Author: L. S. Babinets, MD, PhD, Professor, Department of Primary Health Care and General Practice-Family Medicine, SHEI “I. Gorbachevsky Ternopil State Medical University, Ministry of Health of Ukraine”
The significant increase in the incidence of chronic pancreatitis (CP), constant relapses, high level of temporary disability and disability of patients determine the socioeconomic significance of this disease [7, 10, 12]. The affection of the able-bodied population, an almost 4-fold increase in the incidence of CP in young people (the average age of diagnosis decreased from 50 to 39 years), a 30.0% increase in the proportion of women, and an increase in the incidence of alcoholic pancreatitis from 40.0 to 75.0% make CP an urgent issue in the work of a family doctor [4, 11, 12]. In Ukraine, as of 2018, there are up to one million patients with CP [7].
Among the factors that potentially determine the course and prognosis of CP, the leading place is occupied by the enteropancreatic syndrome and, in particular, colon dysbiosis (CD) [1, 8]. The presence and depth of IBD largely determines the severity of the course of CP, the severity of trophological disorders, namely: multivitamin and polymineral deficiency, secondary immunodeficiency, osteoporotic phenomena, anemia, etc. [2, 3, 12].
Attempts to optimize the treatment of dysbiotic phenomena and polynutrient disorders in patients with CD are also relevant. Pathogenetically justified is the use of pro- and prebiotic drugs (PPD) in the complex treatment of CD, which contribute to the normalization of the composition of the colon microbiocenosis (CMC) and the restoration of the functions of the beneficial colon microflora (BCF) [3, 4, 5, 9].
The aim of the study was to determine the effectiveness of complex treatment of patients with CP with concomitant IBD with the additional use of pro- and prebiotic (synbiotic) Opefer for correction of clinical course and trophological changes.
Materials and methods
We examined 70 patients with CP who were treated in the day hospital of the Ternopil Primary Care Center. The patients were divided into two groups according to the programs of complex treatment. The study of the effect of treatment programs was conducted on an outpatient basis, starting from day 10-14 of the baseline treatment, i.e. in the phase of unstable remission. Patients were divided into 2 groups, comparable in terms of gender, age, duration and severity of the disease. The standard treatment regimen (STR), approved by the Order of the Ministry of Health of Ukraine No. 638 dated 10.09.2014 (“Unified clinical protocol for primary, secondary (specialized) medical care and medical rehabilitation in chronic pancreatitis”), was administered to 37 patients with CP (group 1). This group included 21 (56.8%) women and 16 (43.2%) men. In 24 (64.9%) patients, mild, in 11 (29.7%) – moderate, and in 2 (5.4%) – severe course of CP was observed. 12 patients were diagnosed with grade 1 UC, 13 patients with grade 2 UC, and 12 patients without UC. The average age of patients was 51.89±2.52 years, and the average duration of the disease was 10.00±1.20 years.
Drugs in the SSL complex were prescribed on demand, as patients with CP were in an unstable remission phase. Mandatory components of treatment were patients’ adherence to a balanced diet, normalization of body weight, avoidance of overeating, exclusion of alcohol and smoking. SSR consisted of basic treatment: motility regulators – antispasmodics and/or prokinetics, gastrocepin, H2-histamine receptor blockers and/or proton pump inhibitors (PPIs, pantoprazole), enzyme agents.
The second group (33 patients) received complex SSB, enhanced by the use of a probiotic, 1 capsule after the main meal three times a day for 10 days with a transition to a single dose for up to one month. This group included 16 (48.48%) women and 17 (51.52%) men, the average age of patients was 47.21±1.87 years, the average duration of the disease in these patients was 9.21±1.11 years. 19 (57.6%) patients in this group had mild, 13 (39.4%) – moderate, and 1 (3.0%) – severe course of CP. The group included 12 patients with grade 1 DBC, 10 patients with grade 2 DBC and 11 patients with normal CK parameters.
! To correct the detected dysbiotic changes, the pro- and prebiotic (synbiotic) Opefera (World Medicine) was used. This drug was chosen because of the unique original combination of components in each capsule: live lyophilized bacteria – 1.94×109 CFU (Lactobacillus rhamnosus – 0.5×109 CFU, Lactobacillus plantarum – 0.2×109 CFU, Streptococcus thermophilus – 0.5×109 CFU, Lactobacillus acidophilus – 0.5×109 CFU, Bifidobacterium spp. (Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium infantis) – 0.24×109 CFU); Saccharomyces boulardii – 65 mg; dry extract of chamomile flowers (Matricaria chamomilla L.) – 50 mg; inulin – 200 mg. Opefera prevents the development of: dysbiosis, gastroenteritis, dyspepsia; diarrhea (associated with antibiotics, including Helicobacter pylori eradication); hospital diarrhea, transient intestinal dysfunction (diarrhea, constipation, flatulence, colic associated with dietary changes, travel and other causes).
Lactobacillus and bifidobacteria (Lactobacillus rhamnosus, Lactobacillus plantarum, Lactobacillus acidophilus, Bifidobacterium spp. (Bifidobacterium bifidum, Bifidobacterium longum, Bifidobacterium infantis) have high antagonistic activity against a wide range of pathogenic and opportunistic microorganisms, inhibit the vital activity of staphylococci, shigella, rotaviruses, proteus, enteropathogenic Escherichia coli, some yeast-like fungi, and prevent their adhesion to the intestinal mucosa. Lacto- and bifidobacteria create favorable conditions for the development of beneficial IFC, maintain and regulate the physiological balance of IFC, contribute to the normalization of the gastrointestinal tract microbiocenosis, and increase the body’s nonspecific resistance, have immunomodulatory properties, synthesize amino acids, vitamins (K, B, in particular pantothenic acid), which promote the absorption of iron, calcium, vitamin D. Lactobacilli and bifidobacteria activate parietal digestion, participate in the enzymatic breakdown of proteins, fats, carbohydrates and the metabolism of bile acids and cholesterol. The acidic environment created by lactobacilli promotes the development of bifidobacteria, which make up 85-95% of the IFC [3, 4].
Streptococcus thermophilus має максимальну лактазну активність і синтезує полісахариди, є живильним середовищем для лактобактерій, завдяки чому дані види бактерій вступають у симбіоз, компенсують метаболізм один одного і стимулюють взаємне зростання. Saccharomyces boulardii при проходженні через ШКТ надають біологічну захисну дію відносно нормальної МФК.
Chamomile flower extract (Matricaria chamomilla L.) contains essential oil, which contains hamazulene, prohamazulene, other terpenes and sesquiterpenes, as well as flavonoids, polysaccharides, macro- and microelements, carotene, ascorbic acid, β-sitosterol, choline, organic acids. This complex of biologically active substances has antispasmodic, anti-inflammatory, antimicrobial, astringent, diaphoretic, choleretic and sedative properties, increases secretory activity of digestive glands, stimulates appetite, eliminates intestinal spasms, suppresses fermentation processes, improves functional state of the gastrointestinal tract.
Inulin 200 mgis a plant polysaccharide, fructose D polymer. It has a positive effect on the functional state of IFC, as a prebiotic it stimulates the growth of bifidobacteria, increases the absorption of calcium and magnesium, and helps to normalize lipid and carbohydrate metabolism [4, 8].
In this study, Opefera was administered 1 capsule three times a day after meals with water for 10 days with a transition to a single dose for up to one month.
Etiopathogenetic factors were determined using the clinical and anamnestic method. All patients with CP underwent a standardized clinical and laboratory examination. Quality of life (QOL) was assessed using the SF 36 and GSRS questionnaires. Anthropometric parameters were determined to assess the trophological status [5]. The structural state of the pancreas was studied by ultrasound, evaluated in points according to the Marseille-Cambridge classification [9, 12]; excretory function of the pancreas was evaluated by the level of pancreatic α-elastase by enzyme-linked immunosorbent assay. The data of the coprogram, pancreatic α-amylase in the blood by the Caraway method and urinary amylase were evaluated. Endocrine insufficiency of the pancreas was determined by fasting blood glucose.
Serum iron was determined by a photometric colorimetric measurement kit; total serum iron-binding activity (TSI) – by the Human Total iron-binding activity kit; serum transferrin – by the Transferrin Audit Diagnostics reagent kit; serum ferritin – by the Ferritin Audit Diagnostics reagent kit; serum latent iron-binding capacity (LIC) and transferrin iron saturation (TS) were calculated using specific formulas. To assess IBD, a bacteriological examination of feces was performed with the count of colonies of bifidus and lactobacilli, E. coli, opportunistic pathogens, hemolytic and other pathological microorganisms according to the method of R. V. Epstein-Lytvak and F. L. Vilshanskaya. The depth of DBC was assessed by degrees according to I. B. Kuvaeva and K. S. Lado [1, 4].
To analyze the data obtained, we used parametric indicators (Fisher-Student method of variation statistics), Pearson correlation coefficient (r), and in case of improper data distribution, we used nonparametric methods: Mann-Whitney U test, Wilcoxon T test, Fisher’s method, or χ2 test, Spearman’s correlation coefficient (R).
Results and discussion
Baseline data for all studied parameters in groups 1 and 2 were comparable and did not differ significantly (p>0.05). Before treatment, in group 1 there were 12 patients with grade 1 IBD, 13 patients with grade 2 IBD, and 12 patients without IBD, in group 2 – 12 patients with grade 1 IBD, 10 patients with grade 2 IBD, and 11 patients with normal MFC parameters, which indicates baseline data.
After analyzing the results of fecal bacterial cultures in patients with CP after the use of complex SSA, we found normalization of their indicators. The number of sugary flora increased: lactobacilli – by an order of magnitude, bifidobacteria – by two orders of magnitude; the total number of E. coli and the level of E. coli with altered enzymatic properties decreased by two orders of magnitude, the number of fungi and UPM also decreased to normal levels, and pathogenic hemolytic microorganisms and Staphylococcus aureus were not inoculated at all. After evaluating the effectiveness of including the course of treatment with Opefera in the SSR, a significantly higher level of improvement in group 2 in all parameters than in group 1 was found (p<0.05). The number of lactobacilli in group 2 was an order of magnitude higher than in group 1, bifidobacteria – by two orders of magnitude, respectively, the number of E. coli and fungi – by an order of magnitude lower, and lactose-negative E. coli – by two orders of magnitude, hemolytic microorganisms, Staphylococcus aureus and UPM – by three orders of magnitude lower than in group 1.
Table 1 shows the dynamics of clinical symptoms under the influence of the treatment program with the inclusion of Opefera.
According to the data obtained, complex therapy had the greatest effect on bowel movements: all patients with constipation normalized, and diarrhea was observed in one case. It should also be noted its statistically significant effect on other symptoms: pain syndrome decreased by 54.5%, complaints of pain equivalents disappeared, dyspepsia – by 66.7%, flatulence – by 42.4%, nausea – by 36.4%, severity – by 21.2%, asthenoneurotic manifestations – by 30.3%.
Next, we performed a comparative analysis of anthropometric parameters and indicators of the structural and functional state of the pancreas under the influence of SSL and the combined treatment regimen. The results are presented in Table 2.
After analyzing the data, it was found that complex therapy with the use of Opefer’s PPP had a significant effect on the dynamics of pancreatic α-elastase levels, its level increased from 149.03±5.04 μg/g to 183.58±4.43 μg/g, which indicates the restoration of exocrine function of the pancreas in the examined patients, also received a significantly positive decrease in the data of ultrasound of the pancreas from 3.48±0.16 points to 1.61±0.10 points and the indicators of the coprogram from 3.21±0.12 points to 2.00±0.12 points. Repeated determination of BMI and WC did not reveal any significant statistical changes, but the BMD significantly increased from 25.80±0.69 cm to 26.22±0.64 cm, indicating the beginning of the restoration of the somatic protein pool in the body of patients with CP.
The analysis of the results of treatment in groups 1 and 2 revealed a significantly higher level of positive changes under the influence of a complex treatment regimen with the inclusion of Opefer’s PPP: diastase value became lower by 17.06 g/(h×l), amylase – by 3.52 mg/(h×ml), coprogram – by 0.49 points, ultrasound characteristics of the pancreas – by 0.99 points, the level of pancreatic α-elastase increased by 26.44 μg/g, almost reaching normal levels.
Thus, a significantly higher level of efficacy of complex therapy with the use of PPP compared to SSA was proved. The inclusion of Opefera in standard protocol treatment is effective and appropriate for the restoration of the exocrine function of the pancreas.
The next stage of the study was to compare the effectiveness of the proposed treatment regimens on the dynamics of iron metabolism in patients with CP. The data obtained are presented in Table 3.
After analyzing the results, we found a significant (p<0.05) increase in hemoglobin from 110.85±2.85 g/L to 129.73±1.67 g/L, red blood cells from 3.64±0.06×1012/L to 4, 17±0.07×1012/L, serum iron from 10.98±0.76 µmol/L to 17.35±1.03 µmol/L, ferritin from 40.58±4.51 ng/ml to 61.62±2.30 ng/ml, transferrin iron saturation from 15, 65±1.22% to 28.42±2.05% and a decrease in FPG from 72.83±1.48 mmol/L to 63.39±1.26 mmol/L and LPG from 61.85±2.04 mmol/L to 46.04±2.11 mmol/L, indicating the restoration of iron metabolism and a decrease in the depth of anemia syndrome in patients with CP under the influence of a conventional therapy program. The results of treatment in group 2 of patients with CP were also significantly better than in group 1. The level of hemoglobin in group 2 was 7.49 g/l higher than in group 1, erythrocytes – by 0.31×1012 /l, total protein – by 9.44 g/l, serum iron – by 4.16 μmol/l, NTD – by 9.32%, ferritin – by 13.62 ng/ml; ESR value in group 2 was lower than in group 1 by 2.87 mm/h, ESR – by 9.48 mmol/L, LPO – by 13.63 mmol/L, transferrin – by 49.20 mg/dL. Thus, the use of Opefera significantly increased the effectiveness of the complex treatment of patients with CP with concomitant DBC.
The next stage of the study was to investigate the effectiveness of the impact of complex therapy on QOL in patients with CP according to the scales of the GSRS gastroenterological patient questionnaire. The results are presented in Table 4.
After analyzing the dynamics of the level of QOL according to the scales of a specialized gastroenterological questionnaire when using complex therapy with the inclusion of the Opefer PPP, statistically significant (p<0.05) changes were found in group 2 compared to those before treatment in all parameters, in contrast to group 1, where only three scales (AP, RS and IS) were statistically significant. When comparing the effectiveness of treatment programs in groups 1 and 2, it was found that the value of the AP scale in the first case decreased by 13.7%, and in the second – by 17.1% (p<0.01), RS – by 14.4% and by 18.4% (p<0.05), DS – by 5.0% and by 23.9% (p<0.001), CS – by 4.1% and by 19.0% (p<0.01), IS – by 15.0% and by 24.6% (p<0.01), respectively. This proved the higher statistically significant effectiveness of complex therapy with the use of pro- and prebiotic (synbiotic) Opefer.
Thus, the inclusion of the synbiotic Opefera in the standard protocol therapy of patients with CP with concomitant IBD contributed to a significant increase in QOL by 16.5% according to the GSRS questionnaire, restoration of the exocrine function of the pancreas, and improvement of anemia by an average of 33.9%; complete normalization of the state of the colon microflora (only 10 patients had dysbiotic changes of the 1st degree) (p<0.05), which proved the feasibility of including Opefera for the correction of the detected trophological disorders in the complex treatment of CP with concomitant IBD according to the following scheme 1 capsule three times a day after meals with water for 10 days with a transition to a single dose of Opefera for up to one month.
Published in the medical newspaper “Health of Ukraine of the 21st century” № 3 (448)’2019