Schematic Approach to the Diagnosis of Neonatal Jaundice

EVALUATION OF LIVER FUNCTION

Test based on Detoxification and Excretory Functions
Serum Bilirubin
Breakdown product of the porphyrin ring of heme containing proteins
Found in the blood in two fractions (conjugated and unconjugated)
The unconjugated (indirect fraction) is insoluble in water and is bound to albumin in the
blood
The conjugated (direct) bilirubin fraction is water soluble and can excreted by the kidney
Normal values of total serum bilirubin: 1-1.5 mg/dL with 95% of a normal population
falling between 0.2-09 mg/dL (Van den Bergh Method)
Elevation of the unconjugated fraction of bilirubin is rarely due to liver disease
Isolated elevation of unconjugated bilirubin seen primarily in hemolytic disorders and in
genetic conditions (Crigler-Najjar and Gilberts syndrome)
Conjugated hyperbilirubinemia almost always implies liver or biliary tract disease
The rate limiting step is not conjugation of bilirubin but rather the transport of
conjugated bilirubin into the bile canaliculi
In mostl iver diseases, both conjugated and unconjugated fractions of the bilirubin tend
to be elevated
In viral hepatitis, the higher the serum bilirubin, the greater the hepatocellular damage
Total serum bilirubin correlates with poor outcomes in alcoholic hepatitis
Elevated total serum bilirubin in patients with drug induced liver disease indicates more
severe injury

Urine Bilirubin
Unconjugated bilirubin always binds to albumin an not filtered by the kidney
The presence of bilirubinuria implies the presence of liver disease
Urine dipstick test can theoretically give the same information as fractionation of the
serum bilirubin
Almost 100% accurate
Blood Ammonia
Produced in the body during normal protein metabolism and by intestinal bacteria,
primarily in the colon
Liver plays role in the detoxification of ammonia by converting it to urea which is ecxreted
by the kidneys
Patients with advanced liver disease typically have significant muscle wasting ->
contribution to hyperammonemia
Can be occasionally useful for identifying occult liver disease in patients with mental
status change

Serum Enzymes
Serum enzymes can be grouped to 3 categories:
1. Enzymes whose elevation in serum reflects damage to hepatocytes
2. Enzymes whose elevation in serum reflects cholestasis
3. Enzyme tests that do not fit precisely into either pattern

Enzymes that Reflect Damage to Hepatocytes
The Aminotransferase (AST)
Sensitive indicators of liver cell injury
Most helpful in recognizing acute hepatocellular diseases such as hepatitis
Found in liver, cardiac muscle, skeletal muscle, kidneys, brain, pancreas, lungs, leukocytes
and erythrocytes in decreasing order of concentration
Normally present in the serum in low concentrations
Absolute elevation of the aminotransferases is of no prognostic significance in acute
hepatocellular disorders
Normal range for aminotransferases ranges from 10-40 U/L
Alanine aminotransferase (ALT)
Found primarily in the liver
More specific indicator of liver injury
Most marked rises of both AST and ALT levels may occur with acute hepatocellular injury;
several thousand fold elevation can result from acute viral hepatitis, toxic injury, hypoxia,
or hypoperfusion
In acute hepatitis, the rise in ALT may be greater than the rise in AST
In most acute hepatocellular disorders, ALT is higher than or equal to the AST

Enzymes that Reflect Cholestasis
Serum Alkaline Phosphatase , 5nucleotidase (5NT) and -glutamyl transpeptidase (GGT)
usually elevated in cholestasis
Alkaline Phosphatase , 5nucleotidase (5NT)are found in or near the bile canalicular membrane
of hepatocytes
GGT is located in the endoplasmic reticulum and in bile duct epithelial cells
GGT elevation in serum is less specific for cholestasis than AP or 5-nucleotidase
GGT- to identify patients with occult alcohol use
AP elevations greater than four times normal occur in patients with cholestatic liver disorders,
infiltrative diseases such as cancer and amyloidosis, and bone conditions characterized by rapid
bone turnover (e.g paget dse)
In liver diseases, the elevations almost always due to increased amounts on liver isoenzymes
Level of serum AP is not helpful in distinguishing between intrahepatic and extrahepatic
cholestasis

Test that Measure Biosynthetic Function of the Liver
SERUM ALBUMIN
Synthesized exclusively by hepatocytes
Serum albumin has a long half life: 18-20 days with 4% degraded per day
Not a good indicator of acute or mild hepatic dysfunction
In hepatitis, albumin levels <3 g/dL should raise the possibility of chronic liver disease
Hypoalbuminemia is more common in chronic liver disorders such as cirrhosis; usually reflects
severe liver damage and decreased albumin synthesis

SERUM GLOBULIN
Group of proteins made up of globulins (immunoglobulins) produced by B lymphocytes and
and globulins produced primarily in hepatocytes
globulins are increased in chronic liver disease ( chronic hepatitis and cirrhosis)
Increases in the concentration of specific isotypes of globulins: helpful in the recognition of
certain chronic liver disease
Increases in the IgM levels are common in primary biliary cirrhosis
Increases in the IgA levels occur in alcoholic liver disease

COAGULATION FACTORS
Measurement of the clotting factors is the single best acute measure of hepatic synthetic
function and helpful in both the diagnosis and assessing the prognosis of acute parenchymal
disease
Useful for this purpose is the serum prothrombin time collectively measures factors II, V, VII,
and X
Biosynthesis of factors II, VII, IX, and X depends on vitamin K
The international normalized ratio (INR) used to express the degree of anticoagulation on
warfarin therapy
Prothrombin time may be elevated in hepatitis and cirrhosis as well as in disorders that lead to
vitamin K deficiency such as obstructive jaundice or fat malabsorption of any kind
Marked prolongation of PT, >5s above control and not corrected by parenteral vitamin K
administration is a poor prognostic sign in acute viral hepatitis and other acute chronic liver
diseases

OTHER DIAGNOSTIC TESTS
PERCUTANEOUS LIVER BIOPSY
Proven value in the following situations
1. Hepatocellular disease of uncertain cause
2. Prolonged hepatitis with the possibility of chronic active hepatitis
3. Unexplained hepatomegaly
4. Unexplained splenomegaly
5. Hepatic filling defects by radiologic imaging
6. Fever of unknown origin
7. Staging of malignant lymphoma
Most accurate in disorders causing diffuse changes throughout the liver and is subject to
sampling error in focal infiltrative disorders such as hepatic metastases
Should not be initial procedure in the diagnosis of cholestasis
Biliary tree should first be assessed for signs of obstruction
Contraindications to performing a percutaneous liver biopsy include significant ascites and
prolonged INR
HEPATIC IMAGING PROCEDURES
Plain roentgenographic
1. Suggest hepatomegaly.
2. The liver may appear less dense than normal in patients with fatty infiltration or more
dense with deposition of heavy metals such as iron
3. Hepatic or biliary tract mass may displace an air filled loop bowel
4. Calcifications may be evident in the liver(parasitic/neoplastic disease), in the vasculature
(portal vein thrombosis), or in the gallbladder or biliary tree (gallstones)
5. Collections of gas may be seen within the liver (abscess), biliary tract, or portal circulation
(necrotizing enterocolitis)
Ultrasonography (US)
Provides information about the size, composition, and blood flow of the liver
Increased echogenicity is observed with fatty infiltration, mass lesions as small as 1-2 cm
may be shown
US has replaced cholangiography in detecting stones in gallbladder or biliary tree
In neonates, US can assess gallbladder size, detect dilatation of the biliary tract, and
define a choledochalcyst
In infants with biliary atresia, US findings may include small or absent gallbladder,
nonvisualization of the common duct, and presence of the triangular cord sign, a
triangular/tubular shaped echogenic density in the bifurcation of the portal vein,
representing fibrous remnants at the porta hepatis
In patient with portal HPN, Doppler US can evaluate patency of the portal vein,
demonstrate collateral circulation, and assess size of spleen and amount of ascites
The use of Doppler US has been helpful in determining vascular patency after liver
transplantation
CT-scan
Provides information similar to that obtained by US but is less suitable for use in patients
<2 year of age because of the small size of structures, the paucity of intra-abdominal fat
for contrast and the need for heavy sedation or general anesthesia
CT scan also reveal subtle differences in density of liver parenchyma, the average liver
attenuation coefficient being reduced with fatty infiltration
MRI
Useful alternative. Magnetic resonance cholangiography can be of value in differentiating
billiary tract lesions.
When hepatic tumor is suspected, CT scanning is the best method to define anatomic
extent, solid or cystic nature, and vascularity
In differentiating obstructive from non obstructive cholestasis, CT scanning or MRi
identifies the precise level of obstruction more frequently than US
Radionuclide scanning
Relies on selective uptake of a radiopharmaceutical agent
Commonly used agents include: technetium 99m-labeled sulfur colloid, which undergoes
phagocytosis by Kupffer cells; 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 anatomic resolution possible with hepatic scintiscans is generally less than obtained
with CT scanning, MRI or US
Cholangiography
Direct visualization of the intrahepatic and extrahepatic biliary tree after injection of
opaque material
Maybe 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
Percutaneous transhepatic cholangiography has been used to outline the biliary ductal
system
Endoscopic retrograde cholangiopancreatography (ERCP)
Alternative method of examining the bile ducts in older children
The papilla of vater is cannulated under direct vision through a fiberoptic endoscope, and
contrast material is injected into the biliary and pancreatic ducts to outline the anatomy
Selective angiography of the celiac, superior mesenteric, or hepatic artery can be used to
visualize the hepatic or portal circulation
Both arterial and venous circulatory systems of the liver can be examined
Angiography is frequently required to define the blood supply of tumors before surgery
and is useful in the study of patients with known or presumed portal hypertension
The patency of the portal system, the extent of collateral circulation, and the caliber of
vessels under consideration for a shunting procedure can be evaluated
MRI can provide similar information

TREATMENT OF HYPERBILIRUBINEMIA

The goal therapy is to prevent indirect reacting bilirubin related neurotoxicity while not causing
undo harm
Phototherapy
Clinical jaundice and indirect hyperbilirubinemia are reduced by exposure to a high
intensity of light in the visible spectrum
Exchange transfusion
Remain the primary treatment modalities
Used to keep the maximal total serum bilirubin below the pathologic levels
Intravenous Immunoglobulin
Adjunctive treatment due to isoimmune hemilytic disease
Recommended when serum bilirubin is approaching exhange levels despite maximal
interventions including phototherapy
Reduce the need for exchange transfusion in both ABO and Rh hemolytic disease,
presumably by reducing hemolysis
Metalloporphyrins
Potentially important alternative therapy for hyperbilirubinemia
Proposed mechanism of action is by competitive enzymatic inhibition of the rate limiting
conversion of heme-protein to biliverdin by heme-oxygenase