Alkaline Phosophatase

Overview

Alkaline Phosphatase (ALP) is predominately found in liver and bone but is also produced by placental and intestinal tissue. It is routinely measured as part of the LFT and Bone profiles.

Levels are physiologically higher in childhood, associated with bone growth, and in pregnancy due to placental production.

Pathologically increased levels occur mainly in bone disease (eg, metastatic bone disease and bone fractures) and cholestatic liver disease—for example, primary biliary cholangitis, primary sclerosing cholangitis, common bile duct obstruction, intrahepatic duct obstruction (metastases) and drug-induced cholestasis. Furthermore, hepatic congestion secondary to right-sided heart failure can also lead to cholestasis (elevated ALP levels and/or bilirubin).

When ALP is elevated in isolation, the measurement of γ-glutamyltransferase (GGT) can indicate whether the ALP is of hepatic or non-hepatic origin.

While there are no data on the most likely causes of an isolated raised ALP in an asymptomatic population, the the most common cause is likely to be vitamin D deficiency, or normal increase seen in childhood due to rapid growth.

Investigation of raised ALP

If ALP is raised and a pathological rather than physiological cause is suspected then measure:

• Gamma GT (GGT) - if elevated then liver origin is more likely.
• Vitamin D - to exclude vitamin D deficiency as possible cause.
• Calcium - to rule out hypercalcaemia (due to bone mets).

Raised ALP and GGT

If both GGT and ALP are raised then some, if not all, of the ALP is likely to be of liver origin. Please see the Liver disease page for further details on investigation.

Raised ALP and normal GGT

If GGT is normal then liver disease is not likely and other causes should be considered:

• Bony metastases - undertake thorough history and examination and investigate if malignancy if a concern (see Red Flags section below). Measure calcium levels.
• Paget’s disease - Paget's Disease: Causes, Symptoms, and Treatment | Doctor | Patient
• Drugs - See What medications cause liver enzymes to be elevated? - US site.
• Renal Osteodystrophy - associated with Chronic Kidney Disease (secondary hyperparathyroidism).
• Recent Fracture

If doubt still exists, the use of electrophoresis to separate the isoenzymes of ALP can differentiate hepatic from non-hepatic causes of increased ALP (can be requested on ICE - include clinical details).

ALP may be also be raised in prostatic disease from liver or bone origin and/or reactivity from increased acid phosphatase levels seen in this condition.

Raised ALP and Low Vitamin D

A low Vitamin D suggests release from bone due to Vitamin D deficiency. There is an increase in levels of alkaline phosphatase (total and bone-specific) early in vitamin D deficiency. Serum calcium and phosphate concentrations only fall in longstanding, symptomatic, vitamin D deficiency (2).

Raised ALP in pregnancy

High ALP levels occur in pregnancy due to placental production and the normal reference ranges do not then apply (levels will be dependent on size of the placenta).

Raised ALP in childhood and adolescence

Active bone growth phases in childhood and adolescence may result in ALP levels of 3 - 4 times the adult range.

Red Flags

If ALP is raised and GGT normal and a there is no physiological cause then consider bony metastases.

Take a thorough history and systems enquiry and perform an examination.

If malignancy / bony mets are suspected:

• Measure calcium to exclude Hypercalcaemia - consider urgent admission if symptoms of severe hypercalcaemia.
• Refer via appropriate USC (2WW) pathway if there is a suspected primary site.
• If no obvious primary site of malignancy, consider further investigations as below:

Investigations for non-specific symptoms/ suspected malignancy (3,4):

• Bloods - FBC, Ferritin, UE,LFT, CRP, TFT, B12, Calcium, HbA1c, CA 125 (Female), PSA (Male), serum electrophoresis.
• Urine - dip for haematuria. Bence Jones protein (as part of myeloma screen)
• Stool - FIT
• Imaging  - CXR, consider CT CAP.

Resources

(1) Guidelines on the management of abnormal liver blood tests (shift8web.com)

(2) Raised alkaline phosphatase – GPNotebook

(3) Recommendations organised by symptom and findings of primary care investigations | Suspected cancer: recognition and referral | Guidance | NICE

(4) Non-Specific Symptoms - USC (2WW) - suspended (Remedy BNSSG ICB)

Efforts are made to ensure the accuracy and agreement of these guidelines, including any content uploaded, referred to or linked to from the system. However, BNSSG ICB cannot guarantee this. This guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer, in accordance with the mental capacity act, and informed by the summary of product characteristics of any drugs they are considering. Practitioners are required to perform their duties in accordance with the law and their regulators and nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.

Information provided through Remedy is continually updated so please be aware any printed copies may quickly become out of date.

Efforts are made to ensure the accuracy and agreement of these guidelines, including any content uploaded, referred to or linked to from the system. However, BNSSG ICB cannot guarantee this. This guidance does not override the individual responsibility of healthcare professionals to make decisions appropriate to the circumstances of the individual patient, in consultation with the patient and/or guardian or carer, in accordance with the mental capacity act, and informed by the summary of product characteristics of any drugs they are considering. Practitioners are required to perform their duties in accordance with the law and their regulators and nothing in this guidance should be interpreted in a way that would be inconsistent with compliance with those duties.

Information provided through Remedy is continually updated so please be aware any printed copies may quickly become out of date.