Biomarkers of Liver and Gallbladder Function: Alkaline Phosphatase

Optimal Takeaways

Alkaline phosphatase (ALP) enzymes function at an alkaline pH. They are found primarily in the bone, liver, and biliary tract but also in the kidney, intestine, and white blood cells. Isoenzymes of ALP can be measured to determine which tissue they came from. However, total alkaline phosphatase is most commonly measured.

Low levels are observed in celiac disease, malnutrition, hypothyroidism, pernicious anemia, and vitamin B12, vitamin C, zinc, magnesium, and phosphorus insufficiency. Elevated levels can be seen with bone growth and healing, liver and bone disease or metastases, gallbladder disorders, intestinal ischemia, rheumatoid arthritis, cerebrovascular and cardiovascular risk, fatty liver disease, and metabolic syndrome.

Standard Range: 35.00 - 150.00 IU/L

The ODX Range: 45.00 – 100.00 IU/L        

Low alkaline phosphatase levels are associated with hypothyroidism, malnutrition, vitamin C deficiency, pernicious anemia, celiac disease, milk-alkali syndrome, hypophosphatemia, and hypophosphatasia. Drugs that can decrease ALP include arsenicals, cyanides, fluorides, oxalates, and nitrofurantoin. Excess B vitamin intake may reduce ALP as well (Pagana 2021).

Low ALP may also be seen with cardiac surgery, cardiopulmonary bypass, B12 deficiency, zinc and magnesium insufficiency (Ray 2017), malnutrition, postmenopausal estrogen therapy due to osteoporosis, severe anemia, aplastic anemia, chronic myelogenous leukemia, oral contraceptives (Sharma 2014), cretinism, achondroplasty (Lum 1995), and Wilson’s disease (Lowe 2021). Low alkaline phosphatase is also associated with vitamin C insufficiency (Langlois 2001, Mahmoodian 1996, Cannalire 2023), and protein malnutrition (Cannalire 2023).

High levels of alkaline phosphatase are associated with acute cholecystitis, common bile duct stones (Thapa 2010), cirrhosis, biliary obstruction, primary or metastatic bone or liver tumor, new bone growth, healing ­fractures, hyperparathyroidism, Paget’s disease, rickets, osteomalacia, sarcoidosis, intestinal ischemia, and rheumatoid arthritis. Several drugs can increase ALP, including allopurinol, colchicine, antibiotics, fluorides, verapamil, and nicotinic acid (Pagana 2021). Lead poisoning can also significantly elevate alkaline phosphatase (Kalahasthi 2019).

Higher levels of ALP can also be seen with menopause (Bhattarai 2014), inflammation, atherosclerosis, coronary artery calcification, increased cardiovascular and cerebrovascular risk (Lee 2015), non-alcoholic/metabolic fatty liver disease, metabolic syndrome (Sohrabi 2023), low muscle mass, sarcopenia, and higher C-reactive protein levels (Lee 2021).

Levels may increase up to four times the highest standard range with primary and metastatic liver tumors, cirrhosis, chronic and viral hepatitis, ischemic cholangiopathy, congestive heart failure, intra-abdominal infection, sepsis, Hodgkin’s, osteomyelitis (Lowe 2021), cerebral small vessel disease (Lee 2015), seminoma, untreated celiac disease, and vitamin D deficiency (Sharma 2014).

Overview

Alkaline phosphatase (ALP) represents a group of membrane-bound glycoprotein isoenzymes that help hydrolyze phosphate monoesters at an alkaline pH. These enzymes are found to participate in protein phosphorylation, bone calcification and mineralization, cell growth, and cell apoptosis (Sharma 2014).

The highest alkaline phosphatase concentrations are in the bone, liver, and biliary tract. Identifying the various isoenzyme forms helps determine their source, e.g., ALP-1 from the liver or ALP-2 from the bone. Both zinc and magnesium are essential cofactors for this enzyme. Levels are naturally elevated during childhood and adolescence due to bone growth and development. Outside of accelerated bone growth, most elevations in serum ALP come from the liver or increased osteoblast activity due to bone disorders. Production of ALP increases during biliary obstruction and can remain elevated for weeks afterward. The highest levels of ALP will be seen with cholestasis with a concomitant rise in GGT, suggesting hepatobiliary disease. An elevation in ALP without an increase in GGT suggests bone disease. Interestingly, individuals with type O or type B blood will have increased serum ALP following a meal, so fasting values should be used in clinical assessment (Lowe 2021). Since ALP is also found in abundance in the biliary epithelium, levels increase significantly with intra- and extra-hepatic obstructive biliary disease (Pagana 2021).

One prospective study of 40 subjects with acute cholecystitis and 40 with choledocholithiasis (common bile duct stone) found that both ALP and GGT were elevated in all subjects. A significantly higher ALP was seen in choledocholithiasis versus no choledocholithiasis, i.e., 394 IU/L versus 215.7 IU/L. The increase in ALP represents a 2.5-fold increase above a high normal of 130 IU/L versus a 1.69-fold increase without choledocholithiasis. Levels of GGT increased by 2.2-fold with choledocholithiasis and by 2.8-fold without choledocholithiasis, a difference that was not statistically significant (Thapa 2010).

A literature review suggests that an ALP of 125 IU/L and above indicated common bile duct stones in symptomatic individuals, especially if ALP was more than twice its upper conventional limit (Gurusamy 2015).

Note the hepatobiliary versus non-hepatobiliary causes of elevated ALP (Kasarala 2016):

Hepatobiliary

• Bile duct obstruction
• Benign intrahepatic recurrent cholestasis
• Primary biliary or sclerosing cholangitis
• Medications
• Infiltrating diseases of the liver
• Sarcoidosis
• Hepatic metastasis

Non-hepatobiliary

• Bone disease
• Pregnancy
• Chronic renal failure
• Lymphoma and other malignancies
• Congestive heart failure
• Childhood growth

Increasing ALP may also be associated with increasing cerebrovascular risk, especially in those with compounding risk factors. Research suggests elevated alkaline phosphatase may be related to inflammation, atherosclerosis, and increased vascular calcification. One study of 1,011 neurologically healthy individuals found that ALP in the highest tertile (195 IU/L or above) was significantly associated with increased cerebral small vessel disease indices versus an ALP of 155 IU/L or below. Further breakdown of the lowest tertile was not completed in the study. Researchers suggest elevated alkaline phosphatase may be a marker of impaired cerebral microcirculation (Lee 2015).

In another study of 1,082 neurologically healthy subjects, those with ALP above 63 IU/L and CRP above 5 mg/L had a three-fold increased risk of cerebral infarct versus those with an ALP of 63 IU/L or below and a CRP of 5 mg/L and below (Ryu 2014). Higher ALP was associated with all-cause mortality and vascular death in a prospective study of stroke outcomes in 2,029 subjects. The highest quintiles of ALP, i.e., 82-97 and 97 IU/L and above, were associated with the most significant adverse outcomes (Ryu 2010).

Elevated ALP may also factor into cardiovascular risk. One retrospective study of individuals with stable angina found that mean ALP levels were significantly higher in advanced cardiovascular disease, i.e., 105.4 IU/L versus 78.4 IU/L, respectively (Sahin 2014). In another study of 234 acute coronary syndrome subjects, an ALP above 80 IU/L was independently associated with increased coronary artery calcification and plaque burden (Ren 2021).

Increased alkaline phosphatase may also be associated with metabolic syndrome, a disorder characterized by at least three of the following criteria: a waist circumference of 40 inches (102 cm) or greater in men or 35 inches (88 cm) or greater in women; elevated triglycerides or receiving treatment for triglycerides of 150 mg/dL ( 1.7 mmol/L); low HDL cholesterol or treatment for HDL below 40 mg/dL (1.0 mmol/L) for men and  50 mg/dL (1.3 mmol/L) for women; elevated blood pressure or treatment for systolic blood pressure of 130 mm Hg or above and/or diastolic blood pressure of 85 mm Hg or above; and elevated fasting glucose or treatment for elevated fasting glucose of 100 mg/dL (5.5 mmol/L) or higher. An alkaline phosphatase above 139 IU/L in men and 144 IU/L in women was significantly associated with metabolic syndrome in a cross-sectional analysis of 5,257 individuals from the Amol Cohort Study (Sohrabi 2023).

Alkaline phosphatase plays a vital role in the intestine by detoxifying harmful microbial compounds and reducing the risk of infection and sepsis. Only 1-2% of intestinal alkaline phosphatase is normally released into the blood. Supplementation with exogenous alkaline phosphatase may have therapeutic value in infectious and inflammatory conditions (Estaki 2014).

A low serum ALP may reflect nutrient insufficiency

A low serum ALP may reflect nutrient insufficiency. A study of 42 individuals with low ALP and 45 controls found that ~50% of those with low ALP (below 45 IU/L) were either zinc or magnesium deficient versus 6-13% in controls. Serum levels of zinc and magnesium were significantly lower in cases versus controls. The mean level of zinc was 59.2 ug/dL (9.06 umol/L) in cases versus 73.4 ug/dL (11.23 umol/L) in controls, while mean magnesium was 1.26 mEq/L (1.53 mg/dL, 0.63 mmol/L) in cases versus 1.8 mEq/L (2.19 mg/dL, 0.90 mmol/L) in controls (Ray 2017).

Low alkaline phosphatase may also be associated with an insufficiency of vitamin C, B12, or protein (Cannalire 2023). If alkaline phosphatase levels are trending lower, nutrition status, especially that of zinc, magnesium, vitamin C, B12, and protein, should be assessed further.

References

Bhattarai, Tirtha et al. “Correlation of common biochemical markers for bone turnover, serum calcium, and alkaline phosphatase in post-menopausal women.” The Malaysian journal of medical sciences : MJMS vol. 21,1 (2014): 58-61.

Gurusamy, Kurinchi Selvan et al. “Ultrasound versus liver function tests for diagnosis of common bile duct stones.” The Cochrane database of systematic reviews vol. 2015,2 CD011548. 26 Feb. 2015, doi:10.1002/14651858.CD011548

Kalahasthi, Ravibabu, et al. "Assessment of diagnostic accuracy and optimal cut points of blood lead levels on serum proteins among workers exposed to Pb at a lead battery plant." Int J Med Biochem 2.3 (2019): 81-7.

Kasarala, George, and Hans L Tillmann. “Standard liver tests.” Clinical liver disease vol. 8,1 13-18. 26 Jul. 2016, doi:10.1002/cld.562

Langlois, M et al. “Serum vitamin C concentration is low in peripheral arterial disease and is associated with inflammation and severity of atherosclerosis.” Circulation vol. 103,14 (2001): 1863-8. doi:10.1161/01.cir.103.14.1863

Lee, Han-Bin et al. “Association between Serum Alkaline Phosphatase Level and Cerebral Small Vessel Disease.” PloS one vol. 10,11 e0143355. 18 Nov. 2015, doi:10.1371/journal.pone.0143355

Lee, Jun-Hyuk et al. “Relationship between Serum Alkaline Phosphatase and Low Muscle Mass Index Among Korean Adults: A Nationwide Population-Based Study.” Biomolecules vol. 11,6 842. 5 Jun. 2021, doi:10.3390/biom11060842

Lowe, Dhruv, et al. “Alkaline Phosphatase.” StatPearls, StatPearls Publishing, 11 August 2021.

Lum, G. “Significance of low serum alkaline phosphatase activity in a predominantly adult male population.” Clinical chemistry vol. 41,4 (1995): 515-8.

Mahmoodian, F et al. “Regulation and properties of bone alkaline phosphatase during vitamin C deficiency in guinea pigs.” Archives of biochemistry and biophysics vol. 336,1 (1996): 86-96. doi:10.1006/abbi.1996.0535

Pagana, Kathleen Deska, et al. Mosby's Diagnostic and Laboratory Test Reference. 15th ed., Mosby, 2021.

Ray, Chinmaya Sundar, et al. "Low alkaline phosphatase (ALP) in adult population an indicator of zinc (Zn) and magnesium (Mg) deficiency." Current Research in Nutrition and Food Science Journal 5.3 (2017): 347-352.

Ren, Yongkui et al. “Serum alkaline phosphatase levels are associated with coronary artery calcification patterns and plaque vulnerability.” Catheterization and cardiovascular interventions : official journal of the Society for Cardiac Angiography & Interventions vol. 97 Suppl 2 (2021): 1055-1062. doi:10.1002/ccd.29642

Ryu, W-S et al. “Increased serum alkaline phosphatase as a predictor of long-term mortality after stroke.” Neurology vol. 75,22 (2010): 1995-2002. doi:10.1212/WNL.0b013e3181ff966a

Ryu, Wi-Sun et al. “High serum alkaline phosphatase in relation to cerebral small vessel disease.” Atherosclerosis vol. 232,2 (2014): 313-8. doi:10.1016/j.atherosclerosis.2013.11.047

Sahin, Irfan et al. “Correlation between the serum alkaline phosphatase level and the severity of coronary artery disease.” Coronary artery disease vol. 25,4 (2014): 349-52. doi:10.1097/MCA.0000000000000080

Sharma, Ujjawal et al. “Alkaline phosphatase: an overview.” Indian journal of clinical biochemistry : IJCB vol. 29,3 (2014): 269-78. doi:10.1007/s12291-013-0408-y

Sohrabi, Masoudreza et al. “Serum Alkaline Phosphate Level Associates with Metabolic Syndrome Components Regardless of Non-Alcoholic Fatty Liver; A Population-Based Study in Northern Iran.” Middle East journal of digestive diseases vol. 15,3 (2023): 175-179. doi:10.34172/mejdd.2023.340    

Thapa, P B et al. “Serum gamma glutamyl transferase and alkaline phosphatase in acute cholecystitis.” Journal of Nepal Health Research Council vol. 8,2 (2010): 78-81.