Download Alkaline Phosphatase (ALP)

Alkaline Phosphatase (ALP)
Alkaline phosphatase refers to a family of enzymes that catalyze hydrolysis of phosphate esters
at an alkaline pH.
 ALP is present (in order of increasing abundance) in placenta, intestine, kidney, bone
and liver.
 In adults, more than 80% of serum ALP activity derives from liver and bone.
 In late pregnancy, placental ALP is increased.
 In children and adolescents most serum ALP activity originates in osteoblasts and
correlates with the rate of bone growth.
 The serum half life is seven days.
Several caveats must be remembered in interpreting ALP results
 ALP levels should always be measured after fasting because enzyme levels increase as
much as 30 U/L after food ingestion. Patients with blood group O and B who are
secretors can have increased ALP levels after eating a fatty meal because of the release
of intestinal enzyme.
 In children, ALP is increased up to 3 times the upper limit of normal and in pregnant
patients it can be increased up to 2 times normal.
 ALP levels may double following bone fracture.
 Smokers have 10% higher ALP levels than non-smokers do.
 ALP levels fluctuate approximately 6% from week to week in a healthy individual.
 Reference ranges of ALP are age and sex‐related, being lower in women than men, but
rising in women beyond middle age. Laboratory methods and reference ranges
unfortunately vary by method, and users should acquaint themselves with local ranges.
ALP in cholestatic liver diseases:
Bile duct obstruction results in increased synthesis of ALP by bile duct epithelial cells and release
of ALP into the serum. Alkaline phosphatase may be increased even if only a few small bile ducts
are obstructed and serum bilirubin is normal.
 Serum ALP often exceeds four times the upper limit of normal in extrahepatic and
intrahepatic cholestasis.
 The most common causes of extrahepatic cholestasis are pancreatic cancer, common
duct stones and strictures, and primary sclerosing cholangitis.
 Intrahepatic cholestasis is usually due to primary biliary cirrhosis or drug reactions
(erythromycin, chlorpromazine, estrogens, and methyltestosterone).
 Patients with primary sclerosing cholangitis and primary biliary cirrhosis initially have
elevated ALP and normal bilirubin levels.
Medications reported to increase ALP:
allopurinol, anabolic steroids, captopril, carbamazepine, chlorpromazine, chlorpropamide,
diltiazem, erythromycin, estrogens, flutamide, gold salts, methimazole, methyltestosterone,
phenothiazines, phenylbutazone, phenytoin, quinidine, sulfonamides, tolazamide, tolbutamide,
trimethoprim-sulfamethoxazole, valproic acid, and verapamil.
If ALP level is increased disproportionately to the bilirubin level (e.g. a bilirubin < 1.0 mg/dL and
ALP > 1000 U/L), granulomatous or infiltrative diseases of the liver are likely. Possible diagnoses
include sarcoidosis, fungal infections, tuberculosis, and lymphoma.
ALP levels are increased in hyperthyroidism, cardiac failure, lymphoma, and hypernephroma.
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Relatively lower ALP levels (< 3 times the upper limit of normal) are less specific for cholestatic
liver disease and may be seen with hepatocellular diseases such as acute viral hepatitis, chronic
hepatitis, and cirrhosis. However, it is important to remember that incomplete obstruction by
gallstones may produce mildly elevated ALP levels. Intrahepatic cholestasis secondary to
anabolic steroids or birth control pills may cause mild increases in ALP.
Gamma glutamyltransferase (GGT) can be measured to determine if elevated ALP levels are of
liver origin; increased GGT indicates that ALP is most likely from the liver.
It is useful to look at the relationship of ALP to bilirubin and lactate dehydrogenase (LD) levels.
Pathology
ALP
Bilirubin
LD
Intra or extrahepatic cholestasis
Increased
Increased
Normal
Focal benign cholestasis
Increased
Normal
Normal
Focal malignant cholestasis
Increased
Normal
Increased
Bone
Raised ALP without a concomitant rise in GGT in a non‐pregnant adult is likely to be of bone
origin. Formal distinction can often, be achieved by isoenzyme analysis if uncertainty remains in
the presence of marked abnormalities.
Osteoblastic bone disease can also increase serum ALP. The most common bone disorders
associated with elevated ALP are;
 Paget's disease,
 osteomalacia,
 hyperparathyroidism,
 osteogenic sarcoma,
 bone metastases.
Low alkaline phosphatase levels have been reported in
 patients with magnesium deficiency,
 hypothyroidism,
 malnutrition,
 hemolytic anemia,
 Wilson's Disease,
 Post coronary bypass surgery,
 estrogen replacement therapy,
 And congenital hypophosphatasia.
 Blood transfusion causes transient decreases in ALP, due to chelation of cations by
citrate
Reference range in adults is 40 - 125 IU/L The laboratory reference range contains 95% of the
population values.
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Reference Values
Males
4 years: 149-369 U/L
5 years: 179-416 U/L
6 years: 179-417 U/L
7 years: 172-405 U/L
8 years: 169-401 U/L
9 years: 175-411 U/L
10 years: 191-435 U/L
11 years: 185-507 U/L
12 years: 185-562 U/L
13 years: 182-587 U/L
14 years: 166-571 U/L
15 years: 138-511 U/L
16 years: 102-417 U/L
17 years: 69-311 U/L
18 years: 52-222 U/L
> or =19 years: 45-115 U/L
Specimen Type: Serum
Female
4 years: 169-372 U/L
5 years: 162-355 U/L
6 years: 169-370 U/L
7 years: 183-402 U/L
8 years: 199-440 U/L
9 years: 212-468 U/L
10 years: 215-476 U/L
11 years: 178-526 U/L
12 years: 133-485 U/L
13 years: 120-449 U/L
14 years: 153-362 U/L
15 years: 75-274 U/L
16 years: 61-264 U/L
17-23 years: 52-144 U/L
24-45 years: 37-98 U/L
46-50 years: 39-100 U/L
51-55 years: 41-108 U/L
56-60 years: 46-118 U/L
61-65 years: 50-130 U/L
> or =66 years: 55-142 U/L
Container/Tube: Plain, red top or serum gel
Specimen Volume: 0.5 Ml
Additional Information: Patient's age and sex are required.
Reject Due To
Specimens other than
Serum
Hemolysis
Mild OK; Gross reject
How to investigate an isolated slightly raised alkaline phosphatase in an asymptomatic adult?
Recommendations:
 Checking of liver and bone profiles if not already carried out, to exclude other raised
indices.
 Isolated raised values up to approximately 20% above the ULN (upper limit of normal)
are more likely to reflect a statistical rather than clinical finding.
 If <1.5 ULN: recheck in 1–3 months.
 If >1.5 ULN (2 measurements, 6 months apart): further investigation indicated.
 If >3 ULN (single measurement): further investigation indicated.
Using a typical local reference range of 35–104 IU/l, approximately 2.5% of a normal population
will be expected to have values >104 IU/l (mean (2 SDs)), compared with approximately 0.1%
>121 IU/l (mean (3 SDs)).
ALP has two main sources in the non‐pregnant adult: liver and bone.
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Higher ALP activities are also seen as a normal variant and are associated with a range of
medical conditions (congestive heart failure, hyperthyroidism, pregnancy) and certain drugs
(ibuprofen, acetaminophen, cefotaxime).
Liver
In addition to clinical assessment GGT offers the best means of identifying a hepatic origin.
Although the reference range for women rises with age, the prevalence of primary biliary
cirrhosis also rises. Measurement of antimitochondrial antibodies in cases of persistently
increased ALP >1.5 times ULN of liver origin would therefore seem appropriate.
Bone
Raised ALP without a concomitant rise in GGT in a non‐pregnant adult is likely to be of bone
origin. Formal distinction can often, but not always, be achieved by isoenzyme analysis if
uncertainty remains in the presence of marked abnormalities.
Calcium studies combined with the clinical filter will help in the diagnosis of treatable bone
disease due to osteomalacia and parathyroid disease. The most common reason for raised bone
ALP in older people is (often subclinical) Paget's disease. Paget's disease can also be found in
2.3% of people with normal ALP.
References

David E. Johnston, M.D. Special Considerations in Interpreting Liver Function Tests AAFP
April 15 1999 2223-2233
Limdi JK, Hyde GM; Evaluation of abnormal liver function tests. Postgrad Med J. 2003
Jun;79(932):307-12.
Walsh K, Alexander G; Alcoholic liver disease. Postgrad Med J. 2000 May;76(895):280-6.
W S A Smellie, J Forth, S Ryder, M J Galloway, A C Wood, and I D Watson Best practice in
primary care pathology: review 5 J Clin Pathol 2006;59:1229-1237
Giannini E G, Testa R, Savarino V. Liver enzyme alteration: a guide for
Clinicians. CMAJ 2005.172367–379.
Sherwood P, Lyburn I, Brown S, Ryder S. How are abnormal results for liver function tests
dealt with in primary care? Audit of yield and impact.BMJ. 2001 Feb 3;322(7281):276-8.
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Alkaline phosphatase (ALP) is present in liver, bone, intestine, and placenta.
Rise in ALP activity occurs with all forms of cholestasis more marked in extrahepatic biliary
obstruction (eg, by stone or by cancer of the head of the pancreas) than in intrahepatic
obstruction
If both GGT and ALP are elevated, a liver source of the ALP is likely.
ALP also is elevated in disorders of the skeletal system that involve osteoblast hyperactivity and
bone remodeling, such as Paget's disease, hyperparathyroidism, rickets and osteomalacia,
fractures, and malignant tumors.
Pediatric reference values should be used to properly interpret alkaline phosphatase values in
children and adolescents
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