High alkaline phosphatase

Alkaline phosphatase (abbreviated as ALP) is a group of hydrolase enzymes present in the human body. There are several ALP isoenzymes, known as ALP1, ALP2 and ALP3. ALP1 is usually found in the liver, and ALP2 in the human bone, placenta, and kidneys, while ALP3 is mostly found in the lining of the intestines. These tissues all release ALP into the bloodstream. To work, this enzyme needs an alkaline pH (around 10), and in that surrounding, it can take a phosphorus group of certain molecules. The process is known as de-phosphorylation, and it is performed on alkaloids, proteins, and nucleotides in the body.

The ALP blood tests are measuring the total amount of all ALP isoenzymes in the body. Usually, they are done to diagnose some bone and liver diseases or to establish the toxic effects of medications on the liver. Another reason to perform an ALP test is to detect some other medical conditions, including malnutrition, protein deficiency, alcoholism, liver cirrhosis, gallstones, kidney carcinoma, endocrineoplasia (endocrine glands tumors), etc.

Normal ALP Levels

The level of ALP mainly depends on the age, but also on the activity and stage of growth of bone cells (osteoblasts and osteoclasts). As a normal level of alkaline phosphatase, doctors consider the values between 50 and 75mg/dl (milligrams per deciliter). Teenagers and young adults might normally have slightly higher ALP levels than adults.

Everything over 75mg/dl is considered a high ALP level, and it is not healthy, since it might indicate some bone, placental, intestinal, or liver problems.

What Can Cause High ALP?

Many conditions and diseases could cause high levels of alkaline phosphatase in the blood. As we already said, it is normal for adolescents, but also for some pregnant women, to have slightly increased levels of blood ALP.

Bone diseases and cancers, especially Paget’s disease, can cause high blood ALP and lead to bone deformities, pain, and abnormal bone fractures. Liver cholestasis and congestion, obstruction of the biliary tracts, inflammation caused by medications, or increased levels of toxins in the liver might also cause elevated levels of ALP.

Other causes of high ALP include various conditions, such as virus and parasitic infections, gastrointestinal or systemic infections, congestive heart failure, myocardial and pulmonary infarctions, leukemia, sarcoidosis, amyloidosis, Hodgkin’s lymphoma, rheumatoid arthritis or obstructive pancreatitis, etc.

Abnormal functioning of the glands in the human body might also provoke a high level of alkaline phosphatase in the blood. Overactivity of the thyroid or parathyroid glands, or adrenal cortical hyperfunction can be some of the reasons for high ALP. Different gynecologic malignancies or increased use of contraceptive tablets could also cause high levels of alkaline phosphatase in the bloodstream.

Alkaline phosphatases (ALPs) are a group of isoenzymes located on the outer layer of the cell membrane. They catalyze the hydrolysis of organic phosphate esters found in the extracellular space. Zinc and magnesium are essential cofactors of this enzyme. Despite the diverse tissue distribution and varying physiochemical properties of ALPs, they are classified as true isoenzymes due to their shared ability to catalyze the same reaction.

ALPs are categorized into 2 types—tissue-specific and tissue-nonspecific. Tissue-specific ALPs are exclusively present in the intestine, placenta, and germinal tissue, specifically within the tissues where they are expressed under physiological conditions. Under specific conditions, the tissue-specific ALPs may also contribute to the circulating pool of serum ALP when there is increased stimulation of their production.
Serum ALP levels exhibit age-related variations in healthy individuals. The levels are highest during childhood and puberty due to bone growth and development and then decrease as individuals age. The decline in serum ALP levels within the age group of 15 to 50 is slightly more pronounced in men than in women. These levels increase again during old age, with a notable gender distribution difference. The underlying reasons for these typical fluctuations remain unidentified. Research indicates a positive correlation between body weight and smoking, while an inverse correlation exists with height.
Human ALPs (hALP) are tethered to the cell membrane via glycosylphosphatidylinositol. Their release into the serum occurs through the action of specific phospholipase enzymes. These enzymes have a half-life of 7 days, and their clearance from the serum is independent of the bile duct's patency or the liver's functional capacity. However, the precise site where ALP degradation occurs remains unknown. Serum ALP levels may remain elevated for up to one week after the resolution of biliary obstruction.
ALP is inhibited by metal-complexing anticoagulants, as they impede the enzyme by forming complexes with Mg and Zn, and therefore, they should be avoided. Hemolyzed or lipemic specimens should be rejected if they exhibit a high background absorbance. Significantly, bilirubin at concentrations of up to 20 mg/dL does not interfere with ALP measurements.
When ALP is the sole liver biochemical test that shows elevation, while serum aminotransferases remain within the normal range, or when ALP exhibits a disproportionately high increase compared to other liver biochemical tests, it is imperative to concentrate on identifying the cause and origin of this isolated or disproportionate elevation in ALP. For asymptomatic patients with isolated serum ALP elevation, it is crucial to pinpoint the primary source of the abnormality. ALPs derived from the liver, bone, placenta, and intestines have different physicochemical properties.
Patients with AIDS may also exhibit notably high levels of ALP, often stemming from cholangiopathy related to opportunistic infections such as cytomegalovirus, cryptosporidiosis, or granulomatous liver involvement from tuberculosis.
Transient very high levels of ALP, reaching up to 30 times the upper reference limit, have been documented in children. However, the clinical significance of this finding is unknown. This phenomenon has been termed "transient hyperphosphatasemia" and may involve either the bone or liver isoenzyme. Typically, affected patients are asymptomatic and exhibit an unremarkable medical history, physical examination, and laboratory results. Some patients may have recently experienced mild viral conditions.

In most cases, the initial imaging study ordered is right upper quadrant ultrasonography. If the bile duct is dilated, the choice between endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP) depends on the clinical indication. On the other hand, if the bile duct does not exhibit dilation, the recommended next step is to test for serum antimitochondrial antibody (AMA) to assess for PBC. If the serum AMA level is within the normal range, it becomes essential to evaluate for causes of intrahepatic cholestasis, AMA-negative PBC, sarcoidosis, and other conditions mentioned earlier. In many cases, a liver biopsy is the ultimate diagnostic test used in such situations, as it aids in pinpointing the underlying cause of the elevated serum ALP.

✓ Fact confirmed: Alkaline Phosphatase Dhruv Lowe, Terrence Sanvictores, Muhammad Zubair, Savio John; October 29, 2023.