Introduction
Retinoids are natural or synthetic compounds acquired from vitamin A. Isotretinoin is a synthetic retinoid that has gained popularity in acne treatment. Moreover, oral Isotretinoin is a highly effective treatment used in the management of severe acne. However, Isotretinoin is associated with serious adverse effects and laboratory abnormalities. Hence, laboratory monitoring is advised in patients undergoing Isotretinoin therapy.
What Are the Notable Laboratory Abnormalities Linked to Isotretinoin Therapy?
Isotretinoin is a very successful treatment for acne vulgaris (a common form of acne). But long-term use can lead to some severe side effects. Studies also report an increase in the laboratory values of certain enzymes. The various changes noted in the body are:
1. Lipid Test Abnormalities: There is an elevation of total cholesterol, low-density lipoproteins (LDL), very low-density lipoproteins (VLDL), and triglycerides. However, the high-density lipoprotein (HDL- good cholesterol) level reduces. An elevated triglyceride level is also called hypertriglyceridemia. It is reported that Isotretinoin elevates the triglyceride level in 50 percent and cholesterol in 30 percent of patients. The exact cause of lipid elevation by Isotretinoin is unknown. The retinoids generally bind to plasma albumin. A hypothesis states that tretinoin-albumin interaction in the plasma causes triglyceride displacement from the albumin-triglyceride complex. As a result, it causes serum triglyceride elevation. Another proposed hypothesis is the Isotretinoin interaction with essential proteins or enzymes of lipid metabolism. The following changes can occur following lipid elevation.
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Abnormality of serum lipid parameters may alter the cell membrane and metabolism.
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It can aggravate oxidative stress in the cell.
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Metabolic syndrome can occur in patients on long-term Isotretinoin therapy. Metabolic syndrome involves high blood pressure and blood sugar, excess body fat around the waist, and high cholesterol levels.
2. Elevation of Liver Enzymes: Liver enzymes such as aspartate aminotransferase (AST), alanine transaminase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) are increased. Also, there is an increase in serum total protein level, serum albumin level, lactate dehydrogenase (LDH ) activity, total bilirubin level, and direct bilirubin levels. A chronic elevation of liver enzymes may be indicative of liver damage.
3. Blood Count Abnormalities: Erythrocyte sedimentation rate (ESR) elevation is found. Red blood cells are decreased. As a result, a person can have anemia. Complete blood count (CBC) abnormalities also occur. Others include abnormalities in reticulocyte count, hemoglobin level, neutrophil, eosinophil, basophil, monocyte, lymphocyte, and platelet count. The white blood cells (WBC) and platelet count can decrease during the therapy.
4. Urine Test Abnormalities: The specific gravity of urine is increased. Specific gravity measures the urine electrolytes. Further, the WBC count in urine is also elevated.
5. Kidney Function Test Abnormalities: The blood urea nitrogen (BUN) level, serum uric acid level, and creatine kinase (an enzyme) activity are increased. These enzymes are indicative of kidney pathology.
6. Others: Serum glucose, calcium–phosphate regulation (serum calcium and phosphate level), and semen test abnormalities are seen.
What Is the Optimal Approach to Laboratory Monitoring in Patients Undergoing Isotretinoin Therapy?
A simple approach is applied for laboratory evaluation for patients taking Isotretinoin. The laboratory monitoring recommendations for Isotretinoin are:
1. Females of Reproductive Age:
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In women of reproductive age, two negative pregnancy tests are necessary before Isotretinoin therapy initiation. The first pregnancy test must be up to 30 days before starting the medication. The second pregnancy test must occur at least 19 days after the negative pregnancy test. Further, it should be within the first five days of the menstrual cycle.The patient should record the negative pregnancy test to continue therapy. A final pregnancy test should be 30 days after therapy completion.
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The females of reproductive age must be on two effective forms of birth control. Otherwise, they should be on complete abstinence while receiving Isotretinoin therapy. iPLEDGE (a safety program) has been implemented to ensure that pregnant women do not take Isotretinoin. iPLEDGE defines abstinence as no sexual intercourse with any male 24 hours a day for a week. One of the birth control methods must be a “primary form,” which includes tubal sterilization, intrauterine device, or hormonal contraception. Secondary forms are male latex condoms, diaphragm, cervical cap, or vaginal sponge.
2. Pretreatment Monitoring: Liver function tests (LFTs), fasting lipid profile (including triglycerides), blood glucose, creatinine phosphokinase (CPK), and complete blood counts (CBC) should be done before Isotretinoin. Screening for mood alteration, psychosis, aggression, skin changes, and visual changes should also occur before starting Isotretinoin. This is because Isotretinoin causes these side effects.
3. Ongoing Monitoring: LFTs and lipids require biweekly monitoring until a response is established to Isotretinoin.
4. Healthy Patients: For patients without pre-existing medical conditions, it is sufficient to test liver enzymes and triglycerides once at baseline. It should be done within a month before treatment initiation and a second time at the peak dose. Other tests such as CBC, basic metabolic panel, and specific laboratory tests such as GGT, serum bilirubin, total protein, serum albumin, LDL, HDL, and C-reactive protein (CRP) do not need routine monitoring.
The recommendations for frequent laboratory monitoring are not specific. Some studies suggest that routine laboratory monitoring may have low clinical utility. Further, some studies are against excessive laboratory monitoring. For example, several studies on healthy teenagers and adults have shown that routine CBC tests are unnecessary. Similarly, LFTs and lipid panels ordered at baseline and after two months of therapy are sufficient. Hence, in a nutshell, the recommendations for a healthy patient are:
Before Therapy Initiation (Within a Month) - Check LFTs and a lipid panel.
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Initiation of Isotretinoin - No additional laboratory tests are required.
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At Peak Dose - Recheck LFTs and a lipid panel.
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End of Treatment - No additional laboratory tests are required.
What Are the Disadvantages of Excessive Laboratory Monitoring for Isotretinoin Therapy?
The following are the disadvantages of excessive laboratory testing for Isotretinoin therapy.
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The cost of laboratory testing also includes indirect costs, such as missed time from work.
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The inconvenience of frequent clinic visits may dissuade patients from continuing Isotretinoin therapy. Therefore, it can directly translate to poorer patient outcomes.
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Repeated unnecessary monitoring presents a psychosocial burden for the patients. It is because the patients worry about potential rare abnormalities that may appear on laboratory tests.
Hence, limited testing can reduce the patient’s fear of therapy and its cost.
Conclusion
Frequent laboratory monitoring is advised only during induction and ongoing therapy with Isotretinoin to monitor adverse effects. Besides, more monitoring depends on the patient’s medical history, circumstances, and baseline abnormalities. Hence, an interprofessional medical team approach is necessary.
