Routine laboratory testing is performed quite frequently in the hospital for both diagnostic purposes in symptomatic patients as well as for screening purposes in asymptomatic patients. Many of these screening tests now include serum alkaline phosphatase; although this enzyme is present in tissues throughout the body, it is most often elevated in patients with liver and bone disease. This frequent testing has resulted in a dramatic increase in the number of normal and abnormal chemistry test results that must be evaluated by physicians.
Normal laboratory reference values are defined as those occurring within two standard deviations of the mean calculated from a “normal” population. Therefore, by definition, 5% of normal patients will have abnormalities of any given test (2.5% are above and 2.5% are below the defined two standard deviations). Another way of putting this is that 1 out of every 20 tests ordered may be abnormal for the reference range but normal for the measured population. It is important to emphasize that false positive results are more likely in patients who have a low pretest probability of having disease.
Alkaline phosphatases are a group of zinc metalloenzymes that catalyze the hydrolysis of phosphate esters with widespread tissue distribution. As the name implies, this enzyme works best at an alkaline pH, and thus the enzyme is virtually inactive in the blood. Alkaline phosphatases act by splitting off phosphorous, creating an alkaline environment. They are found predominantly in the liver and bone, with intestinal enzymes contributing up to 20% of total activity; other tissue beds include the kidney, placenta, adrenal cortex, lung.
The origin of serum alkaline phosphatase has interested many workers ever since H. D. Kay (1929) and W.M. Roberts (1930) demonstrated that increased serum activity was found in certain bone and hepatobiliary disorders. It has long been realized that serum alkaline phosphatase arises from tissues rich in the enzyme, and the origin of this enzyme is intricately bound up with that of the mechanisms by which the serum activity is increased in health and in disease.
In order to provide high-quality, cost-effective (fiscal and nonfiscal) health care, a rational approach for the appropriate evaluation of elevated serum alkaline phosphatase is essential for all practicing physicians. The interpretation of all medical tests should be performed within the clinical context of the patient. Thus the initial evaluation for a patient with an elevated alkaline phosphatase must involve an assessment of the patient’s symptoms, risk factors, concomitant conditions, medications or drug use, history and physical exam findings, and even the consideration that there may potentially be a laboratory error.
II. Diagnostic Approach.
A. What is the differential diagnosis for this problem?
Alkaline phosphatase is distributed widely throughout the body, and normally is plentiful in hepatic parenchyma, osteoblasts, intestinal mucosa, placental cells, and renal epithelium. Although the primary importance for measuring alkaline phosphatase is to check for the possibility of bone disease or liver disease, forming a differential diagnosis should focus on the pathology (see below for causes of normal, physiologic elevations) found within each location where the enzymes are found. Because alkaline phosphatase is usually measured collectively within “liver function tests”, it may be helpful to start by organizing the diagnoses into hepatobiliary and non-hepatobiliary causes of elevated alkaline phosphatase.
Hepatobiliary causes of elevated alkaline phosphatase can be further divided into cholestastic/congestive liver disease or infiltrative liver disease:
Obstruction of the bile ducts (intrahepatic or extrahepatic)
Hepatitis (viral, parasitic, alcohol-induced, abscess associated)
Primary biliary cirrhosis
Primary sclerosing cholangitis
Medication induced (including total parenteral nutrition)
Congestive hepatopathy/Congestive heart failure
Organ rejection after transplantation
Adult bile ductopenia
Inherited disorders of cholestasis
Metastases to the liver
Primary malignancy (lymphoma, hepatocellular carcinoma)
Sarcoidosis, tuberculosis, and other granulomatous diseases
Non-hepatobiliary causes of elevated alkaline phosphatase can be further divided into osteoblastic/bone disease and non-bone, non-liver disease:
Paget’s disease (historically known as osteitis deformans)
Phsyiologic and pathologic bone growth (healing fracture, osteoblastic bone tumors, metastatic cancer to the bone, myeloma, osteomalacia)
Hyperparathyrodism (osteitis fibrosa cystica)
Vitamin D deficiency
Treatment of osteoporosis
Non-bone, non-liver disease:
Gastrointestinal inflammation (ulcerations, inflammatory bowel disease)
Cancer (bronchogenic, breast, colon, ovarian, cervical, prostate)
Myocardial, renal, and sometimes pulmonary infarction
Renal failure (renal osteodystrophy, decreased clearance)
B. Describe a diagnostic approach/method to the patient with this problem.
When a serum alkaline phosphatase elevation is detected, it must be interpreted in the clinical setting of the patient’s historical findings and physical examination. The enzymatic activity of alkaline phosphatase is stimulated in tissues during active metabolism, and as such there are both physiologic and pathologic causes of elevations in this enzyme. The first step in the diagnostic approach, therefore, should be to evaluate for physiologic causes of the elevation.
1. Assess for physiologic causes of elevation:
Measure in a fasting state: The serum alkaline phosphatase level can increase (up to two times the upper limit of normal) after food ingestion, particularly those patients with blood type O or B, as a result of the intestinal isoenzyme.
Use age-appropriate reference populations for ranges: In children, serum alkaline phosphatase activity is considerably elevated and correlates well with the rate of bone growth. Additionally, patients over the age of 60 have somewhat higher values (up to 1.5 times normal) than younger adults. At present, separate reference ranges are only required for children, based on age and gender; a single reference range is adequate for adults over the age of 25.
Use appropriate reference ranges for pregnant patients: Women in the third trimester of pregnancy have elevated alkaline phosphatase levels (increases up to 2-3 times normal) because of an influx of placental alkaline phosphatase. A separate reference range is required for pregnant patients.
Ensure a non-genetic cause from family history: There are reports of a benign familial elevation in serum alkaline phosphatase levels because of increased levels of intestinal alkaline phosphatase.
2. Determine the source of alkaline phosphatase:
Because of the diverse sources of the enzyme, the fist step in determining a non-physiologically elevated alkaline phosphatase level is to identify the source of the elevation. Electrophoretic separation into distinct isoenzymes on polyacrylamide gel or Sepharose is the most sensitive and specific way to do this; however, these tests are not widely available and not commonly used. Hepatic origin can, in these cases, be evaluated by obtaining a serum γ-glutamyltransferase or 5′-nucleotidase level.
Both levels of these enzymes are usually elevated in parallel with the elevation in alkaline phosphatase level in patients with hepatobiliary disorders. The finding of an elevated serum alkaline phosphatase level but a normal serum γ-glutamyltransferase or 5′-nucleotidase level should prompt an evaluation for non-hepatobiliary causes of alkaline phosphatase elevation.
Alternatively, the source can be identified using tests that involve heat denaturation of the enzyme. The finding of an elevated serum alkaline phosphatase level in a patient with a heat-stable fraction strongly suggests that the placenta or a tumor (the Regan isoenzyme) is the source. Susceptibility to inactivation by heat increases, respectively, for the intestinal, liver, and bone alkaline phosphatases, bone being by far the most sensitive. This test is unreliable and neither sensitive nor specific as the above testing.
3. Evaluate the tissue specific alkaline phosphatase elevation:
Hepatic alkaline phosphatase:
If the excess alkaline phosphatase is determined to be of liver origin, the patient should be evaluated for cholestatic or infiltrative liver disease. Initial testing should include a right upper quadrant ultrasound, which can assess the bile ducts as well as the parenchyma of the liver, as well as an antimitochondrial antibody, which is highly suggestive of primary biliary cirrhosis.
A finding of biliary dilatation suggests the presence of biliary tree obstruction. In this setting, or in the presence of choledocholithiasis, endoscopic retrograde cholangiopancreatography should be the next test in order to identify the cause of obstruction and, if possible, to intervene.
Patients with serum antimitochondrial antibodies should undergo liver biopsy to confirm the diagnosis of primary biliary cirrhosis.
If both the serum antimitochondrial antibody is negative and the right upper quadrant ultrasound reveals no abnormality, assess the degree of elevation in the serum alkaline phosphatase level. If the level is >50% above the normal level for more than 6 months, a liver biopsy and either endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography is recommended. If the alkaline phosphatase level is less than this, the results of all other liver-enzyme tests are normal, and the patient has no symptoms, observation alone can be pursued.
Non-hepatic alkaline phosphatase:
Because elevations in serum alkaline phosphatase originate predominantly from the liver and the bone, focus on causes of high bone isoenzymes should be pursued if the elevation is determined to be non-hepatic in origin and no other clear source exists.
The bone isoenzyme is elevated as a result of increased osteoblastic activity. The highest total values have been attributed to Paget’s disease and osteomalacia/rickets, with levels correlating with the extent of the disease on skeletal surveys and with parameters of bone resorption. Beyond these disease processes, evaluation of skeletal health and specific bone disorders should be pursued within the clinical context of the patient.
Likewise, concerning the diagnosis of non-bone, non-liver causes of elevated alkaline phosphatase, the diagnostic work-up has the potential to be vast and should be guided by the clinical context of the patient.
1. Historical information important in the diagnosis of this problem.
A complete medical history is perhaps the single most important part of the evaluation of the patient with elevated serum alkaline phosphatase levels, particularly focusing on the common causes as noted above.
Concerning hepatic causes of elevated alkaline phosphatase, the clinical history should focus on the symptoms of liver disease – their nature, pattern of onset, and progression – and the associated risk factors. The symptoms of liver disease include constitutional symptoms such as fatigue, weakness, nausea, poor appetite, malaise as well as the more liver-specific symptoms of jaundice, dark urine, light stools, itching, abdominal pain, and bloating. Major risk factors that should be sought out in the history include details of alcohol use, medications (including herbal compounds, prescribed medications, illicit medications and over-the-counter medications), personal habits, sexual activity, travel, parenteral exposure, recent surgery, recent travel history and family history of liver disease.
Assessment for osteoblastic/bone causes should focus on symptoms of bone pain, history of fractures, bone deformities, muscle spasms, cramps, difficulty walking, arthritis, and numbness/tingling. However, many of these patients are asymptomatic.
2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
The physical examination usually complements rather than replaces the need for additional diagnostic approaches during the evaluation of an elevated serum alkaline phosphatase. Typical findings in liver disease are icterus, hepatomegaly, hepatic tenderness, splenomegaly, spider angiomata, palmar erythema, excoriations, muscle-wasting, ascites, edema, dilated abdominal veins, asterixis, confusion, gynecomastia, testicular atrophy. Skeletal examination may reveal bony tenderness or deformities.
3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
See above in diagnostic approach.
C. Criteria for Diagnosing Each Diagnosis in the Method Above.
Having a high index of suspicion for particular diseases helps guide the diagnostic work-up. Included are diagnostic methods related to common diseases presenting with elevated serum alkaline phosphatase:
Cholestatic/congestive liver disease:
Obstruction of the bile ducts:Dilatation may be initially visualized by ultrasound and confirmed by endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography, which may also be able to diagnose the etiology.
Primary biliary cirrhosis:The presence of anti-mitochondrial antibody in the context of elevated alkaline phosphatase with no overt abnormalities should prompt a liver biopsy demonstrating bile duct destruction and granulomatous cholangitis, which is diagnostic as well as important in staging the disease.
Primary sclerosing cholangitis:p-ANCA is positive in most patients, though endoscopic retrograde cholangiopancreatography or magnetic resonance cholangiopancreatography demonstrating multifocal beaded bile duct strictures is diagnostic.
Medication induced: there are more than 600 medications that have been reported to cause liver injury. Being aware of the side effects of medications (both prescription and non-prescription) is important. Diagnosis of drug-induced liver injury often requires the exclusion of viral, toxic, cardiovascular, inheritable, and malignant causes. Often in clinical practice, a trial without the suspected medication followed by rechecking the serum alkaline phosphatase is performed.
Infiltrative liver disease:
Primary malignancy and metastases to the liver:These lesions are usually demonstrated on ultrasound, occasionally they require biopsy for a tissue diagnosis
Sarcoidosis:Lesions may be seen on ultrasound, often necessitating a liver biopsy, which demonstrates the characteristic noncaseating granulomas, in order to distinguish from malignancy. Exclusion of drugs and other causes of granulomatous disease should occur as well.
Fatty liver:Various radiographic methods can detect the presence of fat within the liver, commonly seen on right upper quadrant ultrasound. Fatty liver can be associated with obesity, diabetes, alcohol ingestion, chemotherapy.
Amyloidosis:Hepatomegaly can be demonstrated on radiographic studies that may show inhomogeneous liver involvement. Liver biopsy demonstrating birefringence with Congo red stain establishes the diagnosis; however, it does not establish the type of amyloidosis. As such, fat, skin, or rectal biopsies are preferred if possible.
Paget’s disease: The diagnosis is primarily made by demonstrating characteristic bone deformities on radiologic imaging in the context of serum markers of bone turnover.
Physiologic and pathologic bone growth:Usually diagnosis is confirmed with radiographic studies.
Hyperthyroidism:Diagnose with serum measurement of thyroid stimulating hormone and thyroxine.
Hyperparathyroidism: Diagnose with serum measurement of calcium and parathyroid hormone.
D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
III. Management while the Diagnostic Process is Proceeding.
A. Management of Clinical Problem Elevated Alkaline Phosphatase.
Rarely will the physician encounter emergent conditions with an isolated elevated alkaline phosphatase that needs to be treated prior to the appropriate diagnostic work-up. In emergent conditions associated with elevated alkaline phosphatase (i.e., acute liver failure, non-hepatobiliary sepsis, thyrotoxicosis), there will be other, more specific findings to help guide the physician toward specific treatment plans.
B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.
IV. What's the evidence?
“AGA Technical Review on the Evaluation of Liver Chemistry Tests”. Gastroenterology. vol. 123. 2002. pp. 1367-1384.
Friedman, SL, McQuaid, KR, Grendell, JH. “Current Diagnosis and Treatment in Gastroenterology”. McGraw Hill. 2003.
Kaplan, MM. “Alkaline Phosphatase”. The New England Journal of Medicine.. vol. 286. 1972. pp. 200-202.
Kasper, DL, Braunwald, E, Fauci, AS. “Harrison's Principles of Internal Medicine”. McGraw Hill. 2005.
Pratt, DS, Kaplan, MM. “Evaluation of Abnormal Liver-Enzyme Results in Asymptomatic Patients.”. The New England Journal of Medicine.. vol. 342. 2000. pp. 1266-1271.
Sarac, F, Saygili, F. ” Causes of High Bone Alkaline Phosphatase”. Biotechnology and Biotechnology Equipment. vol. 21. 2007. pp. 194-197.
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- I. Problem/Condition.
- II. Diagnostic Approach.
- A. What is the differential diagnosis for this problem?
- B. Describe a diagnostic approach/method to the patient with this problem.
- 1. Historical information important in the diagnosis of this problem.
- 2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
- 3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
- C. Criteria for Diagnosing Each Diagnosis in the Method Above.
- D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
- III. Management while the Diagnostic Process is Proceeding.
- A. Management of Clinical Problem Elevated Alkaline Phosphatase.
- B. Common Pitfalls and Side-Effects of Management of this Clinical Problem.
- IV. What's the evidence?