Lviv Clinical Bulletin

8-16

Authors: Abrahamovych M., Ferko M.

Introduction. Liver cirrhosis, accompanied by the disorders of all organs and systems, including the autonomic nervous system disorders, which greatly accelerates the negative prognosis, taking part in the pathogenesis of the leading syndrome – portal hypertension, is a major cause of death of the hepatological patients. According to the principles of clinical and experimental approach, recommended by A. M. Wein, exploring the autonomic nervous system, primarily it is important to assess its functional status according to the results of functional and dynamic studies: tone, autonomic reactivity and vegetative support of the body, the first two of which characterize the homeostatic capabilities of the organism, and the last – adaptive. The most informative non-invasive method to evaluate the autonomic nervous system status is the heart rate variability recording. Despite the high prevalence of the autonomic nervous system dysfunction in patients with liver cirrhosis, the condition of the autonomic nervous system in patients with liver cirrhosis and its dependence on the severity of portal hypertension is insufficiently studied, because clinicians often do not pay attention to it, focusing on the deviations of laboratory parameters and severity of liver disease. Therefore, the aim of our study was to describe the state of the autonomic nervous system in patients with liver cirrhosis and determine its dependence on the severity of portal hypertension according to the study of heart rate variability indices. Materials and research methods. Into the study in randomized manner with the preliminary stratification by the presence of liver cirrhosis were involved 240 patients with varying degrees of portal hypertension severity [65 women (27.1 %) and 175 men (72.9 %); aged 21 to 78 years, average age – (48.4 ± 0.8 years)], who were hospitalized with the aim of the examination and treatment into created on the basis of the Internal Medicine Department N 1 of Lviv National Medical University and Gastroenterological Department of Lviv Regional Clinical Hospital, Lviv Regional Hepatological Center. All the patients underwent a comprehensive clinical-laboratory and instrumental examination of all organs and systems, according to the requirements of modern medicine and also, improved by us, ultrasound doppler-floumetric examination of the abdominal cavity vessels, by our patented method, under which all the patients were stratified into three groups: the first group (PH of the 1st degree) included 122 persons [33 women (27.0 %) and 89 men (73.0 %)] aged 21 to 78 years (average age 46,4 ± 1,0 years), the second (PH of the 2nd degree) – 57 patients [14 women (24.6 %) and 43 men (75.4 %)] aged 27 to 66 years (average age 48.2 ± 1.3 years) and the 3rd group (PH of the 3rd degree) – 61 patients [18 women (29.5 %) and 43 men (70.5 %)] aged 29 to 73 years (average age 50.2 ± 1.3 years). Also were examined 40 healthy individuals [27 women (67.5 %) and 13 men (32.5 %)] aged 19 to 51 years (average age – 22.9 ± 0.9 years), which formed the control group. The study of the autonomic nervous system was also performed by our patented method, which provides a comprehensive evaluation of the indices of non-invasive examination of heart rate variability. According to the results of our study, we can observe the dynamics of heart rate parameter, that, due to the heart rate variability indices in patients with liver cirrhosis before and after the physical activity was significantly (p < 0.05) increasing with the increase of the portal hypertension severity, demonstrating the prevailing of the influence of sympathetic over parasympathetic nervous system with the increase of the disease severity. Indices of the temporal and spectral analysis are significantly reducing with the increase of the pathological process in the liver and indicate the exceptions of the central mechanisms in regulating the autonomic processes with the transition to local – humoral-metabolic level, because despite the compensatory activation of the sympathetic nervous system in patients with liver cirrhosis, its influence remains small, which is associated with the decreased sensitivity of the receptors of the vessels to vasoconstrictors, including to neurotransmitters. When analyzing the influence of various parts of auto­nomic influence it was found, that on the basis of reduced total spectral power was observed the imbalance of the autonomic nervous system with the dominance of the sympathetic nervous system in patients of all three groups, especially pronounced in the probe with physical activity. Conclusions. The state of the autonomic nervous system in patients with liver cirrhosis is characterized by the decrease of the total activity of the autonomic influence on the heart rate by the reducing the sympathetic and parasympathetic influences, as well as humoral component. Study of the heart rate variability, time and spectral analysis parameters using method for the detecting heart rate variability, recording it before and after the physical activity made it possible to verify the presence of autonomic disorders with predominant influences of the sympathetic branch of the autonomic nervous system over the parasympathetic with directly proportional increase of the neurohormonal effects in patients with different severity grades of portal hypertension, diagnosed using advanced by us noninvasive ultrasound doppler-floumetric examination of the abdominal vessels. Increasing of the autonomic dysfunction grade, with the transition of the regulation to local (humoral-metabolic) level, according to the heart rate variability parameters study, directly proportional on the severity of portal hypertension in patients with liver cirrhosis, which confirms the role of the autonomic nervous system in the pathogenesis of portal hypertension occurrence and can serve as a reliable diagnostic criterion of portal hypertension detecting and as one of the “markers” to determine the degree of its severity.

22-25

Authors: Lozynskyy R., Voronyak M., Poluben L., Dmytrenko I., Lozynska M., Vygovska Ya., Maslyak Z.

Introduction. Myelofibrosis is a rare disease affecting myeloid progenitor stem cells. According to the modern criteria of myelofibrosis diagnostics, the confirmation of the clonality of pathological myeloproliferative process is needed. However, the unique pathognomonic marker for this disease is not revealed. Point missense mutation of JAK2 gene in exon 12 – the JAK2V617F mutation, and karyotype abnormalities are the most frequently found in myelofibrosis patients. In case of additional anomalies the disease prognosis worsens dramatically, in particular, because of higher risk of the transformation to acute leukemia. The purpose of the study was to identify informative combination of molecular genetic and cytogenetic clonal markers for diagnosis and prognosis of myelofibrosis. Materials and research methods. 37 patients were recruited in the study (33 with primary myelofibrosis and 4 with secondary post-polycythemia vera myelofibrosis). Cytogenetic studies were performed for 34 patients. All the patients underwent molecular genetic studies of blood to detect the JAK2V167F mutation. The mutational status of JAK2 gene was reexamined in 10 patients from 1 to 2 years after the initial examination. Results of the investigation and their discussion. The presence of the mutation JAK2V167F was confirmed in 59.5 % of the patients. Chromosomal abnormalities were revealed in 38.2 % of patients. The spectrum of abnormalities included deletions and translocations of chromosome 1, deletions of 5q and 20q, trisomies of chromosomes 3, 8, 9 and 12, monosomies of chromosomes 3, 5, 7, 9, 11, 13, 15 and 17, appearance of іsochromosome 17q, and polyploidy. 4 patients had a complex karyotype. The coincidence of investigated point mutation and karyotype abnormalities was revealed in the total of 8 (21.6 %) patients. The presence of the mutant allele V617F was associated with higher frequency of cytogenetical abnormalities. The complete molecular response to the therapy with hydroxyurea and interferon-α was not achieved in any of the 10 patients who underwent the molecular genetic reexamination. The overall mortality of the patients with JAK2V167F mutation was 27.3 % in 24 months. In the absence of the mutation the mortality rate was slightly lower and constituted 20. 0%. Сytogenetic abnormalities were the only detected clonal markers that allowed to confirm the chronic myeloproliferative process in 13.5 % of patients. Conclusions. Simultaneous cytogenetic analysis and the identification of JAK2V167F mutation increased the rate of clonal confirmation of the pathological process in myelofibrosis patients to 73.0 %, in contrast to 38.2–59.5 % using only one method of investigation. The presence of such cytogenetic anomalies as polyploidy and trisomy of chromosome 9 could result in increase of the copy number of JAK2 gene mutant alleles in pathological cells. The patients having both no detectable level of “wild type” allele of JAK2 gene and considerable quantity of lymphocytes in the blood, could possibly be of higher risk of further transformation of myelofibrosis to acute lymphoid, and not only myeloid leukemia.

31-39

Authors: Abrahamovych O., Fayura O., Abrahamovych U.

Introduction. The problem of classification of comorbid diseases is very actual now. Despite this fact, the search for the new variants of combinations of the diseases continues, as their combinations can simply be not yet classified syndromal diseases, or vice versa – to be completely incompatible for the appearance and coexistence in one body. This is the key to solve more and more problems for the diagnosis and treatment of the diseases in the field of the practical medicine. That is why a comprehensive study and detailed systematization of the knowledge with our attempt to create the unified classification of the comorbidities are important steps towards the understanding and solving this problem. Aim. To analyze the literature sources dealing with the study of comorbid diseases and present the modern views of the scientists in relation to these problems in order to unify it. Materials and methods. The work analyzes the literature sources, which deal with the study of comorbid diseases and quite thoroughly reflect the current views of the scientists on this issue, based on which was made a systematization of the received facts and was proposed our own classification. Results. Comorbidity is one of the main problems in modern medicine. But, organizing theoretical and practical knowledge of comorbid diseases, and thus solving the problem as a whole, unfortunately, does not go beyond the scientific debate, about which there is still no coherent understanding of its essence and unification of the used terminology. For standardization of the scientific researches on comorbidity as a random combination of the diseases in one patient, which are different by their etiology and pathogenesis such as nosological syntropy, i.e. natural occurrence of the regular determined diseases combinations, were proposed 12 indices and one simple list of the diseases. It is suggested that all the diseases that occur in the body are divided into monodisease (only one uncomplicated disease in one person) and comorbid disease (2 or more diseases in one person), which, in its turn, are divided into columns, depending on the amount of the diseases, their etiology, сlinical variant of the lesions, relationship between the diseases combined in one body, their origin, the presence of morphological changes, involvement of organs and systems into the process, the order of their appearance, symptomatical dominance, the presence of the complications, prognosis and so on. Conclusions. The given classification is important for the applied medicine, as it can help the doctor to organize and comprehensively assess the disease, to scale the level of injuring of the certain organs or organ systems by the pathological process, the mode of the diseases, the possibility or, conversely, illogicality of the causal connection between them, and then conduct all necessary diagnostic procedures according to their importance for the diagnosis, prescribe treatment without recourse to polypharmacy and get a positive result of this treatment.

43-57

Authors: Abrahamovych M., Tolopko S.

Introduction. The problem of liver disease is one of the most popular in modern gastroenterology, and liver cirrhosis (LC) is the main reason of hepatargy and hepatodepression. The imbalance of vasoactive substances on the one hand, and diffuse fibrosis with formed regeneration nodes on the other, lead to the increased portal vascular resistance and portal hypertension (PH) with the following disorders of systemic hemodynamics and circulation of almost all organs, including the lungs, resulting in hepatopulmonary syndrome (HPS) and portopulmonary hypertension (PPH). The aim of our work was to make an overview of the modern literature on the etiology, pathogenesis, clinical signs, principles of diagnosis and treatment of the lesions of the respiratory system in patients with LC and to describe the clinical cases from our own practice. Materials and methods. The content analysis, the method of system and comparative analysis, the bibliosemantic method of study of actual scientific researches concerning HPS and PPH in patients with LC has been used. Results.According to the classification, adopted in 2003 at the III International Conference in Vienna on the problems of primary pulmonary hypertension, PPH is defined as one of the forms of pulmonary hypertension, associated with PH, which is characterized by the increased pressure in the pulmonary artery more than 25.0 mm Hg resting and above 30.0 mm Hg – during physical activity, and increased pulmonary vascular resistance ≥120.0 dyn/sec/cm-5. Although the incidence of PPH is low, reported in various sources from 2.0 to 8.5 % in patients with PH, timely diagnosis of said condition and its correction is an actual problem of modern medicine, because of the extremely poor prognosis of the disease, when liver transplant is the only effective treatment, because of the absence of proven positive effects of pharmacological treatment. To assess the different pathophysiological aspects of PPH it is important to combine the results of computer angiography of the lungs, magnetic resonance examination of the heart, echocardiography, ventilation-perfusion lung scanning, but the confirmation of the diagnosis is the method of right-heart catheterization with the measurement of pulmonary arterial pressure, cardiac output and pulmonary vascular resistance, that still remains the “gold diagnostic standard”. HPS is an arterial oxygenation defect caused by the dilatation of intrapulmonary vessels or the occurrence of arteriovenous shunts, characterized by the reduction of oxygen partial pressure <70.0 mm Hg and increased alveolar- arterial gradient >20.0 mm Hg. It is believed, that the main role plays pulmonary hyperproduction of nitric oxide (NO) and carbon monoxide and, oddly enough, the E-1 by the increasing of the activity of NO-synthase, and thus NO production, as a result of the effect on EB-receptors. No less important are cytokines, such as the increase of TNFα, IL-1β synthesis and IL-10 decrease as a result of intestinal endotoxemia. There is a hypothesis of so-called alveolar-capillary oxygen imbalance, whereby inadequate hemoglobin oxygen saturation leads to systemic hypoxemia. Diagnosis of the HPS is based on complaints, physical examination results, pulse oximetry, the study of blood gases, lung CT, contrast transthoracic echocardiography, perfusion lung scans, using albumin, radiolabeled with 99Technetium. As for treatment, the most successful method is also a liver transplant, although some recommend medications. It is known, that methylene blue – guanylate cyclase and oxide synthase inhibitor – promotes rapid improvement of the patients after intravenous administration. You can also apply the common antidepressant from a group of selective serotonin reuptake inhibitors – paroxetine and also indomethacin, octreotide, which are potent inhibitors of NO synthesis, but their effectiveness is not yet proven. In the pilot study was noted the possibility of correction of pulmonary gas exchange by pentoxifylline, which is a blocker of TNFα. There have been attempts to use iloprost – selective vasodilator, that reduces pulmonary bypass and increases erythrocytes transit time in lungs. Conclusions. Although at present there are no standard pharmacological treatment for patients with HPS and PPH, such patients require special attention, constant monitoring and prolonged oxygen therapy. Prognosis in such patients is poor, there is a high mortality, requiring their early diagnosis.

58-64

Authors: Svintsitskyy A., Solovyova G., Dynnyk N., Bogomaz V., Baka O.

Introduction. Nonalcoholic fatty liver disease (NAFLD) is considered as one of the most common chronic liver diseases, and among the population of developed countries, this disease occurs in one of three middle-aged people. The aim of this study was to improve the diagnostic algorithm of NAFLD by assessing the capabilities of mod- ern non-invasive diagnosis of steatosis and fibrosis of the liver. Materials and methods. We used the content analysis, method of systematic and comparative analysis in studying the current 73 scientific studies published in English or Ukrainian (PubMed-NCBI, Medline, CochraneLibrary, EMBASE, ResearchGate), of which were selected 25 works which talked about the non-invasive methods of diagnosis with proven high sensitivity and specificity in diagnosis of NAFLD. The results of the analysis are highlighted in the tables. Several non-invasive methods aim at diagnosing and quantifying of hepatic steatosis, while others were designed to predict NASH or significant/advanced fibrosis. The search for the ideal non-invasive test has not been accomplished yet, which explains the vast number of tests available. Imaging techniques, biomarkers and complex models have been studied as tools to predict steatosis, NASH and fibrosis. New methods are usually compared with liver biopsy, that has accuracy far from perfect for NASH and even for fibrosis. For assessing steatosis, US may also be used as comparison, and US cannot detect mild steatosis. In that way, new methods can perform better than the gold standard leading to underestimation of the power of the test. The reliability and importance of the diagnostic tests depend on the disease, the population to which it is applied and the change in management induced by the test’s result. A good screening test should have a high sensitivity even at expense of specificity, whereas a diagnostic test that selects patients for invasive procedures, therapy or clinical trials should have high specificity. Most methods have been evaluated in small pilot studies and have not been externally validated. The majority showed only suboptimal accuracy for NASH. Although discrimination for advanced fibrosis is usually reasonable, no test detects confidently mild/moderate fibrosis. Also, standardization of cut-offs is difficult and most methods lack reproducibility. For the time being, non-invasive tests do not replace liver biopsy, but may avoid it in a large number of cases with low probability or high-risk for having advanced fibrosis/cirrhosis. Ultrasonography still represents the first-line diagnostic tool for simple liver steatosis; its sensitivity could be enhanced by the complex biochemical score SteatoTest. Serum cytokeratin-18 is a promising and accurate non-invasive parameter for the diagnosis of non-alcoholic steatohepatitis (NASH). The staging of liver fibrosis still represents the most important prognostic problem: the most accurate estimating methods are FibroMeter, FIB-4, NAFLD fibrosis score and transient elastography. Conclusions. The calculation of certain clinical and laboratory indices can be used for diagnosis and quantification of the degree of liver damage in patients with NAFLD.