++
Jaundice refers to the yellowish discoloration of skin, sclera,
and mucous membranes due to an excess of bilirubin in the blood.
Other body fluids, such as tears, saliva, and cerebrospinal fluid, may
also be tinged with yellowish hues. Jaundice is clinically evident in
infants with total bilirubin levels of 4 to 5 mg/dl (68–85 μmol/L*);
in older children, bilirubin levels above 2 mg/dl (34 μmol/L)
can be visually evident. Each elevated total bilirubin level should
be fractionated to assess the relative contribution of unconjugated
(indirect) bilirubin and conjugated (direct) bilirubin. The combination
of yellow discoloration of the skin and clear sclera suggests carotinemia,
a condition often seen in children taking a pureed diet containing
yellow, carotene-containing vegetables. Carotinemia is not harmful
to the child, requires no further investigation other than reassurance
to the family, and will resolve as the diet is advanced to more
solid foods. [* mg/dl × 17.1 = μmol/L;
based upon the molecular weight of bilirubin of 584].
+++
Approach to
the Infant with Hyperbilirubinemia
++
The general approach to the evaluation of infant with unconjugated hyperbilirubinemia
is discussed in detail in Chapter 53.3 In
the hyperbilirubinemic infant with jaundice persisting past the first
2 weeks of age further evaluation is important. An elevated conjugated
bilirubin level is likely due to hepatocellular injury or obstruction
of the biliary tract. A conjugated bilirubin level that is greater
than 2 mg/dl or greater than 20% of the total
bilirubin should be considered abnormal. Any elevation of the direct
bilirubin should be repeated within 3 to 7 days to establish a trend
toward either improvement or continued elevation.
++
If the infant has hepatosplenomegaly or ascites pathologic causes
of hyperbilirubinemia are far more likely. Causes of direct hyperbilirubinemia
in the infant are listed in Table 419-3.
++
++
The diagnostic approach to the infant with direct hyperbilirubinemia
varies depending upon the history and clinical presentation. The
perinatal history is important to identify infants at risk for liver
disease. Maternal factors associated with cholestasis in infants
include maternal rubella, hepatitis B, HIV, syphilis, genital herpes
or liver disease; exposures or complications during pregnancy such
as medication or illicit drug use. Polyhydramnios, fever, and a
history of consanguinity are also risk factors. Both acute fatty
liver of pregnancy and the maternal HELLP (hemolysis, elevated liver
tests, and low platelets) syndrome have been shown to be associated
with LCHAD (long-chain 3-hydroxyacyl-CoA dehydrogenase) deficiency in
the infant. Physical examination will determine whether the infant appears “sick” or “well” and
identify whether important features such as a pathologic rash, hepatosplenomegaly,
ascites, excessive bleeding or bruising, or an altered level of consciousness
are present. The most common causes of conjugated hyperbilirubinemia
is sepsis (especially urosepsis with E. coli) and
hypoxia/ischemia. In the otherwise well appearing infant
it is critical to establish whether the disorder is due to a treatable
cause of extrahepatic obstruction. Ultrasound is useful for diagnosis
of choledochal cyst (Chapter 427). Diagnosis
of extrahepatic biliary atresia is critical since early surgical
intervention (before 45 to 60 days of life) improves outcome (Chapter 427). Technitium hepatobiliary scans are used to evaluate
bile duct patency in some centers, however, sensitivity and specificity
are not optimal, and performing the text can delay diagnosis and
therapy. Therefore, in many centers a liver biopsy is performed
if other screening evaluations do not identify an etiology. Liver
biopsy is useful for diagnosis of biliary atresia (bile duct proliferation,
bile plugs and portal fibrosis), metabolic disorders or giant cell
hepatitis, or biliary hypoplasia. Other studies are listed in Table 419-4, being prioritized depending
upon whether the infant appears sick or well. Beyond infancy, jaundice
is much more likely to signal significant liver problems such as
congenital abnormalities of the biliary tract, infections, and inborn
errors of metabolism.
++
+++
Approach to
the Child with Jaundice
++
An isolated elevation of bilirubin without alterations in other
liver enzymes should be considered separately from those disorders
with jaundice with abnormalities of other liver enzymes. In isolated
hyperbilirubinemia, if the direct component is less than 15% an
evaluation for hemolysis should be performed (see Chapter 433). If there is no hemolysis the diagnosis of Gilbert syndrome
is likely (see Chapter 421). If the direct
bilirubin accounts for greater than 15% of the total bilirubin,
a diagnosis of Dubin-Johnson or Rotor's syndrome should be considered.
After the first year of life, jaundice associated with other hepatic
enzyme elevations is likely to have an infectious, autoimmune, or
systemic disease affecting the liver. Table 419-5 lists
those disorders associated with direct hyperbilirubinemia. Tables 419-1 and 419-2 list
disorders commonly associated with biochemical evidence liver disease.
In the patient with jaundice and elevated direct bilirubin it is
essential to assess the severity of the illness. If there is no
antecedent evidence of chronic liver disease, and jaundice is of
rapid onset, urgent evaluation for possible fulminant hepatitis
includes the performance of liver functional tests such as the prothrombin
time, INR, glucose and ammonia levels (see Chapter 424). Similarly, in a patient with liver disease and a rapid
increase in the level of jaundice, assessment of hepatic function
should be assessed. The evaluation based upon the severity of illness
is outlined in Table 419-6. Liver infections
are discussed in more detail in Chapter 237 (see Tables 237-1 and 237-2).
++
++
+++
Evaluation of
Hepatitis in Children
++
Hepatitis is often difficult to recognize in children because
the clinical presentation often is nonspecific and mild, consisting
primarily of a flulike syndrome with fever, malaise, nausea, and
diarrhea. Many children do not develop jaundice, and most will not
manifest other signs, such as ascites and encephalopathy, unless
they progress to end-stage liver failure. In young children, any history
of attending child care should be elicited, including any illnesses
among peers and adult child care workers that may suggest viral hepatitis
exposure. Initial studies in a child with hepatitis should include a
complete blood count with platelet count and a differential, total and fractionated
serum bilirubins, aspartate aminotransferase (AST), alanine aminotransferase
(ALT), gamma-glutamyl-transferase (GGT), and prothrombin time (PT). Slight
elevations of AST and ALT do not always predict mild disease, and
both can fall with end-stage liver failure. The most useful indicator of
hepatic synthetic function is the PT.
++
If the etiology is unknown, serologic tests for viral hepatitis should
be performed including immunoglobulin M (IgM) anti-hepatitis A virus
(HAV), hepatitis B surface antigen (HbsAg), IgM anti-hepatitis B
core (HBc), and anti-hepatitis C virus (HCV). If these tests are
negative, other viral causes including Epstein-Barr virus and cytomegalovirus
can be considered. Symptoms of heart disease, obesity, or endocrine
or muscle disease should be elicited because chronic elevation of
serum transaminases can reflect liver manifestations of systemic
disease (see Chapter 423). A history of exposure
to potentially hepatotoxic medications such as isoniazid, nitrofurantoin, sulfonamides,
and others should be determined. Features or symptoms of autoimmune
disease, inflammatory bowel disease, immunodeficiency, or systemic
illness should be sought. If no cause is identified, the urgency
of further evaluation depends upon the severity and chronicity of
disease.
++
If an elevation of aminotransaminase levels or of other liver
function tests persists for more than 3 months in a child, an aggressive attempt
to define the etiology of liver injury should ensue. In adults a
period of 6 months may be allowed before initiation of an aggressive
evaluation, but in children several of the diseases that cause chronic
hepatitis respond to specific medical therapy, and irreversible
changes may occur over a 6-month period if treatment is not initiated.
Hepatitis A and Epstein-Barr virus do not cause chronic hepatitis.
Chronic hepatitis can be mimicked by primary sclerosing cholangitis,
and patients with chronic hepatitis may present with clinical and
biochemical findings indistinguishable from acute hepatitis
or with ascites or gastrointestinal bleeding from varices.
++
In a child with possible chronic hepatitis, a complete evaluation
includes clinical, biochemical, and histologic assessment as noted above.
Additional laboratory evaluation should include serial monitoring
of serum levels of total and conjugated bilirubin, serum aminotransferases,
alkaline phosphatase, gamma-glutamylpeptidase to assess disease
severity. Measurements of γ-globulin, and a periodic
assessment of liver synthetic capacity by measuring albumin and
prothrombin time is also helpful for monitoring liver function.
Laboratories to evaluate for autoimmune hepatitis (Table
420-1) should be performed if not obtained previously. Histologic
examination of liver tissue is often required to elucidate the cause
of liver disease or to assist in managing the patient because therapy and
prognosis are based on characterization of the histologic lesion rather
than on clinical or biochemical data. Management of chronic hepatitis
varies depending upon the cause and sequelae.
++
Hepatomegaly can be difficult to assess as determination of liver size
is not always a straightforward task owing to its asymmetric shape
and proximity to the rib cage and diaphragm. The liver span most
reliably assesses liver size and is measured as the distance between
the upper and lower margin of liver dullness as determined by abdominal
percussion. The liver span will increase as the child grows older
but should not exceed 10 cm in childhood.
++
Although the liver span is the most precise measure, palpation
of the liver edge is the more conventional method. A liver palpable
2 cm below the right costal margin is considered normal during infancy
and 1 cm below the costal margin is acceptable throughout childhood.
A liver edge palpable below the xiphoid is atypical and may be another
indicator of hepatomegaly. Hepatomegaly can be so massive as to
be missed entirely. It is important to begin the abdominal examination
at or just below the pelvic rim in the right lower quadrant and
carefully advance the examining fingers cephalad to the costal margin. This
maneuver will prevent beginning the examination “on top” of
the liver, thus missing the liver edge. Hepatomegaly that is reported unexpectedly
following a radiological examination (eg, abdominal sonogram, abdominal
flat plate) should be confirmed by careful abdominal examination
before extensive testing is initiated. The presence of a generous
palpable liver edge does not always mean the organ is enlarged. Flattened
diaphragms, as a consequence of pneumonia or bronchial air trapping,
can push the liver downward. Also, a subdiaphragmatic abscess, choledochal
cyst, peritoneal cyst, distended gall bladder, and a renal or adrenal
mass can be mistaken for an enlarged liver. It is important to note that
the absence of other physical signs of liver disease such as jaundice
or splenomegaly should not preclude a proper evaluation of an enlarged liver.
++
The mechanisms of hepatomegaly along with some examples are outlined
in Table 419-7. The approach to the patient
with hepatomegaly must be individualized
to include the physical examination, screening laboratory tests, and
radiographic studies.4 If there is evidence of
hepatocellular injury, then further assessment is necessary. Hepatomegaly in
the absence of aminotransferase abnormalities can occur with liver tumors
(see Chapter 427). A sequential approach to
assess hepatomegaly associated with hepatocellular and/or
bile duct injury is outlined in Table 419-8.
++
++
+++
Isolated Splenomegaly
++
Isolated splenomegaly, while typically associated with an infectious (eg,
Epstein-Barr virus) or oncologic (eg, leukemia, lymphoma) condition,
may also be the only physical finding in a patient with liver disease
(see Chapter 440). Children with cirrhosis
may have a small, non-palpable liver resulting in isolated of splenomegaly
as a consequence of portal hypertension. Cryptogenic cirrhosis, undiagnosed
Alagille syndrome, and sclerosing cholangitis may present in this
manner, and an elevated GGT may be the only biochemical sign of
liver injury.
++
These lesions are the consequence of reflux of biliary phospholipids
into the plasma, which results in an increased plasma cholesterol
concentration in patients with chronic cholestasis. The cholesterol
is transported in blood with lipoprotein X. Cholesterol levels as
high as 2000 mg/dL have been measured in this setting,
which leads to its deposition in skin, mucous membranes, and arteries.
There is no generally accepted treatment regimen for lowering cholesterol
in patients with cholestatic diseases.