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University of California, San Francisco Medical Center, 500 Parnassus Ave., MU 4-East, Box 0136, San Francisco, CA 94143-0136. Fax 415-476-1343; e-mail prosenth{at}peds.ucsf.edu
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Abstract |
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 Top Abstract Tests of Hepatic Synthetic...Tests of Hepatic IntegrityTests of CholestasisHyperbilirubinemiaReferences |
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Key Words: indexing terms: hepatic synthesis • coagulation • cholestasis
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Tests of Hepatic Synthetic Function |
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TopAbstractTests of Hepatic Synthetic...Tests of Hepatic IntegrityTests of CholestasisHyperbilirubinemiaReferences |
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Little data is available regarding reference ranges for serum albumin
concentrations in preterm and term infants (1)(2)(3)(4)(5) (See
Table 1
). In general, postnatal albumin concentrations follow the
gestational trend and increase with gestational age. Acute-phase
proteins may react as albumin, causing false increases in some assays.
Method interferences include hemolysis, icterus, lipemia, and
turbidity, and such affected specimens may need to be corrected for
with a blank.
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Serum albumin concentrations <20 g/L may be associated with the development of clinically apparent edema or ascites. Because serum albumin concentrations do not change acutely in chronic liver disease, they may be monitored weekly unless an acute change in gastrointestinal or renal losses or edema or ascites occurs. Serum albumin measurements should be available throughout the day with a turnaround time of 8 h.
coagulation factors
A rapid test of liver synthetic ability involves the one-stage
prothrombin time (PT) test
(6)(7).1
Vitamin K-dependent clotting factors have
relatively short half-lives and are synthesized by hepatocytes.
Determination of the PT before and after parental administration of
vitamin K has been widely utilized to distinguish abnormal absorption
of vitamin K resulting from poor fat-soluble vitamin absorption from
true liver-cell dysfunction. The PT is a measure of the time it takes
for prothrombin (factor II) to be converted into thrombin in the
presence of tissue extract (thromboplastin), calcium, and activated
clotting factors I, II, V, VII, and X. This reaction is a measure of
the extrinsic pathway of coagulation and is prolonged (>2 s above
control) when factors I, II, V, VII, or X are deficient alone or in
combination.
The partial thromboplastin time (PTT) measures the generation of thrombin by the intrinsic pathway involving all coagulation factors, including IX and VIII and excluding factor VII. All the factors except factor VIII are synthesized in the liver, so an increased PTT with normal factor VIII concentrations suggests hepatic dysfunction.
Caution must be exercised in attributing prolonged PT or PTT in liver patients to only hepatic disease because vitamin K deficiency or disseminated intravascular coagulation (DIC) as seen in sepsis can also prolong these values. A prolonged PTT with low factor VIII concentrations may suggest consumption of clotting factors (DIC) because factor VIII is not synthesized in the liver.
PT and PTT are generally prolonged in the healthy premature infant as
compared with the older child or adult, and reference values have been
published (8)(9)(10) (see Table 1
). PT and PTT should be
available 24 h daily with a turnaround time of <4 h. Specimens
should preferably be drawn by a clean venipuncture to avoid tissue
thromboplastin contamination. Because the PT and PTT measurements are
sensitive to the plasma-to-citrate anticoagulant ratio, adjustment
should be made in the ratio of blood to the citrate anticoagulant in
the specimen tube for hematocrits >50% or <20%. A 5-mL blue-top
tube often used for PT and PTT specimens contains 0.5 mL of 32 g/L
sodium citrate. Special care should be taken for specimens drawn from a
line flushed with heparin, as heparin can alter the PTT.
ammonia
The majority of ammonia clearance occurs in the liver via the urea
cycle. Details of ammonia metabolism are beyond the scope of this
article, and may be obtained in standard texts (11). In a
single pass, 80% of ammonia is removed from the portal vein by the
liver. In chronic liver disease, shunting and altered hepatic function
allow ammonia to bypass the liver and reach the central nervous system.
A rising plasma ammonia concentration may precede the onset of hepatic
encephalopathy. Unfortunately, the stage of hepatic encephalopathy and
the concentration of plasma ammonia have a poor correlation
(12). I have found that the trend of rising plasma ammonia
concentrations may represent a better indicator of impending hepatic
encephalopathy than a single measurement alone. Ammonia may also be
increased in patients with inherited defects of the urea cycle, Reye
syndrome, defects in mitochondrial fatty acid ß-oxidation,
porto-systemic shunts of either congenital or surgical origin, or in
patients with chronic liver disease who have increased protein loads to
the intestine from diet or gastrointestinal bleeding.
The most critical aspect of plasma ammonia testing is the collection
and transport of the specimen. Arterial or venous blood can be used.
The heparinized blood sample should be placed in an ice–water mixture
immediately to stabilize samples and minimize erythrocyte conversion of
glutamine to ammonia. Blood ammonia will increase at ~17 µg/L per
min at 25 °C (13). Samples should be transported to the
laboratory as rapidly as a blood-gas sample, and the plasma separated
immediately. The separated plasma may be stored at 4–8 °C until
analysis. The plasma should be frozen if there will be any significant
(>1 h) delay in measurement. Reference ranges have been published for
infants and children (13)(14) (see Table 1
). Ammonia determinations should be available on a stat basis daily,
with a rapid turnaround time because the test should ideally be
performed within 20 min of sample collection.
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Tests of Hepatic Integrity |
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TopAbstractTests of Hepatic Synthetic...Tests of Hepatic IntegrityTests of CholestasisHyperbilirubinemiaReferences |
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Reference ranges have been reported for infants and children
(21)(22) (see Table 1
). Many automated methods
are available for the measurement of these enzymes, and reference
ranges for the population and instrument utilized should be acquired
ideally by each institution. Pyridoxal phosphate is the coenzyme for
both AST and ALT. In situations in which vitamin B6
(pyridoxine) is deficient, such as a population with a significant
proportion of neonates, low concentrations, especially for ALT, may
occur because enzyme activity is used in the assay as the basis for
measurement (23). These assay reagents contain pyridoxal
phosphate. One may wish to check the assay used at each laboratory. Low
serum concentrations of AST may also occur with uremia
(24)(25). Transaminases should be available
once each day with a turnaround time of 8 h.
lactate dehydrogenase
The dehydrogenases that catalyze oxidation–reduction reactions
may also be utilized to assess hepatic injury. Lactic dehydrogenase
(LDH) is most commonly measured. LDH exists in five isoenzymes distinct
for different tissues. Liver-specific LDH (LD5) may be
useful in helping to discriminate hepatic disease. Increases in LDH may
be observed with myocardial infarction, liver disease, neoplasia,
infectious mononucleosis, hypothyroidism, lung disease, central nervous
system disease, infections, inflammation, hemolytic anemia, muscle
damage and dystrophy, and collagen disease. Hemolysis falsely increases
LDH results, and lipemia may interfere. Reference ranges have been
reported in premature infants and children
(26)(27). Blood should be collected by
venipuncture because tissue concentrations of LDH are 500-fold higher
than whole-blood values. This test has limited usefulness because of
its nonspecificity, and its routine use is not recommended.
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Tests of Cholestasis |
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TopAbstractTests of Hepatic Synthetic...Tests of Hepatic IntegrityTests of CholestasisHyperbilirubinemiaReferences |
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GT)
value may be useful in such a case.
Alkaline phosphatase reference ranges have been reported for infants
and children (28)(29)(30)(31) (see Table 1
). At 1 month, alkaline
phosphatase values may be 5–6 times higher than adult normal values.
Alkaline phosphatase concentrations decrease slowly until puberty where
they may be 3–4 times higher than adult values. Alkaline phosphatase
values reach adult values between ages 16–20 years. Determination of
fractionated alkaline phosphatase and heat-stable or heat-labile
alkaline phosphatase may be helpful in determining if increased
alkaline phosphatase concentrations are of hepatic or osseous origin.
These assays have not found a place in neonatology. Routine alkaline
phosphatase testing should be available daily with an 8-h turnaround
time.
Specimens should be collected in red-top tubes; EDTA tubes should be avoided, as EDTA can complex the magnesium and zinc required to catalyze the enzyme reaction, greatly decreasing test results.
gt
GT is a sensitive but not a specific indicator of hepatic
disease. This enzyme is present in intra- and extrahepatic bile
ductular cells and in hepatocytes. It may also be found in renal
tubules, the pancreas, spleen, brain, breast, and small intestine.
GT does not rise with bone disease or active growth as occurs with
alkaline phosphatase, making GT a useful test when alkaline
phosphatase is increased and its origin is unclear (32).
GT is frequently increased in acute hepatitis and also in
cholestasis (33). Because it is a highly sensitive test,
it may remain increased even during convalescence from liver injury.
Serum GT may also rise after initiation of certain drugs (i.e.,
phenobarbital) that induce microsomal enzyme synthesis
(34)(35). Newborns may have very high serum
GT, up to 5–8 times the upper limit of normal for adults, that
rapidly declines to adult concentrations by age 6 months
(3)(36)(37)(38)(39) (see Table 1
). Premature infants
may have even higher GT values than full-term infants during the
first several days after birth. Immaturity has been proposed as the
cause of the high GT concentrations observed in newborns.
GT should be available, as a nonprofile test, once each day, with an
8-h turnaround time. Gross hemolysis may invalidate the value obtained
and such specimens should be discarded.
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Hyperbilirubinemia |
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TopAbstractTests of Hepatic Synthetic...Tests of Hepatic IntegrityTests of CholestasisHyperbilirubinemiaReferences |
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Evaluation of the clinically jaundiced infant should proceed in a rapid cost-effective and efficient manner (45)(46). Maternal prenatal testing of ABO and Rh(D) typing and a serum screen for unusual isoimmune antibodies should be reviewed if available. If this has not been performed, is not available, or if the mother is Rh-negative, then a direct Coombs test, blood type, and Rh(D) type on the infant are indicated, ideally from cord blood. Cord blood should be saved if at all possible on all infants and certainly if the mother is blood group O. This will allow for testing if required so that blood drawing can be kept to a minimum in the infant. If family history, ethnicity, or geography suggest the possibility of glucose-6-phosphate dehydrogenase deficiency or other hemolytic condition, appropriate laboratory confirmation is indicated. All infants visibly jaundiced within the first 24 h of birth should have a total serum bilirubin concentration obtained. Jaundice may be detected by blanching or pushing down on the skin. Icterus progresses from head to toe in a caudal distribution so that the progression of cephalocaudal jaundice may be helpful in quantifying the degree of jaundice. The use of an icterometer or jaundice meter may be helpful but is not mandatory (47). All infants with feeding difficulty, behavioral fluctuations, apnea, or temperature instability with or without jaundice must be evaluated for the possibility of underlying illness. Mandatory follow-up within 2–3 days by a trained healthcare professional should be provided to all newborns discharged home <48 h after birth. Approximately one-third of healthy breast-fed babies will have persistent jaundice after age 2 weeks (48). However, dark urine or light-colored (acholic, chalky, white) stools mandates quantification of conjugated (or direct-reacting bilirubin by diazo methods) bilirubins. Caution must be exercised when utilizing diazo methods because many diazo methods measure direct bilirubin even when it is not present (49). If jaundice persists beyond age 3 weeks, measurement of total and direct-reacting bilirubin is mandatory to distinguish pathologic conditions that cause conjugated hyperbilirubinemias, usually resulting from obstruction or cholestasis (i.e., biliary atresia), from unconjugated hyperbilirubinemias.
Bilirubin measurements are susceptible to interference from hemolysis and lipemia. This is particularly problematic in the newborn, in whom blood acquisition may require a heelstick, resulting in hemolyzed specimens. Sunlight and ultraviolet light can lower bilirubin values in specimens left standing unprotected from light, especially in the nursery setting where phototherapy is routinely being utilized, so care must be taken to wrap specimens in aluminum foil or utilize amber-colored tubes for collection. Lipemia may cause significant increases in the bilirubin result, especially with direct spectrophotometric methods. Specimen blanking or use of the Jendrassik–Graf method may be utilized to diminish the effect of lipemia on bilirubin measurements. Calibrators for bilirubin glucuronide conjugates do not exist and surrogate calibrators (such as ditaurobilirubin) for direct-reacting bilirubin methods must be used. Bilirubin must be capable of being measured over a large range: <17.1–513 µmol/L (<1–30 mg/dL). Further, precise measurement of bilirubin becomes critical not only to discriminate normal from abnormal values, but to decide whether there is need for therapeutic intervention (50). Because critical therapeutic decisions may depend on the result, accurate results with a rapid turnaround time (usually <1 h but dependent on each clinical site and situation) must be available for total bilirubin concentration measurement.
Analytical sample volumes of 
10 µL are strongly recommended. This
recommendation may obviate the use of "bilirubinometers," which
tend to use larger sample volumes for measurement of total bilirubin.
Measurement of bilirubin–protein conjugates (delta bilirubin) has been investigated in children (51)(52)(53)(54). Because most newborns have unconjugated hyperbilirubinemia, the clinical need for delta bilirubin measurements in the nursery is nonexistent. Thus, measurement of delta bilirubin is not recommended for neonates or adults because of no known diagnostic value.
Treatment of unconjugated hyperbilirubinemia in the newborn is based on
history, clinical course, and physical examination
(45)(46)(55)(56)(57)(58)(59)(60)(61). Of course, the
benefits of any intervention must outweigh the risks. Because severe
unconjugated hyperbilirubinemia is associated with bilirubin
encephalopathy and kernicterus, timely decisions must be made.
Treatment recommendations are based upon the age of the newborn and the
total serum bilirubin concentration (44)(61)
(see Table 1
).
In an infant <24 h old, any jaundice is considered pathologic and requires evaluation. This evaluation should minimally include a serum bilirubin (preferably fractionated) and a workup for hemolytic disease. Phototherapy or exchange transfusion should be considered for any infant with a rapidly rising bilirubin concentration within the first 24 h of life.
Guidelines for therapy (44)(61) depend on the
serum concentrations of bilirubin and the patient's age. For full-term
infants 25–48 h of age, phototherapy usually is considered if the
total serum bilirubin concentration is 
170 µmol/L (12 mg/dL) and is
likely to be instituted if the total serum bilirubin is 260 µmol/L
(15 mg/dL). If phototherapy fails to lower a total serum bilirubin
concentration of 340 µmol/L (20 mg/dL), exchange transfusion is
considered. If the total serum bilirubin concentration rises to 430
µmol/L (25 mg/dL) when the full-term infant is first seen, intensive
phototherapy is usually begun while exchange transfusion preparations
are made. If phototherapy does not lower the bilirubin, exchange
transfusion proceeds. A high bilirubin in a full-term infant age 25–48
h suggests pathology and warrants investigation of the cause.
For full-term infants 49–72 h of age, phototherapy is usually
considered (44)(61) if the total serum
bilirubin concentration is 260 µmol/L (15 mg/dL). Phototherapy is
seriously entertained if the total serum bilirubin concentration is
310 µmol/L (18 mg/dL). If phototherapy does not keep the serum
total bilirubin <430 µmol/L (25 mg/dL), exchange transfusion is
usually considered. If the total serum bilirubin concentration is 510
µmol/L (30 mg/dL) when the full-term infant first presents, intensive
phototherapy is usually begun while exchange transfusion preparations
are made. If the total serum bilirubin concentration does not diminish
with phototherapy, exchange transfusion is usually performed.
For full-term infants >72 h old, phototherapy is usually considered if
the total serum bilirubin is 290 µmol/L (17 mg/dL). Phototherapy is
often utilized if the total serum bilirubin concentration is 340
µmol/L (20 mg/dL). If intensive phototherapy does not lower a total
serum bilirubin concentration 430 µmol/L (25 mg/dL), an exchange
transfusion is usually warranted. If the total serum bilirubin
concentration is >510 µmol/L (30 mg/dL), intensive phototherapy is
usually begun during preparations for an exchange transfusion. If
phototherapy fails to lower the serum bilirubin concentration, an
exchange transfusion is usually performed.
Although breast-feeding should be encouraged in full-term healthy newborns, persistent jaundice may demand consideration of supplementation of breast-feeding with formula or temporary discontinuation of breast-feeding.
Phototherapy can usually be safely discontinued in the full-term healthy newborn when the total serum bilirubin concentration falls below 239–257 µmol/L (14–15 mg/dL). Rebound after phototherapy discontinuation is usually <17.1 µmol/L (1 mg/dL).
Critical clinical decisions are based on accurate total bilirubin measurements. The laboratory must be capable of accurate total bilirubin measurements at critical bilirubin concentrations of 205 µmol/L (12 mg/dL), 257 µmol/L (15 mg/dL), 308 µmol/L (18 mg/dL), 342 µmol/L (20 mg/dL), 428 µmol/L (25 mg/dL), and 513 µmol/L (30 mg/dL). Precision of ±5% to detect changes in response to therapy is imperative at the above total bilirubin concentrations. Routine calibrators and proficiency testing samples in the laboratory usually contain bilirubin in concentrations of 21–81 µmol/L (1.2–4.7 mg/dL), well below the range required for neonatal specimens. Laboratories must strive to become proficient in measuring bilirubins in the neonatal range so that clinicians caring for newborns may make clinical decisions on the basis of accurate bilirubin determinations.
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Footnotes |
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GT, gamma glutamyltransferase. 
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References |
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TopAbstractTests of Hepatic Synthetic...Tests of Hepatic IntegrityTests of CholestasisHyperbilirubinemiaReferences |
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The following articles in journals at HighWire Press have cited this article:
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  P. D. Booker, S. Gibbons, J. I. M. Stewart, A. Selby, E. Wilson-Smith, and M. Pozzi Enoximone pharmacokinetics in infants Br. J. Anaesth., August 1, 2000; 85(2): 205 - 210. [Abstract] [Full Text] [PDF]
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 Laboratory Evaluation of Hepatitis Pediatr. Rev., May 1, 2000; 21(5): 178 - 178. [Full Text]
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