Higado 1
Higado 1
Higado 1
6B
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)
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
Table of Contents
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
Table of Contents
Preer GL, Philipp BL. Understanding and managing breast milk jaundice. Arch Dis Child
Fetal Neonatal Ed. 2011;96:F461-F466.
SECTION 6: Liver
Table of Contents
6B
358
Neonatal Cholestasis
Table of Contents
6Ci
Molly Bozic, MD
359
Previous edition authors: David Brumbaugh, MD and Cara Mack, MD
SECTION 6: Liver
FIGURE 1 Choledochal Cyst Subtypes
Liver
Table of Contents
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
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)
Table of Contents
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
Table of Contents
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.
6Cii
Molly Bozic, MD
365
Previous edition authors: Ramya Ramraj, MD; Daniel Leung, MD; Elizabeth Mileti, DO; and Philip
Rosenthal, MD
SECTION 6: Liver
II. Specific causes of cholestasis in older infants/children
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
Table of Contents
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
Liver US with
Doppler
Dilated bile
Dilated bile Normal/non- Abnormal
ducts/sludge
ducts/sludge diagnostic vascular flow
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
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
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.
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
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
2. Sepsis 6D
3. Intra-abdominal bleed
F. Myopathy 377
1. Viral induced
2. Muscular dystrophy
G. Drug hepatotoxicity
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
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
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
6E. Hepatomegaly
TABLE 1 Differential Diagnosis of Hepatomegaly
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
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
6F
Alisha Mavis, MD
383
Lee M. Bass, MD
Previous edition authors: Khyati Mehta, MD and Simon Ling, MD
I. Overview
II. Pathophysiology
A. The portal system drains the capillaries of the mesentery and spleen and
ends in the hepatic sinusoids (see Figure 1)
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
Resistance to
Portal Flow
Splanchnic
Arteriolar
Resistance
Portal
Pressure
Portal Blood
Inflow
Varices
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
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
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
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
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.
SECTION 6: Liver
Table of Contents
6F
390
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
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
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
VI. Complications
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.
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
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
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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%
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
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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.
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.
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.
Sundaram SS, Alonso EM, Narkewicz MR, et al. Characterization and outcomes of
young infants with acute liver failure. J Pediatr. 2011;159:813-818.
6Ii
Niviann M. Blondet, MD
401
Norberto Rodríguez-Báez, MD
Previous edition author: Charles Vanderpool, MD
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
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
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.
Viral Hepatitis
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6Iii
Niviann M. Blondet, MD
405
Norberto Rodríguez-Báez, MD
Previous edition authors: Brandy Lu, MD and Cara Mack, MD
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
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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
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.
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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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
SECTION 6: Liver
K. Patients immune to HBV (vaccination and previous infection) are considered
to be immune to HDV
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.
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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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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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.
Chronic Hepatitis
Table of Contents
6J
Nanda Kerkar, MD
417
Rula Harb, MD
Previous edition author: Deb Freese, MD
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
Table of Contents
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
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
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.
6K
Voytek Slowik, MD
423
Ryan Fischer, MD
Previous edition authors: Lina Maria Hernandez, MD and Lesley Smith, MD
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
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.
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.
Liver Tumors
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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.
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
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)
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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
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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.
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
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)
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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
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VI. Conclusion
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.
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.
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.
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.
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