Pediatric Liver Disease - Clinical Tree

Key Points

1
The liver is physiologically immature during the perinatal period, and significant maturational changes in hepatic metabolic processes occur in early life. These metabolic processes affect the presentation of and reaction to viral and toxin exposures.

Inherited and metabolic liver diseases commonly present in infants and young children; the etiologies of liver disease in adolescents are more similar to those in adults ( Table 25.1 ).

TABLE 25.1

Clues to a Diagnosis of Metabolic Liver Disease in Neonates, Infants, and Children

History	Physical Examination	Laboratory Findings
Symptoms provoked by illness or fasting Consanguinity in family Maternal liver disease during pregnancy History of miscarriage in previous gestation	Marked hepatomegaly Cataracts Unusual odors Developmental delay, psychomotor retardation, hypotonia, seizures	Hypoglycemia (without severe liver dysfunction) Severe coagulopathy (without severe liver dysfunction) Hyperammonemia (without severe liver dysfunction) Retractable organic acidemia, lactic acidemia

3
Liver diseases in children may manifest as hyperbilirubinemia, hepatomegaly, liver failure, acute or chronic hepatitis, portal hypertension, or systemic disease resulting from the secondary effects of liver disease.
4
The secondary effects of liver disease may be life threatening and include the following:
- ▪
  Metabolic derangements, such as hypoglycemia
- ▪
  Coagulopathy secondary to low levels of vitamin K–dependent clotting factors that may result in intracranial hemorrhage in the infant
- ▪
  Persistent endogenous “toxin” exposure, as may be seen in diseases such as galactosemia or fructosemia
- ▪
  Portal hypertension with hypersplenism and gastrointestinal bleeding

Consequences of Physiologic Immaturity of the Liver

1.
Low postnatal blood glucose concentration: Significant hypoglycemia is uncommon in full-term infants with regular feeding practices; however, there is a potential for hypoglycemia because the process of gluconeogenesis and glycogenolysis rapidly matures after birth. Premature infants are at greatest risk of hypoglycemia because of reduced glycogen reserves and inadequate hepatic ketogenic response to hypoglycemia, which may continue through 8 weeks of postnatal life.
2.
Altered metabolism and clearance of potentially toxic endogenous and exogenous toxic compounds
- ▪
  Hepatic concentrations of cytochrome P-450 are low in infants. Similarly, activities of aminopyrine N -demethylase and aniline p -hydroxylase are low. Hepatic processes, such as clearance of certain drugs or bilirubin that depend on these systems, are inefficient. Therefore, potentially toxic serum levels of these compounds may be reached.
- ▪
  Lower levels of glutathione peroxidase and glutathione S -transferase (GST) are present in infants, thus making the infant liver potentially prone to oxidant injury.
3.
Altered bile acid pool size and composition: This may lead to inefficient micelle solubilization or to the accumulation of harmful atypical bile acids, which may exacerbate cholestasis and liver injury.
4.
Physiologic jaundice
- ▪
  Up to one third of newborns develop unconjugated hyperbilirubinemia within the first week of life; this spontaneously resolves with no complications.
- ▪
  Breast-fed infants have a higher risk of developing jaundice than do formula-fed infants.
- ▪
  Jaundice in preterm infants may present earlier, last longer, and be greater in severity than in term infants.
- ▪
  Physiologic jaundice reflects the transition of clearance and metabolism of unconjugated bilirubin from the maternal system to the infant. The pathogenesis is likely multifactorial:
  - –
    Increased production of bilirubin: The newborn has a large red cell mass, and the cells have a shorter half-life than adult red cells.
  - –
    Reduced intracellular conjugation due to low expression of hepatic uridine diphosphate (UDP)–glucuronyl transferase
  - –
    Increased reabsorption of unconjugated bilirubin via the enterohepatic circulation due to altered intestinal microflora and more endogenous or exogenous beta-glucuronidase
- ▪
  Treatment is usually not required for physiologic jaundice. Interruption of breastfeeding is not necessary.
- ▪
  Although pathologic jaundice is not common, it is important to recognize and obtain further investigations. Warning signs of pathologic jaundice are shown in Box 25.1 .
  
  BOX 25.1
  
  Warning Signs of Pathologic Jaundice in Neonates
  
  Elevated serum bilirubin level occurring before 36 hours of age or lasting longer than 14 days of age
  
  Total serum bilirubin level >12 mg/dL at any time
  
  Conjugated serum bilirubin level >1 to 2 mg/dL, or 20% of total bilirubin, at any time

Hyperbilirubinemia

Pathophysiology

Alterations in any step in bilirubin metabolism may cause jaundice ( Fig. 25.1 ; the numbers in the figure correspond to the numbers [1 to 8] in the following outline).

1.
Increased bilirubin production: This can result from an increase in the release of heme from red blood cells, for the following reasons.
- ▪
  Hemolytic diseases due to blood group incompatibility (ABO, Rh, and other minor blood groups), red cell enzyme defects (glucose-6-phosphate dehydrogenase [G6PD]; or pyruvate kinase [PK], hexokinase [HK]), and structural/red cell membrane defects (congenital spherocytosis, hereditary elliptocytosis)
- ▪
  Reabsorption of hemolyzed blood from a hematoma
2.
Decreased bilirubin uptake into the hepatocyte
- ▪
  This may be caused by hypothyroidism or gestational hormones that may inhibit the uptake of bilirubin across the hepatocyte membrane.
- ▪
  A decrease in the amount of bilirubin bound to serum proteins also results in decreased uptake by hepatocytes. The reduction in bilirubin binding may be the result of hypoalbuminemia, generalized hypoproteinemia, or displacement of bilirubin from these proteins by certain drugs.
3.
Abnormalities of intracellular binding or storage of bilirubin within the hepatocyte: These are rare disorders and include deficiencies or alteration in GST, the primary intracellular binding protein for bilirubin. Treatment is not indicated, because there is no associated morbidity or mortality.
4.
Inefficient conjugation of bilirubin: Within the hepatocyte, bilirubin is conjugated with glucuronic acid by (UDP)–glucuronyl transferase to form bilirubin monoglucuronide or diglucuronide.
- a.
  Gilbert syndrome
  - ▪
    The most common hereditary hyperbilirubinemia syndrome; caused by mutations in the promotor region of the UGT1 gene, resulting in decrease in (UDP)–glucuronyl transferase activity
  - ▪
    The main clinical features are intermittent benign elevations of serum unconjugated bilirubin levels in otherwise asymptomatic subjects; this is especially prominent during periods of stress such as a viral illness. Gilbert syndrome can also contribute to neonatal hyperbilirubinemia and lead to higher serum bilirubin levels.
  - ▪
    The diagnosis is based on exclusion of hemolysis or liver cell injury; genetic testing is available.
  - ▪
    No treatment is required; the only long-term consequence is an increased risk of gallstones.
- b.
  Crigler-Najjar syndrome (autosomal recessive diseases caused by various types of mutations in UGT1 gene)
  - ▪
    Crigler-Najjar syndrome type I is characterized by an absence of bilirubin (UDP)–glucuronyl transferase and leads to severe hyperbilirubinemia (usually >20 mg/dL). This is associated with neurologic effects secondary to kernicterus.
  - ▪
    Crigler-Najjar syndrome type II is caused by a reduction of (UDP)–glucuronyl transferase and has a milder phenotype (total bilirubin usually <20 mg/dL).
  - ▪
    Treatment includes exchange transfusion and aggressive phototherapy to keep bilirubin levels below the threshold for kernicterus. Phenobarbital therapy can be used in Crigler-Najjar syndrome type II, which generally has better prognosis than type I. Liver transplantation is the definitive treatment for Crigler-Najjar type I.
5.
Alterations in the excretion of conjugated bilirubin from the hepatocyte: In normal circumstances, bilirubin diglucuronide is predominantly excreted into the canaliculus by a carrier protein localized to the multidrug resistance–associated protein (MRP2) on the canalicular membrane. A fraction of bilirubin glucuronide is secreted into sinusoidal blood; reuptake into hepatocyte occurs via transporters ( gene /protein) ABCC3/ MRP3 or SLCO1B1/ OATP1B1 and SLCO1B3/ OATP1B3 (OATP stands for organic anion-transporting polypeptide). Diseases that cause alterations of these steps can result in hyperbilirubinemia (both unconjugated and conjugated bilirubin) and include the following:
- a.
  Dubin-Johnson syndrome:
  - ▪
    An autosomal recessive disease caused by a mutation in ABCC2 on chromosome 10q24 that results in alterations in bilirubin excretion via MRP2
  - ▪
    Characterized by elevated serum levels of conjugated and unconjugated bilirubin and otherwise normal liver biochemical test levels; commonly presents in young adulthood
  - ▪
    Hyperbilirubinemia can be accentuated during pregnancy or with use of oral contraceptives.
  - ▪
    The diagnosis is based on normal total coproporphyrin levels in urine but an increase in the percentage of coproporphyrin I. Liver biopsy specimens, if obtained, show a characteristic melanin-like pigment deposited in hepatocytes in an otherwise histologically normal liver.
  - ▪
    Because of the benign nature of this syndrome, no treatment is required.
- b.
  Rotor syndrome:
  - ▪
    An autosomal recessive disease caused by mutations in SLCO1B1 and SLCO1B3 on chromosome 12 that results in an absence of OATP1B1 and OATP1B3 on the basolateral surface of hepatocytes
  - ▪
    Clinically indistinguishable from Dubin-Johnson syndrome
  - ▪
    Urine test is definitive: There is an increase in total coproporphyrin levels.
  - ▪
    Like Dubin-Johnson syndrome, Rotor syndrome is benign, and no treatment is required.
6.
Abnormalities of hepatocyte excretory function or intrahepatic bile ducts (intrahepatic cholestasis [or both]); impairment of canalicular membrane transporters or obstruction of bile flow at the level intrahepatic bile duct. May be the result of a genetic abnormality in a hepatocyte transport protein (a to d, following ), hepatocellular excretory function (e, following ), or intrahepatic bile ducts (f, following ):
- a.
  Progressive familial intrahepatic cholestasis, type I (PFIC-1; FIC1 deficiency) , previously known as Byler disease, is an autosomal recessive disease caused by defects in the ATP8B1 gene on chromosome 18q21–22 that encodes the FIC1 protein.
  - ▪
    FIC1 is a P-type adenosine triphosphatase (ATPase) that functions in the transport of aminophospholipids across the hepatocyte canalicular plasma membrane.
  - ▪
    Patients characteristically have a low serum gamma-glutamyltranspeptidase (GGTP) level in the setting of cholestasis.
  - ▪
    Severe pruritus is noted at an average age of onset of 3 months.
  - ▪
    Because the ATP8B1 gene is distributed in various tissues, extrahepatic features can include growth failure, chronic diarrhea, pancreatitis, and sensorineural hearing loss.
  - ▪
    FIC1 deficiency exhibits a variable clinical course with the potential for progression to cirrhosis and end-stage liver disease.
  - ▪
    Treatment is aimed at ameliorating pruritus. Liver transplantation is curative of the liver disease and typically is required in the first decade of life; however, liver steatosis and chronic diarrhea may be aggravated following liver transplantation.
  - ▪
    A milder form of ATP8B1 mutation is called benign recurrent intrahepatic cholestasis (BRIC) and is characterized by recurrent episodes of jaundice and pruritus without progression to end-stage liver disease.
- b.
  Progressive familial intrahepatic cholestasis, type II (PFIC-2; BSEP deficiency), is clinically similar to PFIC-1 but without extrahepatic features. Both are associated with low serum GGTP levels. The disease results from defects in the hepatocyte bile salt export pump (BSEP) caused by mutations in the ABCB11 gene on chromosome 2q24 leading to accumulation of bile salts within hepatocytes and an eventual effect on hepatocellular function.
  - ▪
    BSEP deficiency can also vary from a mild phenotype (BRIC) to a more severe form requiring liver transplantation.
  - ▪
    A liver biopsy specimen will reveal neonatal hepatitis with giant cell transformation of hepatocytes.
  - ▪
    Patients who are BSEP deficient, especially those with biallelic truncating mutations, are at high risk for the development of hepatocellular carcinoma (HCC). Therefore, surveillance is justified.
- c.
  Progressive familial intrahepatic cholestasis, type III (PFIC-3; MDR3 deficiency) progresses rapidly to cirrhosis and liver failure.
  - ▪
    Unlike other types of PFIC, this syndrome is characterized by elevated serum levels of GGTP.
  - ▪
    PFIC-3 is caused by mutations in the ABCB4 gene on chromosome 7q21-36, which encodes an active export pump involved with the translocation of phosphatidylcholine across the canalicular hepatocyte membrane.
- d.
  TJP2 deficiency is caused by protein-truncating mutations in TJP2 , resulting in failure of protein localization and disruption of tight junction structure. These mutations have been found to be associated with a low-GGTP cholestatic phenotype in infants.
- e.
  Hepatocellular damage caused by various etiologies, such as metabolic disorders, sepsis, urinary tract infection, and drug or toxin toxicity, can also present with hyperbilirubinemia, particularly cholestasis, presumably secondary to hepatocyte damage or altered bile flow (or both).
- f.
  Intrahepatic bile duct paucity, defined as a reduced ratio of interlobular bile ducts to portal tracts (normal is 0.9 to 1.8; paucity is <0.5), may be nonsyndromic or syndromic, as in Alagille syndrome, which is associated with peripheral pulmonic stenosis, butterfly vertebrae, posterior embryotoxon, and characteristic facies.
7.
Structural abnormalities of the extrahepatic biliary tract prevent drainage of bile from the canaliculus into the intestine and can cause accumulation of bile and reflux of bilirubin into the systemic circulation.
- a.
  Biliary atresia is a progressive disease characterized by inflammation and fibrosis of the extrahepatic biliary tract resulting in partial or complete obliteration of the extrahepatic bile ducts.
  - ▪
    Biliary atresia typically manifests as cholestasis (conjugated hyperbilirubinemia) with acholic stools between 2 and 6 weeks of age.
  - ▪
    Phenotypically, there are at least two forms: (1) The majority of patients (85%) present as isolated biliary atresia (also known as the postnatal form); (2) another group is associated with major anomalies with or without laterality defects. Associated anomalies in the latter group included anomalies of spleen (asplenia, polysplenia) and of the cardiovascular, gastrointestinal (intestinal malrotation, atresia), and genitourinary systems; <10% of cases may have cystic dilatation of extrahepatic bile duct in addition to fibrosing obstruction.
  - ▪
    Diagnosis is based on clinical, biochemical, and histologic data. Liver biopsy specimens show portal fibrosis and bile duct proliferation; if extrahepatic bile duct obstruction cannot be ruled out, intraoperative cholangiography should be performed.
  - ▪
    This anomaly is treated initially by surgical creation of a Kasai portoenterostomy, which allows drainage of bile directly from the liver into the intestine. Although the procedure is not curative, it may delay the progression of disease.
  - ▪
    End-stage liver disease secondary to biliary atresia is the most common reason for liver transplantation in children.
- b.
  Choledochal cyst, a cystic dilatation of the biliary tract, may be exclusively extrahepatic or include dilatations of the intrahepatic biliary tract.
  - ▪
    The clinical presentation with abdominal pain and jaundice, with or without a palpable abdominal mass, may occur at any age.
  - ▪
    The diagnosis can be made by ultrasonography, computed tomography (CT), or endoscopic retrograde or magnetic cholangiopancreatography (ERCP, MRCP).
  - ▪
    Treatment is with surgical excision of the dilated segment, rather than bypass or drainage, because of the increased frequency of malignancy in the epithelium of the cyst.
8.
Alterations in the enterohepatic circulation can produce an increase in reabsorption of bilirubin from the intestine. The cause may be intestinal obstruction, as in intestinal atresia or Hirschsprung disease, or alterations in the bacterial flora because of the use of antibiotics.

Fig. 25.1, Steps in bilirubin metabolism. (1) Bilirubin production; (2) uptake of bilirubin into hepatocytes; (3) intracellular binding; (4) conjugation; (5) excretion of conjugated bilirubin; (6) excretion of bile component via hepatocyte membrane transporters to intrahepatic bile ducts; (7) extrahepatic biliary tract; (8) enterohepatic circulation. The numbers correspond to the steps described in the text. The inset shows the genes and corresponding proteins (with their transport products shown outside the upper hepatocyte) mutated in disorders (shown outside the lower hepatocyte) affecting steps 3 through 6. The full names of the genes and proteins are given in the text.

Complications

1.
Unconjugated hyperbilirubinemia
- ▪
  Kernicterus (bilirubin encephalopathy) may result from elevated levels of unconjugated bilirubin. Populations at risk include neonates and individuals with Crigler-Najjar syndrome, type I.
- ▪
  Unconjugated bilirubin levels >30 mg/dL are associated with development of encephalopathy.
- ▪
  Factors that increase the risk of kernicterus include hypoalbuminemia and bilirubin displacement from albumin by drugs or organic anions.
2.
Cholestasis
- ▪
  Malnutrition secondary to intestinal fat malabsorption can lead to failure to thrive and fat-soluble vitamin deficiencies.
- ▪
  Intractable pruritus
- ▪
  Xanthomatosis secondary to alterations in cholesterol metabolism
- ▪
  HCC can occur in many diseases associated with intrahepatic cholestasis, such as FIC1, BSEP, and MDR3 deficiency; surveillance for HCC is required.

Treatment

1.
Unconjugated hyperbilirubinemia
- ▪
  Double-volume exchange transfusion lowers the risk of kernicterus in the newborn by rapidly reducing the serum bilirubin concentration.
- ▪
  Phototherapy: Photoisomerization of bilirubin to a more polar compound allows excretion of bilirubin in the urine.
- ▪
  Bilirubin metabolism can be accomplished by administration of phenobarbital, which induces microsomal enzymes that facilitate bilirubin metabolism.
2.
Cholestasis
- ▪
  Treatment of all forms of intrahepatic cholestasis is symptomatic, with special consideration given to management of malnutrition and pruritus.
- ▪
  Ursodeoxycholic acid, a choleretic bile acid, 15 mg/kg per day in divided doses, can be used to augment bile flow in patients with cholestasis.
- ▪
  Supplementation with fat-soluble vitamins is also necessary because intestinal absorption is poor without normal bile flow.
- ▪
  Liver transplantation may be required in some cases.

You're Reading a Preview

Become a Clinical Tree membership for Full access and enjoy Unlimited articles

Become membership

If you are a member. Log in here