Gastroenterology and Hepatology Board Review: Pearls of Wisdom, Third Edition

Section VIII HEPATOLOGY

CHAPTER 49. Congenital and Structural Abnormalities and Pediatric Diseases of the Liver

Doron D. Kahana, MD, FAAP, CPNS, Chirag S. Desai, MD, and Khalid M. Khan, MBChB, MRCP

Image What percentage of the total blood flow is received by the liver?

About 28%. Seventy-five percent of this comes through the portal vein.

Image What is the significance of hepatic artery blood supply to the liver?

The hepatic artery is the sole supply to the bile duct. Thrombosis of hepatic artery can lead to complete bile duct necrosis and can lead to biloma formation and, ultimately, infection and graft loss after liver transplant.

Image What are the major cell types in the liver?

Hepatocytes comprise about 60% of the total cell population. Thirty-five percent is of mesenchymal origin (Kupffer, stellate, and sinusoidal endothelial cells). The remaining 5% are bile ductular epithelial cells.

Image What is the physiological significance of the zonal division of the hepatic acinus?

Cells are grouped into three zones based on their distance from the portal triad. Cells of zone 1 (periportal area) are closest to nutrient-rich blood and least vulnerable to hypoxia. Zone 3 is the microcirculatory periphery, first to be damaged and last to regenerate after hypoxia. In zones 1 and 2, oxidative processes predominate. In zone 3 (perivenular area), glycolysis is more active. Different pathologies of the liver affect different zones, and the pattern of damage based on zones is useful in the diagnosis.

Image Which part of the small bowel absorbs most of the bile acids? What is the importance of this absorption in relation to the liver?

The enterohepatic circulation of bile acids involves the distal ileum. Small amounts are also absorbed from the proximal small bowel and colon. Many drugs (eg, FK506) and nutrients (eg, long-chain fatty acids, fat-soluble vitamins) have bile acid-based absorption. Deficiency of bile acid absorption results in decreased absorption of such drugs and nutrients.

Image Which of the commonly measured aminotransferases is more liver specific?

Alanine aminotransferase (ALT) is found predominantly in the cytosol of hepatocytes. Aspartate aminotransferase (AST) is found in the cytosol and mitochondria of hepatocytes and in many extrahepatic tissues, such as red blood cells and muscle. Usually, both are elevated with liver cell damage; however, ALT is considered more specific to liver disease, while an increase in AST out of proportion to ALT suggests an extrahepatic cause (eg, hemolysis, muscle damage, or cardiac event).

Image What enzymes are used to evaluate cholestasis?

Alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), and 5′-nucleotidase levels are elevated during cholestasis. The latter is the most specific but least available. Alkaline phosphatase levels may be high in pediatric patients due to active bone growth, rickets, or following a viral infection. The major clinical value of serum GGT is in conferring organ specificity to an elevated value for alkaline phosphatase since GGT activity is not increased in patients with bone disease.

Image What coagulation factors are synthesized in the liver and what test is used to indirectly assess them?

Factors I, II, V, VII, IX, and X are synthesized in the liver. The prothrombin time (PT), a test that evaluates the extrinsic pathway, is prolonged when any of these factors are deficient, either alone or in combination. In liver failure, these coagulation factors are significant prognosticators for recovery. Serum levels of factors V and II are extremely useful in deciding indication for transplant in fulminant hepatic failure and in many European countries they are primary indicators for listing for transplant. Typically, factors V and VIII are used in clinical practice. The latter is an endothelial factor and, therefore, should be normal in liver disease. If both are abnormal, sampling issues should be excluded.

Image In addition to liver synthetic failure, what are the other causes of a prolonged PT?

Congenital coagulation factor deficiency, consumptive coagulopathy, disseminated intravascular coagulation, treatment with coumadin, and vitamin K deficiency.

Image What are the vitamin K-dependent coagulation factors?

Factors II, VII, IX, and X. In theory, comparison of factors V and VII levels should differentiate liver disease from vitamin K deficiency. Clinically, a factor V level after administration of intravenous vitamin K is the most practical way to assess the nature of a prolonged PT.

Image True/False: The liver edge is normally palpable in children.

True. The right lobe may be up to 3.5 cm below the costal margin during the first 6 months, 3 cm below before 4 years, and 2 cm below before 12 years. The upper border is usually in the fifth intercostal space. The latter is important to be aware, particularly in patients with asthma or obstructive airway disease. Percussion of the upper border can help to differentiate true hepatomegaly from downward displacement of the liver with hyperinflation of the lungs.

Image What is the major source of bilirubin?

Hemoglobin metabolism accounts for about 80% of produced bilirubin in mammals. Other heme-containing proteins that are degraded to bilirubin include the cytochromes, catalases, and muscle myoglobin. Daily production of bilirubin in a healthy, full-term infant is about 6–8 mg/kg/day and in a healthy adult, it is about 3–4 mg/kg/day.

Image What is the first enzyme in the pathway converting hemoglobin to bilirubin?

Microsomal heme oxygenase. This enzymatic reaction results in reduction of the porphyrin iron (Fe3+ to Fe2+) and hydroxylation of the alpha methane (=C-) carbon.

Image True/False: Albumin serves the purpose of bilirubin transport from sites of production to the liver and has a very high affinity for bilirubin?

True. Bilirubin is taken up into the hepatocyte from the hepatic sinusoids where it is bound by another protein carrier, glutathione S-transferase.

Image Bilirubin is conjugated within the endoplasmic reticulum with glucuronic acid, the donor of which is?

Uridine diphosphate (UDP). The enzyme responsible for this conjugation is bilirubin glucuronosyltransferase (BGT).

Image How do metalloporphyrins prevent neonatal jaundice?

They block heme oxygenase and prevent bilirubin formation.

Image What are the two main bile acids in humans?

Cholic acid and chenodeoxycholic acid are found at a ratio of approximately 1:1 and make up about 75%–80% of the bile acid pool.

Image Approximately what percentage of the bile acid pool is newly synthesized in adults?

2%–5%. This percentage can be increased in patients with impaired bile acid reabsorption. About 30 g of bile acids is reabsorbed by the intestines every day (enterohepatic circulation) with about 0.2–0.6 g eliminated in the stool.

Image True/False: Bile acids make up the majority of the solute load of bile.

True. Other bile components that exert a solute load and passively draw water into the canaliculi include phospholipids, organic and inorganic anions (eg, chloride), and cholesterol.

Image What is the rate-limiting enzyme for bile acid synthesis?

Cholesterol 7α-hydroxylase.

Image The final step of primary bile acid synthesis is their conjugation with which amino acids?

Taurine and glycine are added to bile acid intermediates to form conjugated primary bile acids.

Image What prevents adults from reabsorbing bilirubin via the enterohepatic circulation?

Bacterial conversion of bilirubin conjugates to urobilinoids. Neonates are at risk for increased intestinal absorption of bilirubin for several reasons including increased amount of beta-glucuronidase in the lumen, which hydrolyzes bilirubin conjugates to bilirubin, absence of intestinal flora to convert bilirubin conjugates to urobilinoids, and a significant amount of bilirubin in meconium.

Image What constitutes physiological jaundice in the newborn?

Increased bilirubin levels to 6–8 mg/dL on days 3 to 4. This is likely due to greater mass of erythrocytes, which carry a shorter life span. Most normal neonates experience unconjugated bilirubin levels greater than 1.4 mg/dL in the first few days. Moderate jaundice (> 12 mg/dL) occurs in about 12% of breast-fed infants and 4% of formula-fed infants. Severe jaundice (> 15 mg/dL) occurs in 2% of breast-fed infants and 0.3% of formula-fed infants.

Image Which characteristics of neonatal jaundice should lead to further evaluation?

• Infant appears ill.

• Jaundice <36 h of age.

• Jaundice >10 days of age.

• Bilirubin >12 mg/dL at any time.

• Direct bilirubin >2 mg/dL at any time.

Image What is breast-feeding jaundice and breast milk jaundice?

Early onset jaundice (days 2 to 4) is considered breast-feeding jaundice and is likely a consequence of suboptimal fluid and calorie intake in the first days of life coupled with meconium excretion. Breast milk jaundice develops after the first week of life and is thought to be caused by inhibition of bilirubin excretion by factors in breast milk. In some cases, evaluation of hemoglobin, reticulocyte count, peripheral blood smear, liver tests, and coagulation studies may be necessary as blood group incompatibility, hemolysis, and hypothyroidism need to be excluded.

Image What hereditary hyperbilirubinemias are caused by defects of bilirubin conjugation?

The autosomal recessive Crigler–Najjar’s syndrome type 1 in which bilirubin glucuronyl transferase is completely absent has the worst prognosis. In the autosomal dominant Crigler–Najjar’s syndrome type 2 (Arias’ syndrome), residual glucuronidase activity provides for a much better prognosis. Gilbert’s syndrome is autosomal dominant and benign with hepatic bilirubin clearance reduced by approximately 50% due to impaired glucuronidation.

Image At what age are familial unconjugated hyperbilirubinemias typically recognized?

Crigler–Najjar’s syndrome types 1 and 2 are recognized in the newborn period while Gilbert’s syndrome is usually not discovered until after puberty.

Image How can Crigler–Najjar’s syndrome types 1 and 2 be differentiated from each other?

By the clinical response to phenobarbital, which induces residual enzyme activity in type 2 and causes a significant drop in total serum bilirubin level.

Image What is the main risk of Crigler–Najjar’s syndrome type 1?

Kernicterus. Serum bilirubin levels typically range from approximately 15 to 45 mg/dL, and there is risk of both neonatal and later kernicterus.

Image What is the mainstay of daily treatment while awaiting transplantation for individuals with Crigler–Najjar’s syndrome type 1?

Phototherapy.

Image True/False: Liver biopsy is indicated for the diagnosis of Gilbert’s syndrome.

False. Unless other biochemical abnormalities are present, a modestly elevated serum unconjugated bilirubin without hemolysis or other laboratory indication of liver disease does not require any further evaluation.

Image How does bile composition differ in Gilbert’s syndrome from normal?

In Gilbert’s syndrome, there are more bilirubin monoglucuronides and less diglucuronides than in normal bile.

Image What is the genetic marker for Gilbert’s syndrome in Caucasians?

Homozygous state for an extra TA in the TATA promoter region of the BGT gene.

Image What liver serologies are abnormal in Gilbert’s syndrome?

Total and indirect bilirubin levels.

Image What is the cause of Dubin–Johnson’s syndrome?

A genetic mutation causing deficient canalicular multispecific organic anion transport (cMOAT) protein in the apical canalicular membrane (cMOAT is also known as MRP2 [multidrug resistance protein]).

Image How does hepatic pigmentation differentiate Dubin–Johnson’s syndrome from Rotor’s syndrome?

Dubin–Johnson’s syndrome has black pigment in hepatocytes while Rotor’s syndrome does not.

Image What is the inheritance pattern, treatment, and prognosis of Dubin–Johnson’s and Rotor’s syndromes?

Both are autosomal recessive, have good prognoses, and do not require treatment.

Image Measurement of what urinary component enables differentiation of Rotor’s syndrome and Dubin–Johnson’s syndrome?

Urinary coproporphyrins. Total coproporphyrin (I and III) is normal in Dubin–Johnson’s syndrome but over 80% is type I. Total coproporphyrin (I and III) is elevated two- to fivefold in Rotor’s syndrome and less than 80% is type I.

Image What is the single test that helps differentiate cholestasis from other forms of jaundice?

Direct bilirubin: a direct fraction >2 mg/dL or >20% of total bilirubin indicates cholestasis.

Image What are the three most common causes of cholestasis in infants?

Extrahepatic biliary atresia (EHBA) and idiopathic neonatal hepatitis are each responsible for about one-third of the cases. Alpha-1 antitrypsin deficiency is found in about 17% of the cases.

Image What is the best nonsurgical method to differentiate EHBA from idiopathic neonatal hepatitis?

Liver biopsy. Histological features of EHBA include bile duct proliferation and bile duct plugs, portal fibrosis and edema, and preservation of normal lobular architecture. In neonatal hepatitis, typically there is inflammatory infiltration of the lobule, hepatocellular necrosis, lobular disarray, and mild portal tract disarray. Multinucleated giant cells and pseudoglandular transformation (cells arranged around a dilated canaliculus) can be present in both.

Image True/False: There is good concordance for EHBA between siblings.

False. The occurrence of EHBA in siblings is extremely rare.

Image True/False: Visualization of the gallbladder rules out EHBA.

False. There still may be distal atresia.

Image True/False: Pigmented stools exclude EHBA.

False. Usually pigment in the stool is proof of biliary patency; however, in some cases of severe hyperbilirubinemia, bilirubin can be excreted through the bowel wall and stools can be mildly pigmented even in the presence of EHBA.

Image True/False: Newborns with EHBA are ill-appearing at birth.

False. Most are full-term and in good condition. Stools may be pale from the outset but may be initially pigmented in 15%–20%.

Image What is the Kasai procedure? What is the most effective time for Kasai’s procedure to get optimum results and avoid the need for liver transplantation?

Surgical excision of the whole extrahepatic biliary system and Roux-en-Y anastomosis of an intestinal conduit to the denuded porta hepatis (portoenterostomy). This procedure is best done before 8–10 weeks of age to have a good outcome.

Image What are the major late complications of the Kasai procedure?

Cholangitis develops in 40%–60% of the patients during the first year. Portal hypertension leads to esophageal varices in 39% of patients.

Image True/False: Biliary atresia is the most common indication for liver transplant in pediatrics.

True, followed by Alagille’s syndrome and fulminant hepatic failure.

Image What is the classical triad of symptoms characteristic of choledochal cysts?

Abdominal pain, mass, and jaundice. However, this occurs in only 38% of pediatric patients. Frequently, it presents as cholestasis indistinguishable from EHBA, recurrent abdominal pain, recurrent pancreatitis, or acute abdomen resulting from cholangitis or perforation.

Image What is the most common type of choledochal cyst?

Type 1, which is saccular or fusiform dilatation of extrahepatic bile duct (EHBD), accounts for 80%–90%.

Image What is the preferred surgical treatment of choledochal cysts?

Radical cyst excision, if possible. If there is complicating hepatic disease, portal hypertension, and cholangitis, an initial drainage procedure may be needed with later revision.

Image What is the histological criterion for the diagnosis of intrahepatic biliary atresia (paucity of interlobular bile ducts [PIBD])?

The normal ratio of interlobular bile ducts to portal tracts is 0.9–1.8; a ratio less than 0.6 suggests PIBD.

Image What is Alagille’s syndrome?

Alagille’s syndrome is also referred to as arteriohepatic dysplasia or syndromic PIBD. In these patients, intrahepatic biliary atresia is associated with cardiac, facial, ocular, and/or vertebral abnormalities.

Image What studies are important in the diagnosis of Alagille’s syndrome?

Echocardiography, renal ultrasound, vertebral imaging, and ophthalmologic exam. A liver biopsy, after the first 3 months of life, should be notable for dysplastic or hypoplastic bile ducts.

Image Alagille syndrome is caused by mutations in which gene?

Jagged 1 on chromosome 20p12 codes for a ligand in the Notch signaling pathway and is believed to be responsible for the majority of cases. The inheritance is autosomal dominant with variable expression. The estimated incidence is 1:100,000 live births.

Image What is the typical cardiac defect in Alagille’s syndrome?

Peripheral pulmonary artery stenosis is most common. A cardiac murmur is present in almost all patients.

Image What eye abnormality is associated with Alagille’s syndrome?

Posterior embryotoxon.

Image What are some treatment options for pruritus associated with cholestasis?

Cholestyramine, colestipol, rifampin, phenobarbital, antihistamines, and ursodeoxycholic acid. A diet rich in polyunsaturated fatty acids may promote fecal excretion of bile acids. Ultraviolet light is also believed to be helpful. Opiate antagonists may provide some relief but have not been studied in children. Refractory cases may benefit from partial external diversion of bile flow.

Image What problems are associated with the administration of cholestyramine?

Poor palatability, interference with absorption of fat-soluble vitamins, and constipation.

Image What are the criteria for diagnosing idiopathic neonatal hepatitis?

Proof of biliary patency and exclusion of all other causes of neonatal cholestasis.

Image True/False: Giant cell transformation is pathognomonic of idiopathic neonatal hepatitis.

False. Although more frequently observed in infancy, it can accompany various liver diseases in different ages. The histogenesis of the hepatic giant cell is not clear.

Image What does the acronym TORCH stand for?

It was introduced as a reminder of the serologic testing for infectious agents that might cause neonatal hepatitis. T (Toxoplasma), O (Other, eg, syphilis, HIV), R (rubella), C (CMV, coxsackie), H (Herpetoviridae: CMV, EBV, HSV). In practice, the most important infectious agents to rule out are CMV, EBV, and HSV.

Image What eye abnormality is commonly associated with infectious neonatal hepatitis?

Chorioretinitis.

Image Biliary atresia and intracranial calcifications suggest what diagnosis?

Cytomegalovirus or Toxoplasmosis.

Image What is the most frequent metabolic cause of cholestasis in infancy?

Alpha-1 antitrypsin deficiency accounts for 17% of neonatal cholestasis cases.

Image True/False: The quantitation of serum alpha-1 antitrypsin level is sufficient to make the diagnosis of alpha-1 antitrypsin deficiency.

False. One of the pitfalls of diagnosis is that alpha-1 antitrypsin is an acute phase reactant and, thus, may rise to normal in cases of hepatitis. The diagnosis of alpha-1 antitrypsin deficiency is made by testing for the molecular phenotype of the protein (protease inhibitor [Pi] type).

Image Which electrophoretic alpha-1 antitrypsin phenotype is associated with the highest probability of liver disease?

The ZZ phenotype.

Image The hallmark of the liver biopsy in patients with alpha-1 antitrypsin deficiency is the deposition of the diastase resistant, mutant alpha-1 antitrypsin glycoprotein that stains positive by what stain?

Periodic acid Schiff.

Image Deficiency of which enzyme is responsible for tyrosinemia type I?

Fumaryl acetoacetate hydrolase—the last enzyme of tyrosine degradation.

Image True/False: Dietary correction of tyrosinemia alters the course of the liver disease.

False. Tyrosine probably does not play a major role in the pathogenesis.

Image What biochemical abnormality is diagnostic of tyrosinemia type I?

Urinary succinyl acetone. This compound can also be measured in amniotic fluid by 15 weeks of gestation.

Image What role does succinyl acetone play in the development of symptoms in tyrosinemia type I?

This compound is hepatotoxic and an inhibitor of delta aminolevulinic acid dehydrogenase. The latter effect is responsible for the appearance of delta aminolevulinic acid in the urine and porphyria-like symptoms.

Image True/False: Galactosuria is diagnostic of galactosemia.

False. Galactosuria may be seen in many severe liver diseases.

Image What eye abnormality is associated with galactosemia?

Cataracts.

Image What monosaccharides make up lactose?

Glucose and galactose.

Image What assay is used for the diagnosis of galactosemia?

Measurement of erythrocyte galactose-1-uridyl-transferase. This assay must be done in any jaundiced, septic, or bleeding neonate if there is history of siblings with cataracts or unexplained death.

Image What is the significance of lactosuria in neonates?

None. Lactosuria may normally occur in healthy newborns.

Image What is the treatment of galactosemia?

Galactose-free diet for life.

Image What enzyme deficiency causes benign fructosemia?

Absence of fructokinase. This is asymptomatic.

Image Deficiency of which enzyme of fructose metabolism causes severe symptoms?

Absence of fructose-1-phosphate-aldolase and fructose-1,6-diphosphatase, both cause severe symptoms.

Image Deficiency of which enzyme of fructose metabolism causes hereditary fructose intolerance?

Absence of fructose-1-phosphate-aldolase.

Image What are typical fructose-containing foods?

Fruit and honey.

Image True/False: Patients with hereditary fructose intolerance are asymptomatic if they avoid fructose.

True. In fact, older children develop an aversion to foods containing fructose.

Image What are the typical presenting symptoms of hereditary fructose intolerance in infancy?

Vomiting, pallor, lethargy, sweating, and/or convulsions following ingestion of fructose.

Image What is the most common physical finding in hereditary fructose intolerance?

Hepatomegaly.

Image True/False: Patients with fructose-1,6-diphosphatase deficiency are asymptomatic if they avoid fructose?

False. Fructose ingestion is not required in fructose-1,6-diphosphatase deficiency for symptoms to develop.

Image What is the toxic substance that accumulates in hereditary fructose intolerance?

Fructose-1-phosphate.

Image How does fructose-1-phosphate cause symptoms?

It results in hypoglycemia by inhibiting glycogenolysis and gluconeogenesis. In addition, it is cytotoxic to the liver, kidneys, and gut.

Image What renal manifestations may develop as a result of fructose-1-phosphate nephrotoxicity?

Renal tubular acidosis, aminoaciduria, hyperuricemia, hypophosphatemia, or hypocalcemia.

Image What methods are used in the diagnosis of hereditary fructose intolerance?

Enzyme assays from intestinal or liver specimens.

Image Which glycogen storage disease is associated with the most severe liver manifestations?

Glycogenosis type IV (branching enzyme defect) regularly progresses to cirrhosis.

Image Which lysosomal storage disease is associated with parenchymal liver disease in children?

Nieman–Pick type C.

Image What metabolites accumulate in the cells of Nieman–Pick disease patients?

Sphingomyelin and cholesterol.

Image What is the most common cause of neonatal ascites?

Obstructive uropathy.

Image What are the most common causes of noncirrhotic, extrahepatic portal hypertension in children?

Congenital hepatic fibrosis and extrahepatic portal vein thrombosis.

Image What medical conditions are associated with congenital hepatic fibrosis and extrahepatic portal vein thrombosis?

Congenital hepatic fibrosis is associated with autosomal recessive polycystic kidney disease. Portal vein thrombosis in children is associated with umbilical vein catheterization (ie, neonatal).

Image What is a surgical porto-systemic shunt and what are the different types?

To decompress esophageal varices for the control of bleeding, when all endoscopic treatment and medical management fail, a surgical shunt may be created between the portal and systemic venous system. A shunt can be selective or nonselective.

Selective shunts decompress the esophageal varices trans-splenically without decompressing the main portal axis. This shunt has a much lower incidence of hepatic encephalopathy. The distal splenorenal shunt is an example of this type of shunt. This shunt leads to augmentation of ascites and, hence, severe ascites is a contraindication for this shunt.

Nonselective shunts directly reduce portal hypertension. Portocaval shunts (end to side [end of portal vein to vena cava] or side to side), mesocaval shunts, and proximal splenorenal shunts are examples of this type of shunt. These shunts carry a higher risk of postsurgical encephalopathy in cirrhotic patients; however, they are very good shunts for noncirrhotic patients and for extrahepatic portal vein obstruction (EHPVO).

• • • SUGGESTED READINGS • • •

McLin VA, Balistreri, WF. Approach to neonatal cholestasis. In: Walker WA, Goulet O, Kleinman RE, et al., eds. Pediatric Gastrointestinal Disease. Hamilton, ON, Canada: BC Decker Inc;2004;1079-1093.

Piccoli DA, Russo P. Disorders of the biliary tract. In: Walker WA, Goulet O, Kleinman RE, et al., eds. Pediatric Gastrointestinal Disease. BC Decker Inc;2004:1094-1145.

Yonem O, Bayraktar Y. Is portal vein cavernous transformation a component of congenital hepatic fibrosis? World J Gastroenterol. 2007;13(3):1928-1929.