The Association Between Somatostatin Receptor Ligand and Vitamin B12 Levels in Patients With Acromegaly

Purpose: Vitamin B12 causes hematologic and neuropsychiatric disorders, so it is important to evaluate it in risky situations. In this study, we aimed to evaluate the association between somatostatin receptor ligands and vitamin B12 levels in patients with acromegaly. Methods: Patients who were followed up with the diagnosis of acromegaly in the Endocrinology and Metabolism outpatient clinic of Istanbul University-Cerrahpaşa Medical Faculty were evaluated. Patients were divided into groups according to their somatostatin receptor ligand use status. The groups were evaluated according to their vitamin B12 levels, demographic data, and biochemical parameters. Results: One hundred fty-two patients were evaluated. Thirteen patients had vitamin B12 deciency. The majority (11/13) of patients with vitamin B12 deciency were patients using somatostatin receptor ligand. In addition, the number of patients with vitamin B12 deciency who received lanreotide autogel treatment was signicantly higher compared with patients who did not use somatostatin receptor ligand (p = 0.011). Vitamin B12 levels were higher in patients who received lanreotide autogel treatment than in patients who did not use somatostatin receptor ligand treatment (p = 0.040). There was a negative correlation between vitamin B12 levels and lanreotide autogel use time, cumulative lanreotide autogel dose. Conclusion: It is important to evaluate the level of vitamin B 12 in the follow-up of patients with acromegaly using somatostatin receptor ligand treatment.

compared with each other in terms of age, sex, alcohol, and smoking status, Vit-B12 level, Vit B-12 de ciency, biochemical parameters, biochemical control status, and PPI, metformin, cabergoline, and pegvisomant use.
This study was approved by the Local Ethics Committee of Cerrahpasa Faculty of Medicine. The study adhered to the tenets of the Declaration of Helsinki.

Statistical Analysis
The Statistical Package for the Social Sciences v.22.0 software was used. The distribution of variables was evaluated using the Kolmogorov-Smirnov test. In normally distributed variables, continuous data are given as means ± standard deviation (SD), in non-normally distributed variables, continuous data are given as median [IQR] and categorical data are given as numbers and percentages. In the comparisons of two groups, the Mann-Whitney U test was performed in the analysis of quantitative, non-normal distribution, and independent data. The independent samples t-test was used in the analysis of quantitative, normal distribution, and independent data. In the comparisons of three groups, for the analysis of quantitative independent data, we used analysis of variance (ANOVA) for data with normal distribution, and in post-hoc analysis, we performed the Bonferroni test. For data with non-normal distribution, we used the Kruskal-Wallis, and Mann-Whitney U test for the analysis of quantitative independent data Bonferroni correction was then performed to account errors due to the multiple comparisons among groups A, B, ad C. The Chi-square test, and, if Chi-square conditions were not be met, Fisher's test was performed in the analysis of qualitative independent data. Statistically signi cant results were considered as P < 0.05. The con dence level was set at 95%.

Results
In our study, 160 patients with acromegaly were assessed. Three patients were excluded due to atrophic gastritis, one due to terminal ileum resection, and four patients due to irregular SRL treatment use. One hundred fty-two patients with acromegaly were evaluated, 71 (46%) of the patients were male and 81 (54%) were female. All data were evaluated according to the period in which the patients were assessed for Vit B-12. The mean age of the patients was 45.3 ± 11.8 years, the mean age at the time of diagnosis was 41.1 ± 12.0 years. The mean duration of the disease was 32. 5  , 6800 [range, 5800-8300] mcL, and 249,000 [range, 200,000-292,000] mcL, respectively. The alcohol consumption and smoking data of 111 patients were obtained. Seven (6%) patients consumed alcohol, and 36 (32%) patients smoked. One (7%) of 13 patients with Vit B-12 de ciency smoked, while none of them consumed alcohol.
Abdominal imaging was present in 102 (67.1%) patients. Of these patients, 97 (63.8%) had abdominal ultrasonography, three (2%) had abdominal magnetic resonance imaging (MRI), two (1.3%) had abdominal computed tomography (CT) imaging. None of these patients had any ndings of pancreatitis. Fifty-three patients had upper gastrointestinal system endoscopy. None of these patients had any ndings of atrophic gastritis. Of the 13 patients with Vit B-12 de ciency, seven (53%) had abdominal imaging, and none had signs of pancreatitis. Upper gastrointestinal endoscopy and endoscopic biopsy were performed in all patients with Vit B-12 de ciency. Only one patient had antrum biopsy, while the others had both antrum and corpus biopsy. Atrophic gastritis was not detected in any of the patients. General features of patients with Vit B12 de ciency are presented in Table 1. No signi cant difference was found among the groups in terms of sex and age (p = 0.631 and p = 0.666, respectively). There was no signi cant difference between the groups in terms of alcohol consumption and smoking (p = 0.701 and p = 0.911, respectively). Vit B-12 de ciency was present in 11 (11.8%) patients in the SRL treatment + group and 2 (3.4%) patients in the SRL treatment -group, which was not statistically signi cantly different (p = 0.070). In addition, the median Vit B  Table 2. In the correlation analysis, a negative correlation was found between Vit B-12 levels and the duration of SRL use (p = 0.030 r = -0.232). However, no correlation was found between Vit B-12 levels and age and total disease duration.

The comparison of groups A (SRL treatment -), B (Octreotide LAR +), and C (Lanreotide autogel +)
There was no statistically signi cant difference between the groups in terms of sex and age (p = 0.464 and p = 0.162, respectively). The disease duration was found to be signi cantly lower in group A (SRL treatment -) (p < 0.05). There was no signi cant difference between the groups in terms of alcohol consumption and smoking (p = 0.533 and p = 0.178, respectively). In terms of Vit B-12 de ciency, the number of patients with Vit B-12 de ciency was found to be signi cantly higher in group C (lanreotide autogel +) than in group A (SRL treatment -) (p = 0.011). Although there was no statistically signi cant difference, the number of patients with Vit B-12 de ciency was higher in group C (lanreotide autogel +) than in group B (octreotide LAR +) (p = 0.091). When analyzed in terms of Vit B-12 levels between the groups, Vit B-12 levels were found to be signi cantly lower in patients using lanreotide autogel (group C) than in patients not using SRL treatment (group A) (p = 0.040). There was no signi cant difference between the groups in terms of anemia and MCV. Although there was a signi cant difference in terms of hemoglobin and hematocrit (p = 0.050 and p = 0.039, respectively), the statistical signi cance disappeared in pairwise comparisons. There was no signi cant difference between the groups in terms of pegvisomant, PPI, and metformin use (p = 0.442, p = 0.221 and p = 0.141, respectively). However, the use of cabergoline was found to be signi cantly lower in group B than in the other groups (p < 0.001 and p < 0.001, respectively). There was no signi cant difference between the groups in terms of GH, IGF-1, IGF-1-ULN, and disease control (p = 0.622, p = 0.752, p = 0.785, and p = 0.706 respectively). The comparison of groups A-B-C are presented in Table 3. There was no statistically signi cant difference among groups, but a signi cant difference was found between Group A and Group C in pairwise comparisons (p = 0.040) c Group C vs. Group A (p = 0.011) d,e There was a signi cant difference in terms of hematocrit (p = 0.048) among groups, but, the signi cance disappeared in pairwise comparisons.
In the correlation analysis, a negative correlation was found between Vit B-12 level and cumulative lanreotide autogel dose (p = 0.048, r = -0.342), the duration of lanreotide autogel use (p = 0.035, r = -0.363) in group C (lanreotide autogel). However, no correlation was found between Vit B-12 levels and age, total disease duration, and dose (mg/28 days). In group B, there was no signi cant correlation between Vit B-12 levels and these parameters (Table 4).

Discussion
The majority of patients with Vit B-12 de ciency were in the SRL (+) treatment group. The number of patients with Vit B-12 de ciency was found to be signi cantly higher in the group that received lanreotide autogel treatment (group C) compared with the patients who did not receive SRL treatment (group A).
In addition, Vit B-12 levels were found to be signi cantly lower in patients who received lanreotide autogel treatment compared with patients who did not receive SRL treatment. Considering the factors affecting Vit B-12 de ciency, a negative correlation was found between the duration of lanreotide autogel treatment, cumulative lanreotide autogel dose and Vit B-12 levels. There was no difference between the groups in terms of PPI, metformin, alcohol consumption, and smoking. Hemoglobin and hematocrit levels were found to be signi cantly lower in patients treated with SRLs.
Although there are data that somatostatin analogs cause Vit B-12 de ciency, there is not robust studies in the literature on this issue. In an early study conducted by Plockinger et al., 10 patients with acromegaly treated with subcutaneous octreotide were prospectively evaluated. In patients with normal Vit B-12 levels at the initiation of octreotide treatment, Vit B-12 levels decreased over time. When the treatment period was prolonged, Vit B-12 levels fell below the normal limits in four patients [12]. In our study, although the level of Vit B-12 was not statistically signi cant, it was found to be lower in the group with SRL treatment. In addition, the number of patients with de cient Vit B-12 levels in patients who received lanreotide autogel treatment was found to be signi cantly higher than in those who did not receive SRL treatment. In addition, Vit B-12 levels were lower in patients who received lanreotide autogel treatment compared with patients who did not receive SRL treatment. However, this difference was not detected in the group receiving octreotide LAR treatment. Interestingly, although the signi cance was found in the group receiving lanreotide autogel treatment, the duration of octreotide LAR treatment was signi cantly longer than lanreotide autogel treatment.
The mechanism by which somatostatin analogues cause Vit B-12 de ciency is also unclear because there has not been much research on this issue. There are two opinions on this subject. First, somatostatin analogs can directly inhibit the release of IF, leading to Vit B-12 de ciency [12]. The other view is that somatostatin analogs may cause Vit B-12 de ciency by preventing acid secretion from gastrin-secreting cells, creating hypochlorhydria [12, 13]. We cannot comment on this subject because our study is retrospective, but this issue needs large, and prospective studies.
Vit B-12 de ciency causes megaloblastic anemia by disrupting DNA synthesis. In addition to anemia, it can cause a decrease in all blood cells (pancytopenia) [14]. In our study, none of the patients with Vit B-12 de ciency had macrocytic anemia or pancytopenia. There was no difference between the groups in terms of MCV. There is not much information on this subject in the literature. In the study of Plockinger et al., although Vit B-12 de ciency was observed in patients receiving octreotide treatment, no hematologic change was detected in any patients [12].
There are several limitations to our study. The IF levels of the patients could not be evaluated because of our study's retrospective design, and pre-SRL treatment Vit B-12 levels were unknown. The course of Vit B-12 could not be evaluated in patients receiving SRL treatment. In addition, neurologic examinations of patients with Vit B-12 de ciency could not be performed.
In conclusion, Vit B-12 levels have an important place in patient follow-up due to their hematologic and neurologic consequences. Evaluation and determination of Vit B-12 levels in the follow-up of patients with acromegaly receiving SRL treatment allow us to perform replacement at the appropriate time. Before pancytopenia and neurological de cit occur, initiation of Vit B-12 replacement can provide positive results in terms of time and economic burden for the patient and healthcare providers.