsatisfactory. Drugs approved for use in children to treat hepatitis B virus (HBV) include interferon α (IFNα) and oral nucleotide analogues. The indications for treatment are persistently elevated serum aminotransferases, presence of hepatitis Be (HBe) antigen with detectable HBV DNA in serum, and features of chronic hepatitis on liver biopsy. IFNα (5 to 10 µ/m ² three times a week) by subcutaneous injection for 6 months has a sustained clearance rate of 20% to 40%, but is no longer used. Trials of the long-acting pegylated IFN are in progress.

Children who have active histology, low HBV DNA levels (less than 1000 pg/mL), high serum aminotransferase enzymes, and horizontal transmission are more likely to respond to therapy. Both lamivudine and adefovir have a 26% seroconversion rate after 12 months of treatment. Viral resistance is an issue, especially with lamivudine. Entecavir has proven to be more effective in achieving virologic response in adults with chronic HBV infection, and phase 3 clinical trials in children are currently being conducted. New-generation nucleotide analogues including telbivudine and tenofovir are under evaluation. Liver transplantation is indicated for children with acute or chronic liver failure. Disease recurrence is not uncommon following transplantation, particularly when chronic and the use of oral lamivudine and hepatitis B immune globulin posttransplantation are recommended.

In contrast, therapy for hepatitis C is more satis­factory. Children who have persistent positivity of hepatitis C virus (HCV) RNA and evidence of liver disease should be selected for therapy that is best tolerated in younger children (3 to 5 years of age). The combination of pegylated IFN and ribavirin given for 12 months achieves early virologic response in 70% and sustained virologic response in 58% of children. Response rates are higher in those with HCV genotype 2 or 3 than in genotype 1 or 4. Discontinuation due to lack of response or viral breakthrough is 15% and 4%, respectively. Relapse occurs in 7% of children. Trials of protease inhibitor therapy and sofosbuvir, which have improved seroconversion rates in adults, are in progress in children.

Nonalcoholic Fatty Liver Disease

Nonalcoholic fatty liver disease (NAFLD) is defined by evidence for hepatic steatosis, by either imaging or histology, in the absence of other causes for secondary hepatic fat accumulation. NAFLD can be further characterized histologically into the following: (1) nonalcoholic fatty liver (NAFL), which is the presence of hepatic steatosis (involving >5% of hepatocytes) with no evidence of hepatocellular injury (i.e., ballooning in the hepatocytes) and (2) nonalcoholic steatohepatitis, defined by the presence of hepatic steatosis and hepatocellular injury with or without fibrosis. NAFLD rarely progresses to liver failure and cirrhosis in childhood, but its global prevalence necessitates its consideration as an entity in childhood liver failure. NAFLD affects an estimated 3% to 10% of children in developed countries, with a 2 : 1 male preponderance. Obesity is a major risk factor, with disease found in 70% to 80% of obese children.

Primary noninvasive evaluation (biochemical parameters, imaging tests) should be used as first line to screen and diagnose NAFLD. Children suspected of NAFLD typically have elevated liver transaminase values from normal to 4 to 6 times the upper limit, although mild elevations of 1.5 to 2 times are typically seen. Novel diagnostics in pediatric NAFLD, such as the pediatric NAFLD fibrosis index (PNFI) and enhanced liver fibrosis (ELF) tests, are still under evaluation. Several radiologic modalities (ultrasound, MRS) have been used to quantify hepatic steatosis, as well as fibrosis (transient elastography) in NAFLD. Ultrasonographic scores correlate with histology when steatosis is moderate to severe (>33% steatosis) and the patient’s body mass index is less than 40. Unfortunately, the diagnostic sensitivity fails to exclude the presence of steatohepatitis or fibrosis. MRS has shown improved sensitivity in the quantification of liver fibrosis, although the cost and need for sedation in children limits its use in practice. Elastography remains to be validated in pediatric populations (see earlier discussion). Liver biopsy is the gold standard and should be considered when there are discordant results with noninvasive tests; liver derangement persists beyond 6 months; and/or to rule out competing diagnoses. Despite its invasiveness, liver biopsy enables grading and staging severity and permits monitoring of disease progression and response to therapy.

Limited evidence exists with respect to therapeutic strategy in NAFLD. Weight loss and increased physical activity are first-line strategies. Dietary recommendations include reductions in sugar, fructose-rich drink, and total fat, increasing the proportion of polyunsaturated fat and intake of fiber. Metformin failed to regress hepatocellular injury in a large clinical trial (Treatment of Nonalcoholic Fatty Liver Disease in Children [TONIC]) in children with NAFLD, although it is notable that vitamin E therapy markedly improved hepatocellular ballooning degeneration in children with NAFLD.

Primary Immunodeficiency

As bone marrow transplantation for primary immuno­deficiency has become increasingly successful, it has been recognized that some children have associated liver disease and may die from liver failure. The most common immunodeficiency is CD40 ligand deficiency—hyperimmunoglobulin M (hyper-IgM) syndrome—in which recurrent cryptosporidial infection of the gut and biliary tree leads to sclerosing cholangitis. In this group of children, it is important to consider bone marrow transplantation before the development of significant liver disease, or to consider combined liver and bone marrow transplantation.

Nutritional Support

The liver has a central role in regulating fuel and metabolism, nutrient homeostasis, and the absorption of a number of nutrients; malnutrition is thus a common complication in patients with liver failure, estimated at 50% to 80% of children with chronic liver failure in Europe and North America. Infants, particularly those with cholestatic disease, are at greatest risk of malnu­trition because of their higher energy and growth requirements.

In children with liver disease, several factors should be considered to contribute to a state of malnutrition. The resting energy requirements of infants and children with liver disease are increased to 120% to 200% of the estimated average requirements (EARs). Anorexia secondary to organomegaly, ascites, and a chronic disease process further impairs the child’s capacity to consume the intake necessary, which is often compounded by behavioral feeding problems and gastroesophageal reflux disease. Reduced carbohydrate metabolism due to lack of glycogen stores increases the propensity for hypoglycemia, and facilitates the utilization of protein and fat as an energy supply. Altered protein metabolism contributes to muscle wasting, hypoalbuminemia, coagulopathy, and encephalopathy. A rise in essential aromatic amino acids, usually metabolized by the liver and a reduction in essential branch chain amino acids, which are metabolized in muscle, have been found to correlate with states of encephalopathy in adults and children.

In the majority of pediatric liver disease there is a reduction in the synthesis and secretion of bile salts, which is most severe in cholestatic diseases such as biliary atresia and PFIC. Consequently, up to 50% of long-chain triglycerides, fat-soluble vitamins, and essential polyunsaturated fatty acids (PUFAs) may not be absorbed. In contrast, 95% of water-soluble lipids, such as medium-chain triglycerides (MCTs), which do not depend on bile solubility, may be absorbed and form the basis for nutritional replacement. Hypercholesterolemia and hypertriglyceridemia are also common in chronic liver disease due to the liver’s role in lipoprotein metabolism and cholesterol synthesis.

Chronic liver disease affects vitamin absorption, metabolism, and storage. Reduction in bile salt secretion leads to malabsorption of the fat-soluble vitamins A, D, E, and K and fat-soluble vitamin deficiency may develop within 6 to 12 weeks of birth. Vitamin A deficiency can also develop secondary to reduction in protein synthesis or depletion of hepatic stores. Vitamin D deficiency can occur either from fat malabsorption or from reduction in hepatic 25-hydroxylation. Vitamin K deficiency arises partly from fat malabsorption and partly from a reduction in intake, particularly in breast-fed infants. Deficiencies in fat-soluble vitamins may be apparent in 30% of severely cholestatic children despite supplementation.

Biochemical deficiencies of water-soluble vitamins such as thiamine and pyridoxine can occur and lead to nutritional cardiomyopathy and peripheral neuropathy. Trace metal deficiencies include iron deficiency secondary to gastrointestinal bleeding or diminished intake, and zinc and selenium deficiencies caused by reduced enteral intake, malabsorption, or increased losses.

The main aim of nutritional support is to provide sufficient caloric intake to prevent protein malnutrition and account for fat malabsorption ( Table 77-2 ). Infants with severe cholestatic jaundice require a calorie intake of 140% to 200% EAR, which can be achieved by concentrating standard infant formulas to increase the kilocalories from 67 to 80 per 100 mL or by supplementing milk feeds with extra carbohydrate (e.g., glucose polymer) and fat to produce an energy density of 1 kcal/mL or more. Breast-feeding should be encouraged with supplementation with a high-caloric-density formula. As such, feeds will have a high osmolality (500 to 800 mmol/L) and should be gradually introduced to enable tolerance. If oral feeding cannot meet caloric needs, supplementation via nasogastric tube is required. If there is no response to an increase in energy intake alone, nocturnal nasogastric feeding should be instituted. If enteral feeding is not tolerated, parenteral nutrition in combination with enteral feeds should be considered.

A formula containing MCTs, which can be absorbed regardless of luminal concentrations of bile acids, is useful and may reduce steatorrhea. Deficiency of essential fatty acids may occur with prolonged cholestasis after maternal stores are depleted, approximately 3 months after birth, or in infants fed high-MCT (>80%) feeds. Thus, it is necessary to increase the total fat intake with both long-chain triglycerides (LCTs) and MCTs, by supplementing feeds with approximately 50% MCTs with essential fatty acids. This will increase the overall amount of fat absorbed and improve growth despite increasing steatorrhea. In older children, MCT oil can be added to meals and should be balanced by fats with high long chain polyunsaturated fatty acids (LCP) content. Chemically modified lipids have been developed to increase the absorption of both medium- and long chain- and essential fatty acids; however, studies of these modified lipids in children are currently in the preliminary stages.

Children with end-stage liver disease require minimal protein intake of approximately 2 to 3 g/kg per day but will tolerate up to 4 g/kg per day without developing encephalopathy or a significant increase in plasma amino abnormalities. Severe protein restriction (less than 2 g/kg/day) might be required for acute encephalopathy but should be avoided in the long term. There is insufficient evidence that adding increased amounts of branched-chain amino acids (BCAAs) improves patient outcome; however, BCAAs have been shown to improve nitrogen retention and protein synthesis.

Fat-Soluble Vitamin Supplementation

Generous oral supplements of the fat-soluble vitamins are essential especially in cholestatic children and should include:

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  Vitamin A, 5 to 15,000 IU/day

  
  
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  Vitamin D (alpha-calcidiol), 50 ng/kg/day

  
  
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  Vitamin E, 50 to 200 mg/day

  
  
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  Vitamin K, 2.5 to 5 mg/day

Pruritus

Pruritus due to cholestasis interferes with quality of life. It is often difficult to treat, and current methods of treatment are aimed at combating two proposed mechanism: reduce bile acid concentration and antagonize opiate receptors. Monotherapy is often ineffective, and multidrug therapy is often required. Medical therapy includes:

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  Cholestyramine (1 to 4 g daily), although effective, is often unpalatable. The mechanism of action is to bind bile salts in the intestinal lumen, thereby interrupting the enterohepatic circulation and reducing bile salt concentration. Side effects include malabsorption of fat-soluble vitamins and drugs, folic acid deficiency, constipation, and acidosis.

  
  
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  Ursodeoxycholic acid (UDCA) may be effective when given in a dose of 20 to 30 mg/kg/day. It is thought to have a choleretic action but is not universally effective.

  
  
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  Phenobarbitone (5 to 10 mg/kg/day) may stimulate bile salt–independent bile flow, decrease jaundice, and control pruritus.

  
  
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  Rifampicin (5 to 10 mg/kg/day) relieves pruritus in at least 50%, producing a significant improvement in the remainder. Results are variable. Side effects include hepatotoxicity in 5% to 10% and thrombocytopenia.

  
  
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  Ondansetron may be effective when used in a dose of 2 to 4 mg twice daily (<12 years) or 4 to 8 mg twice daily (12 to 18 years) and has the advantage of being offered intravenously, orally, or sublingually. The medication is typically well tolerated, with few side effects including diarrhea, headache, and increase in hepatic transaminase level.

  
  
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  Naltrexone (6 to 20 mg/day) has few reported studies of its safety and efficacy in children. Side effects are reported in up to 30% including nausea, diarrhea, and abdominal pain.

  
  
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  Antihistamines are largely ineffective but, because they cause drowsiness, may be useful at night. Toxic side effects include cardiac dysrhythmias.

  
  
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  Partial external biliary diversion, in which part of the jejunum is anastomosed to the gallbladder and brought to the surface of the abdominal wall, may relieve pruritus in some conditions, including PFIC and AGS. The operation is most likely to be successful if performed before significant fibrosis has developed.

  
  
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  The molecular adsorbent recirculating system (MARS), which is a form of albumin dialysis, has produced relief of pruritus for 6 to 12 months.

Portal Hypertension

Therapy with endoscopic sclerotherapy, band ligation, and prophylactic β-blockade therapy is discussed elsewhere. Insertion of a transjugular intrahepatic portosystemic stent (TIPS) may be useful in intractable bleeding. The initial management of acute variceal bleed should be fluid resuscitation with colloid (4% human albumin solution [HAS]) and packed red blood cells. Coagulopathy may be corrected by intravenous vitamin K, but platelets and fresh frozen plasma may also be required. An intravenous dose of an H2 blocker such as ranitidine, or proton pump inhibitor such as omeprazole should be administered. Medications that diminish portal pressure and help to control bleeding (e.g., octreotide, Glypressin, or vasopressin) may need to be given. If bleeding continues, a Sengstaken-Blakemore tube should be passed.

Fluid Balance and Circulatory Changes

Patients with chronic liver failure have fluid retention with ascites. This is managed with diuretics such as spironolactone (1 to 9 mg/kg/day in two to three divided doses) and furosemide (0.5 to 2 mg/kg/day), with salt and water restriction (80% of maintenance). If the patient is symptomatic and serum albumin level is low (<30 g/L), ascites may also be reduced with an infusion of 20% HAS accompanied by an additional dose of diuretic. Peripheral vasodilation, dilation of the splanchnic vascular bed, and arteriovenous shunting are common, as is intravascular depletion. Vigorous diuretic administration or therapeutic paracentesis may further decrease the circulating plasma volume, thereby reducing renal perfusion and increasing sodium retention.

Electrolyte Changes and Renal Failure

Hypoglycemia (blood glucose level less than 40 mg/dL) is caused by depletion of hepatic glycogen stores and impaired gluconeogenesis. Contributing factors include raised serum insulin concentrations as a result of reduced hepatic insulin catabolism and abnormal levels of glucagon and growth hormone. Hyponatremia is frequently present because of decreased water excretion, increased renal sodium retention due to stimulation of the renin-angiotensin-aldosterone system, and decreased activity of the sodium-potassium pump. Hypokalemia often accompanies hyponatremia and may be caused by renal losses and hyperaldosteronism. With severe renal impairment, hyperkalemia may develop. Other electrolyte abnormalities include hypocalcemia and hypomagnesemia. Calcium levels should be corrected for corresponding albumin levels.

Renal excretion of sodium is significantly decreased in patients with well-established cirrhosis, and is an important pathophysiologic cause of ascites formation. In addition to the development of hepatorenal syndrome characterized by redistribution of blood flow away from the renal cortex, renal changes in cirrhosis include glomerular sclerosis and membranoproliferative glomerulonephritis. Acute tubular necrosis is also seen in patients with cirrhosis and is distinguished by a higher fractional excretion of sodium than seen with hepatorenal syndrome. Ascites should be managed with diuretics such as spironolactone or furosemide, and restriction of salt and water. Intervention with hemodialysis and hemofiltration should be considered if acute renal failure or hepatorenal failure develops.

Hepatic Encephalopathy

Chronic hepatic encephalopathy may be present in up to 50% to 70% of patients with cirrhosis. Episodes of encephalopathy usually have a precipitating event such as gastrointestinal hemorrhage, infection, and hypokalemia, which increase ammonia production; systemic alkalosis, which increases diffusion of ammonia across the blood–brain barrier; or hypoxemia, hypotension, and dehydration. In addition, such episodes may be due to portosystemic shunting, for example, after the insertion of a TIPS for the management of esophageal varices. Of children without encephalopathy but with chronic liver disease, those with early onset liver disease (initial symptoms in the first year of life) have reduced intelligence quotient scores when compared with children with chronic liver disease of later onset. This may be due to the vulnerability of an infant’s brain to the metabolic abnormalities accompanying liver disease or to poor nutritional status, including vitamin E deficiency in young children with chronic liver disease.

Although ammonia levels are typically elevated in patients with chronic hepatic encephalopathy, especially those with portosystemic shunting, they correlate poorly with the degree of encephalopathy and are therefore not helpful in following the progression of encephalopathy.

Treatment is directed at identifying and treating precipitating factors, avoiding fasting and sedatives, and reducing protein intake. Although protein restriction may be beneficial in the short term, this may result in growth failure and nutritional depletion in children. Thus, restriction of dietary and/or intravenous protein to 1 to 2 g/kg should be used in only acute or symptomatic encephalopathy, and protein may be reintroduced as the encephalopathy subsides. A reduction in intestinal protein load in the gastrointestinal tract can be achieved by enemas, particularly if an acute episode of encephalopathy is secondary to gastrointestinal hemorrhage, or by lactulose. Antimicrobial agents can be used to reduce bacterial flora and thereby reduce the intestinal production of ammonia. These include amoxicillin, metronidazole, vancomycin, and rifaximin; a recent systematic review concluded that rifaximin has the highest benefit–risk ratio in the overall treatment of hepatic encephalopathy and should be considered first-line therapy, although availability is often the limiting factor. In hyperammonemia associated with inborn errors of metabolism, the use of sodium benzoate and phenylacetate is standard practice.

Nutritional supplements enriched with BCAAs may be useful for treating hepatic encephalopathy because they normalize plasma amino acid profiles.

Pulmonary Disease

Pulmonary arteriovenous shunting with hypoxemia (hepatopulmonary syndrome) may be present in children with chronic liver disease and portal hypertension, and it presents with dyspnea on exertion or with cyanosis. This condition is reversible after liver transplantation.

Coagulopathy

The liver is responsible for the synthesis of factors II, V, VII, VIII, IX, and X. Reduced levels of these factors, and of other proteins important in coagulation, reflect abnormalities of protein synthesis and impaired posttranslational modification of vitamin K–dependent proteins (factors II, VII, IX, X; protein C and S) or malab­sorption of vitamin K in cholestasis. Patients with coagulopathy secondary to liver disease may be asymptomatic or may have bleeding from the gastrointestinal tract, nasopharynx, retroperitoneum, tracheobronchial tree, genitourinary tract, subcutaneous tissues, or intra­cranial bleeding. Petechiae from hypersplenism may cause epistaxis or exacerbate coagulopathy. Treatment consists of adequate vitamin K provision and use of fresh frozen plasma, cryoprecipitate, and platelets as required.

Family and Psychologic Support

Specific attention to the child’s developmental and psychologic needs is essential. Physiotherapy may improve gross motor development, especially in children who require frequent hospitalization. Family education and support are essential, particularly for children with progressive illness requiring liver transplantation.