Evaluating the utility of frequent laboratory monitoring among acne patients receiving isotretinoin. A two-center study

ABSTRACT

Introduction:

Acne vulgaris is a common dermatological disorder with significant sociopsychological impacts. Isotretinoin is the mainstay of treatment for severe cases. Adverse effects, such as liver enzyme elevations and lipid profile changes, are linked to this medication. Despite these risks, the need of monthly laboratory monitoring has been questioned, particularly in healthy individuals without comorbidities.

Aim:

This study investigates the incidence of laboratory abnormalities and evaluates the clinical utility of frequent monitoring in acne patients on isotretinoin therapy in Jeddah, Saudi Arabia.

Methods:

This retrospective study included 265 patients treated with isotretinoin at King Abdulaziz University Hospital and King Fahad General Hospital. Data collected included patient demographics, isotretinoin doses, and laboratory results for liver enzymes, triglycerides (TG), and total cholesterol (TC). Laboratory results were assessed at baseline, after 3 months of treatment, and at the last visit. Statistical analyses included the aligned rank transform ANOVA and Wilcoxon Signed-Rank tests to assess changes in laboratory values over time and their relationship with treatment doses.

Results:

Our study group had a median age of 24 years, with 70.9% being female participants. Abnormal lab values increased from 11.7% at baseline to 15.8% during treatment and 14.7% at the last visit. The most common abnormality was high TC levels, rising from 6.8% at baseline to 11.7% at the last visit. Alanine aminotransferase (ALT) abnormalities increased from 3.0% at baseline to 4.9% during treatment but decreased to 2.6% at the last visit. Triglyceride abnormalities showed minimal variation, increasing from 1.1% at baseline to 1.9% at the last visit. Changes in ALT and TG levels were dose-dependent, whereas aspartate aminotransferase and TC levels were not significantly influenced by the starting dose.

Conclusion:

Our research assessed the importance of monthly monitoring of liver function tests and lipid profiles in patients undergoing isotretinoin therapy. The findings emphasize the significance of a personalized monitoring approach. This approach suggests that monthly laboratory testing may only be necessary for a few patients. However, baseline assessments and patient specific follow-ups remain essential.

Introduction

Acne vulgaris is one of the most common dermatological skin disorders, and it has a significant impact on patients, especially psychological aspects, as it has been associated with depression, anxiety, and low self-esteem.[1,2]

The underlying pathophysiology of Acne vulgaris is influenced by hormonal changes. The most recognizable are androgens, which are responsible for increasing sebum production and causing mild noninflammatory type of acne, which topical Tretinoin could manage. Moreover, this process could facilitate bacterial colonization, which usually leads to the development of the more severe type, inflammatory Acne vulgaris. This inflammatory type could still be managed by topical antibacterial medications, if the dermatologist decided that the affected surface area was relatively small. Nonetheless, in more severe cases of acne, management plan with systemic options such as oral antibiotic or oral isotretinoin must be considered, which are more commonly used, as it inhibits sebum production to reverse the underlying roots of this dermatological condition. Treating these patients with oral options is sometimes a necessity since complications such as post-acne scars and hyperpigmentation occur if the patient does not receive the appropriate management[3] as the duration of the isotretinoin treatment plan depends on the severity of the condition, and the usual targeted cumulative dose is 120–150 mg/kg reached at the end of the course, while the starting dose depends on the patient’s body weight.[4]

Although this drug is highly efficacious, it has been associated with several adverse outcomes, most notably teratogenicity, elevated liver enzymes, hypertriglyceridemia, leukopenia, and thrombocytopenia. Apart from the well-known risk of teratogenicity, the risk of other uncommon adverse effects is still not well established.[5] Nevertheless, frequent laboratory monitoring of liver enzymes, lipid profile, and complete blood count is a common practice for patients being prescribed this drug.[2,6]

A lot of literature studies have been questioning the need for frequent routine laboratory investigations as it has been deemed to be unnecessary in healthy patients who do not suffer from any comorbidities,[7] more specifically those without liver diseases, dyslipidemia, diabetes mellitus, hypertension, or obesity. The rarity of such adverse effects whether in the form of clinical manifestation or abnormal increase in laboratory results led to the latest literature recommendation that these laboratory tests should be individualized based on each patient’s risk factors.[8] Improvement in the quality of care could be achieved in patients currently on isotretinoin by decreasing the number of questionably needed blood investigations, which will relieve patients from the financial burden, social stress, and the rescheduling of their commitments. Furthermore, studies have suggested the elimination of the complete blood count and only performing lipid profile and liver enzymes at baseline, 2 or 3 months, and 6 months and at the end of the treatment course.[7] Despite the current recommendations, ordering frequent laboratory investigations is still a common practice.

Primary healthcare physicians are usually the first point in which acne patients get their diagnosis, education, management plans, outcomes, and cost. Since primary healthcare physicians are the best in knowing their patients’ medical history, they can play a central role by educating and putting acne patients on the right map for cost–benefit management plan, ordering necessary baseline labs to make patients ready for necessary treatment and giving dermatologists necessary information for optimized medical care. Moreover, in many areas, dermatologists are overwhelmed by a high number of patients; here, it comes to primary physicians to assess the patients’ laboratory results and reassure patients if the results were normal or notify the dermatologist if any abnormality was observed.

As far as we are aware, there is a lack of research on the necessity of monthly laboratory monitoring during the course of isotretinoin in Saudi Arabia. There is also a lack of research assessing the extent of financial burden in healthy acne patients receiving oral isotretinoin. Therefore, this study aims to explore the incidence of abnormal lab results and to evaluate the clinical utility of frequent laboratory monitoring among Acne Vulgaris patients treated with oral isotretinoin as data have been collected from two centers: King Abdulaziz University Hospital (KAUH) and King Fahad General Hospital (KFGH).

Methods

We conducted a retrospective study at the Departments of Dermatology at both King Abdulaziz University (Reference No 404-23) and King Fahad General Hospital (Reference No A01870), Jeddah, Saudi Arabia. Ethical approval was obtained prior to the study from the hospital’s Ethics Committee. This study included all acne patients who received oral isotretinoin treatment. The inclusion criteria required patients to have completed a minimum of three isotretinoin laboratory tests during their treatment course. These tests included aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglycerides (TG), and total cholesterol (TC).

Data were extracted from patient medical records, including age, sex, treatment duration, initial dose, dose at the end of treatment, baseline laboratory results, follow-up labs, and results from the final visit. We also incorporated laboratory results taken during the treatment course to assess any dynamic changes in the monitored parameters. Statistical analysis was performed using RStudio software (R version 4.3.1).

The study involved a comprehensive review of laboratory results, comparing baseline values to follow-up, mid-course, and final lab results. We analyzed the relationship between total cumulative isotretinoin dose and laboratory abnormalities, as well as the relationship between body weight and laboratory changes during the treatment course.

Out of a total of 350 patients extracted from a database of two centers, only 265 patients have been included in the study; those who lacked full documentation of their laboratory results during the course of isotretinoin have been excluded. 148 patients at King Abdulaziz University Hospital and 117 patients at King Fahad General Hospital diagnosed with acne vulgaris were identified.

In this study, we evaluated changes in AST, ALT, TG, and TC levels in patients treated with oral isotretinoin. The analysis of these values was based on the National Cholesterol Education Program guidelines. AST and ALT levels were classified as normal (<40 U/L) or high (≥40 U/L). TG levels were classified as normal (≤150 mg/dL) or high (>150 mg/dL), and TC levels were classified as normal (≤200 mg/dL) or high (>200 mg/dL).

Statistical analysis

All statistical analyses were performed using RStudio software (R version 4.3.1). Descriptive statistics were used to summarize demographic and clinical characteristics, including frequencies and percentages for categorical variables and median and interquartile range (IQR) for continuous variables. Given the non-normal distribution of laboratory parameters, aligned rank transform analysis of variance (ANOVA) was applied to assess the effect of time on continuous laboratory parameters, followed by post-hoc pairwise comparisons using a paired Wilcoxon Signed-Rank test. A P value of < 0.05 was considered statistically significant throughout the analysis.

Results

Demographic and clinical characteristics

The study included 265 patients, with a median age of 24.0 years (IQR, 20.0 to 30.0). The majority of participants were female (70.9%), while males accounted for 29.1%. Most patients were Saudi nationals (94.3%). The median BMI was 23.3 (IQR, 21.0 to 27.0), and the median body weight was 59.8 kg (IQR, 52.0 to 72.0). Comorbidities such as liver disease (0%), dyslipidemia (0.8%), hypertension (1.5%), and diabetes mellitus (1.1%) were infrequent. Most patients started treatment at a 20 mg dose (71.3%), with peak doses most commonly being 40 mg [40.4%, Table 1].

Table 1.

Demographic and clinical characteristics

Characteristic	Description
Age	24.0 (20.0 - 30.0)
Gender
Male	77 (29.1%)
Female	188 (70.9%)
Nationality
Saudi	250 (94.3%)
Non-Saudi	15 (5.7%)
BMI	23.3 (21.0 - 27.0)
Body weight	59.8 (52.0 - 72.0)
Liver disease	0 (0.0%)
Dyslipidemia	2 (0.8%)
Hypertension	4 (1.5%)
Diabetes mellitus	3 (1.1%)
Starting dose
10	8 (3.0%)
20	189 (71.3%)
30	25 (9.4%)
40	35 (13.2%)
50	6 (2.3%)
60	2 (0.8%)
Peak dose
20	84 (31.7%)
30	59 (22.3%)
40	107 (40.4%)
50	9 (3.4%)
60	6 (2.3%)

Median (IQR); n (%)

Laboratory abnormalities at different time points

Laboratory abnormalities were observed across different time points, with the proportion of any laboratory abnormality increasing from 11.7% at baseline to 15.8% during treatment, and slightly decreasing to 14.7% at the last visit. The most frequent abnormality was high total cholesterol, increasing from 6.8% at baseline to 11.7% at the last visit. The proportion of patients with high ALT increased from 3.0% to 4.9% during treatment and then decreased to 2.6% at the last visit. High AST was observed in 1.5% of patients at baseline, increasing to 2.6% during treatment, and decreasing slightly to 1.9% at the last visit. Triglycerides showed minimal abnormalities, with 1.1% of patients having high levels at both baseline and during treatment, increasing to 1.9% at the last visit [Table 2 and Figure 1].

Table 2.

The frequencies and proportions of abnormal laboratory concentrations at different time points

Characteristic	Baseline	During the course	Last visit
High AST	4 (1.5%)	7 (2.6%)	5 (1.9%)
High ALT	8 (3.0%)	13 (4.9%)	7 (2.6%)
High triglycerides	3 (1.1%)	3 (1.1%)	5 (1.9%)
High total cholesterol	18 (6.8%)	28 (10.6%)	31 (11.7%)
Any lab abnormality	31 (11.7%)	42 (15.8%)	39 (14.7%)

Figure 1.

The proportions of laboratory abnormalities across different time points

Analysis of changes in laboratory parameters over time

There was a significant effect of time on AST levels, with values increasing from baseline (median = 18.2, IQR = 15.0 to 22.0) to during treatment (median = 19.2, IQR = 16.0 to 23.0) and last visit (median = 19.0, IQR = 15.2 to 23.0, P = 0.007). Pairwise comparisons showed significant increases from baseline to during treatment (P = 0.001) and baseline to last visit (P = 0.020). Triglycerides also increased significantly from baseline (median = 24.9, IQR = 14.2 to 68.1) to during treatment (median = 26.1, IQR = 15.0 to 73.0) and last visit (median = 29.0, IQR = 15.1 to 77.0), with overall P < 0.001. The differences were particularly significant from baseline to during treatment (P < 0.001) and from baseline to the last visit (P < 0.001). Total cholesterol followed a similar trend, rising from baseline (median = 97.9, IQR = 75.8 to 157.7) to during treatment (median = 99.0, IQR = 79.0 to 170.6) and last visit (median = 100.0, IQR = 79.0 to 177.8), with all pairwise comparisons yielding P < 0.001. The statistical differences were significant from baseline to during treatment (P < 0.001) and the last visit [P < 0.001, Table 3].

Table 3.

The analysis of differences in the laboratory parameters across different time points and the interaction with the starting dose of isotretinoin

Parameter	Values at different time points, median (interquartile range)			Effect of time*				Pairwise comparisons§			P for the interaction¥
	Baseline (T1)	During the course (T2)	Last visit (T3)	Df	Df residual	F	P	T1 vs T2	T1 vs T3	T2 vs T3
AST	18.2 (15.0 - 22.0)	19.2 (16.0 - 23.0)	19.0 (15.2 - 23.0)	2	517	5.072	0.007	0.001	0.020	0.891	0.438
ALT	13.7 (11.0 - 18.0)	13.7 (11.0 - 20.0)	13.0 (10.0 - 19.3)	2	517	1.383	0.252	>0.999	>0.999	0.057	<0.001
Triglycerides	24.9 (14.2 - 68.1)	26.1 (15.0 - 73.0)	29.0 (15.1 - 77.0)	2	518	28.874	<0.001	<0.001	<0.001	0.138	<0.001
Total Cholesterol	97.9 (75.8 - 157.7)	99.0 (79.0 - 170.6)	100.0 (79.0 - 177.8)	2	518	30.812	<0.001	<0.001	<0.001	0.063	0.161

*The effect of time on laboratory parameter was based on the results of aligned rank transform ANOVA analysis. ^§P-values are based on a post-hoc pairwise comparison using a paired Wilcoxon Signed-Rank test. ^¥P-value for the interaction between time points and starting dose

The interaction between time points and the starting dose of isotretinoin was significant for some laboratory parameters. For ALT (P < 0.001) and triglycerides (P < 0.001), the interaction was statistically significant, indicating that the effect of time on these parameters was dependent on the starting dose of isotretinoin. This suggests that changes in ALT and triglyceride levels over time varied according to the initial dose patients received. In contrast, for AST (P = 0.438) and total cholesterol (P = 0.161), the interaction between time and the starting dose was not significant. This indicates that the changes in AST and total cholesterol levels over time were consistent across different starting doses, and the initial dose did not significantly impact their trajectory [Table 3].

Discussion

Our study aimed to explore the incidence of abnormal lab results among Acne vulgaris patients treated with oral isotretinoin at King Abdulaziz University Hospital and King Fahad General Hospital to assess the clinical utility of frequent lab monitoring among the patients. The findings of this study reveal significant changes in laboratory parameters during isotretinoin treatment, particularly in liver function tests and lipid profiles. The observed elevations in ALT and triglycerides were notable, showing substantial increases from baseline to treatment, and persisted through the last follow-up visit. These results align with previously reported side effects of isotretinoin, where liver enzyme elevations and dyslipidemia are well-documented complications of treatment. The increase in AST levels, although significant from baseline to the last visit, was less marked compared to the changes observed in ALT and triglycerides. The study also examined the interaction between the starting dose of isotretinoin and changes in the laboratory parameters.[1] While ALT and triglycerides showed dose-dependent variations in response over time, AST and total cholesterol did not exhibit significant differences based on the starting dose. The study also showed consistent elevation in the total cholesterol levels during the treatment.

Demographics of studies

Barbieri et al.[5] had 1863 patients with a median age of 18.2 years, and the gender distribution was 49% female; Alajaji et al.[9] presented 407 patients with a mean age of 22.15 years and a slight male predominance of 51.4%; Shah et al.[7] explored 903 patients, with a majority of females comprising 62.9%, while the mean age for the cohort was 28.6 years. Our study focused on 265 patients who were predominantly female, 70.9%, and younger, with a median age of 24 years. The median age in the large cohort of 13,772 reported by Zane et al.[10] was 19 years, of which 51% were male. Ahmad’s study, which included 58 patients, shows a median age of 20 years, reflecting similar trends in demographics.[11] These differences reflect the variation in the populations being studied, but all demonstrate that most subjects treated with isotretinoin are relatively young.

Laboratory parameter monitoring

Barbieri et al.[5] showed a significant decline in monitoring over time, with specific increases in triglycerides and cholesterol. In contrast, our data indicate that despite an increased rate of laboratory abnormalities, especially in total cholesterol level, the monitoring rate was generally adequate as severe abnormalities continued to be rare. Shah et al.[7] further advised that routine monitoring is not essential for each patient every month and proposed a more personalized management system instead. On the other hand, Zane et al.[10] concluded that normal baseline values do not hinder the occurrence of abnormalities at a later stage, reflecting active monitoring. Other papers discovered that while some alteration in laboratory parameter values did occur, the majority were mild and transient, hence reassuring again regarding not having the requirement for routine extensive monitoring but instead targeted monitoring.[11]

Incidence of laboratory abnormalities

In contrast, our study reported increased laboratory abnormalities in the view of the elevation of total cholesterol from 6.8% at baseline to 11.7% at the last visit. Laboratory abnormalities, in general, increased from 11.7% to 15.8% during treatment, which tended down to 14.7% at the last visit. Grade 3 triglyceride abnormalities (defined as a TG level between 751 and 1500 as per CTCAE grades) were reported as less than 1% by Barbieri et al.,[5] which is consistent with our finding of 1.1% abnormalities in TG level at the baseline and during treatment, and 1.9% at the last visit. Moreover, Alajaji et al.[9] reported an increased ALT of 12.7% and an AST of 5.4%, both of which decreased by the last visit, a result that is also consistent with our findings (levels of AST and ALT at the baseline, during treatment, and at the last visit; 1.5%, 2.6%, 1.9% and 3%, 4.9%, 2.6%, respectively); in contrast, Zane et al.[10] pointed out that, during treatment, there was a significant increase in the incidence of abnormal laboratory values, most notably triglycerides, which increased from 14% to 50%. Ahmad noted that although cholesterol and triglyceride levels did increase, most elevations remained within normal limits. Thus, it would seem likely that isotretinoin can indeed cause laboratory abnormalities but that most are generally mild and perhaps reversible.[11]

Risk factors and associations

Alajaji et al.[9] demonstrated that higher body weight was associated with greater elevations in ALT and triglycerides, complementing the findings of Shah et al.,[7] who identified obesity and a rise in baseline triglyceride as risk factors. Our findings aligned with these observations by demonstrating that individual factors, such as the starting dose of isotretinoin, were a determining factor in laboratory parameters. Zane et al.[12] did not discuss the risk factors extensively, but Ahmad gave hints that although laboratory changes were present, significant clinical improvement was noted with a majority of the patients.[11] This could mean that patient profile knowledge is the key to understanding how to manage the treatment.

Conclusion to monitoring practices

All studies argue the reconsideration of routine monitoring practices throughout isotretinoin therapy. In the light of findings by Barbieri et al.[5] and Shah et al.,[7] though baseline assessments are essential, for all patients, this is not indicated routinely on a monthly basis. Alajaji et al.[9] further supported this by showing that significant morbidity rarely occurred, and thus, monitoring should be tailored to the patient. The findings by Zane et al.[10] insist that monitoring should be thorough, while Ahmad showed that mild laboratory changes do not necessarily equate to clinical worsening.[11] This, in turn, suggests that a balanced, individualized approach to monitoring can minimize patient burden without compromising safety.

General implications

In general, isotretinoin laboratory abnormalities incidences are low and tend to be reversible. The bottom line of the study is that a tailored monitoring approach becomes necessary in relation to patient-specific characteristics, treatment duration, and initial dosing for ultimately increasing safety and efficacy. Any further research into the best practices in monitoring should be one step ahead in realizing the production of these insights to secure patient safety while limiting interventions to those genuinely needed.

Overall, our study, along with the evidence, suggests that patients on isotretinoin therapy can still present with laboratory abnormalities, particularly for liver function tests and lipid abnormalities. Although there was not a significant number of patients in the study who presented with laboratory abnormalities, it still seems beneficial for the patient to be followed up during the treatment to help the patients avoid adverse effects of the therapy. Furthermore, the interaction between starting doses and some laboratory parameters suggests that personalized dose adjustments may be beneficial in minimizing adverse effects for certain patients.

Limitations

During our data collection, some of the patients’ information was not fully recorded. Several patients who have started the course of oral isotretinoin therapy did not complete the course of treatment. Patients would not present to their follow-ups or would not perform their scheduled laboratory tests, which would impede the monitoring of the lab values. Moreover, our sample size was somewhat limited, which may impede the generalizability of the findings.

Conclusion

Our research assessed the importance of monthly monitoring of liver function tests and lipid profiles in patients undergoing isotretinoin therapy. The findings underscore the significance of a personalized monitoring approach, which takes into account patient-specific factors such as previous medical illness, body weight, and starting dose. This approach suggests that monthly laboratory testing may only be necessary for a few patients. However, baseline assessments and targeted follow-ups remain essential. Addressing these challenges in future research will be critical for establishing robust, evidence-based recommendations for isotretinoin monitoring practices.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.