ISOLATED ELEVATION OF THE ALKALINE PHOSPHATASE AND/OR

GAMMA GLUTAMYL TRANSPEPTIDASE

- Serum alkaline phosphatase is derived
o predominantly from the liver and bones.
- although other sources may contribute to serum levels in some settings.
o Women in the third trimester of pregnancy, for example, have elevated
serum alkaline phosphatase due to an influx into blood of placental
alkaline phosphatase.
o Individuals with blood types O and B can have elevated serum alkaline
phosphatase after eating a fatty meal due to an influx of intestinal
alkaline phosphatase.
o Infants and toddlers occasionally display transient marked elevations of
alkaline phosphatase in the absence of detectable bone or liver disease.
o There are also reports of a benign familial occurrence of elevated serum
alkaline phosphatase due to intestinal alkaline phosphatase. (See
"Enzymatic measures of cholestasis (eg, alkaline phosphatase, 5nucleotidase, gamma-glutamyl transpeptidase)" and "Transient
hyperphosphatasemia of infancy and early childhood".)
- Alkaline phosphatase levels also vary with age.
o Alkaline phosphatase levels are generally higher in children and
adolescents because of physiological osteoblastic activity. Levels may be
up to three times higher than in healthy adults, with maximum levels in
infancy and adolescence, coinciding with periods of maximum bone
growth velocity
(figure 1).
Normal ranges for
serum alkaline
phosphatase activity
for boys (blue) and
girls (red).
o Also, the normal
serum alkaline

phosphatase gradually increases from age 40 to 65, particularly in

women.
o The normal alkaline phosphatase for an otherwise healthy 65-year-old
woman is more than 50 percent higher than a healthy 30-year-old
woman.
Determining the source of the alkaline phosphatase
- The first step in the evaluation of an elevated alkaline phosphatase is to
identify its source.
- Although electrophoretic separation on either polyacrylamide gel or
Sepharose is the most sensitive and specific way to do this, these tests are
not widely available.
- If gel electrophoresis is not available, either a 5'-nucleotidase or GGT
should be obtained.
o These tests are usually elevated in parallel with the alkaline phosphatase
in liver disorders but are not increased in bone disorders.
o An elevated serum alkaline phosphatase with a normal 5'-nucleotidase or
GGT should prompt an evaluation for bone diseases (algorithm 2).
Initial testing for alkaline phosphatase of hepatic origin
- Chronic cholestatic or infiltrative liver diseases should be considered in
patients in whom the alkaline phosphatase is determined to be of liver
origin and persists over time.
- The most common causes include
o Chronic cholestatic
partial bile duct obstruction,
primary biliary cirrhosis (PBC),
primary sclerosing cholangitis,
adult bile ductopenia,
and certain drugs such as androgenic steroids and phenytoin.
o Infiltrative diseases include
sarcoidosis,
other granulomatous diseases,
and less often unsuspected cancer metastatic to the liver.
- Initial testing should include a

o right upper quadrant ultrasound (which can assess the hepatic

parenchyma and bile ducts) The presence of biliary dilatation suggests
obstruction of the biliary tree.
In patients with biliary dilatation or choledocholithiasis
cholangiography (either MRCP or ERCP depending upon the clinical
setting and degree of suspicion for a stone) should be done to identify
the cause of obstruction and to allow for an intervention such as stone
removal or stent placement

o and an antimitochondrial antibody (AMA), which is highly suggestive

of PBC (algorithm 2).. Patients with a positive AMA should have a liver

biopsy to verify the diagnosis of PBC.

- Patients in whom initial testing is unrevealing

o We suggest if ANA and/or US are ve and the alkaline phosphatase is
persistently more than 50 percent above normal for more than six
months. a liver biopsy and either an ERCP or (MRCP)
o If the alkaline phosphatase is less than 50 percent above normal, all of
the other liver tests are normal, and the patient is asymptomatic, we
suggest observation alone since further testing is unlikely to influence
management [39].
Gamma glutamyl transpeptidase
- Gamma glutamyl transpeptidase (GGT) is found in hepatocytes and
biliary epithelial cells.
- In normal full-term neonates, serum GGT activity is six to seven times the
upper limit of the adult reference range; levels decline and reach adult
levels by 5 to 7 months of age [40].
- GGT is sensitive for detecting hepatobiliary disease, but its usefulness is
limited by its lack of specificity.
- Elevated levels of serum GGT have been reported in a wide variety of
clinical conditions, including
o pancreatic disease,
myocardial infarction,
o renal failure,
chronic obstructive pulmonary disease,
o diabetes,
and alcoholism.
o High serum GGT values are also found in patients taking medications
such as phenytoin and barbiturates
- Some authorities have advocated using the GGT to identify patients with
occult alcohol use. The reported sensitivity of an elevated GGT for
detecting alcohol ingestion has ranged from 52 to 94 percent [22,41]. Its
lack of specificity makes its use for this purpose questionable.
- A population-based study found that men with increased GGT levels who
also had a hyperechogenic liver by ultrasound (suggesting the presence
of steatosis) has increased all-cause mortality rates but more data are
needed [42].
- We suggest GGT be used to evaluate elevations of other serum enzyme
tests (eg, to confirm the liver origin of an elevated alkaline phosphatase or
to support a suspicion of alcohol abuse in a patient with an elevated AST
and an AST:ALT ratio of greater than 2:1). An elevated GGT with

otherwise normal liver tests should not lead to an exhaustive work-up for
liver disease.
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