1922 Part XVIII The Digestive System

Chapter 355 Table 355-1 Mechanisms of Hepatomegaly

INCREASE IN THE NUMBER OR SIZE OF THE CELLS INTRINSIC
Manifestations of Liver TO THE LIVER
Storage

Disease
Fat: malnutrition, obesity, diabetes mellitus, metabolic liver disease
(diseases of fatty acid oxidation and Reye syndromelike
illnesses), lipid infusion (total parenteral nutrition), cystic fibrosis,
James E. Squires and William F. Balistreri medication related, pregnancy
Specific lipid storage diseases: Gaucher, Niemann-Pick, Wolman
disease
Glycogen: glycogen storage diseases (multiple enzyme defects); total
PATHOLOGIC MANIFESTATIONS parenteral nutrition; infant of diabetic mother, Beckwith syndrome
Alterations in hepatic structure and function can be acute or chronic, Miscellaneous: 1-antitrypsin deficiency, Wilson disease,
with varying patterns of reaction of the liver to cell injury. Hepatocyte hypervitaminosis A, neonatal iron storage disease
injury can be caused by viral infection, drugs or toxins, hypoxia, Inflammation
immunologic disorders, or inborn errors of metabolism. The injury Hepatocyte enlargement (hepatitis)
results in inflammatory cell infiltration or cell death (necrosis), which Viral: acute and chronic
may be followed by a healing process of scar formation (fibrosis) and, Bacterial: sepsis, abscess, cholangitis
Toxic: drugs
potentially, nodule formation (regeneration). Cirrhosis is the end result Autoimmune
of any progressive liver disease. Kupffer cell enlargement
Cholestasis is an alternative or concomitant response to injury Sarcoidosis
caused by extrahepatic or intrahepatic obstruction to bile flow. Sub- Systemic lupus erythematosus
stances that are normally excreted in bile, such as conjugated bilirubin, Macrophage activating syndrome
cholesterol, bile acids, and trace elements, accumulate in serum. Bile INFILTRATION OF CELLS
pigment accumulation in liver parenchyma can be seen in liver biopsy Primary Liver Tumors: Benign
specimens. In extrahepatic obstruction, bile pigment may be visible Hepatocellular
in the intralobular bile ducts or throughout the parenchyma as bile Focal nodular hyperplasia
lakes or infarcts. In intrahepatic cholestasis, an injury to hepatocytes Nodular regenerative hyperplasia
or an alteration in hepatic physiology leads to a reduction in the rate Hepatocellular adenoma
of secretion of solute and water. Likely causes include alterations Mesodermal
Infantile hemangioendothelioma
in enzymatic or canalicular transporter activity, permeability of the
Mesenchymal hamartoma
bile canalicular apparatus, organelles responsible for bile secretion, or Cystic masses
ultrastructure of the cytoskeleton of the hepatocyte. The end result can Choledochal cyst
be clinically indistinguishable from obstructive cholestasis. Hepatic cyst
Cirrhosis, defined histologically by the presence of bands of fibrous Hematoma
tissue that link central and portal areas and form parenchymal nodules, Parasitic cyst
is a potential end stage of any acute or chronic liver disease. Cirrhosis Pyogenic or amebic abscess
can be macronodular, with nodules of various sizes (up to 5cm) sepa- Primary Liver Tumors: Malignant
rated by broad septa, or micronodular, with nodules of uniform size Hepatocellular
Hepatoblastoma
(<1cm) separated by fine septa; mixed forms occur. The progressive Hepatocellular carcinoma
scarring of cirrhosis results in altered hepatic blood flow, with further Mesodermal
impairment of liver cell function. Increased intrahepatic resistance to Angiosarcoma
portal blood flow leads to portal hypertension. Undifferentiated embryonal sarcoma
The liver can be secondarily involved in neoplastic (metastatic) and Secondary or metastatic processes
nonneoplastic (storage diseases, fat infiltration) processes, as well as a Lymphoma
number of systemic conditions and infectious processes. The liver can Leukemia
Histiocytosis
be affected by chronic passive congestion (congestive heart failure) or
Neuroblastoma
acute hypoxia, with hepatocellular damage. Wilms tumor

CLINICAL MANIFESTATIONS INCREASED SIZE OF VASCULAR SPACE

Hepatomegaly Intrahepatic obstruction to hepatic vein outflow
Venoocclusive disease
Enlargement of the liver can be caused by several mechanisms (Table Hepatic vein thrombosis (Budd-Chiari syndrome)
355-1). Normal liver size estimations are based on age-related clinical Hepatic vein web
indices, such as the degree of extension of the liver edge below the Suprahepatic
costal margin, the span of dullness to percussion, or the length of the Congestive heart failure
vertical axis of the liver, as estimated from imaging techniques. In Pericardial disease
children, the normal liver edge can be felt up to 2cm below the right Tamponade
costal margin. In a newborn infant, extension of the liver edge more Post-Fontan procedure
than 3.5cm below the costal margin in the right midclavicular line Constrictive pericarditis
Hematopoietic: sickle cell anemia, thalassemia
suggests hepatic enlargement. Measurement of liver span is carried
out by percussing the upper margin of dullness and by palpating the INCREASED SIZE OF BILIARY SPACE
lower edge in the right midclavicular line. This may be more reliable Congenital hepatic fibrosis
than an extension of the liver edge alone. The 2 measurements may Caroli disease
correlate poorly. Extrahepatic obstruction
The liver span increases linearly with body weight and age in both IDIOPATHIC
sexes, ranging from approximately 4.5-5.0cm at 1wk of age to approx- Various
imately 7-8cm in boys and 6.0-6.5cm in girls by 12yr of age. The Riedel lobe
lower edge of the right lobe of the liver extends downward (Riedel lobe) Normal variant
Downward displacement of diaphragm
and can normally be palpated as a broad mass in some people. An

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 Chapter 355 Manifestations of Liver Disease 1923

enlarged left lobe of the liver is palpable in the epigastrium of some

patients with cirrhosis. Downward displacement of the liver by the Table 355-2 Differential Diagnosis of Unconjugated
diaphragm (hyperinflation) or thoracic organs can create an erroneous Hyperbilirubinemia
impression of hepatomegaly. INCREASED PRODUCTION OF UNCONJUGATED BILIRUBIN
Examination of the liver should note the consistency, contour, ten- FROM HEME
derness, and presence of any masses or bruits, as well as assessment of Hemolytic Disease (Hereditary or Acquired)
spleen size. Documentation of the presence of ascites and any stigmata Isoimmune hemolysis (neonatal; acute or delayed transfusion
of chronic liver disease is important. reaction; autoimmune)
Ultrasound is useful in assessment of liver size and consistency, as Rh incompatibility
well as gallbladder size. Gallbladder length normally varies from ABO incompatibility
1.5-5.5cm (average: 3cm) in infants to 4-8cm in adolescents; width Other blood group incompatibilities
Congenital spherocytosis
ranges from 0.5-2.5cm for all ages. Gallbladder distention may be seen
Hereditary elliptocytosis
in infants with sepsis. The gallbladder is often absent in infants with Infantile pyknocytosis
biliary atresia. Erythrocyte enzyme defects
Hemoglobinopathy
Jaundice (Icterus) Sickle cell anemia
Yellow discoloration of the sclera, skin, and mucous membranes is a Thalassemia
sign of hyperbilirubinemia (see Chapter 102.3). Clinically apparent Others
jaundice in children and adults occurs when the serum concentration Sepsis
of bilirubin reaches 2-3mg/dL (34-51mol/L); the neonate might not Microangiopathy
Hemolytic-uremic syndrome
appear icteric until the bilirubin level is >5mg/dL (>85mol/L). Jaun-
Hemangioma
dice may be the earliest and only sign of hepatic dysfunction. Liver Mechanical trauma (heart valve)
disease must be suspected in the infant who appears only mildly jaun- Ineffective erythropoiesis
diced but has dark urine or acholic (light-colored) stools. Immediate Drugs
evaluation to establish the cause is required. Infection
Measurement of the total serum bilirubin concentration allows Enclosed hematoma
quantitation of jaundice. Bilirubin occurs in plasma in 4 forms: uncon- Polycythemia
jugated bilirubin tightly bound to albumin; free or unbound bilirubin Diabetic mother
(the form responsible for kernicterus, because it can cross cell mem- Fetal transfusion (recipient)
Delayed cord clamping
branes); conjugated bilirubin (the only fraction to appear in urine); and
fraction (bilirubin covalently bound to albumin), which appears in DECREASED DELIVERY OF UNCONJUGATED BILIRUBIN
serum when hepatic excretion of conjugated bilirubin is impaired in (IN PLASMA) TO HEPATOCYTE
patients with hepatobiliary disease. The fraction permits conjugated Right-sided congestive heart failure
bilirubin to persist in the circulation and delays resolution of jaundice. Portacaval shunt
Although the terms direct and indirect bilirubin are used equivalently DECREASED BILIRUBIN UPTAKE ACROSS HEPATOCYTE
with conjugated and unconjugated bilirubin, this is not quantitatively MEMBRANE
correct, because the direct fraction includes both conjugated bilirubin Presumed enzyme transporter deficiency
and bilirubin. Competitive inhibition
Investigation of jaundice in an infant or older child must include Breast milk jaundice
determination of the accumulation of both unconjugated and conju- Lucey-Driscoll syndrome
Drug inhibition (radiocontrast material)
gated bilirubin. Unconjugated hyperbilirubinemia might indicate Miscellaneous
increased production, hemolysis, reduced hepatic removal, or altered Hypothyroidism
metabolism of bilirubin (Table 355-2). Conjugated hyperbilirubine- Hypoxia
mia reflects decreased excretion by damaged hepatic parenchymal Acidosis
cells or disease of the biliary tract, which may be a result of obstruc-
DECREASED STORAGE OF UNCONJUGATED BILIRUBIN IN
tion, sepsis, toxins, inflammation, and genetic or metabolic disease CYTOSOL (DECREASED Y AND Z PROTEINS)
(Table 355-3). Competitive inhibition
Fever
Pruritus
Intense generalized itching can occur in patients with chronic liver DECREASED BIOTRANSFORMATION (CONJUGATION)
Neonatal jaundice (physiologic)
disease often in association with cholestasis (conjugated hyperbiliru-
Inhibition (drugs)
binemia). Symptoms can be generalized or localized (commonly to Hereditary (Crigler-Najjar)
palms and soles), are usually worse at night, are exacerbated with stress Type I (complete enzyme deficiency)
and heat, and are relieved by cool temperatures. Pruritus is unrelated Type II (partial deficiency)
to the degree of hyperbilirubinemia; deeply jaundiced patients can be Gilbert disease
asymptomatic. Although retained components of bile are likely impor- Hepatocellular dysfunction
tant, the cause is probably multifactorial, as evidenced by the symp- ENTEROHEPATIC RECIRCULATION
tomatic relief of pruritus after administration of various therapeutic Breast milk jaundice
agents including bile acid-binding agents (cholestyramine), choleretic Intestinal obstruction
agents (ursodeoxycholic acid), opiate antagonists, antihistamines, and Ileal atresia
antibiotics. Plasmapheresis, molecular adsorbent recirculating system Hirschsprung disease
therapy, and surgical diversion of bile (partial external biliary diver- Cystic fibrosis
sion) have been used in attempts to provide relief for medically refrac- Pyloric stenosis
tory pruritus. Antibiotic administration

Spider Angiomas
Vascular spiders (telangiectasias), characterized by central pulsating
arterioles from which small, wiry venules radiate, may be seen in
patients with chronic liver disease; these are usually most prominent

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1924 Part XVIII The Digestive System

Table 355-3 Differential Diagnosis of Neonatal and Infantile Cholestasis

INFECTIOUS Wilson disease
Generalized bacterial sepsis Neonatal iron storage disease
Viral hepatitis Indian childhood cirrhosis/infantile copper overload
Hepatitides A, B, C, D, E Congenital disorders of glycosylation
Cytomegalovirus Mitochondrial hepatopathies
Rubella virus Citrin deficiency
Herpesviruses: herpes simplex, human herpesvirus 6 and 7
GENETIC OR CHROMOSOMAL
Varicella virus
Trisomies 17, 18, 21
Coxsackievirus
Echovirus INTRAHEPATIC CHOLESTASIS SYNDROMES
Reovirus type 3 Idiopathic neonatal hepatitis
Parvovirus B19 Alagille syndrome
HIV Intrahepatic cholestasis (progressive familial intrahepatic cholestasis
Adenovirus [PFIC])
Others FIC-1 deficiency
Toxoplasmosis BSEP (bile salt export pump) deficiency
Syphilis MDR3 deficiency
Tuberculosis Familial benign recurrent cholestasis associated with lymphedema
Listeriosis (Aagenaes syndrome)
Urinary tract infection ARC (arthrogryposis, renal dysfunction, and cholestasis) syndrome
Caroli disease (cystic dilation of intrahepatic ducts)
TOXIC
Sepsis EXTRAHEPATIC DISEASES
Parenteral nutrition related Biliary atresia
Drug, dietary supplement, herbal related Sclerosing cholangitis
Bile duct stricture/stenosis
METABOLIC
Choledochalpancreaticoductal junction anomaly
Disorders of amino acid metabolism
Spontaneous perforation of the bile duct
Tyrosinemia
Choledochal cyst
Disorders of lipid metabolism
Mass (neoplasia, stone)
Wolman disease
Bile/mucous plug (inspissated bile)
Niemann-Pick disease (type C)
Gaucher disease MISCELLANEOUS
Cholesterol ester storage disease Shock and hypoperfusion
Disorders of carbohydrate metabolism Associated with enteritis
Galactosemia Associated with intestinal obstruction
Fructosemia Neonatal lupus erythematosus
Glycogenosis IV Myeloproliferative disease (trisomy 21)
Disorders of bile acid biosynthesis Hemophagocytic lymphohistiocytosis (HLH)
Other metabolic defects COACH syndrome (coloboma, oligophrenia, ataxia, cerebellar vermis
1-Antitrypsin deficiency hypoplasia, hepatic fibrosis)
Cystic fibrosis Cholangiocyte cilia defects
Hypopituitarism
Hypothyroidism
Zellweger (cerebrohepatorenal) syndrome

in the superior vena cava distribution area (on the face and chest).
Their size varies between 1 and 10mm and they exhibit central clear-
ing with pressure. They presumably reflect altered estrogen metabolism
in the presence of hepatic dysfunction.
Palmar Erythema
Blotchy erythema, most noticeable over the thenar and hypothenar
eminences and on the tips of the fingers, is also noted in patients with
chronic liver disease. Abnormal serum estradiol levels and regional
alterations in peripheral circulation have been identified as possible
causes.
Xanthomas
The marked elevation of serum cholesterol levels (to >500mg/dL)
associated with some forms of chronic cholestasis can cause the deposi-
tion of lipid in the dermis and subcutaneous tissue. Brown nodules can
develop, first over the extensor surfaces of the extremities; rarely, xan-
thelasma of the eyelids develops.
Portal Hypertension
Portal hypertension occurs when there is increased portal resistance
and/or increased portal flow. The portal system drains the splanchnic
area (abdominal portion of the gastrointestinal tract, pancreas, and
spleen) into the hepatic sinusoids. Normal portal pressure is between
3 and 6mmHg. Portal hypertension is defined as a portal pressure
greater than 10mmHg. Clinically significant portal hypertension
exists when pressure exceeds a threshold of 12mmHg or greater.
Portal hypertension is the main complication of cirrhosis, directly
responsible for 2 of its most common and potentially lethal complica-
tions: ascites and variceal hemorrhage.
Ascites
Ascites is a consequence of increased hydrostatic and osmotic pres-
sures within the hepatic and mesenteric capillaries resulting in transfer
of fluid from the blood vessels to the lymphatics that overcomes the
drainage capacity of the lymphatic system. Ascites can also be associ-
ated with nephrotic syndrome and other urinary tract abnormalities,
metabolic diseases (such as lysosomal storage diseases), congenital
or acquired heart disease, and hydrops fetalis. Factors favoring
the intraabdominal accumulation of fluid include decreased plasma
colloid osmotic pressure, increased capillary hydrostatic pressure,
increased ascitic colloid osmotic fluid pressure, and decreased ascitic
fluid hydrostatic pressure. Abnormal renal sodium retention must be
considered.

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Gastrointestinal Bleeding
Chronic liver disease may manifest as gastrointestinal hemorrhage.
Bleeding may result from portal hypertensive gastropathy, gastric
antral vascular ectasia, or varix rupture. Variceal hemorrhage is classi-
cally from an esophageal origin but may be caused by gastric, duode-
nal, peristomal, or rectal varices. Variceal hemorrhage results from
increased pressure within the varix, which leads to changes in the
diameter of the varix and increased wall tension. When the variceal
wall strength is exceeded, physical rupture of the varix results. Given
the high blood flow and pressure in the portosystemic collateral system,
coupled with the lack of a natural mechanism to tamponade variceal
bleeding, the rate of hemorrhage can be striking.
Encephalopathy
Hepatic encephalopathy can involve any neurologic function, and it
can be prominent or present in subtle forms such as deterioration of
school performance, sleep disturbances, depression, or emotional out-
bursts. It can be recurrent and precipitated by intercurrent illness,
drugs, bleeding, or electrolyte and acid-base disturbances. The appear-
ance of hepatic encephalopathy depends on the presence of porto
systemic shunting, alterations in the bloodbrain barrier, and the
interactions of toxic metabolites with the central nervous system. Pos-
tulated causes include altered ammonia metabolism, synergistic neu-
rotoxins, decreased cerebral oxygen metabolism and blood flow, or
false neurotransmitters with plasma amino acid imbalance.
Endocrine Abnormalities
Endocrine abnormalities are more common in adults with hepatic
disease than in children. They reflect alterations in hepatic synthetic,
storage, and metabolic functions, including those concerned with hor-
monal metabolism in the liver. Proteins that bind hormones in plasma
are synthesized in the liver, and steroid hormones are conjugated in
the liver and excreted in the urine; failure of such functions can have
clinical consequences. Endocrine abnormalities can also result from
malnutrition or specific deficiencies.
Renal Dysfunction
Systemic disease or toxins can affect the liver and kidneys simultane-
ously, or parenchymal liver disease can produce secondary impairment
of renal function. In hepatobiliary disorders, there may be renal altera-
tions in sodium and water economy, impaired renal concentrating
ability, and alterations in potassium metabolism. Ascites in patients
with cirrhosis may be related to inappropriate retention of sodium by
the kidneys and expansion of plasma volume, or it may be related to
sodium retention mediated by diminished effective plasma volume.
Hepatorenal syndrome is defined as functional renal failure in patients
with end-stage liver disease. The pathophysiology of hepatorenal
syndrome is related to splanchnic vasodilation, mesenteric angiogen-
esis, and decreased effective blood volume with resulting decreased
renal perfusion. The hallmark is intense renal vasoconstriction (medi-
ated by hemodynamic, humoral, or neurogenic mechanisms) with
coexistent systemic vasodilation. The diagnosis is supported by the
findings of oliguria (<1mL/kg/day), a characteristic pattern of urine
electrolyte abnormalities (urine sodium < 10mEq/L, fractional excre-
tion of sodium of <1%, urine:plasma creatinine ratio <10, and normal
urinary sediment), absence of hypovolemia, and exclusion of other
kidney pathology. The best treatment of hepatorenal syndrome is
timely liver transplantation, because complete renal recovery can be
expected.
Pulmonary Involvement
Hepatopulmonary syndrome is characterized by the typical triad of
hypoxemia, intrapulmonary vascular dilations, and liver disease. There
is intrapulmonic right-to-left shunting of blood resulting from enlarged
pulmonary vessels that prevents red blood cells traveling through the
center of the vessel adequate exposure to oxygen-rich alveoli. Shunting
of vasodilatory mediators from the mesentery away from the liver is
thought to contribute. It should be suspected and investigated in the
child with chronic liver disease with history of shortness of breath or
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Chapter 355 Manifestations of Liver Disease 1925
exercise intolerance and clinical examination findings of cyanosis (par-
ticularly of the lips and fingers), digital clubbing, and oxygen satura-
tions <96%, particularly in the upright position. Treatment is timely
liver transplantation; resolution of pulmonary involvement usually
follows.
Portopulmonary hypertension is a condition characterized by an
increase in the resistance to pulmonary arterial blood flow in the
setting of portal hypertension. It is defined by a pulmonary arterial
pressure >25mmHg at rest and above 30mmHg with exercise, ele-
vated pulmonary vascular resistance with pulmonary arterial occlusion
pressure, or a left-ventricular end-diastolic pressure of <15mmHg.
Although the pathophysiology is unclear, symptoms suggesting a diag-
nosis include exertional dyspnea, fatigue, syncope, palpitations, and
chest pain.
Recurrent Cholangitis
Ascending infection of the biliary system is often seen in pediatric
cholestatic disorders, most commonly because of Gram-negative
enteric organisms, such as Escherichia coli, Klebsiella, Pseudomonas,
and Enterococcus. Liver transplantation is the definitive treatment
for recurrent cholangitis, especially when medical therapy is not
effective.
Miscellaneous Manifestations
of Liver Dysfunction
Nonspecific signs of acute and chronic liver disease include anorexia,
which often affects patients with anicteric hepatitis and with cirrhosis
associated with chronic cholestasis; abdominal pain or distention
resulting from ascites, spontaneous peritonitis, or visceromegaly; mal-
nutrition and growth failure; and bleeding, which may be a result of
altered synthesis of coagulation factors (biliary obstruction with
vitamin K deficiency or excessive hepatic damage) or to portal hyper-
tension with hypersplenism. In the presence of hypersplenism, there
can be decreased synthesis of specific clotting factors, production of
qualitatively abnormal proteins, or alterations in platelet number and
function. Altered drug metabolism can prolong the biologic half-life
of commonly administered medications.
Bibliography is available at Expert Consult.
355.1 Evaluation of Patients with Possible
Liver Dysfunction
James E. Squires and William F. Balistreri
Adequate evaluation of an infant, child, or adolescent with suspected
liver disease involves an appropriate and accurate history, a carefully
performed physical examination, and skillful interpretation of signs
and symptoms. Further evaluation is aided by judicious selection of
diagnostic tests, followed by the use of imaging modalities or a liver
biopsy. Most of the so-called liver function tests do not measure spe-
cific hepatic functions: a rise in serum aminotransferase levels reflects
liver cell injury, an increase in immunoglobulin levels reflects an
immunologic response to injury, or an elevation in serum bilirubin
levels can reflect any of several disturbances of bilirubin metabolism
(see Tables 355-2 and 355-3). Any single biochemical assay provides
limited information, which must be placed in the context of the entire
clinical picture. The most cost-efficient approach is to become familiar
with the rationale, implications, and limitations of a selected group of
tests so that specific questions can be answered. Young infants with
cholestatic jaundice should be evaluated promptly to identify patients
needing surgical intervention.
For a patient with suspected liver disease, evaluation addresses the
following issues in sequence: Is liver disease present? If so, what is its
nature? What is its severity? Is specific treatment available? How can
we monitor the response to treatment? What is the prognosis?
 Chapter 355 Manifestations of Liver Disease 1925.e1

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Balistreri WF: Bile acid therapy in pediatric hepatobiliary disease: the role of
ursodeoxycholic acid, J Pediatr Gastroenterol Nutr 24:573589, 1997.
Balistreri WF: Pediatric hepatology. A half-century of progress, Clin Liver Dis
4:191210, 2000.
Bezerra JA, Balistreri WF: Cholestatic syndromes of infancy and childhood, Semin
Gastrointest Dis 12:5465, 2001.
Bunchorntavakul C, Reddy KR: Pruritus in chronic cholestatic liver disease, Clin
Liver Dis 16:331346, 2012.
Garcia-Tsao G: Current management of the complications of cirrhosis and portal
hypertension: variceal hemorrhage, ascites and spontaneous bacterial
peritonitis, Gastroenterology 120:726748, 2001.
Gastroenterol 18:11761184, 2012.
Jensen MK, Alonso MH, Nathan J, etal: Liver transplantation in children:
indications and surgical aspects. In Suchy FS, Sokol RJ, Balistreri WF, editors:
Liver disease in children, ed 4, Cambridge, 2013, Cambridge University Press.
Ryckman FC, Alonso MH: Causes and management of portal hypertension in the
pediatric population, Clin Liver Dis 5:789818, 2001.
Satapathy SK, Bernstein D: Dermatologic disorders and the liver, Clin Liver Dis
15:165182, 2011.
Suchy FJ, Sokol RJ, Balistreri WF: Liver disease in children, ed 4, Cambridge, 2013,
Cambridge University Press.

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1926 Part XVIII The Digestive System
BIOCHEMICAL TESTS
Laboratory tests commonly used to screen for or to confirm a suspi-
cion of liver disease include measurements of serum aminotransferase,
bilirubin (total and fractionated), and alkaline phosphatase (AP)
levels, as well as determinations of prothrombin time (PT) or interna-
tional normalized ratio (INR) and albumin level. These tests are com-
plementary, provide an estimation of synthetic and excretory functions,
and might suggest the nature of the disturbance (inflammation or
cholestasis).
The severity of the liver disease may be reflected in clinical signs or
biochemical alterations. Clinical signs include encephalopathy, variceal
hemorrhage, worsening jaundice, apparent shrinkage of liver mass
owing to massive necrosis, or onset of ascites. Biochemical alterations
include hypoglycemia, acidosis, hyperammonemia, electrolyte imbal-
ance, continued hyperbilirubinemia, marked hypoalbuminemia, or a
prolonged PT or INR that is unresponsive to parenteral administration
of vitamin K.
Acute liver cell injury (parenchymal disease) caused by viral hepa-
titis, drug- or toxin-induced liver disease, shock, hypoxemia, or meta-
bolic disease is best reflected by a marked increase in serum
aminotransferase levels. Cholestasis (obstructive disease) involves
regurgitation of bile components into serum; the serum levels of total
and conjugated bilirubin and serum bile acids are elevated. Elevations
in serum AP, 5 nucleotidase, and -glutamyl transpeptidase levels are
also sensitive indicators of obstruction or inflammation of the biliary
tract. Fractionation of the total serum bilirubin level into conjugated
and unconjugated bilirubin fractions helps to distinguish between
elevations caused by processes such as hemolysis and those caused by
hepatic dysfunction. A predominant elevation in the conjugated bili-
rubin level provides a relatively sensitive index of hepatocellular disease
or hepatic excretory dysfunction.
Alanine aminotransferase (ALT, serum glutamate pyruvate trans-
aminase) is liver specific, whereas aspartate aminotransferase (AST,
serum glutamic-oxaloacetic transaminase) is derived from other
organs in addition to the liver. The most marked rises of AST and ALT
levels can occur with acute hepatocellular injury; a several thousand
fold elevation can result from acute viral hepatitis, toxic injury,
hypoxia, or hypoperfusion. After blunt abdominal trauma, parallel
elevations in aminotransferase levels can provide an early clue to
hepatic injury. A differential rise or fall in AST and ALT levels some-
times provides useful information. In acute hepatitis, the rise in ALT
may be greater than the rise in AST. In alcohol-induced liver injury,
fulminant echovirus infection, and various metabolic diseases, more
predominant rises in the AST level are reported. In chronic liver
disease or in intrahepatic and extrahepatic biliary obstruction, AST
and ALT elevations may be less marked. Elevated serum aminotrans-
ferase levels are seen in patients with nonalcoholic fatty liver disease
and nonalcoholic steatohepatitis (NASH), the notable characteristic is
histology similar to alcoholic-induced liver injury in the absence of
alcohol abuse.
Hepatic synthetic function is reflected in serum albumin and protein
levels and in the PT or INR. Examination of serum globulin concentra-
tion and of the relative amounts of the globulin fractions may be
helpful. Patients with autoimmune hepatitis often have high -globulin
levels and increased titers of antismooth muscle, antinuclear, and
antiliver-kidney-microsome antibodies. Antimitochondrial antibod-
ies may also be found in patients with autoimmune hepatitis. A resur-
gence in -fetoprotein levels can suggest hepatoma, hepatoblastoma,
or hereditary tyrosinemia. Hypoalbuminemia caused by depressed
synthesis can complicate severe liver disease and serve as a prognostic
factor. Deficiencies of factor V and of the vitamin Kdependent factors
(II, VII, IX, and X) can occur in patients with severe liver disease or
fulminant hepatic failure. If the PT or INR is prolonged as a result of
intestinal malabsorption of vitamin K (resulting from cholestasis) or
decreased nutritional intake of vitamin K, parenteral administration of
vitamin K should correct the coagulopathy, leading to normalization
within 12-24hr. Unresponsiveness to vitamin K suggests severe hepatic
disease. Persistently low levels of factor VII are evidence of a poor
prognosis in fulminant liver disease.
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Interpretation of results of biochemical tests of hepatic structure and
function must be made in the context of age-related changes. The activ-
ity of AP varies considerably with age. Normal growing children have
significant elevations of serum AP activity originating from influx into
serum of the isoenzyme that originates in bone, particularly in rapidly
growing adolescents. An isolated increase in AP does not indicate
hepatic or biliary disease if other liver tests are normal. Other enzymes
such as 5 nucleotidase and -glutamyl transpeptidase are increased in
cholestatic conditions and may be more specific for hepatobiliary
disease. 5 nucleotidase is not found in bone. -Glutamyl transpepti-
dase exhibits high enzyme activity in early life that declines rapidly
with age. Cholesterol concentrations increase throughout life. Choles-
terol levels may be markedly elevated in patients with intra- or extra-
hepatic cholestasis and decreased in severe acute liver disease such as
hepatitis.
Interpretation of serum ammonia values must be carried out with
caution because of variability in their physiologic determinants and the
inherent difficulty in laboratory measurement.
LIVER BIOPSY
Liver biopsy combined with clinical data can suggest a cause for hepa-
tocellular injury or cholestatic disease in most cases. Specimens of liver
tissue can be used to determine a precise histologic diagnosis in
patients with neonatal cholestasis, chronic hepatitis, nonalcoholic fatty
liver disease or nonalcoholic steatohepatitis, metabolic liver disease,
intrahepatic cholestasis, congenital hepatic fibrosis, or undefined
portal hypertension. The sample may be subjected to enzyme analysis
to detect inborn errors of metabolism and to analysis of stored material
such as iron, copper, or specific metabolites. Liver biopsies can monitor
responses to therapy or detect complications of treatment with poten-
tially hepatotoxic agents, such as aspirin, antiinfectives (minocycline,
ketoconazole, isoniazid), antimetabolites, antineoplastics, or anticon-
vulsant agents.
In infants and children, needle biopsy of the liver is easily accom-
plished percutaneously. The amount of tissue obtained, even in small
infants, is usually sufficient for histologic interpretation and for bio-
chemical analyses, if the latter are deemed necessary. Percutaneous
liver biopsy can be performed safely in infants as young as 1wk of age.
Contraindications to the percutaneous approach include prolonged PT
or INR; thrombocytopenia; suspicion of a vascular, cystic, or infectious
lesion in the path of the needle; and severe ascites. If administration
of fresh-frozen plasma or of platelet transfusions fails to correct a
prolonged PT, INR, or thrombocytopenia, a tissue specimen can be
obtained via alternative techniques. Considerations include either the
open laparotomy (wedge) approach by a general surgeon or the tran-
sjugular approach under ultrasound and fluoroscopic guidance by an
experienced pediatric interventional radiologist in an appropriately
equipped fluoroscopy suite. The risk of development of a complication
such as hemorrhage, hematoma, creation of an arteriovenous fistula,
pneumothorax, or bile peritonitis is small.
HEPATIC IMAGING PROCEDURES
Various techniques help define the size, shape, and architecture of the
liver and the anatomy of the intrahepatic and extrahepatic biliary trees.
Although imaging might not provide a precise histologic and bio-
chemical diagnosis, specific questions can be answered, such as
whether hepatomegaly is related to accumulation of fat or glycogen or
is caused by a tumor or cyst. These studies can direct further evaluation
such as percutaneous biopsy and make possible prompt referral of
patients with biliary obstruction to a surgeon. Choice of imaging pro-
cedure should be part of a carefully formulated diagnostic approach,
with avoidance of redundant demonstrations by several techniques.
A plain x-ray study can suggest hepatomegaly, but a carefully per-
formed physical examination gives a more reliable assessment of liver
size. The liver might appear less dense than normal in patients with
fatty infiltration or denser with deposition of heavy metals such as iron.
A hepatic or biliary tract mass can displace an air-filled loop of bowel.
Calcifications may be evident in the liver (parasitic or neoplastic
disease), in the vasculature (portal vein thrombosis), or in the
 Chapter 355 Manifestations of Liver Disease 1927

1
Jaundiced infant
2 to 8 weeks old
2
Is the patient
Yes acutely ill? No
Require urgent
care?
3 4
Manage the acute illness Is there direct
Consider urinary tract or other hyperbilirubinemia?
infection, galactosemia, tyrosinemia,
5
hypopituitarism, fructosemia, iron
storage disease, metabolic disorders, Measure Normal
acute common duct obstruction, serum direct
hemolysis bilirubin
6
Abnormal
7 Indirect
Cholestatic hyperbilirubinemia
Jaundice
8
9
Evaluate
History further
Physical exam (see Chapter
Urinalysis 102.3, Table
Urine culture 355.2)
10 11
Evaluate Yes Findings of
further specific disease?

13 No
12
Is the newborn
Refer for further Yes screen positive for
management galactosemia or
hypothyroidism?

14 15 No

Does bilirubin No Consult Pediatric GI

normalize by 6 CBC, platelet count
weeks of age? Total and direct bilirubin, ALT,
AST, alkaline phosphatase,
Yes glucose
16
Prothrombin time, albumin
No -1 antitrypsin
hyperbilirubinemia Urine reducing substances
Abdominal ultrasound
17
18 19
Pi typing Yes Low Choledochal
Further
-1 antitrypsin? cyst?
management No
20
Consider:
Percutaneous liver biopsy Yes
Scintiscan
Duodenal aspirate
ERCP
Condition
22
21
Consult
Is there
Question Yes pediatric
evidence of
surgery
biliary
Operative
obstruction?
Action cholangiogram
23 No
Medical evaluation:
Infection
Metabolic disorders
Genetic disorders
Other

Figure 355-1 Cholestasis clinical practice guideline. Algorithm for a 2-8wk old. ALT, alanine aminotransferase; AST, aspartate aminotransferase;
ERCP, endoscopic retrograde cholangiopancreatography. (From Moyer V, Freese DK, Whitington PF, etal; North American Society for Pediatric
Gastroenterology, Hepatology and Nutrition: Guideline for the evaluation of cholestatic jaundice in infants: recommendations of the North
American Society for Pediatric Gastroenterology, Hepatology and Nutrition, J Pediatr Gastroenterol Nutr 39:115128, 2004.)

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gallbladder or biliary tree (gallstones). Collections of gas may be seen Percutaneous transhepatic cholangiography has been used to outline
within the liver (abscess), biliary tract, or portal circulation (necrotiz- the biliary ductal system.
ing enterocolitis). Endoscopic retrograde cholangiopancreatography is an alternative
Ultrasound provides information about the size, composition, and method of examining the bile ducts in older children. The papilla of
blood flow of the liver. Increased echogenicity is observed with fatty Vater is cannulated under direct vision through a fiberoptic endoscope,
infiltration; mass lesions as small as 1-2cm may be shown. Ultrasound and contrast material is injected into the biliary and pancreatic ducts
has replaced cholangiography in detecting stones in the gallbladder or to outline the anatomy. The advantage of endoscopic retrograde chol-
biliary tree. Even in neonates, ultrasound can assess gallbladder size, angiopancreatography is that it allows therapeutic interventions of the
detect dilation of the biliary tract, and define a choledochal cyst. In extrahepatic biliary tree (stone extraction, stent placement, etc.).
infants with biliary atresia, ultrasound findings might include small or Selective angiography of the celiac, superior mesenteric, or hepatic
absent gallbladder; nonvisualization of the common duct; and presence artery can be used to visualize the hepatic or portal circulation. Both
of the triangular cord sign, a triangular or tubular-shaped echogenic arterial and venous circulatory systems of the liver can be examined.
density in the bifurcation of the portal vein, representing fibrous rem- Angiography is often required to define the blood supply of tumors
nants at the porta hepatis. Hyperechogenic hepatic parenchyma can be before surgery and is useful in the study of patients with known or
seen with metabolic disease (glycogen storage disease) or fatty liver presumed portal hypertension. The patency of the portal system, the
(obesity, malnutrition, hyperalimentation, corticosteroids). In patients extent of collateral circulation, and the caliber of vessels under consid-
with portal hypertension, Doppler ultrasound can evaluate patency of eration for a shunting procedure can be evaluated. MRI can provide
the portal vein, demonstrate collateral circulation, and assess size of similar information.
spleen and amount of ascites. Relatively small amounts of ascitic fluid
can also be detected. The use of Doppler ultrasound has been helpful DIAGNOSTIC APPROACH TO INFANTS
in determining vascular patency after liver transplantation. WITH JAUNDICE
CT scanning provides information similar to that obtained by ultra- Well-appearing infants can have cholestatic jaundice. Biliary atresia
sound but is less suitable for use in patients younger than 2yr of age and neonatal hepatitis are the most common causes of cholestasis in
because of the small size of structures, the paucity of intraabdominal early infancy. Biliary atresia portends a poor prognosis unless it is
fat for contrast, and the need for heavy sedation or general anesthesia. identified early. The best outcome for this disorder is with early surgical
CT scan may be more accurate than ultrasound in detecting focal reconstruction (45-60 days of age). History, physical examination, and
lesions such as tumors, cysts, and abscesses. When enhanced by con- the detection of a conjugated hyperbilirubinemia via examination of
trast medium, CT scanning can reveal a neoplastic mass density only total and direct bilirubin are the first steps in evaluating the jaundiced
slightly different from that of a normal liver. When a hepatic tumor is infant (Fig. 355-1). Consultation with a pediatric gastroenterologist
suspected, CT scanning is the best method to define anatomic extent, should be sought early in the course of the evaluation.
solid or cystic nature, and vascularity. CT scanning can also reveal
subtle differences in density of liver parenchyma, the average liver Bibliography is available at Expert Consult.
attenuation coefficient being reduced with fatty infiltration. MRI is a
useful alternative that limits radiation exposure. Magnetic resonance
cholangiography can be of value in differentiating biliary tract lesions.
MRI with Eovist (gadoxetate disodium) can assist in the detection and
characterization of known or suspected focal liver lesions. In differen-
tiating obstructive from nonobstructive cholestasis, CT scanning or
MRI identifies the precise level of obstruction more often than ultra-
sound. Either CT scanning or ultrasound may be used to guide percu-
taneously placed fine needles for biopsies, aspiration of specific lesions,
or cholangiography.
Elastography is a novel noninvasive method to assess for the devel-
opment of hepatic fibrosis in patients with liver disease. Both ultra-
sound and MR methods of have been developed. These noninvasive
techniques allow for monitoring fibrosis progression and development
of cirrhosis, improved characterization of hepatic tumors, and prog-
nostic stratification of diseases such as nonalcoholic fatty liver disease
and nonalcoholic steatohepatitis.
Radionuclide scanning relies on selective uptake of a radiopharma-
ceutical agent. Commonly used agents include technetium-99m
labeled sulfur colloid, which undergoes phagocytosis by Kupffer cells;
99m
Tc-iminodiacetic acid agents, which are taken up by hepatocytes and
excreted into bile in a fashion similar to bilirubin; and gallium-67,
which is concentrated in inflammatory and neoplastic cells. The ana-
tomic resolution possible with hepatic scintiscans is generally less than
that obtained with CT scanning, MRI, or ultrasound.
The 99mTc-sulfur colloid scan can detect focal lesions (tumors, cysts,
abscesses) >2-3cm in diameter. This modality can help to evaluate
patients with possible cirrhosis and with patchy hepatic uptake and a
shift of colloid uptake from liver to bone marrow.
Cholangiography, direct visualization of the intrahepatic and extra-
hepatic biliary tree after injection of opaque material, may be required
in some patients to evaluate the cause, location, or extent of biliary
obstruction. Percutaneous transhepatic cholangiography with a fine
needle is the technique of choice in infants and young children. The
likelihood of opacifying the biliary tract is excellent in patients in
whom CT scanning, MRI, or ultrasound demonstrates dilated ducts.

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 Chapter 355 Manifestations of Liver Disease 1928.e1

Bibliography Palermo JJ, Joerger S, Turmelle Y, etal: Neonatal cholestasis: opportunities to

Moyer V, Freese DK, Whitington PF, etal, North American Society for Pediatric increase early detection, Acad Pediatr 12:283287, 2012.
Gastroenterology, Hepatology and Nutrition: Guideline for the evaluation of Shteyer E, Wengrower D, Benuri-Silberger I, etal: Endoscopic retrograde
cholestatic jaundice in infants: recommendations of the North American cholangiopancreatography in neonatal cholestasis, J Pediatr Gastroenterol Nutr
Society for Pediatric Gastroenterology, Hepatology and Nutrition, J Pediatr 55:142145, 2012.
Gastroenterol Nutr 39:115128, 2004.
Ng VL: Laboratory assessment of liver function and injury in children. In Suchy
FJ, Sokol RJ, Balistreri WF, editors: Liver disease in children, ed 4, Cambridge;
New York, 2013, Cambridge University Press.

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For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.