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SECTION

6B

Bilirubin Metabolism and Jaundice


Table of Contents

6B
Geoffrey A. Preidis, MD, PhD
353
Daniel H. Leung, MD
Previous edition authors: Asha Willis, MD; Stephanie Page, MD; James Daniel, MD; and Fred Suchy, MD

I. Mechanisms of hyperbilirubinemia

A. Bilirubin metabolism
1. Unconjugated bilirubin
a. The hydrophobic end product of heme breakdown
b. Circulates bound to albumin, preventing the toxicity of free
(unbound) bilirubin
c. Selectively imported into hepatocytes
d. Conjugated to glucuronic acid to make water soluble by uridine
diphosphate (UDP)-glucuronyl transferase (UGT)
2. Conjugated bilirubin
a. Secreted into bile by adenosine-triphosphate-dependent
transporter ABCC2/MRP2 on the hepatocyte canalicular
membrane
b. Reabsorbed by small intestine, circulates back to liver, and
imported into hepatocytes by transport protein OATP1B
3. Hereditary hyperbilirubinemias result from mutations in bilirubin
transporters or conjugating enzymes (Figure 1)

FIGURE 1 Schematic of the Enzymes Involved in Inherited Disorders of Bilirubin Metabolism

Circulation Hepatocyte Bile Canaliculus

Heme ?Breast milk jaundice


Gilbert
?Breast milk jaundice Crigler-Najjar type II
i.
Crigler-Najjar type I
UGT1A1 Dubin-Johnson
Alb-uBili uBili cBili
UGT1A1
ii. iii.
iv. ABCC2 cBili
Rotor ABCC2/MRP2
v.
SLCO1B
cBili cBili
OATP1B
vi.

Intestine

Enterohepatic Circulation

Alb, albumin; cBili, conjugated bilirubin; uBili, unconjugated bilirubin; Roman numerals, see above.

SECTION 6: Liver
II. Conjugated hyperbilirubinemia
A. Rotor syndrome—defective hepatocyte “reuptake” of circulating conjugated
bilirubin
1. Defect: SLCO1B gene on chromosome 2q37, encoding sinusoidal
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organic anion transporting polypeptide OATP1B 6B


2. Inheritance: autosomal recessive
3. Clinical presentation: episodic jaundice accentuated by pregnancy and 354
steroid hormones; otherwise asymptomatic
4. Physical findings: normal, ± jaundice and icterus
5. Labs
a. Predominantly conjugated hyperbilirubinemia; otherwise normal
liver functions
b. Urine total coproporphyrin levels ↑ 2- to 5-fold, with 60%–80%
isomer I (normal is >75% isomer III)
6. Histology: biopsy not required for diagnosis but would show normal
liver with absent OATP1B immunostaining
7. Genetic testing: sequencing of SLC01B gene; rarely performed
8. Prognosis: excellent
9. Treatment: none necessary
B. Dubin-Johnson syndrome—defective “secretion” of conjugated bilirubin into
bile canaliculi
1. Defect: ABCC2 (formerly MRP2) gene on chromosome 10q24, encoding
ABCC2/MRP2 transporter that couples with ATP hydrolysis to actively
pump organic anions into bile canaliculus
2. Inheritance: autosomal recessive
3. Clinical presentation: chronic, low-grade, nonpruritic jaundice;
↑ in pregnancy and with use of oral contraceptives or other steroid
hormones
4. Physical findings: jaundice and icterus ± mild hepatomegaly; otherwise
normal
5. Labs
a. Mixed (50% conjugated and 50% unconjugated)
hyperbilirubinemia; 2–5 mg/dL at baseline but periodically up to
25 mg/dL; other liver functions normal; no hemolysis
b. Urine total coproporphyrin levels normal, with >80% isomer I
6. Histology: biopsy not required for diagnosis
a. Liver grossly black with pigment deposits (in contrast to Rotor
syndrome)
b. Electron microscopy shows melanin-like pigment in hepatic
lysosomes
7. Genetic testing: sequencing of the ABCC2 gene
8. Prognosis: lifelong mild jaundice and icterus; benign
9. Treatment: none necessary, although avoidance of oral contraceptives
encouraged

6B. Bilirubin Metabolism and Jaundice


III. Unconjugated hyperbilirubinemia
A. Gilbert syndrome
1. Defect: heterologous group of mutations in UGT1A1 gene on
chromosome 2q37 encoding UGT 1A1 (UGT1A1) bilirubin-conjugating
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enzyme → <50% of normal enzyme activity 6B


2. Inheritance: mostly autosomal recessive, affecting 8% of general
population, although can be autosomal dominant 2º to a missense 355
mutation
3. Clinical presentation
a. Seldom detected before puberty
b. Episodic jaundice, often during fasting, a nonspecific viral illness,
poor sleep, or physically strenuous activity (i.e., marathon or
ballet performance)
c. Fatigue, weakness, right upper quadrant discomfort, or dyspepsia
are uncommon and should prompt evaluation for other causes
4. Physical findings: normal, ± jaundice. Most have periodic icterus.
5. Labs: mild (1–4 mg/dL) fluctuating unconjugated hyperbilirubinemia;
remainder of liver function tests normal; no hemolysis
6. Histology: biopsy not required for diagnosis, but if performed, shows
normal liver with ↓ UGT immunostaining
7. Genetic testing: sequencing the UGT1A1 gene (130 known mutations)—
reserved for cases of very high serum bilirubin or patient/parental
anxiety
8. Prognosis: benign; may confer evolutionary advantage—antioxidant
properties of bilirubin may have protective effects on atherosclerosis
and cardiovascular disease
9. Treatment
a. None necessary unless jaundice becomes unsightly
b. Phenobarbital lowers serum bilirubin, often to normal levels
B. Crigler-Najjar syndrome
1. Defect: mutations in UGT1A1 gene on chromosome 2q37 encoding
UGT1A1 bilirubin-conjugating enzyme (same gene as Gilbert syndrome)
with mutations → completely absent (type I) or severely reduced
(<10%, type II) UGT1A1 enzyme activity
2. Inheritance: mostly autosomal recessive
3. Clinical presentation
a. Type I: most severe form; progressive jaundice from first few days
of life; high risk of kernicterus
b. Type II: less severe; lower incidence of kernicterus
4. Physical examination findings: persistent jaundice and icterus ± signs
of kernicterus (extrapyramidal dystonia, choreoathetosis, hearing loss,
and oculomotor paresis)
5. Labs: unconjugated hyperbilirubinemia (type I 15–45 mg/dL; type II
8–25 mg/dL); otherwise normal liver tests
6. Histology: normal liver ↓ UGT immunostaining
7. Genetic testing: sequencing the UGT1A1 gene
8. Prognosis: risk of severe kernicterus and death in type I

SECTION 6: Liver
9. Treatment
a. Type I
1) Lifelong phototherapy for 8–12 hours per day; exchange
transfusions to maintain serum bilirubin levels < threshold
for kernicterus
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2) Consider liver transplantation 6B


b. Type II
1) Lifelong phenobarbital therapy to induce remaining 356
UGT1A1 activity (can ↓ serum bilirubin up to 25%; works
for type II only)
2) Oral binding agents (cholestyramine, calcium phosphate,
and agar) to prevent enterohepatic reuptake of bilirubin;
adverse effects include bile salt depletion and fat
malabsorption
C. Breast milk jaundice
1. Defect
a. Multiple/unknown; may be a specific biochemical in breast
milk that enhances physiologic intestinal bilirubin absorption
or a partial defect in transport of unconjugated bilirubin into
hepatocytes
b. In some cases, a mutation in UGT1A1 gene causes a mild partial
enzyme defect (>50% residual activity), distinct from Gilbert
c. Distinct from “breastfeeding jaundice” associated with inadequate
intake of breast milk (mild dehydration), ↓ stool output, and
↑ reabsorption of bilirubin from gut
2. Inheritance: unknown; occurs in up to 1/3 of healthy, exclusively
breastfed infants
3. Clinical presentation
a. Jaundice presenting after 1–2 weeks in exclusively breastfed,
adequately nourished infants, peaks at 2–3 weeks, and gradually
improves by 12 weeks
b. Distinct from “breastfeeding jaundice” highlighted by poor
feeding, slow weight gain, and ↓ urine output
4. Physical findings: jaundice; otherwise normal, well-nourished infant
5. Labs: unconjugated hyperbilirubinemia (total bilirubin always
<12 mg/dL); otherwise normal liver function tests. Absolutely no
elevation in conjugated bilirubin, e.g., >20% of total bilirubin.
6. Histology: biopsy unnecessary; histology is normal
7. Genetic testing: not indicated
8. Prognosis: benign; not associated with kernicterus; spontaneously
resolves
9. Treatment: continue breastfeeding and anticipate resolution by
12 weeks, although hyperbilirubinemia rapidly improves when formula
is temporarily substituted for breast milk × 48 hours

6B. Bilirubin Metabolism and Jaundice


Recommended Reading
Bartlett MG, Gourley GR. Assessment of UGT polymorphisms and neonatal jaundice.
Semin Perinatol. 2011;35:127-133.
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Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin transport 6B


and conjugation: new insights into molecular mechanisms and consequences.
Gastroenterology. 2014;146:1625-1638. 357

Preer GL, Philipp BL. Understanding and managing breast milk jaundice. Arch Dis Child
Fetal Neonatal Ed. 2011;96:F461-F466.

Strassburg CP. Hyperbilirubinemia syndromes (Gilberg-Meulengracht, Crigler-Najjar,


Dubin-Johnson, and Rotor syndrome). Best Pract Res Clin Gastroenterol.
2010;24:555-571.

SECTION 6: Liver
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6B

358

6B. Bilirubin Metabolism and Jaundice


SECTION
6Ci

Neonatal Cholestasis
Table of Contents

6Ci
Molly Bozic, MD
359
Previous edition authors: David Brumbaugh, MD and Cara Mack, MD

I. Overview of neonatal cholestasis


A. Cholestasis is pathologically reduced bile flow best represented by ↑ bile salts
but more practically by ↑ direct bilirubin of >2 mg/dL or >20% of the total
bilirubin level
B. Neonatal cholestasis may be secondary to a variety of etiologies ranging
from infectious, metabolic, structural, endocrine, and idiopathic
C. All breastfed infants who remain jaundiced at 3 weeks of life and all
formula-fed infants who remain jaundiced at 2 weeks of life should have a
fractionated bilirubin
D. Evaluation and diagnosis of cholestasis in neonates should be done
expeditiously as some conditions, e.g., biliary atresia, require a timely
diagnosis in the first 60 days of life

II. Evaluation of the cholestatic infant


A. Initial laboratory evaluation should include alanine aminotransferase
(ALT), aspartate aminotransferase (AST), α-glutamyl transpeptidase (GGT),
fractionated bilirubin, alkaline phosphatase, albumin, total protein, and
prothrombin time (PT)/international normalized ration (INR)
1. Albumin and PT/INR assess liver synthetic function
B. Abdominal ultrasound evaluates for structural abnormalities, e.g.,
choledochal cyst
C. Physical examination findings can provide many clues to etiology of
cholestasis
1. Situs inversus or dextrocardia → biliary atresia
2. Pulmonic stenosis or other congenital heart defects → Alagille
syndrome
3. Abnormal facies (deep set eyes and pointed chin) → Alagille syndrome
4. Large anterior fontanelle → hypothyroidism
5. Hepatosplenomegaly → metabolic disorders
6. Absent red reflexes → galactosemia
7. Acholic stools → obstructive process, e.g., biliary atresia

III. Differential diagnosis of neonatal cholestasis


A. Anatomical abnormalities
1. Choledochal cyst—5 subtypes (type 1 and type 4 most common)
see Figure 1

SECTION 6: Liver
FIGURE 1 Choledochal Cyst Subtypes

Liver
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RHD
LHD
6Ci
CHD
Cystic duct
1 360
Common bile duct 2

Gall Bladder
Sphincter of Oddi
Type I Type II Type III
Ampulla of Vater

Pancreatic duct

Pancreas
Normal biliary track

Type IV Type V

Image adapted from Choledochal cysts Wikipedia 1 = Gall bladder, 2 = Cyst


(https://en.wikipedia.org/wiki/Choledochal_cysts)

a. Type 1: saccular dilation of extrahepatic bile duct


b. Type 4: saccular dilation of intra- and extrahepatic biliary tree
c. Presentation: jaundice, acholic stools, and palpable right upper
quadrant mass
d. Diagnosis: ultrasound is the gold standard
e. Treatment: surgical resection
f. If untreated, ↑ risk of cholangiocarcinoma
2. Inspissated bile syndrome
a. Impaired bile flow → cholestasis
b. Neonates on chronic total parental nutrition or severe intestinal
disease at risk
c. Ultrasound: bile sludge often seen
d. Treatment: ursodeoxycholic acid can improve bile flow
e. Rarely surgical intervention with saline flushes of biliary tree
required
3. Biliary atresia: obliteration of extrahepatic biliary tree
a. Presentation: typical around 3 weeks of life
b. Rapid, progressive fibrosis → cirrhosis in first few months of life
c. Near 100% mortality by 2 years of age without Kasai
portoenterostomy or Kasai procedure
d. Diagnosis
1) Laboratory: ↑ AST, ALT, GGT, fractionated bilirubin, and
alkaline phosphatase
a) Exclude other etiologies, e.g., α1-antitrypsin
deficiency

6Ci. Neonatal Cholestasis


b) Albumin/PT/INR to assess liver synthetic function
c) Fat-soluble vitamin (A, 25-OH vitamin D, E, and K)
levels are often low, especially after 2–3 months
2) Ultrasound: absent or poorly defined gallbladder.
Triangular cord sign is suggestive. Presence of gallbladder
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does NOT exclude biliary atresia. 6Ci


3) Liver biopsy: proliferation of bile ducts, bile plugs of
intrahepatic bile ducts, fibrosis, and cirrhosis (if later in 361
disease)
4) Intraoperative cholangiogram: the gold standard
diagnostic modality for biliary atresia
e. Treatment
1) Kasai portoenterostomy: timing is CRUCIAL!
a) Effective bile drainage with resolution of jaundice
can be achieved in up to 70% IF portoenterostomy is
performed prior to 60 days of life
b) 40%–50% improved if performed at 60–90 days of
life
c) 25% improved at 90–120 days of life
d) 10%–20% improved at 120 days of life
2) Nutrition: essential prior to and after Kasai procedure
a) Breast milk or medium-chain triglyceride (MCT)-
containing formula necessary for adequate fat
absorption
b) Often have vitamin A, D, E, and K deficiencies
c) Zinc supplementation often required
3) Pruritus resulting from ↑ circulation of bile acids
a) Hydroxyzine may help reduce symptoms
b) Ursodeoxycholic acid may help improve bile flow
f. Post-Kasai complications
1) Cholangitis
a) Presentation: fever, irritability, jaundice, and acholic
stools
b) ↑ AST, ALT, direct bilirubin, alkaline phosphatase,
and GGT above baseline. While some are bacteremic,
blood cultures often negative.
c) Bile lakes at risk of becoming infected
d) Treatment: IV antibiotics
2) Portal hypertension (PHT)
a) Splenomegaly (often with ↓ white blood cells and
platelets)
b) Esophageal or gastric varices
c) Ascites
i. Medical management with diuretics → K+-
sparing diuretics 1st line. Often require added
furosemide.
ii. May require intermittent paracentesis
iii. Risk of spontaneous bacterial peritonitis

SECTION 6: Liver
g. Cirrhosis → end-stage liver disease with synthetic dysfunction
1) Nearly 80% require liver transplantation in childhood
B. Metabolic disorders
1. α1-antitrypsin deficiency (see Section 6N. Metabolic/Genetic Liver
Disease)
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a. One of most common causes of neonatal cholestasis 6Ci


b. Defect results in accumulated α1-antitrypsin in endoplasmic
reticulum in hepatocytes 362
c. Autosomal recessive
d. Laboratory: α1-antitrypsin level AND phenotype
1) MM: normal
2) ZZ: α1-antitrypsin deficiency
3) MZ/MS: heterozygote (carrier: does not have liver disease)
e. No FDA-approved therapy
f. Although pulmonary disease does not occur in childhood, should
counsel against smoking and second-hand smoke exposure
g. Variable course: from mild disease to progressive cirrhosis
requiring liver transplantation in childhood
1) Presence of PHT denotes more severe disease
2. Inborn errors of metabolism (see Section 6N. Metabolic/Genetic Liver
Disease)
a. Consider especially in patients presenting with hypoglycemia or
hepatosplenomegaly
1) Galactosemia
a) Tested on newborn screen; ↓ red blood cell
galactose-1-phosphate uridylyltransferase level is
gold standard
b) Consider in neonates with E. coli sepsis, absent red
reflexes or cataracts
2) Tyrosinemia
a) Can present in fulminant liver failure in neonates
b) Degree of coagulopathy often “out of proportion” to
mild ↑ of liver enzymes
c) Lab: ↑ urine succinylacetone is diagnostic
d) Treatment: NTBC—an inhibitor of an enzyme in the
tyrosine degradation pathway
3) Fructosemia
3. Bile acid synthesis defects (BASDs)
a. Defects in enzymatic steps within bile acids pathway → abnormal
bile acid synthesis and cholestasis
b. Laboratory: total serum bile acids will be below normal in BASDs
compared to being ↑ in all other cholestatic diseases
1) If low, then BASDs are confirmed with measurement of
individual bile acid levels by fast atom bombardment
(urine specimen)
2) GGT also usually not elevated
c. Treatment: oral bile acid supplementation generally effective
C. Genetic disorders

6Ci. Neonatal Cholestasis


1. Alagille syndrome (see Section 6P. Familial Hepatocellular Cholestatic
Disorders)
a. Autosomal dominant with variable penetrance secondary to
mutation of Jagged 1 gene on chromosome 20
b. Cholestasis results from paucity of intrahepatic bile ducts—
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characteristic finding on liver biopsy (note: one can see 6Ci


proliferation early in disease with paucity appearing later)
c. Physical examination: include abnormal facies (deep set eyes and 363
pointed chin); pulmonic stenosis common
d. Multiple organ systems involved
1) Liver: cholestasis from paucity of bile ducts
2) Ophthalmologic: posterior embryotoxon
3) Cardiac: congenital heart disease with pulmonic stenosis
most common
4) Skeletal: butterfly or hemivertebrae
5) Renal: common to have renal disease
e. Those with significant cardiac disease often have ↑ morbidity and
mortality
2. Cystic fibrosis (CF)
a. Up to 5% of patients with CF can present with neonatal
cholestasis
b. Newborn screen: detects via ↑ immunoreactive trypsinogen
c. Sweat Cl– and genetic testing evaluating mutations in CF
transmembrane regulator can confirm diagnosis
d. Pancreatic insufficiency (commonly measured by ↓ fecal elastase)
occurs quite early
3. Progressive familial intrahepatic cholestasis (PFIC) (see Section 6P.
Familial Hepatocellular Cholestatic Disorders)
a. Three types
b. PFIC 1 (FIC1 disease): results from defect in canalicular surface
protein FIC1
1) Low/normal GGT in setting of cholestasis
2) Growth failure and diarrhea common
3) Can present in neonatal period or later
c. PFIC 2 (bile salt export pump [BSEP] disease): results from
mutation in BSEP, affecting bile salt transport into canaliculus
1) Low/normal GGT in setting of cholestasis
2) Pruritus can be severe
3) High risk of hepatocellular carcinoma
d. PFIC 3 (MDR3 deficiency): mutation in gene coding transporter
MDR3—affecting phosphatidylcholine secretion into bile
canaliculus
1) High GGT (unlike low GGT in PFIC 1 and 2)
2) Can present later in life
D. Endocrinopathies
1. Hypothyroidism
a. Can present with cholestasis in neonates
b. Newborn screen can be normal

SECTION 6: Liver
c. Treatment of hypothyroidism → improvement in cholestasis
2. Panhypopituitarism
a. Persistent hypoglycemia in the neonatal period can be a clue
b. Septo-optic dysplasia and optic nerve hypoplasia often associated
c. Can develop adrenal crisis in severe stress if not diagnosed
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d. Laboratory: a.m. cortisol, thyroid-stimulating hormone, free T4, 6Ci


and glucose
e. Radiography: magnetic resonance imaging to evaluate pituitary 364
gland
E. Infectious (see Section 6I. Infectious and Inflammatory Diseases of Brain)
1. TORCH infection: toxoplasmosis, “other”, syphilis, rubella,
cytomegalovirus, and herpes virus
a. Herpes simplex virus 1 and 2 can present with fulminant liver
failure in the neonatal period with high morbidity and morality
2. Bacteremia/sepsis/meningitis in newborns commonly associated with
neonatal cholestasis
3. Urinary tract infections

IV. Management of neonatal cholestasis


A. Nutrition is paramount
1. MCT formula/supplementation (do not require bile salts for intestinal
absorption). Should be continued until cholestasis resolves.
2. Fat-soluble vitamin deficiency common and should be evaluated early
on. Fat-soluble vitamin supplementation frequently required.
B. Pruritus common secondary to ↑ levels of circulating bile acids (see Section
6Cii. Older Child)
1. Hydroxyzine may help improve symptoms
2. Ursodeoxycholic acid may help improve bile flow

Recommended Reading
Balistreri WF, Bezerra JA, Ryckman FC. Biliary atresia and other disorders of the
extrahepatic bile ducts. In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children,
3rd ed. New York, NY: Cambridge University Press; 2007, pp. 247-269.

Emerick KM, Whitington PF. Neonatal liver disease. Pediatr Ann. 2006;35:280-286.

Sokol RJ, Mack C, Narkewicz MR, et al. Pathogenesis and outcome of biliary atresia:
current concepts. J Pediatr Gastroenterol Nutr. 2003;37:4-21.

Suchy FJ. Approach to the infant with cholestasis. In: Suchy FJ, Sokol RJ, Balistreri WF,
eds. Liver Disease in Children, 3rd ed. New York, NY: Cambridge University Press; 2007,
pp. 179-189.

6Ci. Neonatal Cholestasis


SECTION
6Cii

Cholestasis in the Older Child


Table of Contents

6Cii
Molly Bozic, MD
365
Previous edition authors: Ramya Ramraj, MD; Daniel Leung, MD; Elizabeth Mileti, DO; and Philip
Rosenthal, MD

I. Differential diagnosis of cholestasis in the older child


A. The etiology of cholestasis presenting in an older child can be quite varied
1. Infectious etiologies
a. Hepatitis A, B, C, D, and E viruses
b. Adenovirus
c. Epstein-Barr virus, cytomegalovirus, and herpes viruses
d. Influenza
2. Immunological etiologies
a. Autoimmune hepatitis
b. Primary sclerosing cholangitis (PSC)
3. Bile duct obstructions
a. Cholelithiasis
b. Caroli disease
c. Autosomal recessive polycystic kidney disease (ARPKD)
4. Inherited cholestatic/hyperbilirubinemia syndromes
a. Progressive familial intrahepatic cholestasis 1 and 2
b. Gilbert, Dubin-Johnson, Rotor, and Crigler-Najjar syndromes
5. Metabolic
a. α1-antitrypsin deficiency
b. Wilson disease
c. Cystic fibrosis
d. Nonalcoholic fatty liver disease
e. Storage disorders
f. Glycogen storage disorders disease (types 1 and 4)
g. Lipid storage disorders
h. Urea cycle disorders
i. Mitochondrial disorders
j. Peroxisomal disorders
6. Drug-induced hepatotoxicity
7. Vascular
a. Hepatic outflow obstruction (Budd-Chiari and myeloproliferative
disorders)
b. Portal vein thrombosis

SECTION 6: Liver
II. Specific causes of cholestasis in older infants/children

A. Sclerosing cholangitis: chronic progressive disorder resulting in


inflammation, fibrosis, and strictures of the medium- and large-size bile ducts
in intrahepatic and extrahepatic biliary tree
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1. Clinical manifestations 6Cii


a. Associated with inflammatory bowel disease and autoimmune
hepatitis 366
b. Gradual progression of fatigue, anorexia, and weight loss
followed by pruritus and intermittent jaundice
c. Presentation with cholangitis symptoms (right upper quadrant
[RUQ] pain, fever, and jaundice) common
d. Early course is insidious with many asymptomatic when
laboratory abnormalities discovered
e. Progressive nature disease typically results in biliary cirrhosis and
end-stage liver disease
2. Laboratory evaluation
a. No specific laboratory abnormalities unique to PSC
b. ↑ alkaline phosphatase, direct bilirubin, aminotransferases, and
α-glutamyl transpeptidase (GGT) common
3. Radiographic findings
a. Cholangiography is gold standard for diagnosis
b. Characteristic findings on endoscopic retrograde
cholangiopancreatography (ERCP)
1) Irregular narrowing and stricture of hepatic and common
bile ducts
2) Areas of stenosis diffuse or multifocal
3) Characteristic “beaded appearance” resulting from areas
of stricture with intervening areas of normal or minimally
dilated segments
c. Magnetic resonance cholangiopancreatography (MRCP) is a
noninvasive evaluation of biliary tree that allows for evaluation
of intrahepatic ducts proximal to site of obstruction but does not
allow for therapeutic interventions
4. Liver biopsy
a. Fibrous obliteration of small bile ducts with concentric fibrous
tissue rings in an “onion skin” appearance
5. Therapy: no known/studied effective medical therapy in PSC.
Monitoring and management of complications of chronic liver
disease/cirrhosis: portal hypertension, nutritional status, and
fat-soluble vitamin deficiency.
B. Congenital hepatic fibrosis: autosomal recessive disease resulting in ductal
plate malformation of small interlobular bile ducts and resultant biliary
strictures and periportal fibrosis
1. Clinical manifestations
a. Can be associated with ARPKD and frequently presents in
newborns

6Cii. Cholestasis in the Older Child


b. RUQ pain, jaundice, and hepatomegaly
c. 3 different forms may be present: portal hypertensive, cholangitic,
and latent
d. Can present with bouts of cholangitis
e. Can present initially with massive GI (variceal) bleed in toddler
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2. Laboratory evaluation 6Cii


a. ↑ aspartate aminotransferase (AST), alanine aminotransferase
(ALT), GGT, direct bilirubin, and alkaline phosphatase 367
b. Renal dysfunction in those with ARPKD
3. Liver biopsy
a. Fibrous enlargement of portal tracts with abnormally shaped bile
ducts; portal vein branches are often hypoplastic while hepatic
arterial branches can be ↑ in number
b. Liver lesions can progress with time
C. Caroli disease/syndrome—congenital disorder resulting in dilation of
intrahepatic biliary tree
1. Caroli disease
a. Less common
b. Usually sporadic inheritance
c. Disease limited to ectasia or segmental dilation of the large
intrahepatic bile ducts
d. No other hepatic disease present
2. Caroli syndrome
a. More common
b. Autosomal recessive inheritance
c. Bile duct dilation of small or large intrahepatic bile ducts
d. Congenital hepatic fibrosis present
e. Often associated with ARPKD
3. Clinical manifestations
a. Variable presentation ranging from neonatal period to adulthood.
Congenital hepatic fibrosis in association with ARPKD typically
presents in neonatal/newborn period with cholestasis and renal
disease.
b. Jaundice and pruritis
c. Portal hypertension and complications including
hepatosplenomegaly, esophageal varices, and ascites
d. Cholangitis is common
4. Laboratory evaluation
a. ↑ AST, ALT, alkaline phosphatase, direct bilirubin, and GGT are
common
b. Liver synthetic function often preserved until late in disease
c. Coagulopathy 2º vitamin K malabsorption in setting of cholestasis
common
5. Radiographic evaluation: imaging helps establish diagnosis. Imaging
reveals biliary ectasia and irregular, cystic dilation of large proximal
intrahepatic bile ducts.
a. Ultrasound

SECTION 6: Liver
b. MRCP
c. ERCP
d. Computed tomography
6. Liver biopsy: Caroli syndrome will show broad bands of fibrosis and
distorted, dilated bile ducts often in whorls
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D. Alagille syndrome/paucity of intrahepatic bile ducts (see Section 6P. 6Cii


Familial Hepatocellular Cholestatic Disorders): autosomal dominant (AD)
multisystem disorder characterized by liver damage due to paucity of bile 368
ducts affecting the liver, heart, eyes, face, and skeleton
1. AD disorder; genes JAG1 and NOTCH
2. Clinical manifestations
a. Many present in neonatal period with cholestasis; however, some
have mutations that do not cause neonatal liver disease
b. Paucity of intrahepatic bile ducts on liver biopsy is characteristic
in association with ≥3 major findings including:
1) Neonatal cholestasis 95%
2) Congenital heart disease: with peripheral pulmonic
stenosis most common and tetralogy of Fallot
3) Skeletal abnormalities, e.g., butterfly vertebrae,
hemivertegrae spina bifida occulta, hemivertebrae,
absence of 12th ribs, and craniosynostosis. Fractures not
uncommon.
c. Ocular: posterior embryotoxon pigmentary retinopathy, abnormal
retinal vessels, iris hypoplasia, and optic disc abnormalities
d. Characteristic facial features: prominent forehead, hypertelorism,
deep-set eyes, and pointed or protruding chin
e. Renal disease: small, dysplastic, and multicystic kidneys; renal
tubular acidosis. Vascular disease: intracranial vascular anomalies
(usually asymptomatic), intra-abdominal aneurysms, carotid
artery narrowing, and Moyamoya (cerebrovascular blockage
around basal ganglia). Vascular accidents occurring in up to 34%
of these patients.
f. Delayed growth and puberty
g. Can have marked pruritus, significantly impacting quality of life
h. Xanthomata is common
i. Mortality rate variable depending on severity of disease and
organ systems affected. Severe congenital heart disease predicts
early mortality.
j. Liver transplantation needed for some patients
3. Laboratory evaluation
a. ↑ AST, ALT, GGT, alkaline phosphatase, triglyceride, and cholesterol
b. Can have marked ↑ of direct bilirubin (up to 30× normal)
c. Fat-soluble vitamin deficiency 2º to prolonged cholestasis
d. Genetic testing: mutations in JAG1 gene or Notch2 gene
4. Liver biopsy
a. Paucity of intrahepatic bile ducts is characteristic
b. Paucity may not be present in early infancy
c. 15%–20% with periportal and centrilobular fibrosis

6Cii. Cholestasis in the Older Child


d. Progressive liver disease with fibrosis and cirrhosis occurs
between 10% and 50% of patients
5. Treatment: ursodeoxycholic acid (UDCA), antipruritic therapy
(cholestyramine, phenobarbital, rifampicin, naltrexone, ondansetron,
and antihistamines), partial external biliary diversion, and liver transplant
Table of Contents

E. Choledochal cysts: congenital abnormalities of the biliary tree characterized 6Cii


by cystic dilation of extrahepatic or intrahepatic segments of the biliary tract
1. 1:15,000 live births in western hemisphere 369
a. Female predominance
b. Can present at any age and can affect any portion of the bile duct
with 18% presenting <1 year of age
c. 5 subtypes of cysts
1) Type I: cystic dilation of common bile duct—90% of cysts
a) A: large, saccular, cystic dilation
b) B: small localized segmental dilation
c) C: diffuse (cylindric) fusiform dilation
2) Type II: diverticulum of common bile duct and/or
gallbladder
3) Type III: choledochocele (intraduodenal)
4) Type IV: multiple cysts
a) A: cyst both intrahepatic and extrahepatic
b) B: isolated extrahepatic
2. Clinical manifestations
a. Triad of intermittent abdominal pain, jaundice, and palpable RUQ
mass only seen in 20%
b. Cholestasis most common presentation
3. Laboratory evaluation
a. ↑ direct/conjugated bilirubin and ↑ liver enzymes
4. Radiographic findings
a. Ultrasonography diagnostic imaging of choice, demonstrating
large cysts and dilation of intrahepatic/extrahepatic bile ducts
5. Treatment
a. Complete surgical resection of the choledochal cyst with a Roux-
en-Y choledochojejunostomy proximal to most distal lesion
b. Cholangitis occurs in 15% of patients after surgical resection
c. Postsurgical strictures and pancreatitis can occur
d. Risk of malignancy in residual cystic tissue reported and increases
with age (20% greater than general population)
1) Adenocarcinoma of bile duct or gallbladder is most
common
F. Spontaneous perforation of the common bile duct
1. Clinical manifestations
a. Rare entity
b. Mild jaundice, ascites, vomiting, acholic stools, and failure to
thrive are common presenting symptoms
c. Typically presents <3 months of age
d. Abdominal distension is progressive
e. Can see bile staining of umbilical and inguinal hernias

SECTION 6: Liver
f. Paracentesis will often show bile-stained ascites
2. Laboratory evaluation
a. ↑ direct/conjugated bilirubin and ↑ liver enzymes
b. Moderate ↑ direct bilirubin in comparison to mild elevation of
aminotransfersases
Table of Contents

3. Radiographic findings 6Cii


a. Ultrasound may show loculated fluid around the gallbladder
b. Hepatobiliary scintigraphy: radiotracer activity outside the biliary 370
track
c. Operative cholangiogram shows the perforation often with an

FIGURE 1 Algorithm for Evaluation of Cholestasis in the Older Child

History, physical exam, liver panel,


CBC, coagulation studies, hepatitis
panel, creatine kinase levels

Liver US with
Doppler

Dilated bile
Dilated bile Normal/non- Abnormal
ducts/sludge
ducts/sludge diagnostic vascular flow

Additional serologies (A1AT, IgG


MRCP or ERCP if
levels, AIH panel (IgG, F actin,
concern for acute MRI/MRV
anti-LKM ANA), ceruloplasmin
obstruction
levels, 24 hr urinary copper

Stone Stricture
Additional workup for
hypercoagulability (protein C, S,
factor V Leiden levels)
Surgery, Liver biopsy (evaluate for malignancies, systemic
Liver biopsy
ERCP PSC, cholangiopathies) conditions

obstruction seen at distal end of common bile duct


4. Treatment
a. Surgical drainage with surgical closure of perforation
b. Internal diversion with a Roux-en-Y used to establish drainage in
some infants

6Cii. Cholestasis in the Older Child


III. Antipruritic drugs

A. Pathophysiology of pruritus in cholestasis


1. Bile acids, bilirubin, and cholesterol in skin previously thought to cause
pruritus
Table of Contents

2. Recent data suggest pruritus is centrally mediated by opioid 6Cii


neurotransmission
a. Opioid peptides → mast cells to release histamine 371
b. Exogenous opioids cause pruritus relieved only by opioid
antagonists
c. Cirrhotic adults have ↑ endogenous opioids, such as enkephalins
d. Opioid antagonists in cholestatic individuals may cause a
withdrawal response similar to opioid abusers, suggesting that
cholestatic individuals have chronically ↑ circulating opioids
B. Treatment
1. First principle—treat the cause of cholestasis if possible
2. Antihistamine—diphenhydramine
a. Dose 5 mg/kg/day divided in 4 doses (≤300mg/day)
b. Mechanism: H1-receptor blocker competes with histamine for
H1-receptor sites
c. Blocking H1 receptors on peripheral nociceptors ↓ sensitization
and ↓ itching
d. Adverse effects: blurred vision, dry mouth, paradoxical
excitement, and sedation
e. Contraindications: hypersensitivity to diphenhydramine, asthma,
and encephalopathy
3. Antihistamine—hydroxyzine
a. Dose: 2 mg/kg/day divided every 6–8 hours as needed
b. Max single dose <6 years: 12.5 mg; 6–12 years: 25 mg; and >12
years: 100 mg
c. Mechanism of action: competes with histamine for H1-receptor
sites. Has antihistamine properties.
d. Adverse effects: drowsiness, blurry vision, and xerostomia
e. Contraindications: hypersensitivity to hydroxyzine and caution
with asthmatics
4. Ursodeoxycholic acid (UDCA)
a. Drug properties: hydrophilic bile acid stimulates hepatic bile
production and protects hepatocytes against cytotoxicity by
hydrophobic bile acids
b. Dose: 15–30 mg/kg/day in 2–3 divided doses
c. Mechanism of action: reduces toxicity of endogenous bile acids by
competitively inhibiting intestinal absorption
d. Adverse effects: abdominal pain, diarrhea, nausea, and may
worsen pruritus at start of therapy
e. Contraindications: hypersensitivity reaction
f. Caution regarding high-dose ursodiol in PSC: adult study using
high-dose ursodiol (28–30 mg/kg/day) versus placebo in PSC was
terminated after 6 years due to futility. ↑ mortality and serious

SECTION 6: Liver
adverse events noted in UDCA treatment group.
g. UDCA not effective for dissolving radio-opaque stones, bile
pigment stones, and calcified cholesterol stones
5. Cholestyramine
a. Drug properties: bile-binding resin
Table of Contents

b. Dose: 240 mg/kg/day in 3 divided doses; maximum 16 g/day 6Cii


c. Mechanism: binds bile acids in intestine forming nonabsorbable
complex, preventing enterohepatic reuptake of bile salts 372
d. Adverse effects: nausea, vomiting, abdominal pain, and
constipation
e. Contraindications: hypersensitivity reaction, complete biliary
obstruction, and bowel obstruction
f. Cholestyramine interferes with absorption of many medications
and should be given 2 hours before or after administration of
other drugs
6. Rifampin
a. Bactericidal antibiotic
b. Dose: 10 mg/kg/day orally (1 hour prior to meals or 2 hours after
meals to ↓ GI distress)
c. Mechanism: unknown; may inhibit toxic bile acid uptake and
induce cytochrome P450 system to degrade enkephalins and bile
acids, preventing hepatocyte injury
d. Adverse effects
1) Orange discoloration of urine, sweat, and tears
2) ↑ transaminases (monitor liver function tests every
2–4 weeks while on medication)
3) Idiosyncratic hypersensitivity—hemolytic anemia, renal
failure, and thrombocytopenic purpura
e. Contraindications: hypersensitivity reaction
7. Naloxone and naltrexone
a. Opiate antagonists not evaluated in children
b. Mechanism: bind competitively with opioid receptors with high
affinity but without activating receptors
c. Adverse effects
1) Anxiety, headache, insomnia, and withdrawal symptoms
2) Black box warning for naltrexone prohibits use in liver
failure
d. Contraindications: hypersensitivity reaction, concurrent use of
opioid analgesics, and opioid withdrawal or dependency

6Cii. Cholestasis in the Older Child


Recommended Reading
Bergasa NV. Treatment of the pruritus of cholestasis. Curr Treat Options Gastroenterol.
2004;7:501-508.
Table of Contents

Bergasa NV, Jones EA. The pruritus of cholestasis: potential pathogenic and therapeutic 6Cii
implications of opioids. Gastroenterology. 1995;108:1582-1588.
373
Bezerra JA, Balistreri WF. Cholestatic syndromes of infancy and childhood. Semin
Gastrointest Dis. 2001;12:54-65.

Cies JJ, Giamalis JN. Treatment of cholestatic pruritus in children. Am J Health Syst
Pharm. 2007;64:1157-1162.

Kamath BM, Schwarz KB, Hadzić N. Alagille syndrome and liver transplantation.
J Pediatr Gastroenterol Nutr. 2010;50:11-15.

Kelly DA, McKiernan PJ. Metabolic liver disease in the pediatric patient. Clin Liver Dis.
1998;2:1-30.

Lindor KD, Kowdley KV, Luketic VA, et al. High-dose ursodeoxycholic acid for the
treatment of primary sclerosing cholangitis. Hepatology. 2009;50:808-814.

Ng VL, Balistreri WF. Treatment options for chronic cholestasis in infancy and
childhood. Curr Treat Options Gastroenterol. 2005;8:419-430.

Santos JL, Choquette M, Bezerra JA. Cholestatic liver disease in children.


Curr Gastroenterol Rep. 2010;12:30-39.

Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children, 3rd ed. New York, NY:
Cambridge University Press; 2007.

Thornton JR, Losowsky MS. Opioid peptides and primary biliary cirrhosis. BMJ.
1988;297:1501-1504.

SECTION 6: Liver
Table of Contents

6Cii

374

6Cii. Cholestasis in the Older Child


SECTION
6D

Elevated Aminotransferases
Table of Contents

6D
Dania Molla Hosseini, MD
375
Amy Feldman, MD
Previous edition authors: Isabel Rojas, MD and Norberto Rodriguez-Baez, MD

I. Laboratory investigation

A. Used to:
1. Screen for liver injury
2. Identify cellular site of injury
3. Help with prognosis for chronic liver disease
4. Monitor response to treatment
B. No single test provides complete diagnostic or prognostic information; must
be used in combination with other laboratory values, clinical history, and
examination
C. Biochemical liver enzyme tests
1. Alanine aminotransferase (ALT)
a. Cytosolic enzyme present in highest concentrations in liver;
released from damaged hepatocytes
b. More specific for liver injury than aspartate
aminotransferase (AST)
c. Longer plasma half-life (T½) than AST ( 24 hours)
2. Aspartate aminotransferase (AST)
a. Cytosolic and mitochondrial isoenzyme; released from damaged
hepatocytes
b. Also found in heart muscle, skeletal muscle, kidney, brain,
pancreas, lung, leukocytes, and red blood cells
c. Less specific than ALT for liver injury
d. Rise in AST can be an early indication of rejection post-liver
transplant
3. Alkaline phosphatase (alk phos)
a. Found in liver, kidney, bone, placenta, intestine, and white blood
cells
b. In pediatrics, must consider confounding linear growth, bone
disease, and transient hyperphosphatemia of infancy as sources
of ↑ alk phos
c. Normal values vary by age
d. Can indicate biliary epithelial damage, infiltration of biliary
system, cirrhosis, rejection, or osteopenia 2º to vitamin D
deficiency in pediatric liver disease
e. Low alk phos suggests zinc deficiency or Wilson disease

SECTION 6: Liver
4. α-glutamyl transpeptidase (GGT)
a. Found in biliary epithelia and hepatocytes as well as kidney,
pancreas, spleen, brain, breast, and small intestine
b. Not specific for liver disease but useful in differentiating liver
disease from bone growth/bone disease (↑ alk phos in bone
Table of Contents

growth/disease, but GGT will be normal) 6D


c. Can be low/normal in certain pediatric liver diseases (progressive
familial intrahepatic cholestasis 1 and 2, benign recurrent 376
intrahepatic cholestasis, disorders of bile acid synthesis, and
panhypopituitarism)
d. Level is age dependent; highest in neonates
e. Induced by certain anticonvulsants
5. Direct bilirubin ( equivalent to conjugated bilirubin)
a. Indicates biliary obstruction or hepatocyte dysfunction
b. Increased in Dubin-Johnson due to impaired organic anion
transport into bile canaliculus
D. Biochemical liver function tests to measure synthetic function
1. Albumin
a. Synthesized only in the liver. In the absence of urinary or GI losses
or starvation, ↓ albumin indicates chronic liver disease.
b. T½ of 20 days
2. Prothrombin time
a. Vitamin K dependent
b. Indicates vitamin K deficiency or synthetic dysfunction

II. Differential diagnoses for ↑ liver transaminases


A. Infectious
1. Hepatitis A, B, C, D, and E; non A–E hepatitis; cytomegalovirus, Epstein-
Barr virus, influenza, adenovirus, herpes simplex virus, echovirus,
enterovirus, coxsackievirus, and parvovirus
B. Metabolic/genetic
1. α1-antitrypsin deficiency (A1AT)
2. Wilson disease
3. Iron storage disorders
4. Inborn errors of metabolism (fatty acid oxidation disorders, urea cycle
disorders, galactosemia, and hereditary fructose intolerance)
5. Alagille syndrome
6. Cystic fibrosis
7. Tyrosinemia
8. Celiac disease
C. Autoimmune
1. Autoimmune hepatitis (AIH)
2. Primary sclerosing cholangitis
3. Systemic lupus erythematosus
D. Infiltrative/storage
1. Nonalcoholic fatty liver disease
2. Glycogen storage disease

6D. Elevated Aminotransferases


3. Niemann-Pick disease
4. Hemophagocytic lymphohistiocytosis
5. Tumor
E. Trauma/ischemia
1. Hypoperfusion
Table of Contents

2. Sepsis 6D
3. Intra-abdominal bleed
F. Myopathy 377
1. Viral induced
2. Muscular dystrophy
G. Drug hepatotoxicity

III. Clinical pearls

A. No prognostic value for a single level, but trends in values may be predictive
1. Rapid decline in aminotransferases together with rising bilirubin and
coagulopathy reflect massive hepatic necrosis and poor prognosis in
acute liver failure (rather than improvement)
B. Highest elevations in aminotransferases (>1,000 IU) seen in acute viral
hepatitis, toxin- or drug-induced liver injury, ischemic hepatitis, or less
commonly AIH
C. Although the value of AST:ALT ratio is not well documented in children, in the
appropriate clinical setting, these following ratios are suggestive of:
1. <1: nonalcoholic steatohepatitis
2. >2: alcoholic liver disease
3. >4: fulminant Wilson disease
D. Disproportionate rise in AST suggests hemolysis, rhabdomyolysis, myopathic
process, myocardial disease, and recent vigorous physical activity. Solely
↑ AST suggests presence of macro-AST, when AST enzyme complexes with
immunoglobulins → ↓ clearance
E. Disproportionate rise in LDH suggests hemolysis, myopathy, cardiac disease,
and renal infarct
F. Disproportionate rise in CPK and aldolase suggests myopathy
G. Differential diagnosis of ↑ transaminases in a posttransplant patient
includes acute and chronic cellular rejection, de novo AIH, infection, biliary
complications, and vascular complications

SECTION 6: Liver
Recommended Reading
Murray KF and Horslen S. Diseases of the Liver in Children: Evaluation and Management.
New York, NY: Springer Science and Business Media; 2014.
Table of Contents

Suchy FJ, Sokol RJ, Balistreri WF. Liver Disease in Children, 4th ed. New York, NY: 6D
Cambridge University Press; 2014.
378

6D. Elevated Aminotransferases


SECTION
6E

Hepatomegaly
Table of Contents

6E
Emilia Shin, MD
379
Wikrom Karnsakul, MD
Previous edition author: Rima Fawaz, MD

I. Overview
Early identification of hepatomegaly is important to identify diseases for which
specific treatments are available to prevent further injury and progression to liver
failure

A. Liver span: measured along the midclavicular line, with palpation of the lower
margin and percussion of the upper margin
1. Lower margin can be determined using the scratch test: place
stethoscope below the xiphoid and scratching sequentially superiorly
starting from right lower quadrant. Listen for sound enhancement as
the finger crosses the liver edge.
B. Liver edge of >3.5 cm in children <2 years and >2 cm in older children below
the right costal margin suggests enlargement
C. Mean liver span increases linearly with body weight and age in both genders
D. Normal liver span by percussion at:
1. 1 week of age is 4.5–5 cm
2. 12 years; the normal range for
a. Boys is 7–8 cm
b. Girls is 6–6.5 cm
3. A liver span 2–3 cm smaller or larger than mean considered abnormal
E. Hepatomegaly may be a transient finding during systemic infection, but
persistent hepatomegaly should prompt a proper investigation

II. Etiology and pathogenesis


A. Due to 5 mechanisms: inflammation, excessive storage, infiltration,
congestion, and obstruction
B. See Table 1 for differential diagnosis

III. Evaluation
A. History will determine need for further testing
1. Hyperbilirubinemia after 2 weeks of age in a neonate should →
rapid assessment for extrahepatic biliary atresia and other causes of
neonatal cholestasis
2. History of umbilical catheter → ↑ risk for hepatic abscess and
extrahepatic portal vein thrombosis with cavernous transformation

SECTION 6: Liver
3. Birth history → risk factors for perinatal infections
4. Family history of early infant death or neurodegenerative or psychiatric
diseases → metabolic etiology
5. Delayed passage of meconium → cystic fibrosis
6. Medication history → hepatomegaly includes nonsteroidal anti-
Table of Contents

inflammatory drugs, isoniazid, propylthiouracil, and sulfonamides 6E


B. Physical examination
1. Assess liver firmness and nodularity 380
a. Firm, enlarged liver suggests a storage disease, infiltrative process
b. Tender, enlarged liver may indicate an inflammatory process
2. Look for signs of a more generalized disease, i.e., fever—systemic
illness or infection; spider angiomata, xanthomas, and palmer
erythema—chronic liver disease and eye findings, e.g., chorioretinitis in
TORCH
3. Massive splenomegaly more common with storage diseases and
malignancy than with portal hypertension
C. Laboratory evaluation
1. Complete blood count with differential, comprehensive metabolic
panel, albumin, and prothrombin time
2. Urinalysis and reticulocyte count may be helpful
3. More specialized testing based on suspected diagnosis
D. Imaging evaluation
1. Abdominal ultrasound (US)
a. Doppler flow: assesses hepatic portal vein blood flow as well as
collaterals; evaluate for infiltration
b. Can indicate hepatic size and consistency. Abnormal echotexure
suggests fat, fibrosis, or infiltration.
c. Further imaging modalities may be needed for elucidation, e.g.,
computed tomography (CT) scan or magnetic resonance imaging
2. CT to define extent of tumor; superior to US in detecting small focal
lesions such as tumors, cysts, or abscesses
3. Others: radionuclide scanning (distinguishes biliary atresia from
neonatal hepatitis), cholangiography, and magnetic resonance
cholangiopancreatography
E. Pathology
1. Liver biopsy is often needed for definitive diagnosis

6E. Hepatomegaly
TABLE 1 Differential Diagnosis of Hepatomegaly

↑ Number and Size of Cells, ↑ Vascular Space ↑ Biliary Space


Parenchyma and Stroma (Congestion) (Obstruction of Bile Flow)
(Inflammation, Storage, and
Table of Contents

Infiltration)
6E
Inflammation (hepatocyte Intrahepatic Tumors outside of the liver 381
or Kupffer cell enlargement obstruction to hepatic
and inflammatory cells) vein outflow Congenital hepatic
• Viral: hepatitis A–E, • Sinusoidal obstruction fibrosis
cytomegalovirus, syndrome/veno-
Epstein-Barr virus (EBV), occlusive disease
and Coxsackie virus Congenital of acquired
• Hepatic vein
• Bacterial (sepsis, abscess, thrombosis problems of biliary system
and cholangitis) • Hepatic vein web • Choledochal cyst
• Toxic • Caroli disease
• Autoimmune • Biliary atresia
Suprahepatic
• Cholelithiasis
Storage obstruction
• Fat • Congestive heart
Idiopathic (benign?)
• Nonalcoholic fatty failure
liver disease, Reye • Pericardial disease
syndrome/mitochondrial • Tamponade
disease, malnutrition and constrictive
(kwashiorkor), pericarditis
hyperalimentation,
galactosemia, cystic
fibrosis, and diabetes
• Glycogen storage diseases
(GSDs)
• Gaucher disease
• Niemann-Pick disease
• Wolman disease
• α1-antitrypsin deficiency
• Wilson disease
• Hypervitaminosis A (Kupffer
cell hyperplasia)

Infiltration
• Extramedullary
hematopoiesis
• Primary tumors
• Hepatoblastoma,
hepatocellular carcinoma,
hemangioma, and focal
nodular hyperplasia
• Secondary or metastatic
tumors
• Lymphoma, leukemia,
neuroblastoma,
Wilms tumor, and
hemophagocytic
lymphohistiocytosis

SECTION 6: Liver
FIGURE 1 Hepatomegaly Diagnostic Evaluation
*
Hepatomegaly
(History, physical exam,
lab tests)
NO hyperbilirubinemia
Table of Contents

Hyperbilirubinemia
6E
Splenomegaly No Splenomegaly
382
Elevated indirect Elevated direct bilirubin
bilirubin/ mixed
Abdominal ultrasound
w/Doppler
AST/ALT AST/ALT
AlkPhos AlkPhos
Primary and metastatic
Congestive heart Vascular obstruction Liver tumors
failure tumors Infants of diabetic mothers
Hemolysis Metabolic disease
Hepatitis Biliary obstruction Malnutrition
Sepsis
DIC *Wilson disease Choledocal cyst/ Lysosomal storage diseases Autoimmune hepatitis
Drugs/toxins tumors Leukemia/lymphoma **Viral hepatitis
Drugs/toxins Congestive heart failure
TORCH infections Parasitic infections Infectious liver cysts/
Sepsis TPN Parasitic infections abscesses
Metabolic diseases ***Glycogen storage
disease
obesity/steatohepatitis

*May have indirect hyperbilirubinemia when Coombs negative hemolysis is present.


Occasionally, alkaline phosphatase (alk phos) is low in Wilson disease. An alk phos/total bilirubin ratio of <4 and/or
aspartate aminotransferase/alanine aminotransferase ratio >4 highly suggests fulminant hepatitis in Wilson disease.
**Exception: acute EBV infection may present with splenomegaly.
*** GSD type IV can present with splenomegaly, and other GSDs may rarely be complicated by portal hypertension
and present with splenomegaly.
Modified with permission from Pediatrics in Review, Vol. 21, Page(s) 303-310, Copyright © 2000 by the AAP.

Recommended Reading
Lawson EE, Grand RJ, Neff RK, et al. Clinical estimation of liver span in infants and
children. Am J Dis Child. 1978;132:474-476.

Naveh Y, Berant M. Assessment of liver size in normal infants and children. J Pediatr
Gastroenterol Nutr. 1984;3:346-348.

Novak DA, Suchy FJ, Balistreri WF. Disorders of the liver and biliary system. In: McMillan
JA, Feigin RD, DeAngelis CD, et al., eds. Oski’s Pediatrics: Principles & Practice, 4th ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2006, pp. 2013-2039.

Wolf AD, Lavine JE. Hepatomegaly in neonates and children. Pediatr Rev.
2000;21:303-310.

6E. Hepatomegaly
SECTION
6F

Cirrhosis and Portal Hypertension


Table of Contents

6F
Alisha Mavis, MD
383
Lee M. Bass, MD
Previous edition authors: Khyati Mehta, MD and Simon Ling, MD

I. Overview

A. Portal hypertension (PHT) may be caused by a wide variety of pediatric liver


diseases
B. Most common causes of PHT in children are biliary atresia and extrahepatic
portal vein (PV) thrombosis
C. PHT is defined as a portal pressure >10 mm Hg or a hepatic venous pressure
gradient (HVPG) >5 mm Hg

II. Pathophysiology
A. The portal system drains the capillaries of the mesentery and spleen and
ends in the hepatic sinusoids (see Figure 1)

*FIGURE 1 Portal Circulation

Inferior
vena cava
Left, right, and middle
hepatic veins

Portal vein
Liver
Splenic vein Spleen

Superior
Hepatic mesenteric
sinusoids vein Left colon

Inferior
mesenteric
vein
Right colon/small
intestine This figure was published in Sleisenger and Fordtran's
Gastrointestinal and Liver Disease, 10th ed., Feldman M,
Friedman LS, Brandt LJ, Portal hypertension and variceal
bleeding, pp. 1524-1552, Copyright Elsevier 2015.

SECTION 6: Liver
B. PV provides 75%–80% of total hepatic blood flow with partially oxygenated
blood, while the hepatic artery supplies the remaining 20%–25% with highly
oxygenated blood
C. Portal system (P) pressure is proportional to blood flow (q) and resistance to
blood flow (r)
Table of Contents

1. Ohm’s law: P = q × r 6F
D. PHT is caused by hemodynamic changes, leading to an ↑ in flow, an ↑ in
resistance, or a combination of both 384
1. Vasoactive substances play a role in regulating intrahepatic resistance
a. ↓ intrahepatic nitric oxide, ↑ endothelin 1, carbon monoxide,
norepinephrine, angiotensin, prostaglandins, thromboxane,
leukotrienes, and hydrogen sulfide have all been implicated in
PHT
2. Mechanical factors include regenerative nodules, fibrotic bands,
capillarization of the hepatic sinusoids, and hepatocyte swelling
3. Results in a hyperdynamic circulation characterized by ↑ cardiac output,
↓ splanchnic tone, and ↓ splanchnic vasoconstrictor responsiveness
a. Subsequent vasodilatation → ↑ Na+ sodium retention and
↑ vascular volume due to renal response to vasodilation

Association between Portal Pressure, Hemodynamic Changes,


FIGURE 2 and Development of Varices
*

Cirrhosis 1) Passive mechanical - fibrosis &


regenerative nodules
2) Active vascular - vasoconstriction
& decreased production of
vasodilators

Resistance to
Portal Flow
Splanchnic
Arteriolar
Resistance
Portal
Pressure
Portal Blood
Inflow

Varices

6F. Cirrhosis and Portal Hypertension


III. Etiology: PHT can develop at three different levels due to many
different diseases (see Table 1)

TABLE 1 Etiology of Portal Hypertension


Table of Contents

Intrahepatic 6F
Prehepatic Hepatocellular Biliary Other Posthepatic
385
• PV • Autoimmune • Biliary atresia • Nodular • Budd-Chiari
thrombosis hepatitis • Congenital regenerative syndrome
• Arteriovenous • α1-antitrypsin hepatic hyperplasia • Congestive
fistula deficiency fibrosis • Veno-occlusive heart failure
• Splenic vein • Infectious • Cystic fibrosis disease • Constrictive
thrombosis hepatitis • Alagille • Schistosomiasis pericarditis
• Congenital • Wilson disease syndrome • Sarcoidosis • Inferior
stenosis or • Toxins • Primary • Peliosis hepatis vena cava
external • Steatohepatitis sclerosing obstruction
compression cholangitis
of the PV

IV. Clinical presentation

A. PHT should be considered in any child presenting with:


1. Splenomegaly on physical exam or imaging
2. Unexplained splenomegaly or GI bleeding
3. Variceal bleed: hematemesis and/or melena
4. Prominent vascular markings: caput medusa (may have audible venous
hum: Cruveilhier-Baumgarten murmur) or spider hemangiomas
5. Abnormal labs: due to hypersplenism: anemia, leukopenia, and/or
thrombocytopenia
6. Ascites

TABLE 2 Hepatic Venous Pressure Gradients in Different Types of Portal Hypertension

HVPG Measurements
Wedged Hepatic HVPG
HVPG
Types of PHT Venous Pressure Measurements
Prehepatic: portal
Normal Normal Normal
venous obstruction
Intrahepatic:
Mildly ↑ Normal Normal
presinusoidal
Intrahepatic: ↑ ↑
Normal
sinusoidal (cirrhosis)
Posthepatic: hepatic ↑ ↑ Normal
venous obstruction

SECTION 6: Liver
V. Diagnosis
A. Working clinical definition of PHT
1. Presence of both splenomegaly and thrombocytopenia
2. Presence of a complication of PHT (ascites, varices, GI bleeding 2° to
Table of Contents

PHT, and hepatopulmonary syndrome [HpS]) 6F


B. Abdominal ultrasound: may show abnormalities of liver echotexture,
splenomegaly, obstruction of PV and posthepatic venous system, collaterals, 386
and ascites
C. Doppler ultrasound measures the velocity of flow in vasculature and
direction of flow. Hepatofugal flow (flow away from the liver) indicates
more severe PHT.
D. Endoscopy: evaluates for esophageal varices, gastric varices, and portal
gastropathy. It is the gold standard for diagnosis of GI tract lesions from PHT.
E. HVPG: the difference between a wedged hepatic venous pressure (indicates
PV pressure) and a free hepatic venous pressure
1. Measured by interventional radiology via a transjugular approach
2. HVPG > 10 mm Hg is associated with esophageal varices and
HVPG > 12 mm Hg is associated with variceal bleeding and ascites
F. Computed tomography/magnetic resonance: useful for confirming
extrahepatic PV thrombosis and Budd-Chiari syndrome
G. Angiography: effective for assessing the extrahepatic vascular anatomy,
especially in patients with PV thrombosis
H. Liver biopsy: helps assess liver damage in patients with extrahepatic PV
thrombosis

VI. Complications
A. Varices
1. Variceal bleeding is caused by ↑ pressure in the varix → changes in
variceal diameter and ↑ wall tension
a. When the wall tension exceeds the variceal wall strength, the
varix ruptures and bleeding occurs
2. GI bleeding may occur from portal hypertensive gastropathy; gastric
antral vascular ectasia; or esophageal, gastric, duodenal, gallbladder,
peristomal, or rectal varices
3. Large varices, variceal red markings, and presence of gastric varices
↑ risk of bleeding
4. Major cause of morbidity and mortality in patients with PHT
B. Ascites (see Section 6G. Ascites)
1. Hyperdynamic circulation → splanchnic vasodilation → expansion of
plasma volume via Na+ and water retention and Starling forces within
the intestines forcing fluid into the peritoneum
2. Lymph formation exceeds lymph return
3. Hypoalbuminemia and dietary Na+ intake exacerbates ascites
formation
4. An ascitic white cell > 500/mL indicative of spontaneous bacterial
peritonitis in a patient with ascites, abdominal pain, and fever

6F. Cirrhosis and Portal Hypertension


C. Hepatopulmonary syndrome (HpS)
1. Oxygen partial pressure <70 mm Hg or an ↑ in alveolar-arterial oxygen
gradient >15 mm Hg
2. Associated with PHT, intrapulmonary vascular dilation, and hypoxia
3. Hypoxia with activity is characteristic of HpS
Table of Contents

4. Contrast-enhanced echocardiography (CEE or bubble echo) can detect 6F


intrapulmonary vascular dilation
5. Liver transplant is only effective treatment 387
D. Portopulmonary hypertension
1. Pulmonary artery hypertension in a patient with PHT
2. Associated with fatigue, chest pain, syncope, and dyspnea with activity
3. Tricuspid valve regurgitation may be noted on echo with an associated
murmur
E. Hepatorenal syndrome
1. Renal failure associated with PHT
2. Ominous complication of PHT
F. Hepatic encephalopathy
1. Associated with portosystemic shunting typically in setting of advanced
liver disease
2. Minimal hepatic encephalopathy may be present in patients with PV
thrombosis and mild liver dysfunction

VII. Management and treatment


A. Acute variceal bleeding
1. Stabilization: airway; breathing; IV access; fluid resuscitation with
colloid, crystalloid, or blood products; and NPO
2. Avoid overtransfusion (goal hemoglobin 7–8 g/dL) and volume
overload, which → ↑ portal pressure and potentially → further variceal
bleeding
3. Vitamin K if ↑ prothrombin time or international normalized ratio
4. Broad spectrum antibiotic prophylaxis (IV ceftriaxone)
5. Octreotide infusion to ↓ splanchnic blood flow, ↓ PV inflow, and ↓ PV
pressure
6. Blakemore tube
7. IV proton pump inhibitor (PPI)
8. NG tube to monitor ongoing bleeding as well as remove blood from
the GI tract
9. EGD when the patient is stable to determine bleeding source and
possibly treat
B. Endoscopic variceal management (see Section 10A. Endoscopy)
1. Endoscopic variceal ligation (EVL)
a. Band ligation → thrombus of the varix
b. Long-term PPI therapy ↓ the risk of treatment failure after EVL
2. Endoscopic sclerotherapy
a. Used in patients <10 kg in whom the band ligation device is too
large to pass through the upper esophageal sphincter
b. Effective treatment for variceal bleeding and long-term treatment
of varices, however has a higher rate of complications than EVL

SECTION 6: Liver
3. Gastric varices
a. Endoscopic variceal obturation with cyanoacrylate is 1st-line
therapy for acute gastric variceal bleeding
b. Balloon-occluded retrograde transvenous obliteration eliminates
gastric varices in fundus and is performed by interventional
Table of Contents

radiology 6F
C. Prophylaxis of variceal bleeding
1. 1° prophylaxis 388
a. Surveillance endoscopy when there is evidence of hypersplenism
used as primary prophylaxis at many centers
b. The adult guidelines recommend nonselective β-blockers
and/or EVL and screening endoscopy in patients with high risk of
bleeding, but this has not been studied in children
2. 2° prophylaxis
a. Endoscopy with EVL or sclerotherapy every 2–4 weeks until
obliteration of varices recommended to ↓ risk of rebleeding
D. Surgical therapy and transjugular intrahepatic portosystemic shunt (TIPS)
1. Patients who fail to respond to endoscopic therapy or have other
conditions may require surgical management
2. Indications for surgical management
a. Extrahepatic PV thrombosis
b. Variceal bleeding (esophageal and gastric) refractory to medical
and endoscopic therapy when patient does not meet criteria for
liver transplant
c. Refractory ascites
d. Complications due to hypersplenism (e.g., severe pain, platelets
<10,000, and recurrent infections)
e. Medical refractory portosystemic encephalopathy
3. Surgical shunts: should not be considered if liver transplant is expected
in near future
a. Meso-Rex (mesenteric left PV bypass)
1) 1st option for patients with extrahepatic PV thrombosis but
must have normal liver architecture for long-term patency
2) Jugular venous autograft to shunt blood from superior
mesenteric vein into intrahepatic PV
3) Restores hepatopetal flow, decompresses varices, and
↓ spleen size
b. Distal splenorenal
1) Decompresses esophageal and gastric varices through the
short gastric vein, spleen, and splenic vein to the left renal
vein
2) Lower risk of portosystemic encephalopathy than
mesocaval shunts
4. TIPS: performed by interventional radiology
a. Forms a communication between the hepatic and PV, thus
decreasing portal pressure
b. Can be an effective bridge to transplant
c. Indications: recurrent variceal bleeding not responsive to

6F. Cirrhosis and Portal Hypertension


medical/endoscopic therapy, refractory ascites, Budd-Chiari
syndrome, veno-occlusive disease, hepatorenal syndrome,
and HpS
d. Complications: encephalopathy, PV leakage, restenosis,
perforation, infection, and hemolysis
Table of Contents

5. Liver transplantation 6F
a. Treatment of choice for most patients with decompensated
progressive liver disease and medically resistant esophageal 389
varices
b. Prior surgical shunt or TIPS procedure may complicate the
transplant surgery and ↑ morbidity

Recommended Reading
de Franchis R, Baveno V Faculty. Revising consensus in portal hypertension: report of
the Baveno V consensus workshop on methodology of diagnosis and therapy in portal
hypertension. J Hepatol. 2010;53:762-768.

Maruyama H, Sanyal AJ. Portal hypertension: nonsurgical and surgical management. In:
Schiff ER, Maddrey WC, Sorrell MF, eds. Schiff’s Diseases of the Liver, 11th ed. Hoboken,
NJ: Wiley; 2012.

Shah VH, Kamath PS. Portal hypertension and variceal bleeding. In: Feldman M,
Friedman LS, Brandt LJ, eds. Sleisenger and Fordtran’s Gastrointestinal and Liver Disease,
9th ed. Philadelphia, PA: Saunders Elsevier; 2010.

Shneider BL, Bosch J, de Franchis R, et al. Portal hypertension in children: expert


pediatric opinion on the report of the Baveno v Consensus Workshop on Methodology
of Diagnosis and Therapy in Portal Hypertension. Pediatr Transplant. 2012;16:426-437.

Superina R, Bambini DA, Lokar J, et al. Correction of extrahepatic portal vein


thrombosis by the mesenteric to left portal vein bypass. Ann Surg. 2006;243:515-521.

Umeda N, Kamath PS. Hepatopulmonary syndrome and portopulmonary hypertension.


Hepatol Res. 2009;39:1020-1022.

Villanueva C, Colomo A, Bosch A, et al. Transfusion strategies for acute upper


gastrointestinal bleeding. N Engl J Med. 2013;368:11-21.

SECTION 6: Liver
Table of Contents

6F

390

6F. Cirrhosis and Portal Hypertension


SECTION
6G

Ascites
Table of Contents

6G
Erin R. Lane, MD
391
Evelyn K. Hsu, MD
Previous edition authors: Alfredo Larrosa Haro, MD, PhD and Mariana Gómez-Nájera, MD

I. Definition
A. Ascites is the pathologic accumulation of fluid within the peritoneal cavity

II. Pathogenesis
A. Disrupted balance of hydrostatic and oncotic forces that regulate splanchnic,
portal, and hepatic blood and lymphatic flow → in development of ascites
B. In cirrhosis, ascites develops secondary to splanchnic vasodilation,
hyperaldosteronism, and portal hypertension (PHT)
C. Nitric-oxide-mediated vasodilation → a reduction in arterial blood volume
→ activation of the sympathetic nervous system, renal Na+ retention via the
renin-angiotensin-aldosterone system, and secretion of antidiuretic hormone
D. The subsequent renal Na+ retention → expansion of extracellular volume and
accumulation of ascites
E. PHT contributes to the ↑ splanchnic capillary pressure → excess of lymph
formation

III. Etiology
A. Chronic liver disease and cirrhosis are the most common
B. Noncirrhotic causes of fetal and childhood ascites
1. Hepatic causes: Budd-Chiari syndrome (posthepatic), bile duct trauma,
congenital hepatic fibrosis, α1-antitrypsin deficiency, acute hepatitis,
and sinusoidal occlusive disease (veno-occlusive disease)
2. Nonhepatic causes
a. Peritoneal infection: tuberculosis, cytomegalovirus, and Epstein-
Barr virus
b. Intestinal: appendicitis, Crohn disease, eosinophilic enteropathy,
celiac disease, intestinal atresia, meconium ileus, intestinal
malrotation or perforation, and pyloric duplication
c. Pancreatic: acute pancreatitis and pancreatic pseudocyst
d. Inflammatory: systemic lupus erythematosus and Henoch-
Schönlein purpura
e. Metabolic disease
f. Heart failure

SECTION 6: Liver
g. Genitourinary: nephrotic syndrome, obstructive uropathy,
posterior urethral valves, bladder rupture, and ureterocele
h. Chylous ascites: thoracic duct trauma or ligation, intestinal
lymphangiectasia, and total parenteral nutrition extravasation
i. Neoplastic: germ cell tumors, neuroblastoma, pseudoascites
Table of Contents

(ovarian or omental or mesenteric cyst), lymphoma, and Wilms 6G


tumor
j. Hemoperitoneum 392
k. Ventriculoperitoneal shunt

IV. Diagnosis
A. Laboratory: evaluate liver and renal disease (measure transaminases,
albumin, coagulation studies, blood urea nitrogen, creatinine, urinalysis, and
urinary Na+ excretion)
B. Imaging: abdominal sonographic imaging to evaluate hepatic and biliary
anatomy, liver vasculature, assess for evidence of PHT, and estimate the
volume and character (simple versus loculated) of ascitic fluid
C. Percutaneous or transjugular liver biopsy: for histological evaluation (note:
presence of ascites can ↑ the risk of a percutaneous liver biopsy)
D. In the majority of children with ascites, the above tests will confirm cirrhosis
E. When underlying etiology is in question, recommend a diagnostic
paracentesis
F. Examination of the ascitic fluid with:
1. White and red cell counts
2. Albumin
3. Total protein
4. Glucose
5. Bilirubin
6. Lactate dehydrogenase
7. Amylase
8. Triglycerides
9. Bacterial culture
10. Acid-fast smear
11. Cytology
G. Serum-ascites albumin gradient (SAAG): difference of simultaneously
measured (albumin) in serum and ascitic fluid
1. Differentiates cirrhotic from noncirrhotic ascites
2. SAAG of ≤1.1 g/dL effectively rules out PHT as a cause of ascites

V. Management
A. Cirrhotic ascites
1. Treatment strategies focus on mobilizing intraperitoneal fluid and
correcting the relative systemic hypovolemia
2. Na+ restriction: in children, restrict intake to 1–2 mEq Na+/kg/day,
and in adolescents, to 1–2 g Na+/day. Restriction is not necessary for
exclusively breast-fed infants as human breast milk has very low Na+
content. For formula-fed infants, a low-Na+ formula may be utilized.

6G. Ascites
3. Diuresis
a. Spironolactone: counters hyperaldosteronism, which is
characteristic of cirrhosis
1) Works as a competitive inhibitor of aldosterone at distal
renal tubules; acts to ↑ excretion of Na+, Cl–, and H2O water
Table of Contents

and conserve K+ and H+ 6G


2) Dosing: infants 0.5–1 mg/kg/day; older children
1–3 mg/kg/day in 2–3 divided doses up to maximum of 393
100 mg/day
b. Loop diuretics (furosemide): directly inhibits reabsorption of Na+
and Cl– in the ascending loop of Henle and distal renal tubules;
↑ excretion of H2O, Na+, Cl–, Mg2+, and Ca2+. Dosing: 0.5–2 mg/kg/day
(up to maximum of 40 mg/day) in 2–4 divided doses.
c. Response to diuresis in children with ascites best evaluated by
trending daily body weights
d. Spot measurement of renal excretion of Na+ and K+ may be
helpful in evaluating diuretic response, with a goal ratio of urine
Na+/K+ of >1
4. Fluid restriction
a. Fluid restriction generally not recommended unless serum Na+
values <125–130 mEq/L
b. Enteral fluids should be used whenever possible, and IV
crystalloid used cautiously with very close attention to Na+
content—very easy to fluid overload children with a saline bolus in
emergency department
c. Hypertonic and isotonic IV fluids will worsen ascites and fluid
overload
d. Hypotonic maintenance fluids should be utilized to avoid total
body Na+ overload
5. IV albumin
a. Albumin is integral in maintaining intravascular oncotic pressure;
hypoalbuminemia often contributes to or exacerbates the ascites
b. Albumin may be utilized to support intravascular volume when
serum concentration <2.5 g/dL
c. Use of 0.5–1 g/kg of dry weight of 5% or 25% albumin may
be chosen based on desired effect of intravascular volume
expansion
d. To promote diuresis, a loop diuretic (e.g., furosemide) may be
given following albumin bolus
6. Paracentesis
a. Both diagnostic and therapeutic
b. Large-volume paracentesis for diuretic-refractory ascites can be
safe and effective in children
7. Infection (spontaneous bacterial peritonitis [SBP])
a. SBP may result in sepsis, encephalopathy, and renal failure and
carries a high risk of mortality
b. Clinical signs include fever, increasing ascites, encephalopathy,
abdominal pain, ileus, and renal failure

SECTION 6: Liver
c. Measuring the number of polymorphonuclear leukocytes (PMNs)
in ascitic fluid supports the identification of SBP (ascitic
fluid > 250 PMN/mm3 sensitive for SBP)
d. High morbidity and mortality
e. Empiric treatment: 3rd-generation cephalosporin or β lactamase
Table of Contents

inhibitor with penicillin, such as piperacillin tazobactam 6G


8. Surgical management
a. Shunts are often utilized as a bridge to liver transplantation 394
b. Transjugular intrahepatic portosystemic shunting: intrahepatic
stent inserted between 1 hepatic vein and the portal vein via
transjugular approach

VI. Complications

A. Ascites may → significant lung restriction and compromised ventilation, ↑ risk


of infection, GI hemorrhage, encephalopathy, renal failure, and death

Recommended Reading
Giefer MJ, Murray KF, Colletti RB. Pathophysiology, diagnosis, and management of
pediatric ascites. J Pediatr Gastroenterol Nutr. 2011;52:503-513.

Ginès P, Cárdenas A, Arroyo V, et al. Management of cirrhosis and ascites. N Engl J Med.
2004;350:1646-1654.

Kramer RE, Sokol RJ, Yerushalmi B, et al. Large-volume paracentesis in the


management of ascites in children. J Pediatr Gastroenterol Nutr. 2001;33:245-249.

Runyon BA, Montano AA, Akriviadis EA, et al. The serum-ascites albumin gradient is
superior to the exudate-transudate concept in the differential diagnosis of ascites.
Ann Intern Med. 1992;117:215-220.

6G. Ascites
SECTION
6H

Acute Liver Failure


Table of Contents

6H
Orith Waisbourd-Zinman, MD
395
Kathleen M. Loomes, MD
Previous edition author: Naim Alkouri, MD

I. Background
A. Acute liver failure (ALF) is a rapidly progressive clinical syndrome that is the
final common pathway for many separate liver diseases
B. ALF accounts for 10%–15% of pediatric liver transplants. Identification of the
underlying etiology, potential for specific treatment of disease, and potential
comorbidities, necessary for survival, must all be considered.
II. Definition
A. Adult definition: onset of hepatic encephalopathy (HE) and coagulopathy
within 8 weeks of onset of liver disease in absence of pre-existing liver
disease
B. Pediatrics: encephalopathy may be difficult to detect, and liver failure may be
the first presentation of a previously unrecognized disease
1. The Pediatric Acute Liver Failure Study Group defines ALF in children
as:
a. Biochemical evidence of liver injury
b. No history of known chronic liver disease
c. Coagulopathy not corrected by vitamin K
d. International normalized ratio (INR) > 1.5 if the patient has HE or
>2.0 if the patient does not have HE
III. Etiology
A. A specific etiology cannot be identified in about 50% of pediatric cases
B. Toxins and medications
1. Acetaminophen: dose-dependent hepatotoxicity
a. Conversion to highly reactive metabolite—N-acetyl-p-benzo-
quinone imine (NAPQI)
b. Diagnostic criteria: toxic level on the Rumack nomogram and
acute ingestion of ≥100 mg/kg within 24 hours
c. ↑↑↑ aminotransferase levels with relatively low bilirubin level
d. Chronic exposure can also result in hepatotoxicity
2. Anticonvulsants (phenytoin, carbamazepine, and valproic acid)
a. Can be accompanied by fever, skin rash, and eosinophilia
b. Valproic acid can induce ALF by unmasking a more generalized
mitochondrial disorder
3. Mushrooms

SECTION 6: Liver
4. Isoniazid
5. Amiodarone
6. Ecstasy
C. Metabolic
1. Wilson disease
Table of Contents

a. Serum ceruloplasmin may be normal in ALF 6H


b. Very low alkaline phosphatase, high bilirubin:alkaline
phosphatase ratio, and hemolytic anemia are clinical clues 396
c. Poor prognosis in fulminant presentation without liver
transplantation
2. Galactosemia
a. Infant consuming lactose-containing formula and positive urine-
reducing substances
b. May be associated with Gram-negative sepsis, particularly
E. coli
3. Tyrosinemia
a. Profound coagulopathy and normal or near normal serum
aminotransferase
b. May be associated with Gram-negative sepsis
4. Urea cycle defect
a. Ornithine transcarbamylase deficiency is most common and
X-linked
b. Very high NH3 levels without acidosis
5. Fatty acid oxidation (FAO) defects
a. Present with a Reye-like syndrome and hypoketotic hypoglycemia
6. Hereditary fructose intolerance
a. Problems with introduction of fruit/sucrose
b. Some drugs and vitamins are made up in a sucrose suspension
7. Mitochondrial disorders
a. Mostly with associated systemic mitochondrial dysfunction
characterized by progressive neurologic deficiencies or
cardiomyopathy or myopathy but may have isolated hepatic
involvement
b. Elevated lactate:pyruvate ratio >20
D. Immune
1. Autoimmune hepatitis (AIH)
a. Histology shows severe hepatic necrosis with interface hepatitis
and plasma cell infiltration
b. Treatment with steroids may permit survival without liver
transplantation
2. Hematophagocytic lymphohistiocytosis
a. Fever, hepatosplenomegaly, marked ↑ in serum aminotransferase
levels, cytopenias, hypertriglyceridemia, hyperferritinemia, and
hypofibrinogenemia
3. Gestational alloimmune liver disease (previously known as neonatal
hemochromatosis)
a. Affects the fetus and newborn with recurrence in subsequent
pregnancies

6H. Acute Liver Failure


b. Severe coagulopathy, with relatively normal transaminases and
↑ ferritin and α-fetoprotein
c. Abdominal magnetic resonance imaging demonstrates siderosis
in pancreas and liver
d. Buccal mucosal biopsy to demonstrate iron granules in salivary
Table of Contents

glands 6H
E. Infections
1. Hepatitis A and E are the most common causes of ALF in endemic 397
areas
2. Herpes simplex virus (HSV), human herpesvirus 6, varicella zoster virus,
cytomegalovirus, and Epstein-Barr virus have been reported to cause
ALF in both immunocompromised and immunocompetent hosts
3. Adenovirus, dengue fever, and enterovirus family
F. Ischemic: ALF can result from reduced or absent arterial blood flow to the
liver
1. Shock
2. Budd-Chiari syndrome
3. Congenital heart disease
4. Cardiac surgery
G. Malignancy
H. Indeterminate (50%)
I. The etiologic agents vary by age, as seen in charts below:

FIGURE
* 1 Etiologies of ALF in Infants and Children

Etiology of Acute Liver Failure in Infants Etiology of Acute Liver Failure in Children
Ages 0-3 Ages 3-18

Metabolic
Metabolic Viral 7%
15% 4%
Other
7%
Viral
8% Drugs
6%
Indeterminate Indeterminate
54% Autoimmune 46%
Other 8%
12%
Drugs
0.5%
Acetaminophen
Autoimmune 18%
4%
Ischemia
Acetaminophen 4%
3% Ischemia
4%

IV. Clinical presentation: varies based on etiology


A. Hepatic dysfunction with hypoglycemia, coagulopathy, and encephalopathy;
jaundice is a late feature
B. Typically, a healthy patient presents with flu-like prodrome, with malaise,
myalgia, nausea, vomiting, and jaundice

SECTION 6: Liver
C. Laboratory tests: ↑ aminotransaminases, hyperbilirubinemia, and
coagulopathy
1. Rapidly falling enzymes with worsening coagulopathy suggests
exhaustion of hepatocyte mass
D. Liver histology: typically liver cell necrosis. Pathologic diagnosis by liver
Table of Contents

biopsy has not been considered critical in patient management because of 6H


associated risks and relatively low yield in establishing the diagnosis.
398
V. Complications
A. Hypoglycemia: due to failure of synthesis and release of glucose, along with
hyperinsulinemia due to failed degradation
B. Hepatic encephalopathy
1. ↑ intracranial pressure (ICP) and cerebral edema are major causes of
mortality
2. Factors that play a central role in the pathogenesis of HE
a. Hyperammonemia: which is associated with ↑ levels of glutamine
in astrocytes → cell swelling
b. ↑ cerebral blood flow may contribute to the development of
cerebral edema
c. Enhanced inflammatory response and inflammatory cytokines,
such as tumor necrosis factor α
3. Symptoms: personality changes, irritability, apathy, insomnia,
disturbed sleep wake cycles, and poor oral intake
4. May result in cerebral edema: prevention is critical with careful
attention to fluid balance and caution with blood products
5. Coagulopathy
a. ↓ procoagulant factors: V, VII, X, and fibrinogen
b. ↓ anticoagulant factors: protein C, protein S, and antithrombin
c. Treat in the setting of active bleeding or in anticipation of an
invasive surgical procedure
d. Assure adequate vitamin K (IV/intramuscular vitamin K
supplementation)

TABLE 1 A Scale to Assess Hepatic Encephalopathy in Children Younger than 4 Years

Stage Clinical Signs Reflexes Neurologic Signs

Insonsolable crying, sleep


Early (I and II) reversal, inattention to Hyper-reflexic Untestable
task

Somnolence, stupor, Most likely


Mid (III) Hyper-reflexic
combativeness untestable
Comatose, arouses with
Decerebrate or
Late (IV) painful stimuli (IVs) or no Absent
decorticate
response (IVb)
Revised from Clin Liver Dis., Vol. 10, Bucuvalas J, Yazigi N, Squires RH, Jr., Acute liver failure in children.,
Pages 149-168, Copyright 2006, with permission from Elsevier.

6H. Acute Liver Failure


VI. Management

A. Treat above noted complications


B. Specific therapy
1. Acetaminophen → N-acetylcysteine
Table of Contents

2. Drug-induced → remove offending drug 6H


3. Galactosemia → remove dietary lactose
4. Tyrosinemia → NTBC 399
(2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione)
5. FAO defects → IV glucose and avoid fasting
6. Wilson disease → liver transplantation
7. AIH → corticosteroids
8. Herpes → acyclovir; also consider if suspected HSV
9. Neonatal hemochromatosis → IV immunoglobulin (IVIG) and
plasmapheresis; IVIG in future pregnancies
C. Supportive care
1. Consider transfer to a center able to provide liver transplant
2. Manage ICP and multiorgan failure while awaiting recovery of liver
function or liver transplant
3. Maintain adequate glucose infusion rate
4. Electrolyte replacement (correct hypokalemia and hypophosphatemia)
5. Encephalopathy: medical therapy with lactulose. Minimize sedation,
treat sepsis, and lower protein intake. ICP monitoring is controversial.
Consider mannitol, hyperventilation, hypothermia, or barbiturate coma
for cerebral edema.
6. Coagulopathy: correct prothrombin time (PT)/INR with fresh frozen
plasma or recombinant factor VII only in the setting of active bleeding
or in anticipation of an invasive procedure
7. Prophylactic acid-suppressive therapy
8. Patients may develop hepatorenal syndrome or acute tubular necrosis
and require dialysis or continuous veno-venous hemofiltration
9. Obtain blood cultures and start antibiotics if indicated (↑ susceptibility
to infections)
D. Liver transplantation
1. Pediatric ALF (PALF) results in death or liver transplantation in up to
45% of pediatric patients
2. Patients with ALF are more likely to be critically ill at the time of
transplant than most end-stage liver disease recipients and may die
from multisystem organ failure or neurologic complications
a. Studies show 1-year survival of 80%–90% after liver
transplantation
3. Several scoring systems help predict PALF outcome and the need to
proceed with transplantation
4. The liver injury unit (LIU) scoring system, with LIU = [3.584 × peak
total bilirubin (mg/dL)] + [1.809 × peak PT (seconds)] + [0.307 × peak
NH3 ammonia (μmol/L)], was found by the PALF study group to be a
better predictor of transplant-free survival than other scoring systems.

SECTION 6: Liver
However, making the decision to move forward with transplantation
still remains challenging.
5. In general, progressive encephalopathy, worsening coagulopathy, and
worsening cholestasis associated with poor outcome of the native liver
Table of Contents

6H
Recommended Reading
400
Amin MD, Harpavat S, Leung DH. Drug-induced liver injury in children. Curr Opin
Pediatr. 2015;27:625-633.

Bucuvalas J, Yazigi N, Squires RH, Jr. Acute liver failure in children. Clin Liver Dis.
2006;10:149-168.

D’Agostino D, Diaz S, Sanchez MC, et al. Management and prognosis of acute liver
failure in children. Curr Gastroenterol Rep. 2012;14:262-269.

Hegarty R, Hadzic N, Gissen P, et al. Inherited metabolic disorders presenting as acute


liver failure in newborns and young children: King’s College Hospital experience. Eur J
Pediatr. 2015;174:1387-1392.

Lu BR, Zhang S, Narkewicz MR, et al. Evaluation of the liver injury unit scoring system
to predict survival in a multinational study of pediatric acute liver failure. J Pediatr.
2013;162:1010-1016.

Rajanayagam J, Coman D, Cartwright D, et al. Pediatric acute liver failure: etiology,


outcomes, and the role of serial pediatric end-stage liver disease scores. Pediatr
Transplant. 2013;17:362-368.

Schwarz KB, Dell Olio D, Lobritto SJ, et al. Analysis of viral testing in nonacetaminophen
pediatric acute liver failure. J Pediatr Gastroenterol Nutr. 2014;59:616-623.

Squires RH, Jr., Shneider BL, Bucuvalas J, et al. Acute liver failure in children: the first
348 patients in the pediatric acute liver failure study group. J Pediatr. 2006;148:652-658.

Squires RH, Dhawan A, Alonso E, et al. IV N-acetylcysteine in pediatric patients with


nonacetaminophen acute liver failure: a placebo-controlled clinical trial. Hepatology.
2013;57:1542-1549.

Sundaram SS, Alonso EM, Narkewicz MR, et al. Characterization and outcomes of
young infants with acute liver failure. J Pediatr. 2011;159:813-818.

6H. Acute Liver Failure


SECTION
6Ii

Congenital Hepatic Infections


Table of Contents

6Ii
Niviann M. Blondet, MD
401
Norberto Rodríguez-Báez, MD
Previous edition author: Charles Vanderpool, MD

I. Newborns may acquire infections transplacentally


(toxoplasmosis, rubella, cytomegalovirus [CMV], syphilis, and hepatitis B virus),
during delivery (Listeria, herpes simplex virus [HSV], and CMV), or after birth (via
breast milk)

II. Bacterial and protozoal infections—background

A. Hepatomegaly and jaundice may be clinical signs of neonatal sepsis


B. Immature immune systems in newborns impair their ability to handle
infections
C. Gram-negative > gram positive bacteria
1. Hepatotoxicity due to endotoxin from the bacterial cell walls—↓ bile
flow
D. Most frequent organism is Escherichia coli; Listeria monocytogenes can also
cause hepatic manifestations
E. Liver abscess from umbilical catheterization is uncommon
F. Urinary tract infections
1. May be associated with hepatomegaly
2. Laboratory: direct hyperbilirubinemia, mildly ↑ aminotransferases,
leukocytosis, and pyuria
3. Most common causative organism: Escherichia coli
4. Histology: nonspecific bile stasis, periportal inflammation, and Kupffer
cell hyperplasia
G. Congenital syphilis
1. Transplacental transmission of Treponema pallidum spirochetes
2. Transmission rate 90% if mother has untreated 1º or 2º syphilis
3. ~60% of infants are asymptomatic at birth
a. Severe infections: prematurity, apnea, hepatosplenomegaly,
jaundice, hydrops fetalis, skin and mucosal lesions, rhinitis,
osteochondritis, osteomyelitis, periostitis, and pseudoparalysis
b. Mild: anicteric hepatitis, poor weight gain, and purulent nasal
discharge (“snuffles”)
4. Histology: intralobular dissecting fibrosis with centrilobular
mononuclear infiltration
a. Silver stain may demonstrate spirochetes

SECTION 6: Liver
5. May lead to fulminant hepatic failure with subsequent liver
calcifications
6. Diagnosis: serologic testing of serum and cerebrospinal fluid (CSF) for
treponemal specific antibodies
a. Nonspecific tests (venereal disease research laboratory and
Table of Contents

rapid plasma reagin) can help make diagnosis, but serology may 6Ii
be positive in unaffected infants for up to 3 months after birth
because of passively acquired maternal antibodies 402
b. Definitive diagnosis: identification of spirochetes in skin or
mucosal lesions
7. Treatment: penicillin (with desensitization if allergic)
H. Congenital toxoplasmosis
1. Caused by Toxoplasma gondii (intracellular protozoan)
2. Transmission: ingestion of food containing cysts or oocysts present in
cat feces → maternal infection passed transplacentally to fetus
3. Majority of infected newborns asymptomatic at birth
4. Manifestations: hepatitis (with or without jaundice),
hepatosplenomegaly, purpura, microcephaly, chorioretinitis,
intracranial calcifications, meningoencephalitis, and psychomotor
retardation
5. Histology: generalized hepatitis with areas of necrosis, intracellular bile
stasis, and periportal infiltration
a. T. gondii organisms seen using fluorescent antibody staining
6. Abdominal X-ray: hepatic microcalcifications due to necrosis
7. Diagnosis: polymerase chain reaction (PCR), immunoglobulin M (IgM),
or IgG (persistent for >12 months)
8. Treatment: pyrimethamine and sulfadiazine
I. Tuberculous hepatitis
1. Spread by inhalation with pulmonary involvement or aspiration of
contaminated amniotic fluid
2. Respiratory symptoms predominate
3. Hepatic lesions have caseating necrosis with surrounding giant cells
and epitheloid cells with tubercle bacilli
4. If suspected, treatment should be started with isoniazid, pyrazinamide,
rifampin, and streptomycin

III. Viral infections


A. CMV
1. Acquired transplacentally, at delivery, or postnatally from infected
secretions (saliva or breast milk) or blood transfusion
2. 85%–90% asymptomatic at birth
3. Manifestations: conjugated hyperbilirubinemia, hepatosplenomegaly,
low birth weight, microcephaly, periventricular cerebral calcifications,
chorioretinitis, thrombocytopenia, purpura, deafness, and
psychomotor retardation
4. Histology: large intranuclear inclusion bodies in bile duct epithelium
and occasionally in hepatocytes or Kupffer cells and intracytoplasmic

6Ii. Congenital Hepatic Infections


inclusion bodies in hepatocytes
5. Diagnosis: PCR (saliva) or viral culture (nasopharynx, saliva, or urine)
6. Long term: may develop portal hypertension in absence of cirrhosis
7. Treatment: ganciclovir, foscarnet (if resistance or intolerance), and CMV
immune globulin
Table of Contents

B. HSV 6Ii
1. Majority (85%) of neonatal infections acquired perinatally from HSV
lesions (symptomatic or asymptomatic) in maternal genital tract at 403
delivery
2. Fetal scalp monitoring, prolonged rupture of membranes, prematurity,
and low birth weight may ↑ the risk of infection
3. Symptoms may not appear until 4–8 days of age (incubation period)
4. Manifestations: microcephaly and necrotic, ulcerative, vesicular, or
purpuric lesions on mucosa or skin; jaundice; hepatosplenomegaly;
and coagulopathy
5. Diagnosis: isolation of HSV by culture from skin, eye, mouth, rectum,
urine, blood, or CSF; HSV DNA PCR from blood and CSF
6. Histology: necrosis with characteristic intranuclear acidophilic
inclusions in hepatocytes and multinucleated giant cells
7. Treatment: IV acyclovir. High mortality in untreated disseminated
infections.
a. Consider liver transplant if no evidence of disseminated disease
C. Rubella
1. Infants affected if mother contracts infection in 1st trimester of
pregnancy
a. Not generally affected if rubella contracted in 3rd trimester
2. Symptoms: cholestasis, ↑ aminotransferases, thrombocytopenia,
hepatomegaly (always present), splenomegaly, sensorineural deafness,
ophthalmologic involvement (cataracts, microphthalmia, glaucoma,
and chorioretinitis), cardiac defects (patent ductus arteriosus,
peripheral pulmonic stenosis, atrial septal defect, and ventricular
septal defect), purpuric skin lesions (“blueberry muffin”), microcephaly,
meningoencephalitis, psychomotor retardation, and growth
retardation
3. Congenitally infected infants may shed rubella virus in nasopharyngeal
secretions and urine for up to 1 year
4. Histology: mononuclear infiltrates of the portal zones with intralobular
fibrosis, extramedullary hematopoiesis, giant cell transformation, focal
areas of necrosis, cholestasis, and bile duct proliferation
5. Diagnosis: isolation of virus from nose and tissue culture (throat swab,
urine, blood, and CSF)
a. Positive IgM antibody indicates recent postnatal or congenital
infection
6. Treatment: vaccination of mother effective at preventing congenital
rubella syndrome; supportive care for infected infants
D. Enterovirus
1. Transmission may occur during prenatal, intrapartum, or perinatal
periods

SECTION 6: Liver
2. Presentation: poor feeding, fever, lethargy, diarrhea, jaundice, or skin
rash
3. Diagnosis: viral isolation from the throat, rectum, or biopsy material
4. Treatment: supportive; IV immunoglobulin for life-threatening neonatal
infections
Table of Contents

E. Human immunodeficiency virus (HIV) 6Ii


1. Manifestations: hepatitis, splenomegaly, failure to thrive, oral
candidiasis, recurrent diarrhea, generalized lymphadenopathy, 404
parotitis, cardiomyopathy, nephropathy, central nervous system
disease, opportunistic infections, and malignancies
2. Histology: lymphocytic infiltration, piecemeal necrosis, hepatocellular
and bile duct damage, sinusoidal cell hyperplasia, and endothelialitis
3. Diagnosis: HIV PCR if <18 months old or antibody testing if older
4. Treatment: antiretroviral therapy

Recommended Reading
Boppana SB, Ross SA, Shimamura M, et al. Saliva polymerase-chain-reaction assay for
cytomegalovirus screening in newborns. N Engl J Med. 2011;364:2111-2118.

Centers for Disease Control and Prevention. Congenital syphilis - United States, 2003-
2008. MMWR Morb Mortal Wkly Rep. 2010;59:413-417.

Hill DE, Chirukandoth S, Dubey JP. Biology and epidemiology of Toxoplasma gondii in
man and animals. Anim Health Res Rev. 2005;6:41-61.

Rosenthal P. Neonatal hepatitis and congenital infections. In: Suchy FJ, Sokol RJ,
Balistreri WF, eds. Liver Disease in Children, 3rd ed. New York, NY: Cambridge University
Press; 2007, pp. 232-246.

6Ii. Congenital Hepatic Infections


SECTION
6Iii

Viral Hepatitis
Table of Contents

6Iii
Niviann M. Blondet, MD
405
Norberto Rodríguez-Báez, MD
Previous edition authors: Brandy Lu, MD and Cara Mack, MD

I. Hepatitis A virus (HAV)

A. Description: single-stranded, nonenveloped, RNA virus


B. Epidemiology: endemic in developing countries and areas with limited
sanitation
1. Incidence in United States has declined since routine vaccination
instituted
C. Transmission: fecal-oral route
1. Although rare, neonatal cholestasis from perinatal transmission
reported
D. Clinical manifestations: nausea, anorexia, fever, malaise, abdominal pain,
jaundice, and ↑ serum aminotransferase levels
1. Young children usually asymptomatic: with milder course than adults
E. Diagnosis
1. Serum immunoglobulin M (IgM) anti-HAV is gold standard for the
detection of acute illness
2. Serum IgG anti-HAV indicates past infection or vaccination
F. No HAV carrier state or chronic infection
1. Relapsing symptoms have been described
G. Treatment: supportive
H. Prevention: good hygiene and vaccination
1. HAV vaccine recommended for all children at 1 year of age and for
high-risk groups, e.g., international travelers and patients with chronic
liver disease
I. Postexposure prophylaxis for individuals with recent exposure accomplished
with the HAV vaccine or immune globulin
J. HAV-infected mothers can breast feed as long as proper hygiene is practiced

II. Hepatitis B virus (HBV)

A. Description: double-stranded DNA virus composed of a nucleocapsid core


(hepatitis B core antigen) and an outer lipoprotein coat (envelope) containing
the surface antigen (hepatitis B surface antigen [HBsAg]). Viral nucleocapsid,
containing the DNA and hepatitis B envelope antigen (HBeAg), is located
within the envelope.
B. Epidemiology

SECTION 6: Liver
1. Eight known genotypes (A through H) vary in prevalence geographically
2. Genotype C is more prevalent in patients with cirrhosis
a. ↑ risk of hepatocellular carcinoma (HCC)
3. Rate of seroconversion and therapeutic response vary among
genotypes
Table of Contents

C. Transmission 6Iii
1. Vertical (mother-to-neonate), parenteral, percutaneous, or sexual
2. Perinatal transmission rates vary from 20%–90%, depending on 406
maternal HBsAg titer and HBeAg status
D. Immune response to HBV: hepatocyte damage caused by immune-mediated
injury not by cytopathic injury
E. Clinical manifestations
1. Anorexia, fever, fatigue, jaundice, and an “arthritis-dermatitis”
prodrome may occur during acute infections
2. Perinatal HBV acquisition usually asymptomatic. If mother is HBeAg
positive at birth, infants have ↑ risk of developing acute liver failure.
3. Children usually asymptomatic in chronic state
F. Associated with other conditions: polyarteritis nodosa and
glomerulonephritis
G. Diagnosis
1. Infection is confirmed with detection of HBsAg
2. Positive HBeAg represents active viral replication with high infectivity
H. Chronic infection and carrier state can occur
1. Chronic infection is persistence of HBsAg > 6 months
2. Development of chronic disease varies based on age of HBV

TABLE 1 Hepatitis B Serologic Testing Interpretation

HBsAg Negative
Anti-HBc Positive Immune due to previous infection
Anti-HBs Positive

HBsAg Negative
Anti-HBc Negative Immune due to vaccination
Anti-HBs Positive

HBsAg Positive
Anti-HBc Negative Acutely infected
Anti-HBs Negative

HBsAg Positive
Anti-HBc Positive
Chronically infected
IgM anti-HBc Negative
Anti-HBs Negative

HBsAg Negative
a) Resolved or resolving acute infection
Anti-HBc Positive
b) “Low level” chronic infection
Anti-HBs Negative
Adapted from CDC Web site. http://www.cdc.gov/hepatitis/HBV.

6Iii. Viral Hepatitis


acquisition: 90% for infants, 25%–50% for children 1–5 years, and
5%–10% for children >5 years
3. Children with chronic HBV infection require routine monitoring of
transaminases, α-fetoprotein, HBeAg/anti-HBe status, and HBV DNA
level
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4. Carrier state: persistent infection with positive HBsAg, negative HBeAg, 6Iii
and positive hepatitis B envelope antibody (HBeAb) (seroconversion).
HBV carriers are infectious. 407
5. ~20% of carriers have flare-ups of hepatitis, revert to HBeAg-positive
immune active hepatitis, or progress to the HBeAg, all characterized by
↑ HBV DNA and transaminases
I. Treatment
1. To be considered for treatment: alanine aminotransferase (ALT) > 1.5×
the upper limit of normal (ULN) over ≥6 months if HBeAg positive or
12 months if HBeAg negative and HBV DNA >20,000 IU/mL
a. Interferon
1) Recommended >12 months of age
2) Contraindicated if cirrhotic or decompensated liver disease
3) Continue treatment for >6–12 months before declaring
treatment failure, unless decompensating
4) Factors associated with positive response: ALT >2× ULN,
low-level HBV DNA, active inflammation on biopsy,
female sex, and younger age
5) Adverse effects: flu-like symptoms, fever, bone marrow
toxicity, growth delay, depression, suicidal ideation, and
thyroid dysfunction
b. Nucleos(t)ide analogues*
1) Lamivudine
2) Adefovir
3) Entecavir
4) Telbivudine
5) Tenofovir
*Resistance and lactic acidosis can occur. Consider HBV genotypic
testing if suspecting resistance.
2. Treatment response: nondetectable HBV DNA and seroconversion to
HBeAb positive (HBeAg negative)
J. Histology: “ground glass appearance” of hepatocytes
K. Prevention
1. HBV vaccine universally recommended for all infants and high-risk
population including HBV-exposed family members or close contacts
2. HBV immune globulin recommended for infants born to HBsAg-
positive mothers and for postexposure prophylaxis for unimmunized
patients
3. Universal precautions for handling blood. Do not share toothbrush,
shavers/razors, nail clippers, or tweezers.
4. ↑ risk of HCC
a. Annual screening: α-fetoprotein and hepatic ultrasound
recommended

SECTION 6: Liver
L. Liver transplant: associated with a high rate of recurrence → severe graft
disease
M. Hepatitis B in pregnancy
1. Perinatal transmission can occur from a chronic hepatitis B carrier or
mother with an acute infection in 3rd trimester of pregnancy
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2. Perinatal transmission rates vary from 20%–90%, depending on 6Iii


maternal HBsAg titer and HBeAg status
3. Infants whose mothers are HBsAg positive should receive hepatitis B 408
immunoglobulin and hepatitis B vaccine within 12 hours of birth

III. Hepatitis C virus (HCV)


A. Description: single-stranded RNA virus
1. 6 genotypes worldwide
2. Genotype 1 most common in the United States
3. Genotypes 2 and 3 have high probability of achieving virological cure
on interferon-based treatments
B. Transmission
1. Vertical, parenteral, percutaneous, or sexual
2. Perinatal transmission is 1%–5% but increases to 10%–15% with
maternal coinfection with human immunodeficiency virus (HIV)
a. Maternal viral load influences transmission
C. Clinical manifestations
1. Usually asymptomatic, but can present with jaundice during an acute
infection
2. Spontaneous resolution can occur by 3 years or earlier
a. Genotype 3 more likely to clear spontaneously
D. Chronic infection occurs in 60%–80% of exposed children
E. Risk factors for severe disease: obesity, immunosuppressed state, and
coinfection with HBV or HIV
F. Associated with other conditions: autoimmune hepatitis, cryoglobulinemia,
and glomerulonephritis
G. Diagnosis
1. HCV antibody for screening, but not recommended before 18 months
of age
2. Antibody-based testing cannot distinguish acute from chronic infection
3. Active infection can only be confirmed with positive HCV RNA
4. HCV RNA recommended for diagnosis before 18 months of age but
should be obtained after 2 months of age
5. Obtain HCV genotype since treatment is determined by genotype
H. Treatment
1. Children have a slower rate of progression to end-stage liver disease
2. Follow-up without treatment is an option for many children
3. Children with persistently ↑ transaminases or progressive disease
should be considered for treatment
4. Consider liver biopsy if hepatic decompensation or prior to therapy
5. Histology: portal lymphoid aggregates or follicles, sinusoidal
lymphocytes, and steatosis

6Iii. Viral Hepatitis


6. Pegylated interferon (PEG-IFN-α) subcutaneously weekly × 48 weeks
(genotypes 1 or 4) or 24 weeks (genotypes 2 or 3) plus oral ribavirin for
children >3 years
7. Children coinfected with HCV/HIV should receive 48 weeks of treatment
8. Monitor HCV RNA to determine response to treatment
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9. Factors associated with good response: genotypes 2 and 3 and low 6Iii
viral load
10. Adverse effects from IFN: fever, flu-like symptoms, fatigue, myalgia, 409
bone marrow toxicity, growth delay, depression, suicidal ideation,
thyroid dysfunction, and development or exacerbation of autoimmune
phenomena
11. Ribavirin is teratogenic and can cause hemolytic anemia
12. IL28B genotype: important predictor of development of chronic HCV
and response to IFN-based treatments
13. New direct-acting antivirals, which inhibit viral proteins involved in HCV
life cycle, approved for adults. Effective, well-tolerated, all-oral, and
allow IFN-free treatment.
14. Liver transplantation
a. After transplant, graft infection almost universal
b. Development of chronic HCV, cirrhosis, and death occurs in ⅓ of
adult transplant recipients
c. ~30% of children require retransplantation
I. Prevention
1. HCV vaccine and immune globulin: not available
2. Universal precautions for handling bleeding. Do not share toothbrush,
shavers/razors, nail clippers, or tweezers. No contraindication for
sharing utensils, toilet seats, attending daycare, or participating in
contact sports.
3. Breastfeeding not contraindicated unless the nipples are bleeding or
coinfection with HIV

IV. Hepatitis D (Hepatitis Delta virus [HDV])


A. Description: defective RNA virus
B. Replication depends on an obligatory association with HBV
C. Hepatocyte injury is caused by direct virus cytotoxicity
D. Transmission: vertical, parenteral, percutaneous, or sexual
E. Clinical manifestations: fatigue, lethargy, anorexia, nausea, and jaundice
F. Acute hepatitis D can occur in 2 different forms:
1. Coinfection: simultaneous acquisition of HBV and HDV
2. Superinfection: appearance of acute HDV in a chronic carrier of HBV
G. Coinfection of HBV with HDV ↑ the severity and accelerates the progression
of HBsAg-associated liver disease (cirrhosis and HCC), occasionally to
fulminant failure
H. Can progress into a chronic carrier state
I. Diagnosis: anti-HDV antibody
J. Treatment: supportive
1. Consider liver transplant in end-stage liver disease or fulminant failure

SECTION 6: Liver
K. Patients immune to HBV (vaccination and previous infection) are considered
to be immune to HDV

V. Hepatitis E virus (HEV)


Table of Contents

A. Description: nonenveloped, single-stranded RNA virus 6Iii


B. Transmission: fecal-oral route
C. Clinical manifestations: anorexia, malaise, fever, headache, vomiting, 410
diarrhea, and jaundice
D. Usually a self-limited disease
E. Fulminant hepatitis more likely in pregnant women, malnourished patients,
or those with pre-existing liver disease
F. Diagnosis: anti-HEV IgM; HEV polymerase chain reaction in serum or feces
G. No HEV carrier state. Chronic infection has been described in organ
transplant recipients or patients with profound immunosuppression.
H. Histology: ballooning degeneration, cholestasis, and gland-like changes in the
hepatocytes
I. Treatment: supportive

Recommended Reading
Ghany MG, Strader DB, Thomas DL, et al. Diagnosis, management, and treatment of
hepatitis C: an update. Hepatology. 2009;49:1335-1374.

Hochman JA, Balistreri WF. Acute and chronic viral hepatitis. In: Suchy FJ, Sokol RJ,
Balistreri WF, eds. Liver Disease in Children, 3rd ed. New York, NY: Cambridge University
Press; 2007, pp. 369-446.

Jonas MM, Block JM, Haber BA, et al. Treatment of children with chronic hepatitis
B virus infection in the United States: patient selection and therapeutic options.
Hepatology. 2010;52:2192-2205.

Mack CL, Gonzalez-Peralta RP, Gupta N, et al. NASPGHAN practice guidelines: diagnosis
and management of hepatitis C infection in infants, children, and adolescents. J Pediatr
Gastroenterol Nutr. 2012;54:838-855.

Mast EE, Margolis HS, Fiore AE, et al. A comprehensive immunization strategy
to eliminate transmission of hepatitis B virus infection in the United States:
recommendations of the Advisory Committee on Immunization Practices (ACIP) part 1:
immunization of infants, children, and adolescents. MMWR Recomm Rep. 2005;54:1-31.

6Iii. Viral Hepatitis


SECTION
6Iiii

Bacterial, Parasitic, and Other


Table of Contents

6Iiii
Infections of the Liver 411
Niviann M. Blondet, MD
Norberto Rodríguez-Báez, MD
Previous edition author: Sabina Ali, MD

I. Bacterial infections

A. Pyogenic abscess
1. Presentation: fever and right upper quadrant (RUQ) abdominal pain
a. Hepatomegaly can be seen
2. Risk factors: pre-existing biliary tract disease, immunocompromised
status, trauma, and use of umbilical venous catheters in neonates
3. Pathogenesis: portal vein bacteremia from intra-abdominal infectious
process/extension from contiguous sites (perforated appendicitis and
inflammatory bowel disease)
4. Etiology: polymicrobial
a. Streptococcus sp., Staphylococcus aureus, enteric gram negative
organisms, and anaerobes
5. Laboratory
a. Aminotransferases may be elevated
b. ↑ bilirubin if abscess causing obstruction
c. Blood culture positive in 50% of cases
6. Diagnosis: computed tomography (CT) scan and ultrasound are the
best choice
a. Magnetic resonance imaging (MRI) is useful in detecting small
lesions
7. Treatment
a. Percutaneous drainage and antibiotic coverage to cover gram-
positive aerobes, gram-negative bacilli, and anaerobes. Initiation
of antibiotics should not be delayed pending drainage.
b. Needle aspiration for small abscess
c. Surgical drainage should be considered for multiple or loculated
abscesses or abscess not responding to antibiotics and
percutaneous drainage
1) Complications from drainage: peritonitis, fistula formation,
hepatic laceration, and hemorrhage
B. Cholangitis
1. Presentation: fever, RUQ abdominal pain, and jaundice (Charcot triad)
a. 50%–75% of patients have all 3 symptoms

SECTION 6: Liver
2. Risk factors: pre-existing biliary tract disease (risk of 40%–50% following
portoenterostomy for biliary atresia—highest within 3 months of the
surgery), choledocholithiasis, choledochal cyst, and Caroli disease
3. Etiology: translocation of bacteria from the portal system or duodenum
into biliary tree
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a. Escherichia coli is the most common organism 6Iiii


b. Can be polymicrobial
4. Laboratory: leukocytosis, hyperbilirubinemia, and ↑ alkaline 412
phosphatase and transaminases (rise above baseline)
a. Blood culture positive in 50% of cases
5. Diagnosis: imaging: ultrasound or CT to evaluate for abscess, biliary
stones or other obstructing lesions, and biliary tree dilation
6. Treatment: empiric antibiotic therapy (3rd-generation cephalosporin
plus aminoglycoside) for 10–14 days
7. Repeated episodes can result in impaired bile flow
C. Perihepatitis (Fitz-Hugh-Curtis syndrome)
1. Associated with salpingitis/history of pelvic inflammatory disease
2. Pathophysiology: infection from genital tract or hematologic spread
3. Presentation: acute severe RUQ abdominal pain
a. A friction rub may be present over the anterior liver surface
4. Laboratory: leukocytosis and ↑ inflammatory markers.
Aminotransferases may be normal.
5. Imaging: CT scan may reveal hyperemia of anterior liver surface
6. Laparoscopic findings: “violin string” adhesions between the hepatic
capsule, abdominal wall, and diaphragm
a. Later findings consist of hemorrhagic spots and white fibrous
plaques on liver surface
7. Diagnosis: isolation of Neisseria gonorrhoeae and/or Chlamydia
trachomatis from cervix, urethra, or rectum
8. Treatment: antibiotics for underlying infection
D. Mycobacterium complex
1. M. tuberculosis
a. Presentation: hepatomegaly is common
1) Biliary obstruction may result from perihilar adenopathy
b. Imaging: plain film may reveal large, confluent calcifications in the
liver and common bile duct
c. Diagnosis: culture of gastric aspirate or sputum
d. Histopathology: small granulomas in portal areas
1) Positive stain for acid fast bacteria
e. Treatment: rifampin, isoniazid, and pyrazinamide
2. M. avium
a. Hepatic disease usually associated with HIV virus infection
b. Diagnosis: culture of blood, sputum, or feces
c. Histopathology: granulomas containing foamy macrophages
d. Treatment: ethambutol and clarithromycin with or without
rifabutin

6Iiii. Bacterial, Parasitic, and Other Infections of the Liver


E. Leptospirosis
1. Caused by Leptospira interrogans (motile spirochete)
2. Presentation: biphasic fever, abdominal pain, conjunctivitis, rash, and
lymphadenopathy
a. Patients can have meningitis and myocarditis
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3. Weil disease (icteric leptospirosis) is most severe form of disease; 6Iiii


characterized by fever, jaundice, renal failure, and hemorrhage
4. Infection via exposure to fluids from hosts (cattle, hogs, horses, and 413
rats)
5. Laboratory: ↑ aminotransferases and bilirubin, leukocytosis,
thrombocytopenia, and proteinuria. Coagulopathy can be present.
6. Diagnosis: urine contains leptospires from onset of symptoms until the
3rd week of infection
a. Blood and cerebrospinal fluid cultures may be positive during the
first 7–10 days of symptoms
7. Treatment: IV penicillin
F. Lyme disease
1. Caused by Borrelia burgdorferi (tick-borne spirochete)
2. Presentation: erythema chronicum migrans, fever, malaise, headache,
arthralgia, myalgia, and lymphadenopathy
3. Laboratory: ↑ aminotransferases
4. Diagnosis: serology for B. burgdorferi
5. Treatment: doxycycline; penicillin G used in children <8 years old
G. Cat-scratch disease
1. Caused by Bartonella henselae
2. Presentation: lymphadenitis, encephalitis, pneumonia, arthritis, fever,
and abdominal pain
3. Hepatosplenic disease (peliosis hepatis) due to systemic dissemination
of the organism
4. Laboratory: aminotransferases and bilirubin are usually normal
5. Imaging: multiple small, hypodense lesions in liver and spleen
6. Diagnosis: serology for B. henselae
7. Histopathology: necrotizing granulomatous hepatitis
8. Treatment: azithromycin for mild cases; rifampin plus azithromycin for
hepatosplenic disease
H. Typhoid hepatitis
1. Caused by Salmonella typhi and Salmonella paratyphi
2. Most US cases occur among travelers from endemic countries
3. Presentation: fever, headache, and abdominal pain
a. Hepatosplenomegaly, pneumonia, encephalitis, intestinal
perforation, or bleeding can be seen
4. Laboratory: mildly ↑ aminotransferases
5. Diagnosis: blood culture positive in 40%–80% of patients
6. Treatment: antibiotic based on geographic location and susceptibilities
I. Brucellosis
1. Caused by Brucella melitensis, Brucella abortus, and Brucella suis
2. Transmission: contact with infected animals or ingestion of
unpasteurized/raw dairy products

SECTION 6: Liver
3. Presentation: fever, weight loss, malaise, arthralgia, back pain, and
headache
a. 25% have hepatosplenomegaly
4. Complications: abscess formation, meningoencephalitis, pneumonia
osteomyelitis, nephritis, and endocarditis
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5. Laboratory: ↑ inflammatory markers; mildly ↑ aminotransferases 6Iiii


6. Diagnosis: blood or body fluid culture, polymerase chain reaction (PCR)
of infected tissue, or serology 414
7. Treatment: tetracycline or doxycycline with or without rifampin;
trimethoprim-sulfamethoxazole for children <8 years old

II. Parasitic infections


A. Amebic liver abscess
1. Caused by Entamoeba histolytica
2. Transmission: ingestion of cysts (oro-fecal route)
3. Clinical: fever, abdominal pain, and tender hepatomegaly. Colonic
infection may be asymptomatic or may manifest as invasive disease
with abdominal pain, bloody diarrhea, and presence of “pipe stem”
ulcers.
4. Hepatic disease occurs when trophozoites reach liver via portal vein
and penetrate hepatic parenchyma and form abscesses, mostly in right
lobe
5. Laboratory: ↑ inflammatory markers and leukocytosis. Mildly
↑ aminotransferases. ↑ alkaline phosphatase and ↑ GGT. Cholestasis is
uncommon.
6. Imaging: ultrasound or CT usually identifies the lesions
7. Diagnosis: indirect hemagglutination assays (IHA) or complement
fixation assays are positive in ~95%. Examination of stools for
trophozoites or cysts positive in <50% of patients with hepatic abscess.
8. Drainage: reddish-brown sterile fluid (“anchovy paste”)
9. Treatment: metronidazole
B. Echinococcal disease
1. Caused by Echinococcus granulosus
2. Transmission: ingestion of ova excreted by infected dogs and livestock
3. Hepatic involvement: presence of cysts, most often in right lobe
4. Presentation: RUQ abdominal pain
a. Compression of hepatic veins → Budd-Chiari syndrome
b. Release of cyst fluid → anaphylaxis
5. Laboratory: ↑ aminotransferases. Eosinophilia may be present.
6. Imaging: ultrasound may demonstrate hydatid sand, septations, and
daughter cysts. CT and MRI are more sensitive.
7. Diagnosis: serology (IHAs or enzyme-linked immunosorbent assay)
8. Treatment: mebendazole or albendazole. Historically, drainage avoided
due to concerns for cyst rupture and anaphylaxis; surgical intervention
preferred. Percutaneous aspiration used safely in recent years.
C. Ascariasis
1. Caused by Ascaris lumbricoides (roundworm)

6Iiii. Bacterial, Parasitic, and Other Infections of the Liver


2. Hepatic involvement occurs when worms pass through ampulla of
Vater, causing obstruction
a. Worms migrate to gallbladder and bile ducts
b. Death of worms in the bile ducts leads to the release of eggs and
development of suppurative cholangitis and hepatic granulomas
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3. Treatment: pyrantel pamoate 6Iiii


D. Malaria
1. Caused by Plasmodium falciparum, Plasmodium vivax, Plasmodium 415
malariae, and Plasmodium ovale via a mosquito vector
2. Sporozoites invade hepatocytes, where parasites divide until rupture of
hepatocytes releases merozoites, which then invade erythrocytes
3. Presentation: cyclic fever, nausea, vomiting, diarrhea, headache,
myalgia, and delirium; tender hepatomegaly and jaundice is common
4. Laboratory: ↑ aminotransaminases and hyperbilirubinemia (hemolysis)
5. Histopathology: hypertrophied Kupffer cells containing red blood cells
and malarial pigment
6. Diagnosis: detection of organism in peripheral smears
7. Treatment: chloroquine phosphate

III. Fungal infections

A. Candida
1. Hepatosplenic candidiasis occurs mostly in neutropenic patients
2. Presentation: fever, abdominal pain, hepatomegaly, and splenomegaly
3. Imaging: ultrasound can identify “bull’s eye” lesions
4. Diagnosis: blood culture. Liver biopsy with periodic acid-Schiff stain.
5. Treatment: fluconazole
B. Coccidioidomycosis
1. Caused by Coccidioides immitis
2. Risk factor: travel to endemic area—San Joaquin Valley of California
3. Hepatic involvement common in disseminated disease
4. Presentation: fever and pulmonary symptoms
5. Diagnosis: serology or PCR
6. Treatment: amphotericin B
C. Histoplasmosis
1. Caused by Histoplasma capsulatum
2. Risk factor: travel to endemic areas—Ohio, Missouri, and Mississippi
River valleys. Organism found in soil in areas inhabited by bats and
birds, such as caves and chicken coops.
3. Hepatic involvement occurs in disseminated disease
4. Presentation: fever, malaise, and marked hepatomegaly
5. Laboratory: pancytopenia. May have moderate ↑ aminotransaminases.
6. Diagnosis: serology. Blood culture positive in 50%–70% of patients with
progressive disseminated disease.
7. Treatment: amphotericin B or itraconazole

SECTION 6: Liver
Recommended Reading
Novak DA, Lauwers GY, Kradin RL. Bacterial, parasitic, and fungal infections of the liver.
In: Suchy FJ, Sokol RJ, Balistreri WF, eds. Liver Disease in Children, 3rd ed. New York, NY:
Cambridge University Press; 2007, pp. 871-896.
Table of Contents

6Iiii
Palaniappan RU, Ramanujam S, Chang YF. Leptospirosis: pathogenesis, immunity, and
diagnosis. Curr Opin Infect Dis. 2007;20:284-292. 416

Rosing DK, De Virgilio C, Nguyen AT, et al. Cholangitis: analysis of admission prognostic
indicators and outcomes. Am Surg. 2007;73:949-954.

6Iiii. Bacterial, Parasitic, and Other Infections of the Liver


SECTION
6J

Chronic Hepatitis
Table of Contents

6J
Nanda Kerkar, MD
417
Rula Harb, MD
Previous edition author: Deb Freese, MD

I. Autoimmune hepatitis (AIH)

A. Progressive inflammatory disorder of unknown etiology characterized by


elevated aminotransferases, serum immunoglobulin G (IgG), non-organ-
specific antibodies, interface hepatitis, and response to immunosuppressive
treatment
B. Antibodies
1. Type 1 AIH—antinuclear antibody (ANA) ± smooth muscle antibody
(SMA)
2. Type 2 AIH—liver kidney microsomal antibody (LKM) or liver cytosol
type 1 antibody (LC1)
3. Antibody to soluble liver antigen (SLA)—signifies worse disease and
may be seen in type 1 or 2 AIH
4. Asialoglycoprotein receptor antibody—may be positive when
conventional antibodies are negative
5. Perinuclear staining antineutrophil antibody (p-ANCA)—may be seen in
overlap syndrome of AIH with primary sclerosing cholangitis (SC)
C. Epidemiology
1. All ethnic groups; female preponderance
2. Prevalence variable—1 per 200,000 in the US general population to
20 per 100,000 in females over 14 years of age in Spain
3. 20% of chronic hepatitis among the Caucasian populations of North
America and West Europe
D. Pathogenesis
1. In genetically predisposed individuals, an unknown trigger is believed
to initiate autoimmune activity, causing liver damage
2. The trigger may be a virus or a drug, using a mechanism of molecular
mimicry, i.e., structural similarity between virus and liver autoantigen
a. Virus: hepatitis A–C, herpes simplex virus, cytomegalovirus, and
Epstein-Barr virus
b. Drugs: minocycline, nitrofurantoin, statins, anti-tumor necrosis
factor agents, adalimumab, and infliximab
3. Liver injury is secondary to both cellular and humoral autoimmune
activity
4. AIH is associated with human leukocyte antigen DR3 and DR4 (type 1)
and DR7 and DR3 (type 2)
a. Those positive for DR7 have a worse prognosis

SECTION 6: Liver
E. Clinical features
1. Presentation is variable
a. Acute hepatitis—non-specific malaise, nausea, and vomiting,
followed by jaundice in 40% of children
b. Insidious onset in 30%; some asymptomatic, while others have
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weight loss and intermittent jaundice over weeks and months 6J


c. Complications of portal hypertension (hypersplenism, ascites, and
gastrointestinal bleeding) at presentation in 10%–15% 418
d. Acute liver failure (ALF) in 10%–15%
2. Family history of autoimmune disease in 40%
3. May have other autoimmune disorders, like thyroiditis, vitiligo, type 1
diabetes, and inflammatory bowel disease
4. Syndromes associated with AIH
a. Autoimmune polyendocrinopathy-candidiasis-ectodermal
dystrophy syndrome (APCED)
b. Immunodysregulation polyendocrinopathy enteropathy X-linked
syndrome (IPEX), common variable immunodeficiency, and hyper-
IgM syndrome
F. Laboratory tests and histology
1. ↑ aminotransferases with/without elevated α-glutamyl transpeptidase
(GGT), elevated total/conjugated bilirubin, high total protein , ↑ α low
serum albumin WITH high total protein, and ↑ IgG
2. Positive autoantibodies: ANA, SMA, LKM, and SLA (may be negative in
ALF setting)
3. May have low platelets/low white blood cell count if hypersplenism
4. May have prolonged international normalized ratio if ALF presentation
or vitamin K deficiency
5. Histology: characteristic interface hepatitis with lymphocyte and
plasma cell infiltration of the portal tracts with spilling into the liver
lobules; bridging inflammation/necrosis; bridging fibrosis or cirrhosis
G. Overlap of AIH with SC
1. Features of both AIH and SC present
a. ↑ GGT along with elevated transaminases
b. ↑ IgG and positive autoantibodies, usually ANA, SMA, and p-ANCA.
LKM positivity is unusual in overlap syndrome.
c. Imaging—characteristic irregular narrowing ± strictures of
the extrahepatic and/or intrahepatic bile ducts by magnetic
resonance cholangiopancreatography or endoscopic retrograde
cholangiopancreatography
d. Histology may show interface hepatitis seen in AIH along with
characteristic bile duct changes seen in SC, including ductular
proliferation and “onion skin appearance”
e. Treatment: immunosuppression used in AIH plus ursodiol
H. Management
1. Prednisone 2 mg/kg once daily in the morning—maximum daily dose
40–60 mg
2. Adverse effects of steroid use include hyperglycemia, hypertension,
acne, hirsutism, striae, Cushingoid facies, and growth failure

6J. Chronic Hepatitis


TABLE 1 Autoimmune Hepatitis - Type 1 and Type 2

Type 1 AIH Type 2 AIH


Antibodies ANA/SMA LKM/LC1
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Age at
Relatively older children Younger children
6J
presentation
More often chronic 419
Clinical More often acute presentation,
presentation, i.e., cirrhosis
presentation i.e., ALF more common
more common
Overlap with SC More common Unusual
May be weaned off
Treatment Lifelong immunosuppression
immunosuppression

3. Budesonide, a glucocorticoid with high hepatic first pass effect, has


been used to avoid steroid adverse effects—most effective when used
in combination with azathioprine
4. Ursodeoxycholic acid (UDCA) 10 mg/kg/dose b.i.d. in children with
overlap sclerosing cholangitis
5. Check thiopurine methyltransferase (TPMT) activity prior to using
azathioprine
a. Start azathioprine around 1–2 mg/kg if TPMT activity is normal
and child is not in ALF
b. Metabolites 6-thioguanine and 6-methyl mercaptopurine may be
used to adjust dosing and monitor adherence
6. If azathioprine unresponsive or not tolerated, consider:
a. Mycophenolate mofetil or sirolimus
I. Transplantation (2%–3% of pediatric AIH)
1. Indications for transplant
a. Acute/fulminant liver failure, failure of medical therapy, and
hepatocellular carcinoma
2. AIH may recur in a third of AIH and may also occur “de novo,” i.e.,
recipients who have not been transplanted for AIH can develop AIH
posttransplant (rare)

II. Granulomatous hepatitis


A. Presence of granulomas on liver biopsy; usually indicative of underlying
systemic disease.
B. Four types of granulomas are described
1. Caseating granulomas: central necrosis; associated with an infectious
etiology
2. Noncaseating granulomas: no central necrosis; associated with a
noninfectious cause
3. Fibrin-ring granulomas: fibrin ring surrounding the epithelioid cells
may be seen in Q fever
4. Lipogranulomas: a central lipid vacuole and associated with mineral oil
ingestion

SECTION 6: Liver
C. Epidemiology
1. Incidence 2%–15%; recent data suggest only 3%–6% due to decreasing
opportunistic infections in human immunodeficiency virus/acquired
immune deficiency syndrome (AIDS) and hepatitis C
D. Etiologies
Table of Contents

1. Autoimmune/immunologic 6J
a. Sarcoidosis
1) Systemic disease of unknown etiology that may be 420
autoimmune
2) One of the most common causes of hepatic granulomas in
the United States
3) Incidence varies by ethnic group; high in African Americans
and Scandinavians. Hepatic involvement uncommon, but
hepatic noncaseating epithelioid granulomas are often
found microscopically in portal tracts.
4) Biochemically, there may be ↑ in alkaline phosphatase and
GGT
5) Most hepatic sarcoidosis has a benign course
a) 1% develop cirrhosis and portal hypertension
6) Treatment with steroids not recommended unless portal
hypertension or cirrhosis
b. Primary biliary cirrhosis
1) Autoimmune disorder with destruction of intrahepatic
biliary epithelium and chronic cholestasis
a) Primarily seen in middle-aged women
2) Biochemically: elevated alkaline phosphatase and GGT,
+ antimitochondrial antibodies, and elevated serum IgM
3) Treatment: UDCA
c. Other: Crohn disease and Wegener granulomatosis
2. Systemic infections
a. Tuberculosis (TB)
1) Mycobacterium tuberculosis causes hepatic granulomas,
especially in the miliary form
2) Granulomas may be caseating
3) Biochemically, alkaline phosphatase is elevated ± elevated
transaminases
b. Other bacterial
1) Brucellosis: Brucella abortus, B. canis, or B. melitensis and is
acquired from infected cattle. Noncaseating granulomas
are seen in 70%.
2) Q fever: Coxiella brunette, a rickettsial organism. If liver is
involved, granulomas are fibrin ring granulomas.
3) Lyme disease (Borrelia burgdorferi), cat scratch (Bartonella
henselae), Listeria, Salmonella (typhoid fever), Yersinia, and
bacilli Calmette-Guérin disease
c. AIDS—related/immunocompromised: Mycobacterium avium
complex has been associated with hepatic granulomas in these
patients

6J. Chronic Hepatitis


d. Fungal
1) Hepatic infection with Candida causes suppurative
granulomas
2) Histoplasmosis (Histoplasma capsulatum): endemic in the
Ohio and Mississippi river valleys; liver involvement has
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been reported 6J
3) Coccidioidomycosis (Coccidioides immitis) is endemic in the
southwestern United States, and hepatic disease may be 421
seen in disseminated infection
e. Viral: both hepatitis C and hepatitis B have been reported as
causes of hepatic granulomas. Hepatitis C virus granulomas are
epithelioid and noncaseating.
f. Parasitic: schistosomiasis has also been associated with
granulomatous hepatitis. Granulomas typically contain abundant
eosinophils.
3. Drug: many drugs implicated in hepatic granulomas formation,
including:
a. Sulfa drugs, allopurinol, isoniazid, quinidine, chlorpropamide, and
etanercept
b. Granulomas may be of any size and are located anywhere in the
liver
c. Presence of eosinophils is a clue to drug etiology
4. Malignancy: Hodgkin lymphoma may be associated with hepatic
granulomas
a. Granulomas have also been described in non-Hodgkin’s
lymphoma and renal cell carcinoma
5. Idiopathic: if an extensive workup is negative for cause of hepatic
granulomas, consider idiopathic granulomatous hepatitis
a. Symptoms include fever, weight loss, myalgias, arthralgias, and
hepatosplenomegaly
b. Diagnosis is one of exclusion, and laboratory findings are
nonspecific, usually with an ↑ erythrocyte sedimentation rate
c. Noncaseating granulomas are present in all cases and are
randomly distributed. Treatment is with a short course of steroids
and/or methotrexate.
d. TB and other infections must be ruled out prior to starting on
immunosuppressive medications

SECTION 6: Liver
Recommended Reading
Flamm SL. Granulomatous liver disease. Clin Liver Dis. 2012;16:387-396.

Kerkar N, Mack CL. Autoimmune hepatitis. In: Suchy FJ, Sokol RJ, Ballistreri WF, eds.
Table of Contents

Liver Disease in Children, 4th ed. New York, NY: Cambridge University Press; 2014, pp. 6J
311-321.
422
Lagana SM, Moreira RK, Lefkowitch JH. Hepatic granulomas: pathogenesis and
differential diagnosis. Clin Liver Dis. 2010;14:605-617.

Manns MP, Czaja AJ, Gorham JD, et al. Diagnosis and management of autoimmune
hepatitis. Hepatology. 2010;51:2193-2213.

6J. Chronic Hepatitis


SECTION
6K

Vascular Disease of the Liver


Table of Contents

6K
Voytek Slowik, MD
423
Ryan Fischer, MD
Previous edition authors: Lina Maria Hernandez, MD and Lesley Smith, MD

I. Budd-Chiari syndrome (BCS)


A. Definition
1. Thrombotic or nonthrombotic postsinusoidal hepatic venous outflow
obstruction
2. May occur anywhere from venules to right atrium
3. Does not include cardiac, pericardial, or sinusoidal disease
B. Epidemiology
1. BCS accounts for approximately 2%–5% of cases of liver failure in
children and adults
2. Of total BCS cases, only 5% found in patients ≤12 years old
C. Pathogenesis
1. Primary: venous disease (thrombosis or phlebitis)
a. Acquired prothrombotic disease: myeloproliferative disorders
(MPDs) account for 30%–50% of BCS, antiphospholipid syndrome,
oral contraceptive use, and others
1) Mutation of JAK2 in chronic MPD found in 40% of primary
BCS
b. Inherited prothrombotic disease: factor V Leiden mutation,
protein C/S deficiency, antithrombin-III deficiency, and others
2. Secondary: compression or invasion external to venous system
(expanding tumor, cystic structure, abscess, etc.)
D. Presentation
1. Can be asymptomatic (15%), fulminant (5%), acute (20%), and
subacute/chronic (60%)
2. Symptoms and signs: right upper quadrant (RUQ) abdominal pain,
hepatomegaly, abdominal distention with ascites, RUQ pain, portal
hypertension (PHT), jaundice, renal insufficiency, and liver insufficiency
or failure in fulminant disease
3. Labs: ↑ aminotransferases, hyperbilirubinemia, ↑ international
normalized ratio, and serum ascites-albumin gradient <1.1 gm/dL
E. Diagnosis
1. Demonstration of venous outflow tract obstruction
a. Doppler ultrasound (US) diagnostic in 95% of cases
b. Triphasic computed tomography (CT) scan, magnetic resonance
imaging, and direct or retrograde venography if US nondiagnostic
F. Treatment

SECTION 6: Liver
1. Supportive care and treatment of resulting PHT and liver failure
(ascites, varices, coagulopathy, encephalopathy, etc.)
2. Treatment of underlying etiology
a. e.g., anticoagulation for thrombosis or surgical removal of tumor
3. Transjugular intrahepatic portosystemic shunt if medical management
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fails 6K
4. Liver transplantation if fulminant liver failure despite therapy
424
II. Sinusoidal obstruction syndrome or hepatic veno-occlusive
disease (VOD)
A. Definition: obstruction of sinusoids (small terminal venules) of liver
B. Epidemiology: dependent on etiology and specific offending agent
1. Classically with hematopoietic stem cell transplant (HSCT) induction
2. Also seen with chemotherapy, radiation, transplantation, herbal
remedies, hepatectomy, or VOD with immunodeficiency
C. Pathogenesis: toxic injury followed by occlusion and obliteration of sinusoids
and fibrosis
D. Presentation
1. Usually within 1 month of HSCT
2. RUQ abdominal pain, hepatomegaly, ascites, weight gain, evidence of
liver injury (hyperbilirubinemia and ↑ transaminases), coagulopathy,
and PHT
E. Diagnosis
1. Significant risk of mortality if untreated; requires high index of
suspicion
a. Clinical signs and symptoms listed above can be sufficient for
diagnosis
2. Liver biopsy recommended only when diagnosis unclear
a. Progression of sinusoidal dilation and congestion, lack of terminal
hepatic veins, collagen deposition, and fibrosis
3. Exclude graft-versus-host disease, BCS, drug toxicity, and infection
F. Treatment
1. Supportive care with careful fluid management
a. Mitigate fluid overload with diuresis
2. Defibrotide (anticoagulant) for moderate and severe disease
a. Potential role for IV methylprednisolone
3. Liver transplantation for those with severe liver failure but good
expected outcomes

III. Hepatic epithelioid hemangioendothelioma


A. Definition: rare vascular neoplasm of endothelial origin with malignant
potential often reported as a primary liver lesion but can occur anywhere in
the body
B. Epidemiology
1. <1% of all vascular tumors
2. Can occur at any age, typically in 3rd and 4th decades but as early as

6K. Vascular Disease of the Liver


infancy
3. >85% multifocal lesions; 35% with extrahepatic involvement
4. Female:male ratio is 3:2
C. Pathogenesis
1. No single etiology identified; gene translocation and environmental
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exposures have been correlated 6K


D. Presentation
1. 25% are asymptomatic 425
2. Symptoms: from vague discomfort, hepatosplenomegaly, PHT, to liver
failure
3. 15% have normal labs, but associated with ↑ alkaline phosphatase and
γ-glutamyl transpeptidase
a. Normal α-fetoprotein, carcinoembryonic antigen, and cancer
antigen 19-9
E. Diagnosis
1. US will show variable echogenicity of lobular lesions, not usually
suggestive of vascular tumors
2. CT will show hypoattenuated lesions, which can show peripheral
enhancement (“halo”) in portal venous phase after arterial
enhancement
3. Histology: cords of epithelioid endothelial cells spreading within
sinusoids that stain positively for factor VIII, CD31, and CD34
a. Possible biomarkers include vascular endothelial growth factor
and podoplanin
F. Treatment
1. Chemotherapy and radiation often ineffective; steroids or interferon
reported to accelerate involution
2. Liver resection of unifocal lesion is effective but can stimulate
aggressive behavior in remaining hepatic lesions
a. Available option in only 10% of cases
3. Liver transplantation recommended for multifocal or large lesions
with good survival (64%–83% at 5 years) but can recur in 30% of
transplanted cases
4. Transarterial chemoembolization recommended for symptomatic
lesions that cannot be resected

IV. Hepatic hemangioma – see Section 6L. Liver Tumors

A. Definition: a benign tumor characterized by an abnormal proliferation of


vascular tissue

SECTION 6: Liver
Recommended Reading
Akamatsu N, Sugawara Y, Kokudo N. Budd-Chiari syndrome and liver transplantation.
Intractable Rare Dis Res. 2015;4:24-32.
Table of Contents

Ercolani G, Grazi GL, Pinna AD. Liver transplantation for benign hepatic tumors: a 6K
systematic review. Dig Surg. 2010;27:68-75.
426
Fan CQ, Crawford JM. Sinusoidal obstruction syndrome (hepatic veno-occlusive
disease). J Clin Exp Hepatol. 2014;4:332-346.

Fernandez-Pineda I, Cabello-Laureano R. Differential diagnosis and management of


liver tumors in infants. World J Hepatol. 2014;6:486-495.

Kathuria R, Srivastava A, Yachha SK, et al. Budd-Chiari syndrome in children: clinical


features, percutaneous radiological intervention, and outcome. Eur J Gastroenterol
Hepatol. 2014;26:1030-1038.

Kochin IN, Miloh TA, Arnon R, et al. Benign liver masses and lesions in children: 53
cases over 12 years. Isr Med Assoc J. 2011;13:542-547.

Mistry AM, Gorden DL, Busler JF, et al. Diagnostic and therapeutic challenges in hepatic
epithelioid hemangioendothelioma. J Gastrointest Cancer. 2012;43:521-525.

6K. Vascular Disease of the Liver


SECTION
6L

Liver Tumors
Table of Contents

6L
Jillian S. Sullivan, MD, MSCS
427
Previous edition authors: Jillian Sullivan, MD and Shikha Sundaram, MD, MSCI

Primary tumors of the liver are rare and represent 0.3%–4% of all pediatric
solid tumors.

I. Benign liver tumors

A. Infantile hepatic hemangioma (IHH)


1. Epidemiology
a. Vascular lesion and most common (>70%) benign hepatic
tumor in infancy
b. Most cases (85%) are diagnosed within the first 6 months of life
c. Slight female predominance (female:male 1.3–2:1)
d. 0.4%–7.3% prevalence in autopsy studies
2. Pathogenesis
a. Abnormal proliferation of endothelial cells during fetal
development with a multifactorial etiology
1) Vascular endothelial growth factor identified as a key
pathway component
3. Presentation
a. Usually an asymptomatic, abdominal mass; incidental finding on
ultrasound (US)
b. Multiple cutaneous hemangiomas (≥5) a risk factor
c. Hypothyroidism may be present due to tumor expression of
iodothyronine deiodinase type 3, which inactivates thyroid
hormone
d. Kasabach-Merritt syndrome (thrombocytopenic coagulopathy)
e. Asymptomatic abdominal mass, normal labs (α-fetoprotein [AFP]),
and abdominal distention
f. Anemia, thrombocytopenia, and consumptive coagulopathy
g. Hypothyroidism (from thyroid catabolism of the tumor)
h. Cutaneous hemangiomas and high-output cardiac failure
4. Varying hepatic involvement
a. Focal: well-defined, solitary, spherical tumor
1) Usually asymptomatic
2) Rarely accompanied by cutaneous hemangiomas
3) Does not stain positive for Glut-1
4) Focal lesions stop growing after birth and usually involute
over 12–18 months

SECTION 6: Liver
b. Multifocal: multiple individual spherical tumors; arteriovenous
shunts present
1) Usually asymptomatic; should spontaneously involute
a) Accompanied by multiple cutaneous hemangiomas
2) Multifocal grow postnatally (0–1 year) and slowly involute
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(1–5 years) 6L
c. Diffuse: extensive hepatic involvement; near total replacement of
hepatic tissue with hemangiomas 428
1) More likely to have serious effects, including
thrombosis, necrosis, compression of inferior vena cava,
respiratory compromise from compression of thoracic
cavity, abdominal compartment syndrome, severe
hypothyroidism, and high-output cardiac failure
5. Diagnosis usually made on imaging
a. Usually diagnosed by US (lobulated, well-defined margins;
homogenous, hyperechoic mass)
b. If US unclear, can confirm with triple-phase computed
tomography (CT) (hypoattenuating mass showing peripheral
pooling and central enhancement) or magnetic resonance
imaging (MRI)
c. Histologic diagnosis may be required in suspicious lesions when
imaging is nondiagnostic
6. Treatment
a. Should have normal AFP (consider cancer antigen 19-9 and
carcinoembryonic antigen [CEA] in older patients)
b. Screen thyroid-stimulating hormone and platelet counts
c. Monitor for resolution with serial US
d. Symptomatic lesions need treatment with propranolol,
corticosteroids, or vincristine. Note: 6% on α-interferon therapy
developed spastic diplegia or motor abnormalities
e. Severe lesions may require embolization, resection, irradiation, or
transplantation
B. Mesenchymal hamartoma (MH)
1. Cystic/multicystic lesion; origin/biology are poorly understood
2. Accounts for 6% of all pediatric liver tumors; 85% occur in children
<2 years
3. Slight male predominance (male:female 3:2)
4. Presentation
a. Abdominal distention, vomiting, anorexia, and possibly
respiratory distress
b. May be diagnosed by prenatal US
c. May have ↑ AFP
5. Imaging
a. US: multiple echogenic cysts or echogenic mass (if cysts are small)
b. CT: well-circumscribed, multilocular, multicystic mass
6. Clinical course variable
a. Tumor usually ↑ in size over 1st months of life and then stabilizes,
continues to grow, or spontaneously regresses
b. Small risk of malignant change into embryonal sarcoma

6L. Liver Tumors


7. Management is controversial but includes:
a. Nonoperative management in asymptomatic cases, as lesion will
spontaneously regress (must consider risk of malignancy)
b. Incision/drainage of individual cysts or complete tumor resection
c. Transplantation in unresectable lesions or with severe symptoms
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d. Prenatal intervention 6L
C. Focal nodular hyperplasia (FNH)
1. Benign epithelial tumor; represents 2% of all pediatric liver tumors 429
a. Well-circumscribed, lobulated lesion with central stellate scar
b. Varies in size from a few mm to 20 cm
c. Can present with hepatocellular carcinoma (HCC), prompting
consideration of tissue sampling to confirm diagnosis
2. Presentation
a. Usually in toddlers but can occur at any age
b. More common in females
c. Typically diagnosed on routine physical examination
d. May have abdominal pain
e. Normal AFP
3. Imaging
a. US: well-demarcated, hyperechoic, homogenous lesion ± central
scar
b. CT: central scarring is clearer
4. Management
a. Nonoperative management recommended for asymptomatic
patients
b. Excision of tumor may improve abdominal pain associated with
FNH
D. Hepatic adenoma
1. Usually occurs in young women on oral contraceptives or during
pregnancy
2. Associated with glycogen storage disease
3. Presentation
a. Usually incidental finding
b. Larger lesions can present with pain or a right upper quadrant
(RUQ) mass
c. May also present with hemorrhage/RUQ
4. Carries risk of transformation to HCC
5. May be difficult to diagnose
a. CT/MRI findings can be nonspecific (homogenous enhancement in
arterial phase, hemorrhage, fat deposition, calcifications, and lack
of central scar)
b. May need tissue sample for diagnosis
1) Histology: hepatocytes arranged in organized cords
2) May also look like well-differentiated HCC (AFP may help to
differentiate)
6. Management: surgical resection and radiofrequency ablation
E. Other benign tumors: teratoma, inflammatory myofibroblastic tumor,
angiomyolipoma, and biliary cystadenoma

SECTION 6: Liver
II. Malignant liver tumors
A. Hepatoblastoma (HB)
1. Most common pediatric liver tumor (~40% of all liver tumors in
children)
Table of Contents

2. Usually presents <age 3 years; male predominance (male:female 6L


1.4–2.0:1)
3. Most tumors have many histologic patterns 430
a. Embryonic histology is most common
b. Other histologic types include fetal and embryonal, small cell
undifferentiated, mixed, teratoid, and rhabdoid
4. Multiple known risk factors
a. Familial adenomatous polyposis syndrome
b. Beckwith-Wiedemann syndrome
c. Metabolic/genetic associations: tyrosinemia and glycogen storage
disease
d. Low birth weight (LBW) (<1,000 g)/prematurity
e. Environmental risks: parental occupational exposures and
cigarette smoking
5. Presentations vary
a. Asymptomatic RUQ mass that is firm, nontender, and irregular
b. Weight loss, anorexia, abdominal pain, vomiting, and rarely
jaundice
6. Labs: anemia (70%), thrombocytosis (35%), and ↑ AFP (90%)
a. Consider normal changes in AFP based on postgestational age
1) Normal AFP: 25,000–100,000 ng/mL at birth; by age 1 year:
<10 ng/mL
7. Imaging
a. US: variable echogenicity/echotexture, circumscribed, lobular
lesions; replacing most of liver
b. CT: predominantly low attenuation mass ± discrete calcifications
8. Diagnosis confirmed by biopsy
9. Management: (based on PRETEXT stage)
a. PRETEXT I/II: surgical resection followed by chemotherapy
1) PRETEXT STAGING: uses left lateral, left medial, right
anterior, and right posterior sections
2) PRETEXT
a) One section is involved and three adjoining sections
are free
b) One or two sections are involved, but two adjoining
sections are free
c) Tumor involves three liver sections and one liver
section is free of tumor
d) All four sections are involved; no liver section free of
tumor
b. PRETEXT III/IV: chemotherapy followed by delayed primary
resection
c. Consider liver transplantation in patients with unresectable

6L. Liver Tumors


primary tumors and lack of metastatic disease following
chemotherapy
1) Important prognostic factor: decreasing tumor size or
reduction in AFP levels after chemotherapy
2) Refer to liver transplant center if patients have multifocal
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PRETEXT IV or unifocal PRETEXT II/III tumors 6L


3) Contraindications to transplant: persistence of
extrahepatic metastases despite chemotherapy 431
B. HCC
1. Most common hepatic malignancy of adolescence
2. Most are de novo tumors but can be associated with chronic liver
diseases
a. Viral hepatitis (particularly hepatitis B and C)
b. Inborn errors of metabolism (e.g., tyrosinemia)
c. Biliary atresia and Fanconi syndrome
3. Other risk factors include androgenic steroids, oral contraceptives, and
methotrexate
4. Presentation
a. Abdominal distention, weight loss, weakness, and hepatomegaly

TABLE 1 Liver Tumor Summary

Tumor Presentation Labs Imaging Management


Focal: will likely
Palpable mass,
Focal, multiple, resolve; multifocal
distention, congestive
IHH Normal or diffuse or diffuse: may
heart failure, and
hemangiomas need resection or
hemangiomas (infant)
transplant
Abdominal distention + Single/multiple Resection if
Normal
MH prenatal US cysts; can look possible (risk of
± ↑AFP
(infant/toddler) like solid tumor malignancy)
Can occur
Asymptomatic, palpable Homogenous with HCC. If
FNH mass, and can present Normal mass with asymptomatic,
with pain central scar no surgical
intervention.
Incidental finding;
Resection versus
pregnancy/oral Nonspecific
Adenoma Normal ablation (risk of
contraceptive pills; findings
malignancy)
rupture/RUQ mass
Asymptomatic mass; Resection,
weight loss/pain; familial chemotherapy
CT: large mass;
adenomatous polyposis, (high risk may get
HB ↑AFP may have
Beckwith-Wiedemann chemotherapy
calcifications
syndrome, precocious first); possible liver
puberty, and LBW transplant
↑AFP Large Chemotherapy
Hepatomegaly, weight
HCC heterogeneous and resection/liver
loss, pain, and fatigue (60%–80%)
mass transplant

SECTION 6: Liver
b. May present with precocious puberty (HCC producing human
β-chorionic gonadotropin or testosterone)
c. Labs: ↑ AFP in 60%–80% of cases
5. Imaging
a. US: large, heterogeneous mass
Table of Contents

b. CT: areas of arterial phase hyperenhancement with rapid wash 6L


out on delayed phase imaging
6. Management 432
a. PRETEXT staging (similar to HB)
b. Chemotherapy, surgical resection, and may consider liver
transplant for unresectable HCC
C. Other malignant tumors: rhabdoid tumor, yolk sac tumor,
rhabdomyosarcoma, sarcoma, leiomyosarcoma, nested stromal epithelial
tumor, and neuroblastoma stage IV-S (extra-adrenal only to liver) involutes

Recommended Reading
Emre S, Umman V, Rodriguez-Davalos M. Current concepts in pediatric liver tumors.
Pediatric Transplant. 2012;16:549-563.

López-Terrada D, Finegold MJ. Tumors of the liver. In: Suchy FJ, Sokol RJ, Balistreri WF,
eds. Liver Disease in Children, 4th ed. New York, NY: Cambridge University Press; 2014,
pp. 728-759.

Meyers RL, Aronson DC, Von Schweinitz D, et al. Pediatric liver tumors. In: Pizzo PA,
Poplack DG, eds. Principles and Practice of Pediatric Oncology, 6th ed. Philadelphia, PA:
Lippincott Williams & Wilkins; 2011, pp. 838-860.

Rozell JM, Catanzano T, Polansky SM, et al. Primary liver tumors in pediatric patients:
proper imaging technique for diagnosis and staging. Semin Ultrasound CT MR.
2014;35:382-393.

6L. Liver Tumors


SECTION
6M

Nonalcoholic Fatty Liver Disease and


Table of Contents

6M
Steatohepatitis (NAFLD/NASH) 433
Amy Taylor, MD
Rohit Kohli, MBBS, MS
Previous edition authors: Elizabeth Yu, MD; Jeffrey Schwimmer, MD; and Joel Lavine, MD, PhD

I. Epidemiology
A. Estimating the prevalence of nonalcoholic fatty liver disease (NAFLD) limited
by lack of reliable noninvasive testing and reliance on liver biopsy for
diagnosis and staging of nonalcoholic steatohepatitis (NASH)—the severe
form of the disease
B. The best estimate is by Schwimmer et. al., reporting the prevalence based on
autopsy liver tissue findings of nonhospitalized deceased (incidental cause)
children ages 2–19 years
1. Overall NAFLD prevalence of 9.6%
a. More prevalent in ages 10–19 years old (11.3%–17.3%)
b. Differs by race: Hispanic (11.8%), Asian (10.2%), white (8.6%), and
black (1.5%)
c. More prevalent with ↑ body mass index (BMI) (overweight 16%;
obese 38%)
d. More prevalent in males than females (11% versus 7.9%)
C. The clinical course of patients with NAFLD is predicted to be progressive
1. Natural history study in pediatric patients. 66 children enrolled at ages
3–19 years old, followed for 410 person years (longest 20 years).
a. 66% of patients with obesity
b. 2 patients died and 2 others required liver transplant → an overall
↓ transplant-free survival rate compared to population norms
c. 4/5 patients with repeat liver biopsy demonstrated fibrosis stage
advancement

II. Defining the disease


A. The 2012 American Association for the Study of Liver Diseases (AASLD)
practice guideline defines NAFLD as hepatic steatosis based on histological or
radiographic findings in absence of other etiologies
B. Spectrum includes NAFLD to NASH characterized by inflammation and/or
fibrosis that can progress to cirrhosis and end-stage liver disease
C. Studies have evaluated pediatric patients with NAFLD and identified
variations in histopathology when compared to adult patients
1. 100 pediatric patients averaging 12 years old (2–18 years old); 98%

SECTION 6: Liver
overweight/obese and elevation of liver enzymes had histological
findings categorized into 2 groups
a. Type 1 (51%): hepatic steatosis with ballooning and fibrosis of
perisinusoidal areas without portal involvement (similar to adult
findings)
Table of Contents

b. Type 2 (17%): hepatic steatosis with both portal inflammation and 6M


fibrosis without ballooning hepatocytes
2. 130 pediatric patients averaging 12 years old (4–18 years old); 82% 434
obese; median BMI 31 kg/m2; 82% with findings of both type 1 and
type 2 NASH
a. 100% macrovesicular steatosis; 20% with microvesicular steatosis
b. 92% with lobular inflammation; 73% with hepatocyte ballooning
c. 85% with portal inflammation and/or fibrosis, predominately in
zone 3
d. Aspartate aminotransferase (AST) level and stage of fibrosis was
not predictive of advanced fibrosis
3. 483 pediatric patients averaging 12.9 years old (5–18 years old) with
varying alanine transaminase (ALT) levels (19% normal or mildly
elevated versus 81% elevated) and NAFLD were compared
a. ↑ ALT associated with ↑ prevalence of NASH and fibrosis, including
↑ fibrosis scores

III. Disease pathogenesis


A. Disease mechanisms of NAFLD include a combination of genetic and
environmental risk factors
B. Environment: our obesogenic environment has contributed to the rise of
childhood obesity rates that are associated with the metabolic syndrome
overall and NAFLD in particular
1. Nutrition
a. Abundant and freely available, relatively inexpensive, calorie-
dense foods
b. Fructose—especially in the form of food additive high-fructose
corn syrup—is associated with ↑ rates of fibrotic NASH
2. Genetics/ethnicity
a. Genome-wide association pediatric studies have correlated
patatin-like phospholipase-domain-containing 3 mutations with
↑ risk of NAFLD and NASH
b. Variation in risk of NASH based on ethnicity (Hispanic and South
Asian descent having increased risk for NASH at lower BMI,
compared to Caucasian and African origin)
3. Lipotoxicity/hepatocellular inflammatory response
a. Polyunsaturated fatty acids (PUFA)
1) Omega-6 fatty acids (FAs) ↑ inflammation while omega-3
FAs ↓ inflammation
b. The inflammatory component in NASH thought to be related to
both innate and adaptive immunity, culminating in
apoptosis/necrosis of hepatocytes

6M. Nonalcoholic Fatty Liver Disease and Steatohepatitis (NAFLD/NASH)


IV. Evaluation

A. 2012 AASLD guidelines pediatric clinical frameworks for diagnosis


B. Patients with overweight/obesity and concern for NAFLD
1. Screening tests
Table of Contents

a. Liver profile and α-glutamyltransferase (GGT) 6M


b. Complete blood count with differential to evaluate for
hypersplenism associated with portal hypertension and cirrhosis 435
2. Exclusion of additional liver diseases
a. Autoimmune hepatitis
b. Wilson disease
c. α1-antitrypsin deficiency
d. Viral hepatitis
e. Metabolic liver diseases (mitochondrial hepatopathies and
cholesterol sterol storage disease) in younger patients
3. Evaluation for metabolic syndrome, insulin resistance, and type 2
diabetes
a. Fasting lipids (total cholesterol, low-density lipoprotein [LDL],
high-density lipoprotein [HDL], and triglycerides), fasting insulin,
and fasting glucose
4. Anthropomorphic measurements and vital signs
a. Height, weight, and waist circumference
b. Blood pressure
5. Consider imaging to evaluate for steatosis
a. Ultrasound techniques: transient elastography and acoustic
radiation force impulse imaging
1) Traditional ultrasound is not sensitive for detection of
fibrosis
2) Advantages: noninvasive, accurate, and reliable
3) Disadvantages: operator dependent, does not evaluate the
entire liver, limitation with ↑ body habitus, and less able to
distinguish degrees of intermediate fibrosis
b. Magnetic resonance elastography/proton density fat fraction
1) Advantages: noninvasive and assesses the entire liver
2) Disadvantages: expensive and limited data available

V. Treatment
A. Dietary and lifestyle modification as the mainstay of pediatric NAFLD
treatment
B. A double-blind placebo controlled study showed that vitamin E had
therapeutic benefit in children with biopsy-proven NASH
C. DeVore et al. published a study of 39 patients with NAFLD, average 14 years
old, and appointment with gastroenterologist, dietician, and nurse for
30 minutes 4 times in a year (spaced 3 months apart)
1. Stabilized BMI z-score
2. ↓ aminotransferases
3. ↓ cholesterol (total and LDL)

SECTION 6: Liver
D. 53 pediatric patients randomized to dietary changes and exercise in addition
to vitamin E + vitamin C versus placebo for 2 years improved histological
changes in both groups, regardless of vitamin supplementation
E. 173 pediatric patients with NAFLD were given vitamin E, metformin, or
placebo in a double-blind randomized controlled trial
Table of Contents

1. No difference in decreasing ALT 6M


2. Vitamin E and metformin versus placebo improved hepatocyte
ballooning in patients with NASH 436
F. 76 pediatric patients with NAFLD randomized to take omega-3 FAs or
omega-6 FAs (control) demonstrated ↓ serum biochemistries including AST
and GGT
G. Another study demonstrated that 6 months of docosahexaenoic acid (DHA)
↓ hepatic steatosis and improved hypertriglyceridemia and hyperinsulinemia
in 51 pediatric patients with NAFLD
H. The role of bile acids and bile acid signaling targets are being increasingly
investigated as potential regulators of hepatic fat deposition, perhaps lending
themselves to modulation for NAFLD/NASH therapy
I. In the morbidly obese teenager with NASH, bariatric surgery is now being
investigated as a therapeutic option of last resort

VI. Conclusion

A. NAFLD is today the most common chronic liver disease in children


B. NASH is predicted to soon be the leading cause for liver transplantation in
adults
C. Pediatric gastroenterologists will therefore be increasingly charged to help
intervene and treat this disease

6M. Nonalcoholic Fatty Liver Disease and Steatohepatitis (NAFLD/NASH)


Recommended Reading
Alisi A, Feldstein AE, Villani A, et al. Pediatric nonalcoholic fatty liver disease: a
multidisciplinary approach. Nat Rev Gastroenterol Hepatol. 2012;9:152-161.
Table of Contents

Carter-Kent C, Yerian LM, Brunt EM, et al. Nonalcoholic steatohepatitis in children: a 6M


multicenter clinicopathological study. Hepatology. 2009;50:1113-1120.
437
Carulli L, Gabbi C, Bertolotti M. Bile acids and nonalcoholic fatty liver disease: an
intriguing relationship. Hepatology. 2016;63:1739-1740.

Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-
alcoholic fatty liver disease: practice guideline by the American Association for the
Study of Liver Diseases, American College of Gastroenterology, and the American
Gastroenterological Association. Hepatology. 2012;55:2005-2023.

DeVore S, Kohli R, Lake K, et al. A multidisciplinary clinical program is effective in


stabilizing BMI and reducing transaminase levels in pediatric patients with NAFLD.
J Pediatr Gastroenterol Nutr. 2013;57:119-123.

Feldstein AE, Charatcharoenwitthaya P, Treeprasertsuk S, et al. The natural history of


non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years. Gut.
2009;58:1538-1544.

Janczyk W, Lebensztejn D, Wierzbicka-Rucińska A, et al. Omega-3 fatty acids therapy in


children with nonalcoholic fatty liver disease: a randomized controlled trial. J Pediatr.
2015;166:1358-1363.

Lavine JE, Schwimmer JB, Van Natta ML, et al. Effect of vitamin E or metformin for
treatment of nonalcoholic fatty liver disease in children and adolescents: the TONIC
randomized controlled trial. JAMA. 2011;305:1659-1668.

Mansoor S, Collyer E, Alkhouri N. A comprehensive review of noninvasive liver fibrosis


tests in pediatric nonalcoholic fatty liver disease. Curr Gastroenterol Rep. 2015;17:23.

Molleston JP, Schwimmer JB, Yates KP, et al. Histologic abnormalities in children
with nonalcoholic fatty liver disease and normal or mildly elevated alanine
aminotransferase levels. J Pediatr. 2014;164:707-713.

Nobili V, Manco M, Devito R, et al. Lifestyle intervention and antioxidant therapy


in children with nonalcoholic fatty liver disease: a randomized, controlled trial.
Hepatology. 2008;48:119-128.

Nobili V, Svegliati-Baroni G, Alisi A, et al. A 360-degree overview of paediatric NAFLD:


recent insights. J Hepatol. 2013;58:1218-1229.

Nobili V, Vajro P, Dezsofi A, et al. Indications and limitations of bariatric intervention in


severely obese children and adolescents with and without nonalcoholic steatohepatitis:
ESPGHAN Hepatology Committee Position Statement. J Pediatr Gastroenterol Nutr.
2015;60:550-561.

SECTION 6: Liver
Pacifico L, Bonci E, Di Martino M, et al. A double-blind, placebo-controlled randomized
trial to evaluate the efficacy of docosahexaenoic acid supplementation on hepatic fat
and associated cardiovascular risk factors in overweight children with nonalcoholic
fatty liver disease. Nutr Metab Cardiovasc Dis. 2015;25:734-741.
Table of Contents

Schwimmer JB, Behling C, Newbury R, et al. Histopathology of pediatric nonalcoholic 6M


fatty liver disease. Hepatology. 2005;42:641-649.
438
Schwimmer JB, Deutsch R, Kahen T, et al. Prevalence of fatty liver in children and
adolescents. Pediatrics. 2006;118:1388-1393.

Wree A, Broderick L, Canbay A, et al. From NAFLD to NASH to cirrhosis—new insights


into disease mechanisms. Nat Rev Gastroenterol Hepatol. 2013;10:627-636.

6M. Nonalcoholic Fatty Liver Disease and Steatohepatitis (NAFLD/NASH)