Features of the course of ulcerative colitis

Relevance

Ulcerative colitis (UC) occupies a significant place in the structure of abdominal surgical pathology; however, it remains one of the least studied and most challenging diseases in clinical management. Epidemiological data demonstrate considerable variability in disease prevalence depending on the geographical region, ranging from 5.3 to 505 cases per 100,000 population, with an average annual incidence of 20–28 cases per 100,000 individuals. To date, the global population of patients with ulcerative colitis exceeds 4 million people, indicating the scale of this medical and social problem [1–6].

The paradox lies in the fact that, despite ongoing attention to this pathology in the global scientific and clinical literature, the introduction of new pharmaceutical agents in recent years has not led to a significant improvement in therapeutic outcomes. This is due to the high rate of disability among individuals of working age, reaching 40% or more, as well as postoperative mortality exceeding 17%. This situation is explained not only by the insufficient effectiveness of current treatment approaches but also by the multifactorial nature of the pathogenesis of ulcerative colitis [7–9]. Contemporary understanding of the disease’s genesis places great emphasis on hereditary and genetic factors; however, the data accumulated in this area are often characterised by uncertainty and internal inconsistency. Further investigation of the genetic aspects of ulcerative colitis will enable the refinement of personalised approaches to the treatment and prevention of this patient population [2, 10–14].

Key problems hindering the optimisation of treatment include the absence of clear and objective criteria for determining the optimal extent of surgical intervention, its indications, and timing. Prognostic criteria for the course of the pathological process, necessary for timely preventive therapy and prevention of relapses, remain largely undeveloped. The lack of objective prognostic markers precludes the timely administration of preemptive therapy, ultimately leading to a reduced quality of life and impaired social adaptation of patients [9, 15, 16].

The foregoing circumstances confirm the high relevance of comprehensive research into both the therapeutic and preventive aspects of ulcerative colitis. The development of methods for predicting the course of the disease and determining optimal treatment strategies is an important and promising task in modern abdominal surgery and gastroenterology.

Objective

To improve treatment outcomes in patients with ulcerative colitis based on predicting its course.

Materials and Methods

The work is based on clinical observations and specially conducted studies of 144 patients with UC who were hospitalised in coloproctology, gastroenterology, and surgery departments in the Yaroslavl, Vologda, Kostroma, and Ivanovo regions over a period of 20 years. The studies were both retrospective and prospective in nature. All patients were hospitalised on an emergency basis. The diagnosis of ulcerative colitis was established based on a comprehensive assessment of clinical manifestations, ultrasound data, colonoscopy, laparoscopy, surgical intervention, morphological studies, as well as monitoring of the disease course by a gastroenterologist and surgeon after hospital discharge. Existing clinical guidelines were taken into account.

Among the examined individuals, there were 67 women (46.5%) and 77 men (53.5%). Patient age ranged from 14 to 87 years, with a mean of 45 years. The highest incidence of the disease was observed in the age group from 31 to 60 years (91 patients, 63.1%). In the older age group (over 60 years), clinical manifestations were observed in only 24 patients (16.8%). In more than 20% of cases, the disease developed in young patients. In the vast majority of cases, disease duration did not exceed 5 years (61.8%). Disease duration of up to 10 years was found in 16.7%, up to 20 years in 17.4%, and more than 20 years in only 4.2% of cases. It should be noted that in more than 20% of cases, the disease developed in patients under 30 years of age.

According to disease severity, mild severity was observed in 27.8%, moderate in 43.1%, and severe in 29.1% of cases (Truelove and Witts classification, 1955). An acute course of the disease occurred in 31.9%, chronic continuous in 36.8%, and chronic relapsing in 31.25% of observations. When assessing disease activity according to the Schroeder endoscopic classification (1987), minimal activity was found in 31.45%, moderate in 37.1%, and severe in 31.45% of cases. Regarding the localisation of the pathological process, isolated rectal involvement was observed in only 10 (7%) patients, left-sided colitis in 31 (21.5%), and total colonic involvement in 103 (71.5%) patients.

All patients received conservative treatment in accordance with clinical guidelines, also taking into account the severity of the UC attack. Conservative treatment alone was administered to 76 patients aged 19 to 83 years. In this group, there were 39 men and 37 women. Disease duration ranged from 10 days to 30 years. Mild UC was observed in 37.9%, moderate in 50.6%, and severe in 11.5% of cases. An acute course of the disease was identified in 17.2%, chronic continuous in 38%, and chronic relapsing in 44.8% of cases. Severe disease activity was found in only 13.3% of patients. Conservative treatment was carried out in a specialised department by a gastroenterologist, in consultation with a surgeon when necessary.

Surgical treatment was performed in 68 patients, accounting for 47.2% of all examined patients. In this group, there were 36 men and 32 women. Patient age ranged from 14 to 87 years. Patients over 40 years of age predominated. In the surgical treatment group, severe activity (65.9%) and severe attack severity (58.8%) dominated, against a background of acute course (38.2%) and total colonic involvement (72.1%). Indications for surgery were: ineffectiveness of conservative therapy (hormonal resistance, inefficacy of biological therapy) – 30.5%; intestinal complications of UC (toxic dilatation, bowel perforation, intestinal bleeding, colonic stenosis) – 66.2%; and colorectal cancer or high risk thereof – 3.3%. The extent of surgical intervention was determined by the extent of the inflammatory process and involved removal of the affected colon (see Table 1). Completion of surgical intervention with primary anastomosis was performed in 8 (11.7%) patients: after resection of the colon – 5 (7.3%), after coloproctectomy – 2 (2.9%), after subtotal colectomy – 1 (1.4%). In 41 (60.2%) patients, the operations were completed with Brook ileostomy: after subtotal colectomy – 7 (10.2%), after colectomy – 13 (19.1%), after coloproctectomy – 21 (30.8%). Ileostomy reconstruction due to stenosis was performed in 5.8% of cases.

Table 1. The extent of surgical intervention and mortality rate in ulcerative colitis

In 3 patients, the postoperative period was complicated by the development of peritonitis due to small bowel perforation. Wound complication in the form of suppuration occurred in 2.9% of cases. Fatal outcomes were observed in 19 patients (27.9%) and were mainly associated with progressive baseline multiple organ failure. Among deceased patients, an acute course of the disease and total colonic involvement predominated – 13 (27.1%) patients, with a severe attack in 12 (30.0%) patients. In these cases, the mortality rate reached 50%. Postoperative mortality was determined not only by the variants of UC course but also by the extent of surgery. In particular, high mortality rates prevailed after coloproctectomy in the setting of severe endoscopic activity and severe disease attack (28.6% and 23.8%, respectively). In the acute course of the disease, the highest mortality rates were observed after coloproctectomy and hemicolectomy (23.8% and 40%, respectively). These data should apparently be considered as starting points when choosing the extent of surgery and the optimal timing for its performance.

The research methods were primarily aimed at identifying disturbances in vital body functions. Homeostasis disorders were assessed by parameters of central hemodynamics [Shishmarev Yu.N. et al., 1989; Zabolotskikh I.B. et al., 1998], peripheral blood indicators [Menshikov V.V., 1987], and variational pulsometry [Baevsky R.M., 2001]. The control group consisted of 40 individuals without concomitant somatic pathology. Upon admission and during examination, all patients underwent ultrasound examination of the abdominal cavity; in 88.8% of observations, diagnostic video colonoscopy was performed. When acute intestinal obstruction or perforation of a hollow organ was suspected, X-ray examination of the abdominal cavity was performed (65%). Colonic stenosis of various localisations and extents was detected in 8 (6.25%) patients, suspicion of colorectal cancer – in 6 (4.7%) patients. Colonic wall thickening according to ultrasound data averaged 7.833±2.194 mm. Patient quality of life was assessed using the SF-36 health status questionnaire [Ware J.E., 1994]. Morphological studies of resected bowel were performed in 24 patients. The studies were conducted at the Department of Pathological Anatomy, Yaroslavl State Medical University (Head of Department – Prof. S.V. Kulikov). To assess connective tissue metabolism, the concentration of free hydroxyproline in blood plasma was determined (method of Sharayev P.N., 1981) in 21 patients with ulcerative colitis. The control group consisted of 10 donors.

Data processing was carried out using Microsoft Excel 2016, STATISTICA 8.0, Biostatistics, and MedCalc v.18.2. The distribution of results was assessed using the Kolmogorov–Smirnov and Shapiro–Wilk tests. When the distribution was normal, results were presented as M ± m, where M is the mean and m is the standard error of the mean, and parametric tests were used for analysis. Among parametric methods, Student’s t-test and analysis of variance for dependent and independent samples were used. Among nonparametric methods, the Mann–Whitney paired test was used; for comparison of more than two independent samples, the Kruskal–Wallis test was used. For the assessment of non-numerical values, Fisher’s exact test and the χ² test were used. Correlation analysis between studied parameters was carried out using Pearson’s criterion with Yates’ correction. A difference was considered significant at p <0.05. To assess the prognostic effect of risk factors and their possible combinations, Receiver Operating Characteristic (ROC) analysis and logistic regression analysis were used.

Results and Discussion

The spectrum of clinical manifestations in ulcerative colitis is quite diverse. The leading clinical symptom is diarrhoea, which was identified in 81% of all patients. The next most frequent sign is blood in the stool, which appears against the background of diarrhoea in more than 69% of cases. The frequency of diarrhoea per day can reach 8–10 times. The appearance of persistent diarrhoea accompanied by melena can largely be qualified as an early manifestation of ulcerative colitis with all the ensuing consequences. Against this background, weakness and malaise develop in 57% of patients, and abdominal pain occurs in 58% of cases. It should be noted that the frequency of fever is relatively low (23.6%), as is that of nausea and vomiting (9.9%). A very important clinical symptom is weight loss (14.8%), apparently as a result of long-standing bowel dysfunction. During this period of the disease, the activity of the ulcerative process is evident, and a comprehensive set of therapeutic measures is greatly needed. In the group of patients who subsequently required surgical treatment, the frequency of diarrhoea increased by 11%, melena by 17%, fever by 304%, and nausea and vomiting by more than threefold. At the same time, the frequency of pain syndrome and weight loss did not undergo significant changes.

Regarding gender differences, it should be noted that in women, the frequency of pain syndrome (by 23%) and dyspeptic disorders (twofold) increases against the background of a decreased frequency of diarrhoea (by 9%). Depending on the severity of the UC attack, a clear trend towards an increase in symptom frequency is observed as the inflammatory process progresses. In particular, compared with moderate attack, the frequency of pain syndrome in severe UC attack increases by 6.1%, nausea and vomiting – threefold, fever – 3.2-fold, diarrhoea – by 11.5%, melena – by 25.6%, weakness and malaise – 1.5-fold, and weight loss – by 49%. A similar trend is observed with increasing endoscopic activity of the disease. This is most pronounced for fever, weight loss, and dyspeptic disorders. The degree of increase in these indicators with severe activity compared to moderate activity is 5.7, 2.7, and 7.5 times, respectively.

The frequency of symptoms in ulcerative colitis acquires certain clinical significance depending on the extent of the inflammatory process and its localisation in the colon. When only the rectum is involved, diarrhoea occurs in all cases, and melena manifests in half of the patients. When the left side of the colon is involved, the frequency of diarrhoea decreases to 83%. However, melena develops in more than 75% of patients, and pain syndrome in 72.5% of cases. With total colonic involvement, no significant changes in frequency are observed; however, an increase in the frequency of fever to 27.8% and dyspeptic disorders to 13% should be noted.

Changes in the complete blood count mainly manifested as the disease progressed. In severe disease compared with mild severity, haemoglobin levels decreased by 26.5% (p <0.05), total protein by 26.1%, potassium by 12.8% (p <0.05), with relative stability of chlorides and sodium. It should be noted that the detected disturbances developed against the background of the appearance and increase of intoxication. In the overall patient group, the mean leukocyte intoxication index (LII) was 2.335±0.05 arbitrary units. As the pathological process progressed, it increased more than 1.5-fold (p <0.05).

Regarding hemodynamic parameters, the changes were quite substantial. Stroke volume (SV) increased to an average of 110.1±1.75 mL, cardiac output (CO) to 6603.5±104.96 mL, against a background of a more than 3.6-fold decrease in peripheral vascular resistance (PVR) (568.9±12.27 dyn·s/cm) (p <0.05). At the same time, the gradation of these parameters depending on the course of the disease and gender differences was not significant. However, changes in autonomic homeostasis were quite considerable. In the overall patient group, variational pulsometry indicators were as follows: Mode (Mo 0.79±0.016 s), amplitude of mode (AMo 66.1±1.3%), variational range (Δ% 0.08±0.008 s), stress index (SI 848.7±54.79 arbitrary units) (see Table 2).

Table 2. Variational pulsometry indicators in ulcerative colitis

Note: * — significance relative to the control group (p <0.05).

As the disease progresses, sympathetic activity increases quite substantially. In particular, in severe pathological process compared with the initial period of the disease, Mo decreased by 16.7% (p <0.05), accompanied by a 1.6-fold increase in stress index (p <0.05). At the same time, treatment method, localisation of the pathological process, and gender differences did not have a significant effect on the change in sympathetic activity. However, sympathetic activity increased with increasing patient age.

Morphological examination of the specimens revealed the appearance of epithelial dysplasia (Fig. 1).

a
b
c

Fig. 1. Variants of epithelial dysplasia in ulcerative colitis
a — mild dysplasia of tubular glandular epithelium with slight atypia. Hematoxylin and eosin stain. Magnification: 200;
b — moderate dysplasia of glandular epithelium with irregular shape and pronounced atypia. Hematoxylin and eosin stain. Magnification: 100;
c — severe dysplasia of solid glandular epithelium with pronounced atypia. Hematoxylin and eosin stain. Magnification: 200.

The identified morphological changes led us to study the content of hydroxyproline in peripheral blood as a marker of the functional state of connective tissue. Studies were conducted in 21 patients with ulcerative colitis. It was found that in ulcerative colitis, there is a decrease in plasma hydroxyproline to 15.9±0.97 µmol/L, i.e., by 11.1% compared with the control. Depending on the course of the disease, significant differences were observed in moderate severity: 17.0±1.33 µmol/L (p <0.05). The obtained data suggest that the activity of collagen biodegradation in ulcerative colitis is low.

An integral indicator of the general condition of patients with ulcerative colitis is undoubtedly their quality of life (see Table 3).

Table 3. Quality of life indicators in patients with ulcerative colitis

Note: * — significant (p <0.05) compared to the previous group.

Analysis of quality of life in 80 patients with this disease over a period of 30 years showed that patients’ quality of life is determined by the course of the disease, its duration, the nature of therapeutic interventions, patient age and gender, as well as the localisation of the pathological process. Depending on disease duration, indicators tend to decrease with disease duration of 6–10 years and 21–30 years. Physical functioning (PF) scores for disease duration of 11–20 years are 15.4% higher than for duration of 6–10 years. Similarly, levels of role physical (RP) (by 38.6%) and social functioning (SF) (by 5.2%) determined by physical condition increase. In addition to the physical component of health (PH), the psychological status of patients improves over time. Levels of mental health (MH) and role emotional (RE) increase by 4.3% and 42.6%, respectively (p <0.05), for disease duration of 11–20 years. Physical functioning scores with minimal activity are 26.9% higher than with severe activity. Similarly, the level of role physical (by 49.8%) and social functioning (by 34.7%) determined by physical condition decreases. As endoscopic disease activity decreases over time, the psychological status of patients improves by 16.8% (see Table 3). Regarding the type of treatment received, the pain intensity score was 17.2% higher in patients after surgical treatment.

To improve the treatment outcomes of ulcerative colitis, predicting the course of the disease is undoubtedly important. This allows timely prescription of preventive therapy and thereby reduces the possibility of disease relapse, and when surgical treatment is indicated, enables surgical intervention to be performed in a more favourable period. In this regard, a study using multivariate statistical methods was conducted. To this end, the logistic regression method was used. The applied multifactorial system for predicting the effectiveness of treatment choice in ulcerative colitis was based on the following significant predictors: patient gender (G), anamnestic features (AF), endoscopic activity (EA), stool frequency (SF), and coded data on the acuteness of the course (AC). The stated goal is achieved by calculating the prognostic coefficient for the effectiveness of conservative and surgical treatment methods for ulcerative colitis (PCml) by solving the logistic regression equation using the formula:

PCml = G × ValP1 – AF × ValP2 + EA × ValP3 + SF × ValP4 + AC × ValP5 – Const., where

ValP1...5 — observed value for the corresponding sample variable;
Const. — constant for the given population.

If the prognostic coefficient is less than or equal to 0.7215, high effectiveness of applying the conservative approach in the treatment of ulcerative colitis is predicted; if it is higher, high effectiveness of applying surgical treatment for this pathology is predicted. As the analysis of fatal outcomes showed, in the surgical treatment of ulcerative colitis, the highest mortality was observed in severe attacks of the disease. Timely prediction of its development when indications for surgical treatment arise will certainly help optimise the specific timing for surgical intervention with all the ensuing consequences. The clinical implementation of the obtained results of predicting the course of ulcerative colitis confirmed their appropriateness. Since the development of the prediction model, 4 patients with total colonic involvement aged 32 to 65 years, in whom the development of a severe attack was predicted, have undergone surgery. All of them were operated on before the attack developed. In all cases, subtotal colectomy was performed with a favourable outcome. Apparently, the clinical criteria developed for prediction may serve as a basis for personalised treatment of this patient population.

Thus, the results of the study showed a significant decrease in the quality of life of patients with ulcerative colitis, both in the short term and in the long term, and a high level of postoperative mortality. Improvement of treatment for this pathology will certainly be associated with predicting the course of the disease. This will allow timely initiation of preventive therapy and performance of surgical intervention in the optimal period. It has been established that the implementation of a personalised approach contributes to improved surgical outcomes.

Conclusions

1. The number of patients with ulcerative colitis in specialised hospital departments is steadily increasing. In terms of age, patients aged 20 to 50 years predominate. Total colonic involvement exceeds 73%.

2. The leading clinical symptoms in ulcerative colitis are diarrhoea (81%) and melena (68%). The frequency of pain syndrome (58%) and fever (23.6%) increases as the disease progresses and when inflammation is localised in the left side of the colon. The severity of clinical manifestations is accompanied by the development of anaemia, hypoproteinaemia, intoxication, and disturbances of central haemodynamics.

3. In ulcerative colitis, sympathetic activity is increased. The degree of disturbances is determined by the severity of the disease and the extent of the inflammatory process. In these cases, the stress index increases by 6.2–16%. The maximum values are observed after subtotal colectomy.

4. Quality of life in ulcerative colitis is determined by the severity and course of the disease, its extent, and the method of treatment. Positive dynamics in the physical component are most pronounced five years after disease onset, in chronic relapsing course and with conservative treatment. The psychological component decreases after surgical intervention (by 5.25%).

5. The level of postoperative mortality in ulcerative colitis depends on the degree of progression of the pathological process. The highest frequency of adverse outcomes is observed in severe attacks of the disease.

6. When predicting indications for surgery in ulcerative colitis using logistic regression analysis, the most significant criteria are patient gender, disease duration, endoscopic activity of inflammation, and stool frequency.