11 Causes of Elevated Alkaline Phosphatase with Normal Liver Enzymes (ALT, AST).

The most common causes of elevated alkaline phosphatase with normal liver enzymes include bone diseases, younger ages, pregnancy, some cancers, partial biliary obstruction, and others.

Today, we will deep-dive into all possible causes of the isolated increase in alkaline phosphatase. Keep reading.

A. Understanding alkaline phosphatase.

The different locations of alkaline phosphatase in your body.

Alkaline phosphatase is present in a wide variety of locations inside your body and is not restricted to your liver or biliary tract.

Most (80%) of alkaline phosphatase is present in your liver and bones. Therefore, liver and biliary tract diseases typically cause the elevation of alkaline phosphatase and liver enzymes.

Different locations of alkaline phosphatase include (reference):

• The liver.
• Bone (liver and bone alkaline phosphatase represent 80% of the total amount of the enzyme).
• The gastrointestinal tract (mainly the small intestine).
• The placenta (during pregnancy).
• The kidney.
• Germ cells (in testicles and ovaries).
• In some cancer cells (particularly lymphoma cells).

Diseases affecting the Alkaline Phosphatase (ALP) outside the liver (non-hepatic ALP) are often why Alkaline Phosphatase is elevated with normal liver enzymes.

The normal levels of alkaline phosphatase in adults.

Alkaline phosphatase reference ranges are widely different according to:

• Age
• Gender.
• Pregnancy.
• Blood type.
• And many other factors.

The reference range also differs from laboratory to laboratory. For example, in adults aged more than 20 years, normal alkaline phosphatase levels range from 44-121 (reference).

Does elevated alkaline phosphatase always mean a disease?

If you have an elevated alkaline phosphatase with normal liver enzymes, always consider normal physiological conditions that lead to elevated alkaline phosphatase.

Common physiological causes include pregnancy (third trimester), during growth (children & adolescents), aging (above the age of 40), and in people with blood groups O and B (reference).

What does it mean to have alkaline phosphatase elevation with normal liver enzymes?

Several causes exist for an isolated increase in alkaline phosphatase. The normal liver enzymes often exclude liver diseases as a cause of elevated alkaline phosphatase.

The main causes of the isolated increase in alkaline phosphatase can be either:

• Physiological causes (such as pregnancy).
• Bone diseases.
• Gastrointestinal diseases.
• Malignancy.
• Kidney diseases.
• Thyroid diseases.

The causes are discussed in detail in the next section.

B. Possible causes of elevated alkaline phosphatase & normal liver enzymes?

1. Pregnancy (third trimester).

Alkaline phosphatase is found in the placenta during pregnancy. In addition, pregnant women may have elevated alkaline phosphatase levels with normal liver enzymes, especially during the third trimester.

One study assessed the average levels of alkaline phosphatase during different trimesters of pregnancy, and here are the numbers:

• The first trimester: 68.5 U/L on average.
• The second trimester: 75.9 U/L.
• The third trimester:
  – 7th month: 126.7 U/L
  – 8th month: 178.8
  – 9th month: 234 U/L.

Note that these elevations are the averages. Alkaline phosphatase may reach even higher levels in the third trimester with normal liver enzymes (reference).

The degree of elevation during pregnancy in pregnant women who experience vomiting during the first trimester and those who receive alpha-methyldopa (an antihypertensive).

2. Individuals with blood types O and B (after eating).

Normally, your intestinal alkaline phosphatase reaches the circulation after eating (especially with a high-fat diet). However, its blood levels don’t increase because it soon binds to the red blood cells.

Patients with blood groups O and B have decreased ability to bind to the intestinal alkaline phosphatase. So, they have increased alkaline phosphatase levels after eating (reference).

This condition often runs in families.

3. Infants, children, and adolescents.

Children and adolescents may have an isolated increase in alkaline phosphatase with normal liver enzymes. The elevation is greatest during periods of growth.

Also, infants and young children may experience short periods of marked elevations of alkaline phosphatase. The condition is well recognized and called (transient hyperphosphatemia of infancy and early childhood).

The exact cause of this phenomenon is still not fully understood (reference).

4. Liver diseases (isolated increase in ALP is uncommon).

Liver diseases often don’t cause an isolated increase in alkaline phosphatase. Instead, most liver diseases often lead to abnormal liver enzymes or bilirubin levels.

Although rare, the isolated rise of alkaline phosphatase may occur with certain liver diseases such as (reference):

• Drug-induced liver affection as with androgenic steroids and phenytoin.
• Amyloidosis of the liver.
• Sarcoidosis of the liver.
• Other granulomatous diseases of the liver.
• Some metastatic liver cancer.

Although the liver enzymes (ALT, AST) and bilirubin are normal in such conditions, the enzyme Gamma Glutamyl transferase (GGT) is often elevated; So, so doctors use it to determine if the increased ALP is of hepatic origin.

5. Aging.

Alkaline phosphatase often increases gradually after the age of 50. The exact cause of this phenomenon is still unknown (reference).

The elevations in alkaline phosphatase are often not marked, and they’re often.

6. Diabetes mellitus.

Isolated elevations of alkaline phosphatase are noted among diabetic patients (reference).

The elevation is often mild and may be associated with increased GGT (gamma-glutamyltransferase).

7. Bone diseases.

Bones are one of the most common locations of the alkaline phosphatase enzyme. Bone diseases and conditions are among the most common causes of an isolated increase in alkaline phosphatase with normal liver enzymes.

Common diseases include (reference):

• Healing bone fractures.
• Bone cancers (osteogenic sarcomas).
• Bone metastases.
• Paget’s disease of bone.
• Osteomalacia.
• Hyperparathyroidism.

8. Some diseases of the biliary system.

The biliary system consists of:

• The bile ducts inside the liver (intrahepatic biliary ducts).
• The bile ducts outside the liver (extrahepatic biliary ducts), such as the right and left hepatic ducts and the common bile duct.
• The gallbladder.

A disease affecting the biliary system typically causes elevations in bilirubin and/or liver enzymes. However, in some cases, there may be an isolated rise in alkaline phosphatase.

Examples of the disease that may cause an isolated rise in ALP (reference):

• Partial (not complete) obstruction of the bile ducts (by a stone, tumor, or structure).
• Primary biliary cholangitis (immune-mediated inflammation of the biliary system).
• Sclerosing cholangitis.
• AIDS cholangiography.
• Ascaris lumbricoides infection of the biliary tract.

9. Some cancers.

Some cancers may produce an isolated rise in alkaline phosphatase levels with normal liver enzymes.

Common examples include:

• Hodgkin’s lymphoma.
• kidney cancer
• Bone cancer (osteosarcoma).
• Metastatic bone cancer.
• Gastric cancer.
• Lung cancer.
• Head and neck cancers.
• Ovarian cancer.
• Uterine cancer.

10. Hyperthyroidism

Increased thyroid gland activity, as with subacute thyroiditis and hyperthyroidism, may lead to increased levels of alkaline phosphatase with or without a rise in liver enzymes (reference).

Hyperthyroidism cause elevated alkaline phosphatase levels

11. Other causes.

• Drugs and toxins associated with cholestasis, such as phenytoin and anabolic steroids.
• Total parenteral nutrition.
• Covid-19.
• Sickle cell disease.
• Sepsis.
• Heart failure.
• Peritonitis.
• Uncomplicated stomach ulcers.