Diseases » Chronic liver disease

Jaundice

Jaundice: Excerpt from The Diagnostic Approach to Symptoms and Signs in Pediatrics

Jaundice,yellow discoloration of skin and sclera, is produced by depositionof bilirubin in these tissues. Increase in unconjugated or conjugatedbilirubin or both produce jaundice, which is visible when totalserum bilirubin is >2 mg/dL.

Conjugated hyperbilirubinemia existswhen >2 mg/dL is conjugated or when >15% oftotal serum bilirubin is conjugated.

Because causes of increases in unconjugatedand conjugated bilirubin differ, each is discussed in turn. In eachcase, time of onset (neonatal or postneonatal) is clinically important.

Principal Causes of Unconjugated Hyperbilirubinemia

1. Neonatalonset
   1. Increasedbilirubin production
      1. Physiologic
      2. Hemolytic anemia
         1. Isoimmunization
         2. Red cell enzyme defects
            1. Glucose-6-phosphatedehydrogenase deficiency
            2. Pyruvate kinase deficiency
            3. Other enzyme defects
         3. Red cell membrane defects
            1. Hereditaryspherocytosis
            2. Hereditary elliptocytosis
            3. Hereditary stomatocytosis
            4. Infantile pyknocytosis
         4. Septicemia
      3. Polycythemia
      4. Enclosed hematoma
   2. Decreased bilirubin uptake, storage,or metabolism
      1. Physiologic
      2. Hypoxia and acidosis
      3. Hypoalbuminemia
      4. Increased serum fatty acids
      5. Septicemia
      6. Drugs
      7. Hypothyroidism
      8. Lucey-Driscoll syndrome (transientfamilial neonatal hyperbilirubinemia)
      9. Crigler-Najjar syndrome (types I andII)
   3. Increased enterohepatic circulation
      1. Physiologic
      2. Breast-feeding–related jaundice
      3. Intestinal obstruction
2. Postneonatal onset
   1. Increasedbilirubin production
      1. Hemolytic anemia
      2. Septicemia
   2. Decreased bilirubin uptake, storage,or metabolism
      1. Gilbertsyndrome
      2. Septicemia

Clinical Features and Diagnosis: Unconjugated Hyperbilirubinemia(Neonatal Onset)

Increased Bilirubin Production

Physiologic

Physiologicjaundice is most common cause of jaundice in newborns. Certain mechanismsproduce physiologic jaundice:

Decrease in life span of red cells (70–80days)

Increase in number of red cells incirculation (normal hematocrit range in newborns, 45–65%)

Increase in blood volume of newborns(85–90 mL/kg)

Enhanced enterohepatic circulationsecondary to diminished intestinal motility

Decrease in activity of enzyme uridinediphosphate glucuronyl transferase, which catalyzes conjugationof bilirubin with glucuronic acid

In term infants, jaundice appears after24 hrs of age, peaks at 2–4 days of age, and resolves at1–2 wks of age.

In preterm infants, maximum serum bilirubinis usually 3–5 mg/dL higher than in term infants.It peaks at 5–7 days of age and usually returns to normalby 2 mos. Maisels and Gifford (1986) reported that ninety-seventhpercentile for maximum serum bilirubin concentration is 12.4 mg/dLfor bottle-fed infants and 15.7 mg/dL for breast-fed infants.

Diagnosis of physiologic jaundice isone of exclusion.

Hemolytic Anemia

Isoimmunization

ABO incompatibilityis most common cause of isoimmunization in newborns. Potential ABOincompatibility exists with type O mother and type A or B infant.Serum bilirubin varies with degree of hemolysis, which is usuallymild. Direct Coombs test is usually positive.

Rh isoimmunization is uncommon nowbecause anti-D immune globulin can be given to Rh-negative motherafter delivery of her infant or after an abortion. Otherwise, Rhisoimmunization can be anticipated by prenatal Rh testing and monitoredwith serial amniocenteses during pregnancy. Intrauterine transfusioncan be performed if necessary.

If not recognized prior to delivery,Rh incompatibility may cause anemia, jaundice, hepatosplenomegaly,and cardiac failure at birth or in first 24 hrs of life. Positivedirect Coombs test of infant's blood indicates that maternalimmunoglobulin G (IgG) has crossed placenta and attached to infant'sred cell antigens.

Minor group antibodies against otherRh antigens and Lewis, Kell, and Duffy systems also may cause hemolysis.

Red Cell Enzyme Defects

Glucose-6-Phosphate Dehydrogenase Deficiency

X-linkeddisorder that is most common red cell enzyme deficiency.

Incidence among African-American malesis about 10%, but hemolysis is unusual except with infectionor exposure to certain drugs (e.g., sulfonamides).

In some infants, jaundice may occurwithout exposure to known hemolytic agents.

Quantitative assay of enzyme in redcells confirms diagnosis [see Chap. 45, Pallor (Anemia)].

Pyruvate Kinase Deficiency

Second mostcommon red cell enzyme deficiency.

May present in neonatal period withhemolytic anemia and jaundice.

Assay of enzyme in red cells confirmsdiagnosis [see Chap.45, Pallor (Anemia)].

Other Enzyme Defects

Hemolyticanemia and jaundice also can occur with deficiencies of certainred cell enzymes:

Hexokinase

Glucose phosphate isomerase

Phosphofructokinase

Triose phosphate isomerase

Glyceraldehyde-3-phosphate dehydrogenase

Phosphoglycerate kinase

2,3-Bisphosphoglycerate mutase

Pyrimidine-5′-nucleotidase

Measuring concentration of deficientenzyme in red cells confirms diagnosis.

Red Cell Membrane Defects

Hereditary Spherocytosis

Most commonred cell membrane defect.

Usual manifestations are hemolyticanemia, mild jaundice, and splenomegaly. Blood smear shows densemicrospherocytes.

Positive incubated osmotic fragilitytest result confirms diagnosis [see Chap. 45, Pallor (Anemia)].

Hereditary Elliptocytosis

May produce hemolytic anemia and mild jaundicein neonatal period. Presence of elliptocytes on blood smear confirmsdiagnosis [see Chap.45, Pallor (Anemia)].

Hereditary Stomatocytosis

Stomatocytesare red cells with slit-like area of pallor in their center.

In some cases severe hemolysis canproduce jaundice and splenomegaly.

Presence of stomatocytes on blood smearis diagnostic [see Chap.45, Pallor (Anemia)].

Infantile Pyknocytosis

Transientabnormality of erythrocyte morphology whose cause is unknown.

Hemolytic anemia usually peaks at 3–4wks of age.

Diagnostic blood smear shows densespiculated red cells called pyknocytes.

Spontaneous resolution occurs in afew months as soon as normal red cells replace abnormal ones.

Septicemia

May cause hemolysis with increase in unconjugatedbilirubin and jaundice. Resolution occurs with successful treatmentof septicemia.

Polycythemia

During first2 days of life, about 5% of newborns have polycythemia,which is defined as a venous Hct >65%.

Possible causes include delayed clampingof umbilical cord, maternal-fetal or twin-twin transfusion, intrauterinehypoxia, and maternal diabetes mellitus. Destruction of larger redcell mass than normal leads to unconjugated hyperbilirubinemia.

Enclosed Hematoma

Birth trauma may produce large cephalohematoma,subdural hematoma, or sequestered blood in abdomen or chest. Destructionof red cells produces increase in unconjugated bilirubin that usuallyresolves by 1–2 wks of age.

Decreased Bilirubin Uptake, Storage, or Metabolism

In addition to causes discussed below, unconjugatedhyperbilirubinemia due to decreased bilirubin uptake, storage, ormetabolism can have physiologic or septicemic causes.

Hypoxia and Acidosis

May contribute to increase in serum bilirubinconcentration because of decreased binding of bilirubin with albumin.

Hypoalbuminemia

If serum level of albumin is decreased, lessis available to bind bilirubin, and jaundice may occur.

Increased Serum Fatty Acids

Primary metabolic products of intravenousfat emulsions are free fatty acids. In high concentration, theycan block binding of bilirubin and albumin, which leads to higherserum bilirubin concentration.

Drugs

Sulfonamides and ceftriaxone displace bilirubinfrom secondary albumin-binding sites, which can lead to increasein serum bilirubin concentration.

Hypothyroidism

Althoughjaundice may be one presenting sign of primary hypothyroidism inneonates, pathogenesis is unclear.

Clinical features of hypothyroidismare discussed in Chap. 23, GrowthDeficiency: Weight and Height.

Low thyroxine (T₄)and high TSH serum levels confirm diagnosis.

Jaundice resolves with proper treatmentof hypothyroidism.

Lucey-Driscoll Syndrome (Transient Familial Neonatal Hyperbilirubinemia)

Rare disorderthat occurs during first few days of life.

In many cases, kernicterus developsunless exchange transfusions are performed. Serum bilirubin levelcan reach ≥60 mg/dL in untreated infants.

Unidentified inhibitor of uridine diphosphateglucuronyl transferase has been found in maternal and infant serum.

Inhibitory effect declines by about2 wks of age.

Crigler-Najjar Syndrome (Types I and II)

Autosomal-recessivedisorder that is caused by deficiency in enzyme activity of uridinediphosphate glucuronyl transferase, whose gene locus has been mappedto chromosome 2q37. Because of severe decrease in enzyme activityin type I, severe jaundice occurs.

Hyperbilirubinemia is milder in typeII because of less severe decrease in enzyme activity. Distinguishingcharacteristic is decrease in serum bilirubin seen in type II afteradministration of phenobarbital compared to no response in typeI.

Liver biopsy with enzyme assay is confirmatory.

Increased Enteropathic Circulation

In addition to causes discussed below, unconjugatedhyperbilirubinemia due to increased enteropathic circulation canhave physiologic causes.

Breast-Feeding–Related Jaundice

When itoccurs as early as 2–4 days of age, it is called breast-feeding–associatedjaundice. When it occurs later (4–7 days of age), it hasbeen called breast milk jaundice syndrome. Overlap occurs betweenthese 2 entities, and evidence to support 2 distinct conditionsis meager.

Mechanisms thought to explain jaundiceassociated with breast-feeding are decreased caloric intake andincrease in enterohepatic circulation of bilirubin.

Evidence for inhibitory substancesin breast milk is conflicting.

Intestinal Obstruction

Contributesto delay in bowel transit time that allows more time for bilirubindeconjugation and reabsorption.

Unconjugated hyperbilirubinemia mayoccur with pyloric stenosis, duodenal or ileal atresia, Hirschsprungdisease, and meconium ileus.

Jaundice resolves with proper treatmentof the basic lesion.

Clinical Features and Diagnosis: Unconjugated Hyperbilirubinemia(Postneonatal Onset)

In addition to hemolytic anemia and Gilbertsyndrome, septicemia may cause unconjugated hyperbilirubinemia.

Increased Bilirubin Production

Hemolytic Anemia

Any hemolytic anemia may produce unconjugatedhyperbilirubinemia. See Chap.45, Pallor (Anemia).

Decreased Bilirubin Uptake, Storage, or Metabolism

Gilbert Syndrome

Onset ofthis disorder, which may be transmitted as autosomal-dominant or-recessive trait, is generally in childhood or adolescence.

Uridine diphosphate glucuronyl transferaseactivity is <50% of normal, which results in mild,fluctuating unconjugated hyperbilirubinemia. Illness, fasting, andstress can exacerbate jaundice. Remainder of liver function testsare normal and there is no hemolysis.

Administration of phenobarbital candecrease serum bilirubin level.

Diagnostic Approach: Unconjugated Hyperbilirubinemia

Most commoncauses of neonatal unconjugated hyperbilirubinemia are physiologic jaundiceand breast-feeding–related jaundice.

Diagnostic tests should be performedin

Neonateswho become clinically jaundiced during first 24 hrs of life

Term bottle-fed infants whose maximumserum bilirubin exceeds 12 mg/dL

Term breast-fed infants whose maximumserum bilirubin exceeds 15 mg/dL

Preterm infants

Certain tests should be performed initially:

Maternal andinfant blood groups and Rh types

Unconjugated and conjugated serum bilirubin

CBC and differential

Reticulocyte count

Direct Coombs test

Analysis of blood smear

If jaundice persists, red cell G6PDactivity and T₄ and TSH levels should bedetermined.

If diagnosis remains uncertain, moreextensive studies for rarer forms of hemolytic disease and enzymeassay for uridine diphosphate glucuronyl transferase activity shouldbe considered. Tests for hepatocellular disease need to be performedonly when there is significant increase in conjugated bilirubin.

In infancy and childhood, most commoncause of unconjugated hyperbilirubinemia is hemolytic anemia [see Chap. 45, Pallor (Anemia)].

Principal Causes of Conjugated Hyperbilirubinemia (NeonatalOnset)

1. Neonatalhepatitis syndrome
   1. Idiopathic
   2. Viral infection
      1. Enteroviruses
      2. Herpes simplex virus
      3. Cytomegalovirus
      4. Varicella-zoster virus
      5. Rubella virus
      6. Parvovirus B19 infection
   3. Bacterial infection
      1. Septicemia
      2. Syphilis
   4. Parasitic infection
      1. Toxoplasmosis
2. Bile duct obstruction
   1. Biliaryatresia
   2. Choledochal cyst
   3. Alagille syndrome
   4. Caroli disease
   5. Cholelithiasis
   6. Inspissated bile (bile plug) syndrome
   7. Spontaneous perforation of the commonbile duct
3. Metabolic disorders
   1. Cysticfibrosis
   2. Alpha1-antitrypsin deficiency
   3. Galactosemia
   4. Hereditary fructose intolerance
   5. Glycogen storage disease type IV
   6. Tyrosinemia
   7. Niemann-Pick disease
   8. Gaucher disease
   9. Wolman disease/cholestrolester storage disease
   10. Disorders of bile acid synthesis
       1. 3-Beta-hydroxy-C₂₇ steroiddehydrogenase/isomerase deficiency
       2. Delta⁴-3-oxosteroid5-Beta-reductase deficiency
   11. Disorders of bile acid transport
   12. Zellweger syndrome
4. Endocrine disorders
   1. Hypothyroidism
   2. Hypopituitarism
5. Toxic disorders
   1. Totalparenteral nutrition
   2. Drugs
6. Ischemic liver injury

Clinical Features and Diagnosis: Conjugated Hyperbilirubinemia(Neonatal Onset)

In general, conjugated hyperbilirubinemiais due to defective excretion of conjugated bilirubin by liver cellsor to obstruction of bile flow. Numerous disorders can cause conjugatedhyperbilirubinemia.

Neonatal Hepatitis Syndrome

Idiopathic

This disorder,whose cause remains unknown after an exhaustive search, causes cholestasis.

These infants tend to be prematureor small for gestational age compared to those with extrahepaticbiliary atresia, who are usually term infants.

Characteristic findings include jaundiceand hepatomegaly.

Liver biopsy shows extensive giant-celltransformation of hepatocytes with inflammation, but bile ductsgenerally appear normal.

Viral Infection

Enteroviruses

Enteroviruses(echoviruses, Coxsackie viruses) can cause systemic illness withsevere hepatitis and acute liver failure in neonates.

Infant is jaundiced with high serumaminotransferases. Myocarditis and meningoencephalitis also mayoccur.

Isolation of virus from pharynx, stool,or spinal fluid is diagnostic. Detection of enteroviral DNA in spinalfluid or 4-fold increase in antibody titer is also diagnostic.

Herpes Simplex Virus

Types 1and 2 can cause perinatal infection. Transmission usually occursby ascending infection or passage through infected birth canal.Less common sources of infection are postnatal transmission by parentsfrom nongenital source (e.g., mouth or hands) or from another infectedinfant or caregiver in nursery. In some cases no evidence of clinicalinfection exists in the mother during pregnancy.

Illness usually occurs 1–3wks after birth and is variable in presentation. Vesicular lesions ofskin, eyes, or mouth; isolated encephalitis; or disseminated infectionwith or without encephalitis may occur. Skin vesicles, jaundice,hepatosplenomegaly, and pneumonia are common findings with disseminatedinfection.

Rapid diagnostic tests include directfluorescent antibody staining of scrapings or enzyme immunoassaydetection of herpes simplex virus antigens. Viral isolation fromany vesicular lesion or from nasopharynx, blood, rectum, or spinalfluid is also diagnostic. Polymerase chain reaction (PCR) is particularlyuseful in detection of herpes simplex virus DNA in spinal fluid.

Cytomegalovirus

Maternalprimary infection or reactivation of infection may produce intrauterineinfection with cytomegalovirus.

Although most infections with thisvirus in neonates are asymptomatic, some infants may have low birthweight, microcephaly, jaundice, hepatosplenomegaly, chorioretinitis,sensorineural deafness, and intracranial calcifications.

Isolation of virus from urine or positiveserum IgM anti-cytomegalovirus antibody is diagnostic.

Varicella-Zoster Virus

Infectionin neonates may occur when mother contracts varicella during last2 wks of pregnancy.

Manifestations include skin macules,papules, and vesicles; jaundice; pneumonia; and meningoencephalitis.

Characteristic appearance of skin lesionsis usually diagnostic. Isolation of virus from skin lesion is confirmatory.

Rubella Virus

Now rarebecause of prior immunization.

Characteristic findings include intrauterinegrowth disturbance, cataracts, chorioretinitis, thrombocytopeniawith purpuric rash, hepatosplenomegaly, sensorineural deafness,congenital heart disease (patent ductus arteriosus, peripheral pulmonicstenosis), meningoencephalitis, and developmental delay. Liver biopsyshows giant-cell hepatitis.

Rubella virus can usually be isolatedfrom cultures of nasal secretions. Pharyngeal, urine, blood, andspinal fluid cultures also may yield virus. Detection of rubella-specificIgM antibody or ≥4-fold increase in antibody titer also indicatesinfection.

Parvovirus B19 Infection

May produce severe anemia leading to hydropsand fetal death. Spectrum of illness in newborns includes jaundice,hepatomegaly, anemia, coagulopathy, and dermal erythropoiesis (blueberrymuffin rash). Detection of parvovirus B19 by PCR in serum is diagnostic.

Bacterial Infection

Septicemia

Jaundice associated with septicemia may bedue to combination of mechanisms, including endotoxin-mediated canaliculardysfunction, liver necrosis, and hemolysis. Pathogens include gram-negative entericbacteria (most commonly E. coli), S. aureus, Streptococcus species,and L. monocytogenes.

Syphilis

Should besuspected in neonate whose mother had history of this disease duringpregnancy that may have been improperly treated. Transplacentaltransmission of spirochete causes this infection.

Clinical features include fever, jaundice,hepatosplenomegaly, chorioretinitis, encephalitis, periositis oflong bones, and diffuse macular or papular rash, which may desquamateor progress to bulla formation.

Presumptive diagnosis is possible usingcombination of serologic nontreponemal and treponemal tests. Standardnontreponemal tests are Venereal Disease Research Laboratory (VDRL)slide test and rapid plasma reagin test. Positive nontreponemaltest result should be confirmed with treponemal test (e.g., fluorescenttreponemal antibody absorption). For evaluation of possible CNSinvolvement, VDRL test should be performed on spinal fluid.

Parasitic Infection

Toxoplasmosis

Althoughunusual in newborns, it is more likely to be caused by maternalinfection in third trimester than earlier in pregnancy.

Clinical features include neonatalhepatitis, chorioretinitis, and either hydrocephalus or microcephaly.

Skull radiograph may show cerebralcalcification.

Presence of IgM-specific antibody detectedby ELISA is diagnostic.

Bile Duct Obstruction

Biliary Atresia

Most commoncause of extrahepatic obstruction. Involves progressive destructionof extrahepatic bile ducts with subsequent damage to small and medium-sizedintrahepatic ducts.

Clinical features include persistentjaundice, hepatomegaly, and acholic stools.

Characteristic liver biopsy shows portalfibrosis, bile duct proliferation, and bile duct plugs.

Abdominal U/S helps excludeother causes (e.g., choledochal cyst).

Diagnosis is confirmed at time of surgeryby intraoperative cholangiography.

Choledochal Cyst

May presentwith abdominal mass, jaundice, or both.

Abdominal U/S confirms diagnosis.

Alagille Syndrome

Autosomal-dominantdisorder with variable expression that is characterized by unusualfacies (broad forehead, deep-set eyes, pointed chin), cardiac defects(peripheral pulmonic stenosis), vertebral anomalies (butterfly vertebrae),ocular abnormalities (posterior embryotoxon), cholestasis, and impairedgrowth.

Gene locus has been mapped to chromosome20p12.

Clinical findings and characteristicliver biopsy that shows paucity of intrahepatic bile ducts confirmdiagnosis.

Caroli Disease

Sacculardilatations of intrahepatic bile ducts characterize this disorder,which can occur at any age. Recurrent bouts of cholangitis and abscessesoccur.

Clinical findings include fever, jaundice,pruritus, and tender liver.

Abdominal U/S is often adequatefor diagnosis. Otherwise, cholangiography can be performed.

Cholelithiasis

Severalfactors may contribute to gallstone formation including diuretictherapy and septicemia. Biliary tract obstruction results in jaundice.

Radiopaque stones can be seen on plainabdominal radiographs. Otherwise they can be visualized by abdominalU/S.

Inspissated Bile (Bile Plug) Syndrome

Caused byobstruction of a major bile duct by thick bile.

Common cause is cystic fibrosis; however,in most cases cause is unknown.

Obstruction usually resolves over time,but severe cases may require more definitive treatment.

Spontaneous Perforation of Common Bile Duct

May presentwith neonatal hepatitis syndrome with jaundice, acholic stools,and abdominal distension. More common presentation is abdominalpain resembling acute peritonitis.

Finding of bile in ascitic fluid ispathognomonic.

Hepatobiliary scan may show site ofleakage. Typically, there is no drainage into the intestine.

Diagnosis may be confirmed by operativecholangiography.

Metabolic Disorders

Cystic Fibrosis

Spectrumof hepatic pathology resulting in conjugated hyperbilirubinemiain this disease includes giant-cell hepatitis, extrahepatic bileduct obstruction by inspissated bile, and paucity of small (portaltract) bile ducts.

Clinical findings include jaundice,hepatomegaly, and failure to thrive.

Abnormal sweat test is diagnostic.

Alpha₁-Antitrypsin Deficiency

Autosomal-recessivedisorder that is caused by mutations in gene that encodes for alpha₁-antitrypsin.

Gene locus has been mapped to chromosome14q32.1. Usual phenotype associated with liver disease is PI ZZ.

Neonates who develop liver diseasehave jaundice, hepatomegaly, and acholic stools.

In homozygotes diagnosis is made bydemonstration of low serum alpha₁-antitrypsinlevels and determination of phenotype (PI) by isoelectric focusing.

Galactosemia

Classicform of this autosomal-recessive disorder is due to deficiency inactivity of galactose-1-phosphate uridyl transferase.

Gene locus has been mapped to chromosome9p13. There is accumulation of galactose-1-phosphate, which is toxicto liver.

Infants appear normal at birth, butvomiting and diarrhea usually occur within a few days of milk feedings.Jaundice, hepatomegaly, and cataracts are other prominent features.Septicemia also may occur, especially with E. coli. Because of neonatalscreening, few cases present now with jaundice.

Urine that is positive for reducingsubstances but negative for glucose suggests diagnosis. Diagnosisis confirmed by quantitative assay of enzyme in red cells. Chorionicvillus sampling is available for antenatal diagnosis.

Hereditary Fructose Intolerance

Autosomal-recessivedisorder caused by deficiency in activity of fructose-1-phosphatealdolase.

Point mutations have been describedin gene encoding this protein at the chromosome 9q22.3 locus.

Age of presentation depends on ingestionof sucrose or fructose. Ingestion of sucrose-containing formulas(Isomil, Nursoy) can cause illness in newborn period with vomiting,diarrhea, jaundice, hepatomegaly, and renal tubular dysfunction.Acute liver failure may occasionally occur.

Urine is positive for reducing substancesand negative for glucose.

Diagnosis may be confirmed by liverbiopsy with enzyme assay or by molecular genetic analysis.

Tyrosinemia

Deficiencyin activity of fumarylacetoacetase is cause of this autosomal-recessive disorder.

Several mutations have been describedat the chromosome 15q23-q25 locus.

Common presentation in infancy is acuteliver failure with jaundice, ascites, coagulopathy, and encephalopathy.Older infants may have hepatosplenomegaly, failure to thrive, coagulopathy,and rickets. Renal tubular dysfunction with glycosuria, phosphaturia,and generalized aminoaciduria may occur at any age.

Lab findings include increase in serumaminotransferases, alkaline phosphatase, alpha-fetoprotein, tyrosine,phenylalanine, and methionine.

Presence of urinary succinylacetoneis pathognomonic but not invariable finding. Measurement of enzymeactivity in skin fibroblasts or lymphocytes is definitive.

Niemann-Pick Disease

Types Aand B are caused by deficiency of sphingomyelinase activity.

Type A may produce prolonged neonataljaundice, hepatosplenomegaly, and lymphadenopathy. Developmentaldelay usually occurs by 6 mos of age and is followed by neurologicregression.

Onset of type B is usually in infancyor childhood, with hepatomegaly or splenomegaly or both. Childrenwith type B have normal intelligence but may develop cirrhosis andportal hypertension.

In both types, enzyme assay of leukocytes,liver, or cultured fibroblasts is diagnostic.

Type C is caused by defect in cholesterolesterification that leads to secondary deficiency of sphingomyelinase.

Clinical findings include hepatosplenomegalyand progressive encephalopathy.

Liver or bone marrow biopsy shows characteristicfoam cells.

Demonstration of impaired cholesterolesterification confirms diagnosis.

Disorders of Bile Acid Synthesis

Deficiency of several enzymes involved inbile acid synthesis may be associated with neonatal cholestasis.2 enzymes are 3-beta-hydroxy-C₂₇-steroiddehydrogenase/isomerase and delta⁴-3-oxosteroid5-beta-reductase.

3-Beta-Hydroxy-C27-Steroid Dehydrogenase/IsomeraseDeficiency

Characterizedby neonatal onset of progressive cholestasis, hepatomegaly, fat-soluble vitaminmalabsorption, and mild steatorrhea. Onset of cholestasis also mayoccur in childhood.

Lab tests reveal conjugated hyperbilirubinemia,increased serum aminotransferases, normal serum gamma-glutamyltransferaseconcentration, and normal serum bile acid concentration (when measuredby normal methods).

Fast atom bombardment–massspectroscopy (FAB-MS) and gas chromatography–mass spectrometry(GC-MS) have been used to identify unusual intermediates in urinearising from defective bile acid synthesis to help make specificdiagnosis.

Delta⁴-3-Oxosteroid 5-Beta-ReductaseDeficiency

Familial disorder that causes progressiveneonatal cholestasis. There is increase in serum concentration ofaminotransferases, conjugated bilirubin, and generally gamma-glutamyltransferase.FAB-MS and GC-MS analysis of urinary bile acids is diagnostic.

Disorders of Bile Acid Transport

Progressivefamilial intrahepatic cholestasis (types 1, 2, and 3) comprisesgroup of autosomal-recessive disorders involving bile acid transport.Onset is usually in neonatal period or in infancy with cholestaticliver disease. Progression of disease eventually leads to liverfailure.

In type 1 (Byler disease), gene locushas been mapped to chromosome 18q21.

Characteristic features include recurrentepisodes of jaundice that ultimately fail to resolve, pruritus,normal serum cholesterol and gamma-glutamyltransferase concentrations,and high serum primary bile acids.

Milder disorder known as benign recurrentcholestasis has the same chromosome locus as type 1.

Gene locus of type 2 has been mappedto chromosome 2q24. More severe at onset compared with type 1, withno resolution of jaundice and rapid occurrence of liver failure.

Type 3 can be distinguished from types1 and 2 by high serum gamma-glutamyltransferase and ductular proliferationon liver biopsy. Gene locus in type 3 has been mapped to chromosome 7q21.

Other

Glycogen storage disease type IV, Gaucherdisease, Wolman disease/cholesterol ester storage disease,and Zellweger syndrome are discussed in Chap. 13, Developmental Delay,and Chap. 30, Hepatomegaly.

Endocrine Disorders

Hypothyroidism

Usually associated with unconjugated hyperbilirubinemia;however, it also may be associated with neonatal hepatitis syndrome.Low T₄ and high TSH serum levels are diagnostic(see Chap. 23, Growth Deficiency:Weight and Height).

Hypopituitarism

Causes includedevelopmental defects (septooptic dysplasia, holoprosencephaly),genetic defects of growth hormone or growth hormone–releasinghormone, head trauma, and infiltrative lesions (tumors).

Clinical features in neonates includejaundice, hypoglycemia, and, in boys, micropenis.

Evaluation of pituitary function shouldbe guided by a pediatric endocrinologist.

Toxic Disorders

Total Parenteral Nutrition

Total parenteralnutrition may cause progressive cholestasis in infants who receiveit for ≥2 wks. These are usually critically ill, often prematureinfants.

Most infants have hepatomegaly, conjugatedhyperbilirubinemia, and increased serum aminotransferases, alkalinephosphatase, and gamma-glutamyltransferase.

Serum albumin and prothrombin timeare usually normal.

Drugs

Prolonged use of chloral hydrate in newbornshas been associated with conjugated hyperbilirubinemia not associatedwith other signs of liver toxicity.

Ischemic Liver Injury

Conjugated hyperbilirubinemia and increasein serum aminotransferases have been associated with ischemic liverinjury from various causes (e.g., septicemia and shock). Hepatomegalyand coagulopathy may also occur.

Principal Causes of Conjugated Hyperbilirubinemia (PostneonatalOnset)

1. Manydisorders listed under neonatal onset
2. Viral hepatitis
   1. HepatitisA
   2. Hepatitis B
   3. Hepatitis C
   4. Hepatitis D
   5. Hepatitis E
3. Toxic hepatitis
   1. Drugs
      1. Antipyretics
         1. Acetaminophen
      2. Antiinflammatory drugs
         1. Acetylsalicylicacid (aspirin)
         2. Methotrexate
      3. Antiepileptics
         1. Phenytoin
         2. Carbamazepine
         3. Phenobarbital
         4. Valproic acid
      4. Antibiotics
         1. Isoniazid
         2. Rifampin
         3. Sulfonamides
         4. Erythromycin
         5. Ketoconazole
      5. Anesthetics
         1. Halothane
      6. Chemotherapeutic agents
      7. Other drugs
   2. Toxins
      1. Carbon tetrachloride and related substances
4. Autoimmune hepatitis
5. Biliary tract disorders
   1. Cholecystitis
   2. Cholelithiasis
   3. Cholangitis
6. Cirrhosis
7. Hepatic neoplasms
8. Vascular disorders
   1. Cardiacfailure
   2. Budd-Chiari syndrome
   3. Venoocclusive disease
9. Metabolic disorders
   1. Cysticfibrosis
   2. Alpha1-antitrypsin deficiency
   3. Disorders of bile acid synthesis andtransport
   4. Wilson disease
10. Ischemic liver injury
11. Inherited disorders of bilirubin conjugation
    1. Dubin-Johnsonsyndrome
    2. Rotor syndrome
12. Hemolytic anemia

Clinical Features and Diagnosis: Conjugated Hyperbilirubinemia(Postneonatal Onset)

Many disorders that cause conjugated hyperbilirubinemiain neonatal period also can occur in infancy. These are describedpreviously.

Viral Hepatitis

Acute viralhepatitis is most common cause of conjugated hyperbilirubinemiain childhood and adolescence.

5 types of hepatitis virus that causeillness have been identified: A, B, C, D, and E. Incubation period,mode of transmission, and serologic tests help distinguish them.

Other viruses that may cause hepatitisinclude Epstein-Barr virus, cytomegalovirus, varicella-zoster virus,herpes simplex virus, and human herpesvirus 6. Some are discussedin previous section, whereas remainder are discussed in other chapters.

Hepatitis A

Incubationperiod is about 4 wks, with range of 2–6 wks. Transmissionis by fecal-oral route.

Infection is usually asymptomatic inchildren <5 yrs of age. Older children usually have fever,malaise, anorexia, and nausea for 2–7 days before onsetof jaundice.

Serum aminotransferase levels are 10–100times normal. Fulminant infection is rare, and chronic infectiondoes not occur.

Diagnosis is confirmed by presenceof anti–hepatitis A virus IgM.

Hepatitis B

Primarysources of infection are individuals with acute hepatitis B infectionor chronic carriers.

Transmission occurs by oral or sexualcontact, or by blood and body fluids through break in skin or mucousmembranes.

Incubation period is 2–6 mos.

Clinical findings are same as withhepatitis A virus infection. In infancy and childhood, can occuras acute or subclinical illness followed by recovery or chronichepatitis.

Chronically infected individuals areat risk for development of hepatocellular carcinoma later in life.

Detection of hepatitis B surface antigen(HBsAg) and IgM antibody to hepatitis B core antigen (IgM anti-HBc)is diagnostic of acute infection. However, in infants affected perinatally,IgM anti-HBc is usually not present.

Appearance of hepatitis B surface antibody(anti-HBs) signifies recovery and immunity, whereas persistenceof HBsAg beyond 6 mos defines carrier state.

Hepatitis C

Clinicalpresentation is similar to that of hepatitis A and B infections.Transmission of infection can occur by parenteral exposure to bloodand blood products from persons infected with hepatitis C virus;however, for most infected children, no specific source can be found.

Jaundice occurs in about 25% ofcases. About 65–70% of affected individuals develop chronichepatitis and 20% develop cirrhosis.

Primary hepatocellular carcinoma alsocan occur.

Diagnosis is confirmed by presenceof anti–hepatitis C virus.

Hepatitis D

Causes hepatitis,but only in individuals with acute or chronic hepatitis B infection.

Presence of anti–hepatitisD virus IgM confirms diagnosis.

Hepatitis E

Producesillness similar to hepatitis A.

Endemic hepatitis E has not been recognizedin U.S. but does occur in Africa, Asia, and Mexico.

Diagnostic tests available in researchlabs include anti–hepatitis E virus IgM and viral DNA detectedin stool and serum by PCR.

Toxic Hepatitis

Drugs

Liver injurymay result from normal use or toxic ingestion of certain drugs.History of any drug exposure with subsequent jaundice suggests possibledrug-induced liver injury.

Some commonly used drugs that may causeliver injury are discussed in following section.

Antipyretics

Acetaminophen

Toxic doseis >140 mg/kg in single ingestion. Toxic intermediatescause hepatocellular necrosis and jaundice.

Serum aminotransferases are markedlyincreased, and results of coagulation studies may be abnormal.

History, physical exam, serum druglevel, and clinical course are diagnostic.

Hepatic toxicity also may occur whenlarge doses of acetaminophen (30–70 mg/kg) aregiven at regular intervals (2–4 hrs) for several days (Heubiet al., 1998).

Antiinflammatory Drugs

Acetylsalicylic Acid (Aspirin)

Hepatitis may occur with high-dose aspirintreatment, but jaundice is uncommon.

Methotrexate

Can cause hepatic fibrosis and eventual cirrhosisif high doses are used.

Antiepileptics

Phenytoin

Phenytoinhepatotoxicity may present as hepatitis along with features of drugsensitivity syndrome (e.g., fever, lymphadenopathy, rash, eosinophilia,and atypical lymphocytosis).

Serum aminotransferases are usuallyincreased, and jaundice also may occur.

In severe cases, liver failure mayoccur with altered sensorium and coagulopathy.

Carbamazepine

May affect liver by producing hepatitis.Other findings of drug sensitivity syndrome also may occur.

Phenobarbital

Drug hypersensitivity syndrome may occuralong with hepatitis.

Valproic Acid

Some children may develop abnormal serumaminotransferase levels, but this is dose related and resolves whendose is decreased. Acute hepatic failure is rare complication withnormal dosage of drug. Mechanism of hepatocellular injury is unknown.

Antibiotics

Isoniazid

Isoniazid in normal dosage may cause increasein serum aminotransferases. Some children develop acute hepatitiswith jaundice, and fatal hepatic necrosis has been reported.

Rifampin

Rifampin in normal dosage may cause cholestasiswithout serious consequences. Serum aminotransferases may returnto normal even in some individuals who continue taking the drug.

Sulfonamides

Spectrum of liver disease can occur, includinghepatitis and liver failure. Use of these drugs is often associatedwith drug hypersensitivity reaction.

Erythromycin

Erythromycin estolate may cause cholestatichepatitis.

Ketoconazole

May cause hepatitis and significant hepatotoxicity.

Anesthetics

Halothane

Can cause hepatitis, and acute liver failureoccasionally may develop.

Chemotherapeutic Agents

Certain chemotherapeutic drugs may causeliver injury: azathioprine (acute hepatitis), chlorambucil (acutehepatitis), methotrexate (cirrhosis), and 6-mercaptopurine (acutehepatitis, fulminant hepatitis, cirrhosis).

Other Drugs

Pemolinecan cause asymptomatic increase in serum aminotransferases as wellas acute hepatitis of variable degree.

Chlorpromazine, imipramine, griseofulvin,and nitrofurantoin may cause cholestasis.

Toxins

Carbon Tetrachloride and Related Substances

Overdose of carbon tetrachloride, cleaningfluids containing trichloroethylene, glue containing toluene, orchlorophenothane (DDT) may cause acute or fulminant hepatitis.

Autoimmune Hepatitis

Inflammatoryprocess of unknown cause.

Presentation is commonly that of persistenthepatitis or liver failure. Vasculitis, nephritis, arthritis, andthyroiditis also may occur.

Lab findings include increased serumaminotransferases (usually <1,000 IU/L), normalor increased serum bilirubin (2–10 mg/dL and predominantlyconjugated), low serum albumin, prolonged prothrombin time, mildlyincreased alkaline phosphatase, increased serum IgG, hemolytic anemia (Coombspositive), and characteristic autoantibody patterns.

Type I is most common form and is characterizedby antiactin antibodies and antinuclear antibody. Antiliver kidneymicrosomal antibody is major marker in type II. Antibodies to solubleliver antigen characterize type III. These antibody patterns andcharacteristic histologic findings found on liver biopsy confirmdiagnosis.

Biliary Tract Disorders

Cholecystitis

Cause ofacute cholecystitis in children is usually unknown.

Characteristic clinical findings arenausea, vomiting, right upper quadrant pain, and sometimes palpableabdominal mass.

Jaundice is result of obstruction ofcommon bile duct by gallstones, which can be detected by abdominalU/S.

Cholelithiasis

Most commoncause in children and adolescents is chronic hemolytic anemia.

Usual presentation consists of rightupper quadrant pain, fever, and vomiting. Conjugated hyperbilirubinemiaoccurs with obstruction of common bile duct.

Plain radiograph of abdomen may showopaque stones in right upper quadrant. Increase in serum alkalinephosphatase usually occurs, whereas serum aminotransferases areusually normal.

Abdominal U/S can detect gallstones.

Cholangitis

Common complicationafter portoenterostomy for biliary atresia.

Usual findings include fever, jaundice,and abdominal pain.

Common pathogens are gram-negativeenteric bacteria. If blood culture is negative and child remainsill, liver biopsy should be performed for culture and histologicexam.

Primary sclerosing cholangitis is characterizedby chronic inflammation of intrahepatic and/or extrahepaticbile ducts. May occur as isolated disorder or in association withother disorders (e.g., inflammatory bowel disease and cystic fibrosis).

Clinical manifestationsinclude abdominal pain, fever, jaundice, and hepatosplenomegaly.

Most consistent biochemical abnormalitiesare increases in serum aminotransferases (mild), alkaline phosphatase,and gamma-glutamyl transferase. Positive antinuclear, anti–smooth-muscle,and antineutrophil cytoplasmic antibodies also may be found.

Most characteristic histologic featureis lamellar (onion skin) fibrosis around interlobular bile ducts.

Cholangiographic visualization of typicalbile duct lesions of irregular strictures and duct dilatations isdiagnostic.

Cirrhosis

Representsend stage of many childhood liver diseases. Normal acinar liverstructure is replaced by regenerating nodules surrounded by variousamounts of connective tissue that distort normal liver architecture.

Liver may be enlarged or shrunken butis usually firm or nodular.

Jaundice, ascites, and portal hypertensionare usual findings.

This is a pathologic diagnosis confirmedby liver biopsy.

Hepatic Neoplasms

Tumors of liver usually present with hepatomegalyand not primarily with jaundice unless they obstruct bile flow (see Chap. 1, Abdominal Masses).

Vascular Disorders

Cardiac Failure

Severe cardiac failure may cause chronicliver congestion with hepatomegaly or hepatosplenomegaly, but jaundiceis uncommon (see Chap. 7, CardiacFailure).

Budd-Chiari Syndrome

Obstructionof hepatic veins or suprahepatic vena cava. Causes include anatomicdisorders (obstructing membranes) and disorders that predisposeto thrombosis (sickle cell disease, pregnancy, oral contraceptives,protein C deficiency, inflammatory bowel disease, tumor invasion,collagen vascular disease).

Should be suspected with acute onsetof abdominal pain, hepatomegaly, and ascites. Jaundice is usuallymild.

Useful diagnostic tests include DopplerU/S of hepatic veins, CT, MRI, and hepatic venography.

Venoocclusive Disease

Obstructionis at level of terminal hepatic venules.

Causes include chemotherapy and totalbody irradiation in preparation for bone marrow transplantationand chronic ingestion of herbal teas or foods containing pyrrolizidinealkaloids.

Clinical findings include abdominalpain, hepatomegaly, ascites, and jaundice.

Diagnosis may be confirmed by pulsedDoppler U/S or liver biopsy.

Metabolic Disorders

Many metabolic disorders that cause jaundicein infancy have been discussed in section Clinical Features and Diagnosis: ConjugatedHyperbilirubinemia (Neonatal Onset). Wilson diseasealso may cause jaundice in infancy and childhood.

Wilson Disease

Excessiveamount of copper accumulates in liver, cornea, kidney, nervous system, andother organs in this autosomal-recessive disorder.

Gene locus has been mapped to chromosome13q14.3-q21.1.

Clinical presentation is variable.

Hepatic diseasewith acute hepatitis, cirrhosis, or fulminant liver failure mayoccur several years before any neurologic involvement.

Neurologic manifestations usually beginafter 10 yrs of age and include worsening school performance, clumsiness,intention tremor, emotional lability, and choreoathetosis.

Psychiatric manifestations includeimpulsiveness, phobias, and depression.

Hemolytic anemia also may occur.

Granular accumulation of copper inDescemet membrane at lateral margin of the cornea (Kayser-Fleischerring) is useful in diagnosis. Deposits are brown to green in colorand may be seen by unaided eye; however, slit-lamp exam is usuallynecessary. These eye findings almost always occur in individualswith neurologic disease but may be absent in young children withliver disease alone.

Usual lab findings are low serum ceruloplasmin,high serum copper, increased urinary copper excretion, and increasedliver copper content on liver biopsy.

Clinical and lab findings confirm diagnosis.

Ischemic Liver Injury

Ischemicliver injury from various causes (e.g., septicemia and shock) canresult in cholestasis.

There is marked increase in serum aminotransferaseswithin 24–48 hrs of initial insult.

Hepatomegaly, jaundice, and coagulopathyare common findings.

Inherited Disorders of Bilirubin Conjugation

Dubin-Johnson Syndrome

Autosomal-recessivedisorder caused by mutations in canalicular multispecific organicion transporter, whose gene locus has been mapped to chromosome10q24. Results in diminished excretion of non-bile salt anions atthe canalicular membrane.

Usual onset is in childhood or earlyadolescence with conjugated hyperbilirubinemia.

Measurement of urinary excretion ofcoproporphyrin isomers I and III can confirm diagnosis.

Although total coproporphyrin urinaryexcretion is normal, ratio of coproporphyrin I to III is 4:1 (normalratio is 1:3).

Rotor Syndrome

Conjugatedhyperbilirubinemia also occurs in this autosomal-recessive disorder, whosepathogenesis is uncertain.

Total serum bilirubin concentrationranges from 2 to 7 mg/dL and ≥50% of bilirubin isconjugated. Other liver function tests are normal.

Urinary excretion of coproporphyrinis increased and liver biopsy is normal.

Hemolytic Anemia

Virtually any hemolytic anemia, if severeenough, can cause conjugated as well as unconjugated hyperbilirubinemia.Hepatosplenomegaly usually occurs as well [see Chap. 45, Pallor (Anemia)].

Diagnostic Approach: Conjugated Hyperbilirubinemia

Neonatal Onset

There aremany causes of conjugated hyperbilirubinemia in neonates, but mostcommon are neonatal hepatitis syndrome, extrahepatic biliary atresia,alpha₁-antitrypsin deficiency, and totalparenteral nutrition.

Besides history, physical exam, andnoting color of stools, certain tests are useful and should be consideredin evaluating neonates with conjugated hyperbilirubinemia:

CBC with differential

Analysis of blood smear

Reticulocyte count

Blood glucose

Liver function tests (total protein,albumin, conjugated and unconjugated bilirubin, serum aminotransferases,alkaline phosphatase, gamma-glutamyltransferase)

Serum cholesterol and bile acids

Prothrombin time

Blood, urine, and spinal fluid cultures

Serum alpha₁-antitrypsinconcentration and PI phenotype

Urinary reducing substances

Urine and serum quantitative aminoacids

Sweat test

Thyroxine and thyroid-stimulating hormone

Abdominal U/S

Percutaneous liver biopsy

If specific congenital infection issuspected, appropriate tests should be performed. If diagnosis remainsuncertain after these investigations, open liver biopsy and intraoperativecholangiography should be performed.

Postneonatal Onset (Infancy, Childhood, Adolescence)

Most commoncauses of conjugated hyperbilirubinemia in infancy, childhood, and adolescenceare hepatitis A, hemolytic anemia, and drug-related liver injury.

Besides history and physical exam,certain tests are useful depending on clinical circumstances:

CBC with differential

Analysis of blood smear

Reticulocyte count

Coombs test

Hemoglobin electrophoresis

Liver function tests (serum aminotransferases,prothrombin time, conjugated and unconjugated bilirubin, alkalinephosphatase, gamma-glutamyltransferase, total protein, and albumin)

Serum glucose and ammonia

Anti–hepatitis A virus (IgMand IgG)

HBsAg

Monospot test

IgG and IgM antibody to viral capsidantigen of Epstein-Barr virus

Urinary reducing substances

Sweat test

Serum alpha₁-antitrypsinconcentration and PI phenotype

Serum ceruloplasmin

Drug serum levels

Abdominal U/S

Abdominal CT

Liver biopsy

References

1. Altschuler SM, Liacouras CA, eds. Clinicalpediatric gastroenterology. Philadelphia: Churchill Livingstone,1998.
2. Balistreri WF. Inborn errors of bile acid biosynthesisand transport. Gastroenterol Clin North Am 1999;28:145–172.
3. Behrman RE, et al., eds. Nelson textbook of pediatrics,16th ed. Philadelphia: WB Saunders, 2000.
4. Fanaroff AA, Martin RJ, eds. Neonatal-perinatal medicine:diseases of the fetus and infant, 7th ed. St. Louis: Mosby-YearBook, 2002.
5. Farrell GC. Drug-induced hepatic injury. J GastroenterolHepatol 1997;12(suppl):242–250.
6. Heubi JE, et al. Therapeutic misadventures with acetaminophenhepatotoxicity after multiple doses in children. J Pediatr 1998;132:22–27.
7. Jacquemin E. Progressive familial intrahepatic cholestasis:genetic basis and treatment. Clin Liver Dis 2000;4:753–763.
8. Kelly DA, ed. Diseases of the liver and biliary systemin children. Oxford: Blackwell Science, 1999.
9. Kirks DR. Practical pediatric imaging: diagnostic radiologyof infants and children, 3rd ed. Philadelphia: Lippincott–Raven,1998.
10. Long SS, et al., eds. Principles and practice of pediatricinfectious diseases. New York: Churchill Livingstone, 1997.
11. Maisels MJ. Jaundice. In: Avery GB, et al., eds. Neonatology:pathophysiology and management of the newborn, 5th ed. Philadelphia:Lippincott Williams & Wilkins, 1999:765–819.
12. Maisels MJ, Gifford K. Normal serum bilirubin levelsin the newborn and the effect of breast-feeding. Pediatrics 1986;78:837–843.
13. Online Mendelian Inheritance in Man (OMIM). McKusick-NathansInstitute for Genetic Medicine, Johns Hopkins University (Baltimore,MD) and National Center for Biotechnology Information, NationalLibrary of Medicine (Bethesda, MD), 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omim.
14. Pickering LK, ed. 2000 Red book: report of the Committeeon Infectious Diseases, 25th ed. Elk Grove Village, IL: AmericanAcademy of Pediatrics, 2000.
15. Rudolph AM, ed. Rudolph's pediatrics, 20thed. Stamford, CT: Appleton & Lange, 1996.
16. Sherlock S. Hepatic reactions to drugs. Gut 1979;20:634–648.
17. Suchy FJ, et al. Acute hepatic failure associated withthe use of sodium valproate. Report of two fatal cases. N Engl JMed 1979;300:962–966.
18. Suchy FJ, et al., eds. Liver disease in children, 2nded. Philadelphia: Lippincott Williams & Wilkins, 2001.
19. Walker WA, Durie PR, Hamilton JR, et al., eds. Pediatricgastrointestinal disease, 3rd ed. Hamilton, Ontario, Canada: BCDecker, 2000.

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Book Source Details

• Book Title: The Diagnostic Approach to Symptoms and Signs in Pediatrics
• Author(s): Paul S. Bellet
• Year of Publication: 2006
• Copyright Details: The Diagnostic Approach to Symptoms and Signs in Pediatrics, Copyright © 2006 Lippincott Williams & Wilkins.

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