Alkaline Phosphatase (ALP)

Abnormally low ALP levels are less common but can occur due to: 

→ malnutrition

→ nutrient deficiencies

→ hypothyroidism

→ and some rare inherited disorders that affect ALP or liver function

Persistently low levels of ALP could indicate hypophosphatasia (HPP), a rare genetic disorder characterized by impaired mineralization (“calcification”) of bones and teeth.

------------------------

Although high levels of ALP are more common than low levels, low levels may be medically meaningful in some circumstances. For example, low levels of ALP are sometimes found in the following medical situations:

• Wilson’s disease (a rare genetic condition where copper builds up in your body)
• Zinc deficiency
• Pernicious anemia (a decrease in red blood cells that occurs when the intestines cannot properly absorb vitamin B12.)
• Celiac disease (a serious autoimmune disease that occurs in genetically predisposed people where the ingestion of gluten leads to damage in the small intestine.)
• Congenital hypophosphatasia [absence or low levels of serum alkaline phosphatase due to mutations in the gene encoding tissue-nonspecific alkaline phosphatase (TNSALP)]

ALP can be used in diagnosis of these and related conditions. It is also sometimes used to monitor these conditions after treatment.

Abnormally low ALP values may be the result of:

• Achondroplasia (a form of dwarfism)
• Aplastic anemia (anemia caused by bone marrow failure)
• Congenital iodine deficiency
• Inflammatory bowel disease (IBD), including ulcerative colitis and Crohn’s disease

Elevated ALP can be indicative of liver or bone diseases as well as many other types of conditions. But high ALP levels are not always a sign of a problem. Interpretation of your test results can involve consideration of multiple factors:

→ The degree of elevation: Very high levels are often seen with blockages of the bile ducts, but these levels alone cannot distinguish between liver problems and other conditions.

→ Other test measurements: ALP is often measured along with other enzymes, such as aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (GGT), and/or 5′-nucleotidase (5’-NT), and the levels of ALP relative to these enzymes can help determine the significance of your test result.

→ Your overall health: Any symptoms you are experiencing will be considered alongside your ALP levels.

Your doctor can account for the fact that ALP levels can be elevated without any underlying illness. For example, ALP is usually higher in pregnant women, growing children and adolescents, and older adults. ALP produced in the intestine can also increase after fatty meals for people with certain blood types.

Some conditions cause large amounts of ALP in the blood. These conditions include: 

→ rapid bone growth (during puberty)

→ bone disease (such as Paget's disease or cancer that has spread to the bones)

→ a disease that affects how much calcium is in the blood (hyperparathyroidism)

→ vitamin D deficiency

→ or damaged liver cells.

----------------------------

Higher-than-normal levels of ALP in your blood may indicate a health concern with your liver or gallbladder. This could include a blockage in your bile ducts, gallstones, cirrhosis, liver cancer, and some forms of hepatitis.

High levels may also indicate a concern related to the bones such as rickets, Paget’s disease, bone cancer, or an overactive parathyroid gland.

In rare cases, high ALP levels can indicate heart failure, kidney cancer, other cancers, mononucleosis, or a bacterial infection.

Very high ALP levels:

Very high levels of ALP can be caused by liver problems, such as hepatitis, blockage of the bile ducts (obstructive jaundice), gallstones, cirrhosis, liver cancer, or cancer that has spread (metastasized) to the liver from another part of the body.

High ALP levels can be caused by bone diseases, such as Paget's disease, osteomalacia, rickets, bone tumors, or tumors that have spread from another part of the body to the bone, or by overactive parathyroid glands (hyperparathyroidism). Normal healing of a bone fracture can also raise ALP levels.

Heart failure, heart attack, mononucleosis, or kidney cancer can raise ALP levels. A serious infection that has spread through the body (sepsis) can also raise ALP levels.

Women in the third trimester of pregnancy have high ALP levels because the placenta makes ALP.

Abnormally high ALP values may be the result of:

• Bacterial infections
• Cholangiocarcinoma (bile duct cancer)
• Cholelithiasis (gallstones)
• Biliary obstruction or dyskinesia (lack of motility)
• Bone cancers, including osteosarcoma and chondrosarcoma
• Bone conditions, including osteomalacia and osteoporosis
• Cholecystitis (gallbladder inflammation)
• Cirrhosis (scarring of the liver)
• Congestive heart failure
• Drug-induced liver toxicity
• Hepatitis, infectious and non-infectious
• Hepatocarcinoma (liver cancer)
• Hyperthyroidism (overactive thyroid gland)
• Hyperparathyroidism (overactive parathyroid gland)
• Kidney cancers, including renal cell carcinoma
• Lymphoma (cancer of the lymphatic system)
• Metastatic cancer to the liver or bone
• Mononucleosis (a viral infection)
• Myelofibrosis (a disease of the bone marrow)
• Myocardial infarction (heart attack)
• Paget's disease (a disorder causing accelerated bone growth)
• Prostate cancer
• Rickets (softening of bones usually due to vitamin D deficiency)
• Sarcoidosis (a disease that causes granular masses)
• Sepsis (an extreme inflammatory response to an infection)

Very high levels can also be found if significant liver damage is causing the poor flow of bile out of the ducts. This might happen due to the autoimmune disease primary biliary cholangitis, liver injury from drug use, or from severe hepatitis from alcohol use. Diseases that infiltrate the liver can also cause this issue, such as cancer, sarcoidosis, or amyloidosis.

Slightly elevated ALP levels:

If elevation is not quite that high, other possibilities are more likely. For example, this might happen due to:

• Cirrhosis of the liver
• Viral hepatitis
• Congestive heart failure
• Abdominal infections
• Hodgkin lymphoma
• Hyperparathyroidism
• Hyperthyroidism
• Osteomyelitis
• Bone cancer or cancer spread to the bone
• Osteomalacia (softening of the bones)

What are the next steps if your ALP levels are elevated?

If the ALP level is high, more tests may be done to find the cause. The amounts of different types of ALP in the blood may be measured and used to determine whether a high level is from the liver or bones. This is called an alkaline phosphatase isoenzymes test.

You might not need extensive medical evaluation if your ALP is only a little elevated. Instead, your clinician may choose to monitor you with repeated blood tests. Somewhat increased ALP can occur in some individuals, even though no real problem is present. However, high levels need further medical investigation.

Follow-up tests will depend on the medical context: your symptoms and physical exam, your other past and present medical conditions, other test findings, etc. You may have gotten your ALP test in the context of other tests that help evaluate the liver, which can provide more information about what your test results mean. If not, other blood tests that are often given to evaluate the liver may be needed.

Sometimes it’s helpful to get a specific blood test called γ-glutamyl peptidase (GGTP) if one’s ALP is elevated. This test can help determine if the liver is the source of the increase or if it’s probably coming from another place.

It is also sometimes helpful to run a different type of ALP test (electrophoresis). This test gives information about the fraction of ALP that comes from different organs, indicating the probable organ of concern. Most of the time, these tests find the increase coming from bone disease or liver or gallbladder problems.

Other blood tests may also be needed, depending on the context. For example, if your clinician is concerned that hepatitis might be the cause of your symptoms and ALP results, you might need to test for hepatitis B and hepatitis C virus. Additional blood tests may also be necessary, such as antimitochondrial antibody (AMA). AMA is a blood test that helps diagnose primary biliary cholangitis, which is a disease which damages bile ducts in the liver and predominantly affects women.

Abdominal ultrasound can also be useful as the first imaging modality to evaluate the liver, gallbladder, and related structures. If necessary, other techniques may be performed as well, like endoscopic retrograde cholangiopancreatography (ERCP) or magnetic resonance cholangiopancreatography (MRCP).

Other investigations, like liver biopsy, might be needed under specific circumstances. Your clinician will work with you to identify the underlying cause.