Is an elevation in alkaline phosphatase (alk phos) acceptable after starting a statin (HMG-CoA reductase inhibitor)?

From the Guidelines

A mild elevation in alkaline phosphatase (alk phos) can be acceptable after starting a statin, but significant elevations warrant further evaluation. According to the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol 1, statins like atorvastatin, rosuvastatin, and simvastatin primarily affect liver transaminases (ALT and AST), with alkaline phosphatase typically being less affected. While monitoring liver function tests is recommended when starting statin therapy, isolated mild elevations in alkaline phosphatase (less than 3 times the upper limit of normal) without symptoms generally don't require discontinuation of the medication.

Some key points to consider when evaluating alkaline phosphatase elevations in patients on statin therapy include:

• The degree of elevation: mild elevations (less than 3 times the upper limit of normal) are generally less concerning than significant elevations (more than 3 times normal)
• The presence of symptoms: symptoms like fatigue, abdominal pain, or jaundice may indicate a more serious underlying condition
• The patient's underlying medical conditions: patients with pre-existing liver conditions may require more frequent monitoring and closer evaluation of alkaline phosphatase elevations

However, if alkaline phosphatase rises significantly (more than 3 times normal) or is accompanied by elevated bilirubin or symptoms like fatigue, abdominal pain, or jaundice, the statin should be temporarily discontinued and the patient evaluated for other causes of liver injury or biliary obstruction. The mechanism behind statin-induced liver enzyme elevations involves altered hepatocyte membrane permeability and mitochondrial dysfunction, though these changes are usually transient and resolve with continued therapy or after brief interruption. Regular monitoring of liver function tests at baseline, 12 weeks after initiation, and periodically thereafter is prudent, especially in patients with pre-existing liver conditions, as recommended by the 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol 1.

From the FDA Drug Label

Metabolic and Nutritional System: transaminases increase, liver function test abnormal, blood alkaline phosphatase increase, creatine phosphokinase increase, hyperglycemia An elevation in alkaline phosphatase (alk phos) after starting a statin (HMG-CoA reductase inhibitor) is not explicitly stated as acceptable in the provided drug label.

• The label does mention blood alkaline phosphatase increase as an adverse reaction reported in placebo-controlled trials, but it does not provide guidance on whether this elevation is acceptable or not.
• Elevations in liver enzyme tests are discussed in the label, and it is stated that persistent elevations occurred in 0.7% of patients who received atorvastatin calcium in clinical trials 2. It is recommended to exercise caution and monitor liver enzyme tests when using statins, including atorvastatin. If an elevation in alk phos occurs, it is best to consult the prescribing physician for guidance on how to proceed.

From the Research

Elevation in Alkaline Phosphatase after Starting a Statin

• The available evidence does not directly address whether an elevation in alkaline phosphatase (alk phos) is acceptable after starting a statin 3, 4, 5, 6.
• However, one study found that there were no statistically significant differences between statin treatment groups regarding the mean activity levels of alkaline phosphatase 3.
• Another study compared the effects of different statins on lipid profiles, but did not report on alkaline phosphatase levels 4, 5.
• A study on the metabolism and pharmacodynamics of statins found that statin acids inhibit HMG-CoA reductase, but did not discuss alkaline phosphatase levels 6.
• A study on exercise and hypertension is not relevant to the question of alkaline phosphatase elevation after starting a statin 7.

Statin Therapy and Liver Enzymes

• Statin therapy may improve serum aminotransferase levels, but its effect on alkaline phosphatase is not clear 3.
• Statins can improve adverse outcomes of conditions associated with non-alcoholic steatohepatitis (NASH), such as hyperlipidemia, diabetes mellitus, and metabolic syndrome 3.
• However, the evidence is limited, and more studies are needed to fully understand the effects of statins on liver enzymes, including alkaline phosphatase.