Jaundice, or icterus, is a yellowish discoloration of tissue resulting

from the deposition of bilirubin. Tissue deposition of bilirubin occurs

only in the presence of serum hyperbilirubinemia and is a sign of

either liver disease or, less often, a hemolytic disorder. The degree of

serum bilirubin elevation can be estimated by physical examination.

Slight increases in serum bilirubin are best detected by examining

the sclerae, which have a particular affinity for bilirubin due to their

high elastin content. The presence of scleral icterus indicates a serum

bilirubin of at least 51 μmol/L (3 mg/dL). The ability to detect scleral

icterus is made more difficult if the examining room has fluorescent

lighting. If the examiner suspects scleral icterus, a second place to

examine is underneath the tongue. As serum bilirubin levels rise, the

skin will eventually become yellow in light-skinned patients and even

green if the process is long-standing; the green color is produced by

oxidation of bilirubin to biliverdin.

The differential diagnosis for yellowing of the skin is limited. In

addition to jaundice, it includes carotenoderma, the use of the drug

quinacrine, and excessive exposure to phenols. Carotenoderma is

the yellow color imparted to the skin by the presence of carotene; it

occurs in healthy individuals who ingest excessive amounts of vegetables

and fruits that contain carotene, such as carrots, leafy vegetables,

squash, peaches, and oranges. Unlike jaundice, where the

yellow coloration of the skin is uniformly distributed over the body,

in carotenoderma, the pigment is concentrated on the palms, soles,

forehead, and nasolabial folds. Carotenoderma can be distinguished

from jaundice by the sparing of the sclerae. Quinacrine causes a

yellow discoloration of the skin in 4–37% of patients treated with it.

Unlike carotene, quinacrine can cause discoloration of the sclerae.

Another sensitive indicator of increased serum bilirubin is darkening

of the urine, which is due to the renal excretion of conjugated

bilirubin. Patients often describe their urine as tea- or cola-colored.

Bilirubinuria indicates an elevation of the direct serum bilirubin

fraction and, therefore, the presence of liver disease.

Increased serum bilirubin levels occur when an imbalance exists

between bilirubin production and clearance. A logical evaluation of

the patient who is jaundiced requires an understanding of bilirubin

production and metabolism.

MEASUREMENT OF SERUM BILIRUBIN

The terms direct and indirect bilirubin, conjugated and unconjugated

bilirubin, respectively, are based on the original van den

Bergh reaction. This assay, or a variation of it, is still used in most

clinical chemistry laboratories to determine the serum bilirubin

level. In this assay, bilirubin is exposed to diazotized sulfanilic acid,

splitting into two relatively stable dipyrrylmethene azopigments

that absorb maximally at 540 nm, allowing for photometric analysis.

The direct fraction is that which reacts with diazotized sulfanilic

acid in the absence of an accelerator substance such as alcohol. The

direct fraction provides an approximate determination of the conjugated

bilirubin in serum. The total serum bilirubin is the amount

that reacts after the addition of alcohol. The indirect fraction is the

difference between the total and the direct bilirubin and provides an

estimate of the unconjugated bilirubin in serum.

With the van den Bergh method, the normal serum bilirubin

concentration usually is 17 μmol/L (<1 mg/dL). Up to 30%, or 5.1

μmol/L (0.3 mg/dL), of the total may be direct-reacting (conjugated)

bilirubin. Total serum bilirubin concentrations are between 3.4 and

15.4 μmol/L (0.2 and 0.9 mg/dL) in 95% of a normal population

MEASUREMENT OF URINE

BILIRUBIN

Unconjugated bilirubin is always

bound to albumin in the serum, is

not filtered by the kidney, and is

not found in the urine. Conjugated

bilirubin is filtered at the glomerulus

and the majority is reabsorbed by the

proximal tubules; a small fraction is

excreted in the urine. Any bilirubin

found in the urine is conjugated bilirubin.

The presence of bilirubinuria

implies the presence of liver disease.

A urine dipstick test (Ictotest) gives

the same information as fractionation

of the serum bilirubin. This

test is very accurate. A false-negative

test is possible in patients with prolonged

cholestasis due to the predominance

of conjugated bilirubin

covalently bound to albumin