O. Abrahamovych, O. Fayura, U. Abrahamovych

Danylo Halytsky Lviv National Medical University

The topicality of the subject of the publication is determined by the fact that prevention and treatment of chronic diseases are defined by the World Health Organization as priority project of the second decade of XXI c. aimed at improving human quality of life [29, 39, 69, 80, 137, 142]. Therefore, for the last years there is a general tendency to conduct a largescale epidemiological research in different fields of medicine using modern statistical methods [69, 104], which made it possible to state negative changes in health characteristics, morbidity and mortality of people. Every year, human population health deteriorates increasingly and, nowadays, there is almost nobody who suffered from one disease only and in its classic condition. It is proved that very often comorbidities worsen the course of primary condition and/or result in its chronization [33], and are the reason for disability and premature death of able-bodied population [14, 26, 47, 93].

With this in view, there is a tendency to discuss a problem of disease combination in modern scientific literature. If in 1990-2000 only single researches on the topic were published, then in 2001-2010 the number reached several tens [55] and grows steadily [24, 108]. Every day population and clinical research are carried out, evidence-based data bank is formed, guides and recommendations on patient treatment with comorbidity are processed, elaborations of improved medical care for patients with comorbid diseases are implemented, patients registers are designed and possibilities for international cooperation are determined, search for innovative diagnostic and therapeutic methods continue. Modern basic recommendations (ESC/EAS, 2011; ESH/ESC 2013, 2014; GOLD, 2012, ESC/HFA, 2012; ACR/AHA, 2013; KDIGO 2012; ADA, 2014 and others) focus on secondary risk factors, disease associations and improvement of diagnostic and treatment strategies. In regard of current situation, the last ESC congress (2014) “Innovation and the Heart” concentrated on integrative processes, innovation in the field of science, clinical elaboration and implementation, constant learning, improvement of clinical practice in order to unite practical physicians, scientists, epidemiologists.

During 2014 new manuals were elaborated taking into account availability of associated pathological conditions: “ESC/EACTS Guidelines in Myocardial Revascularisation”; “Acute Pulmonary Embolism (Diagnosis and Management of)”, “Hypertrophic Cardiomyopathy”; “Aortic Diseases”; “ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management”.

The following issues for discussion included: Comorbidities and coronary artery disease; Integrative physiology and control mechanism; Diabetes and obesity – a deadly combination; Risk scores; Smoking – major problem in clinical practice; Target organ damage in hypertension. The necessity to join forces in order to reduce burden of cardiovascular diseases in the world, an importance of integrative prevention measures and a correction of cardiovascular risk factors, uppermost population motivation for healthy lifestyle were stressed (Fadyeyenko H. D., Nesen A. O., 2015) [35].

International Research Community on Multimorbidity (IRCM) has been founded, the journal “J. Morbidity” has been published since 2010 [38]. A joined working group has been created: Department of Medicine, Division of Nephrology, Institute for Clinical Research and Health Policy Studies, Center for Clinical Evidence Synthesis, Tufts University School of Medicine, USA. Its aim is to elaborate a manual (consensus recommendations) with regard to multimorbidity (Guidelines for Multimorbid Patients Study Group, 2014) [39]. Its specialists state that a number of patients of all ages suffer from several combined diseases (pathological conditions), however, doctors lack clear instruction on how to make tough clinical decision in such situations, as most available recommendations and manuals focus on the study of single mononosological diseases. The information in these manuals (Clinical Practice Guidelines) is based on the research carried out excluding many diseases of a patient and it is concentrated mainly on the description of treatment schemes of certain diseases, per se. Thus, further largescale research should precede the elaboration of guidelines for patients with comorbidities (Fedienko H. D., Nesen A. O., 2015) [35].

The sources of information for scientists and researchers, who analyze the problem of polypathy, are medical histories [76], health records [67] and other medical documentations of family doctors [109], insurance companies [145], and archives of boarding care homes for seniors [66]. According to the results of the research by WHO experts, people under 40 years have 2-4 diseases, under 60 – have a number of 5-7 diseases, over 70 – 8-10 and more. So-called polymorbidity increases from 10.0% in people at the age of 19 up to 80.0% in people over 80 [44, 109, 121].

Especially, in Great Britain, a part of patients with several diseases, who refer to a general practitioner, makes over 80.0% [103]. According to the results carried out in the Netherlands, 7 % of individuals aged 45-64 years have 4 diseases and more, group aged 65-74 years – 30.0 %, people over 75 – 55.00 % [101]. According to the survey carried out in Brazil among people aged 40 years and over, above 88.0 % have at least one disease of chronic course, and 26.0 % have 3 diseases and more [122]. In the view of the fact that comorbidity is extremely common for patients hospitalized in therapeutic hospitals, many scientists studied it in therapeutic clinics. Patients with comorbidity are rather the rule at the stage of primary care, than an exception. Having analyzed 980 medical histories obtained for the research in daily practice of family doctors, Fortin M. stated that prevalence of comorbidities is 69.3 % in patients aged 18-44 years, 92.8 % – 45-64 years, 98.7 % – 65 years and more; multimorbidity increases from 10.0% in patients aged 0-19 years up to 78.0 % in patients over 80 years [95].

The results of the analysis of 3,239 autopsies in patients with somatic diseases are remarkable. These patients were taken to multidisciplinary hospitals after decompensation of certain chronic diseases (average age – 67.8 ± 11.6 years) [7], since it is an autopsy that enables to reliably determine the structure of combined diseases and immediate cause of death regardless of age, sex and gender so to avoid subjectivism in the results. Their frequency was 94.2 %; the combination of two and three nosologies prevailed, and in rare cases (up to 2.7 %) patient had 6-8 diseases at the same time [7].

Practicing physicians are well aware that combination of diseases deteriorates the course of each disease separately. In particular, cardiovascular diseases significantly (+78.0 %) increase morbidity in patients with type 2 diabetes mellitus (DM) undergoing peritoneal dialysis [62]. According to the research results by

Marti S. et al. (2006) [47], for the patients with chronic obstructive pulmonary disease (COPD), who underwent oxygen therapy for a long time, if M. E. Charlson comorbidity index [17, 58, 70, 79, 102] was 0, 1 or 2 and more, mortality after 3 years was 55.0 %, 65.0 % and 85.0 %, respectively. It was also found that patients with COPD with each 10.0 % of reduced volume of forced exhalation for 1 sec have a 28.0 % higher mortality chance caused by cardiovascular diseases, and almost 20.0 % – the number of nonfatal coronary events [134, 135]. The use of long-term oxygen therapy in patients with severe respiratory failure can reduce mortality caused by respiratory diseases, while there is a higher death probability caused by circulatory and digestive systems diseases [5, 74].

Comorbidity leads to increased expenses for diagnostic examination and treatment, prolongs hospitalization period of patients, and therefore, medical care provision requires increased costs in health care system [56, 103]. A typical example are the results of the research by Vertkin A. L. et al. [17], according to which, the presence of several diseases is the most common reason for non-core hospitalization of patients in surgical departments, which leads to reduced operational activity and increased mortality. In USA, according to Medicare federal program, almost 80.0 % of insurance costs are spent to cover claims of the patients aged 65 years with four or more chronic diseases [71, 112]. However, despite the prevalence of comorbidities, most patients try to be consulted and get recommendations by specialized professionals, who do not evaluate individual condition with integral indicators, treat a disease with exclusively specialized view of the problem, which leads to adverse or fatal effects [2, 5, 10].

According to the history of the issue, there was an interest in polypathy as early as XIX c. A French physician Bouchard Ch. [49] proposed a term arthritimus, which explained a tendency of the human body (a certain individual or his/her relatives) to have either a single disease, or in different combinations. The author was aware of such diseases as gout, DM, obesity, gallstone disease (GSD), kidney stone disease (KSD), “early” atherosclerosis, arthritis, migraine, neuralgias, dermatitis, some skin conditions. He stated that these diseases peculiarly inhibit metabolism (bradytrophy) (Nikolayev Yu. A., 2014) [113]. According to Bouchard Ch., these are bradythrophy and inherited disorders that cause the combination of athropathy, obesity, DM and “early atherosclerosis” (Puzyrev V. P., 2015) [30].

In 1970 a prominent American clinician, professor, researcher and epidemiologist Feinstein A.  proposed a notion of “comorbidity” (Lat. co- together, morbus – disease) [75]. He found it necessary to use the term in case additional clinical conditions (diseases, pathological syndrome, pregnancy, extreme diet for a long time or post-treatment complications) are present or can occur in a patient with a primary condition (Puzyrev V. P., 2015) [30]. He demonstrated comorbidity by the case of somatic patients with acute rheumatic fever, prognosing the worst outcome for the patients with several conditions simultaneously (Vertkin A. L. and other, 2011) [17].

Soon comorbidity was studied as a separate scientific and research direction.

Due to a multi-year analysis of the combination of somatic and mental diseases in psychiatry [27, 35, 51, 90, 127, 129], comorbid conditions were found in patients with various mental disorders, first comorbidity models were designed. The problem of comorbidity impact on clinical course of primary somatic disease, drug treatment efficiency, the nearest and remote prognoses for patients in many countries of the world were also studied by other specialized clinicians [5, 6, 8, 19, 21, 55, 59, 83, 84, 92,108, 110, 118, 121,131, 143].

It is vital to note that there are numerous synonyms for the term “comorbidity”, including frequently used “polymorbidity”, “multimorbidity” [53, 55, 109], “multifactor diseases”, “polipathy”, “multicausal diagnosis” [13], “double diagnosis”, “pluripathology” etc. This fact complicates understating of the sense of the problem and minimizes possibilities to use scientific achievements in clinical practice.

The term “bicausal diagnosis” is frequently used in the Ukrainian literature to describe comorbidity, when the primary disease is presented by two nosological units, and polymodbidity – “multicausal diagnosis” – to describe three pathological conditions and more in a single individual [32]. The terms “comorbid diseases”, “comorbid conditions” are mostly used in the English scientific literature [53, 55].

In the mid-90s of the last century, Kraemar H. C. [95] and Van de Akker M.  [143] defined comorbidity as a combination of several chronic diseases in a single patient, but only those having a common cause or mechanism of pathogenesis, and sometimes they explained so the similarity of their clinical manifestations, and this fact at the same time complicated the differentiation of nosology.

Other authors [19, 43, 88] proposed the definition of comorbidity as multiple diseases with a proved mutual pathogenic mechanism, and in case of multiple diseases with different pathogenic mechanism the term “polymorbidity” was considered; however, [83, 125] earlier, the scientists defined polymorbidity as a combination of various functional disorders and chronic diseases in an individual without indication of common or different pathogenesis. Grumbach K. (2003) assumes that the term “comorbidity” should be defined as co-existance of two or more pathological conditions, when one of them dominates [86]. Starfield B. (2006) [136] notes in her work that comorbidity is a presence of numerous clinical diseases and conditions in an individual simultaneously, one of which is primary (index), and the others are concominant; and multimorbidity is a presence of numerous clinical diseases or conditions, and none of them can be considered as primary (index). According to Valderas J. M. et al. [71], comorbidity can be interpreted as either a random combination of diseases of different etiology and pathogenesis in a single patient, or as a nosological syntropy i.e. occurrence of naturally predetermined combinations of diseases.

Some scholars define comorbidity as a presence of more than one disease in a person in a certain period of time, and some state that it is a relative risk of a person to acquire another one. Some researchers [53, 55] use the term “comorbidity” to define simultaneous damage to only some organs or systems of the body, or a presence of only two diseases, others use the terms “comorbidity” or “polymorbidity”, when there are 3 or more diseases [50, 53, 55]. The authors of the works [52, 142] characterize “polymorbidity” as a condition caused by numerous pathological processes, which can be qualified as clinical and diagnostic signs and symptoms, syndromes, nosological units. Goldberg D. [82] states that it is more appropriate to use the term “comorbidity” to explain the combination of diseases of the body and mental illnesses. There is a statement that this term should be used in case of existence of two or more diseases, which occur in a person more frequently than expected randomly, and “hypocomorbidity”, unlike “anticomorbidity” (impossible co-occurrence of diseases in a single person) which is used for diseases combined more rarely than expected (Jakovljević M., Ostojić L., 2013) [89].

Thus, as for now, there is no unified terminology, which is based on a unified definition of the above-mentioned notions.

Immediate causes of comorbidity are anatomical closeness of damaged organs, common pathogenesis, cause – effect relationship or a random combination of diseases [2, 10, 19, 23, 53, 71]. However, it is vital to remember about iatrogenesis. In particular, a long-term drug use can lead to adverse phenomena, which can develop into a particular disease [19, 28, 33].

The causes of comorbidity of human being can be distinguished as a chronic infection, inflammation, involutive and systemic metabolic changes, iatrogenesis, social status, ecology and genetic predisposition, and the main reason is cause-effect relationship. The presence of certain disease first leads to functional and then to organic lesions and occurrence of numerous nosologies. As an example of “a chain” of diseases is an occurrence of chronic pancreatitis in persons with chronic gastritis and/or gastric ulcer, which leads to occurrence of chronic cholecystitis and GSD or occurrence of chronic enteritis in patients with chronic pancreatitis, which results in absorption disorder in gastro-intestinal suction (GIS) and consequently anemia occurs. Chronic colitis can result in constipations and hemorrhoid, and it is a risk factor for anemia. The chain of such unfavorable factors gives rise to several gastroenterological diseases simultaneously, if other somatic lesions are present; senior patients, who referred to gastroenterologists, were diagnosed with five to eight nosologies simultaneously [23]. The occurrence of comorbidity in case of the combination of digestive diseases and generally somatic diseases can be influenced by the same factors. Thus, disorder of cholesterol metabolism leads to bladder cholestasis, GSD, hepatosis (streatohepatitis) and they are direct risk factors of atherosclerotic lesions of heart vessels, brain and arterial hypertension (AH) (Belousov Yu. V., 2012) [2].

According to genetic scientists, comorbid conditions are only a part of all well-known random or genetically predetermined combination of two or more diseases [20, 30, 31]. Genetic research of multifactor diseases proves genetic roots of such combinations, in particular, in case such combinations occur frequently in patients, whose relatives had lesions of such organs or systems in their medical history as compared to general population [30, 31, 124].

Ecological genetics is a prospective research study. Over 5 million chemical matters have been discovered (atmospheric pollutants, pesticides, pharmaceutical products, cosmetics, food additives etc.) and also bad habits constantly influencing human being and many of them are etiologically connected with multifactor diseases (disease of hereditary predisposition). Currently ecological genetics considers identification of different populations of specific genes and environmental factors, interaction of which “forms” a new norm of resistance of human being and his/her adaptation capacity to changes in human habitat.  The most interesting genetic markers for ecogenetic research of multifactor diseases are genetic polymorphic types of genes of biotransformation enzymes, the expression of which, as compared to other classes of genes, is directly regulated by the influence of chemical factors of the environment. However, despite increasing environment pollution, a high level of chemurgy in industry, agriculture and daily life, the study of ecogenetic mechanisms of the occurrence of multifactor diseases has been out of the limelight of scientific research so far [9].

Regardless of certain success in the study of comorbidity, according to the results of the conducted research, there has been a lack of unified classification, which would meet the needs of clinicians. The most common classifications are the following.

According to the classification by Feinstein A. R. (1970) [75], there are primary and secondary comorbidities, on the basis of which, scientist proposed distinguishing the following comorbid diseases: chronologically determined; cause and effect; symptomatically dominant [94]. For example, the peculiarities of condition and symptoms of a patient diagnosed with DM, who has depression, can significantly differ from the similar peculiarities in a patient who had depression and later acquired DM, however, both of them having depression and DM simultaneously [71]. Such differentiation of diseases is necessary to define cause and mechanisms of co-occurrence of comorbid conditions. 

Diseases are divided into simultaneous (occur simultaneously) and consecutive by priority of occurrence [12]. Thus, Kraemer H. C. [95] names comorbidity as “a non-random concomitant disease” and distinguishes epidemiological, clinical and family comorbidities.

According to the classification by Angold A. et al. (1999) [42], there are etiological (causal) comorbidity, which occurs as a result of simultaneous lesion of different organs and body systems by a single pathological factor (multiple lesions in case of chronic alcohol abuse, smoking, systemic collagenoses), and non-etiological comorbidity (several diseases are associated with each other, however, most probably they are not a cause of a certain etiological factor or the one is a consequence of the other two).

According to the results of the research of other scientists in the field of comorbidity, the classification determines such variants: transsyndromal – existence of two and/or more pathogenetically related syndromes in a single patient; transnosological – existence of two and/or more pathogenetically related diseases [34, 56].

According to the classification by Samet S. et al. (2004) [128], organic and nonorganic comorbidities are distinguished. In case of organic comorbidity, a lesion in human body is initiated and potentiated by an organic factor. In case of non-organic comorbidity, it is impossible to detect whether an organic factor was a stimulus for comorbidity lesions to occur.

According to the classification by Van Weel C., Schellevis F. G. (2006) [142], comorbid diseases are divided into four groups: causal – in case of two or more diseases with a common mechanism of occurrence; complication of primary disease; concurrent – non-related to each other diseases; intercurrent – if a patient with a chronic disease obtains an acute one [63].

Chernobrivkyna T. V. and Kershenholts B. M. (2006) [37], who examined comorbidity in patients with alcohol abuse, propose a different classification. By origin, there are extranosological comorbidity, in case other diseases “join” alcohol abuse, when the cause of it is not the addiction (tuberculosis (TB), psoriasis, endogenic psychosis, DM) and intranosological in case a disease occurs as a secondary and it is caused by alcohol use disorder (pancreatitis, cardiomyopathy, anemia, alcohol-related psychosis, alcohol-related suicide).

These authors distinguish chronological comorbidity (to certain extent it generalizes intra- and extranosological comorbidity), which is a phenomenon of simultaneous course of certain stages of alcohol use disorder during the period of the occurrence (acute) pathological conditions caused, for example, by consequences of occupational risk factors, military action, traumatic brain injury (TBI), infectious and other diseases, every day or food poisoning, surgeries, or phenomena of common course of alcohol use disorder stages with psychogenic traumas, post-traumatic syndrome (as a result of military conflicts, accidents, natural  disasters, as a result of large-scale or acute social changes, adverse effects of meteorological factors).

There are two types of chronological comorbidity: synchronic and non-synchronic. In case of alcohol use disorder chronic synchronic comorbidity includes disease associated with biorhythms. As a rule, they occur with biorhythms regularity, for example, as an aggravation of comorbid diseases in the period of seasonal, age and other physiological cycles. In fact, these are almost indispensable comorbid diseases “accompanying” drug abuse and, by their occurrence period coincide with age, seasonal, day and other rhythms. Non-synchronic chronological comorbidity is typical when a comorbid disease occurs unpredictably and randomly (diseases associated with a cyclic chronology of alcohol use disorder, but not necessarily so as they belong to individual alcohol sensitivity, random organ lesion). Diseases defined as non-synchronic comorbidity frequently occur repeatedly (however, not in all patients with alcohol abuse) at the same time with individual alcoholic symptoms and syndromes, which cyclically repeat (for example, alcohol withdrawal syndrome, personal, family or occupational decompensation syndrome, alcohol-induced psychotic disorder syndrome), so reflecting the conglomerates of associated and non-associated lesions of different origin: consequences of SBT, infectious and other diseases and also occupational risk factors.

As per type of common course of alcohol use disorder and other diseases, Chernobrivkina T. V. and Kershenholts B. M. (2006) distinguish transnosological (during all the period of the course of primary disease), transchronologic (“accompanies” not the whole period of alcohol addiction, but only at a particular stage, phase) and transbiographical (it is observed through all the life of a person) comorbidities. Differentiating by time, transchronological comorbidity can be synchronic (chronologically synchronic to primary disease) and asynchronic (it does not coincide chronologically with the signs of manifestation or reverse course of primary disease) [1, 37].

The research by Bonavita V. and De Simone R. (2008) [48] showed that comorbid diseases can have a well-known cause of co-occurrence or cannot have one and occur by chance, and can be divided into non-directed and bidirectional.  Comorbidity direction is a ratio between occurrence possibilities of each disease until the onset of the other one. For example, numerous patients with celiac disease suffer from migraine, but only some of them do have celiakia (Jakovljević M., Ostojić L., 2013) [89].

There is also a division into diagnostic and prognostic comorbidity. Diagnostic comorbidity refers to associated diseases; their manifestations can simulate symptoms of each other, for example, pneumonia and lung infarction [71]. In such case, diagnostic criteria and symptoms of the diseases are not specific [101]. Prognostic comorbidity refers to diseases classified according to expected effects from their treatment and life expectancy. Disorders, which lead to the occurrence of other disorders and complications, are prognostic comorbidity [71].

Angold A. et al. [42], Valderas J. M. et al. [71] propose differentiating homotypic and heterotypic comorbidity. Homotypic comorbidity is a disease within certain diagnostic group, for example, depression and bipolar disorders and cyclothymia. Heterotypic comorbidity includes diseases of different diagnostic groups, for example, major depressive disorder and behavioral disorders, depression and cancer. Nonspecific symptoms can be typical for heterotypical comorbidity, which can be a marker of severity of patient’s condition.

There are such categories as concordant and disconcordant comorbidities [71]. Comorbidity is concordant in case a disease is a part of similar pathophysiological risk profile with similar treatment methodology. For example, most adults with type 2 DM have at least one comorbid disease and 40.0 % have three and more [46]. An example of concordant comorbidity can be either microvascular complication of DM such as retinopathy, nephropathy and neuropathy, or macrovascular complications, such as coronary heart disease, cerebrovascular disease. Concordant AH and retinopathy are pathophysiological risks in patients with DM, that is why it is necessary to consider them in the program of curation of diabetes [46]. Disconcordant comorbidity is considered to occur in case there are diseases indirectly related to any pathogenesis or disease treatment tactics and do not have a common stimulus factor, for instance, type 2 DM and irritable bowel syndrome or depression and rheumatoid arthritis.

Some authors [4, 56, 88, 111] distinguish several types of comorbidity:

– causal – caused by synchronic lesion of different organs and systems provoked by mutual pathological agents (for example, alcohol visceropathy in patients with chronic alcohol intoxication, a range of diseases associated with smoking, systemic lesions in patients with colagenoses) [4, 56, 88, 111];

– complicated – a result of primary disease and usually occurring gradually after some time of its destabilization [88, 111], as a lesion of targeted organs (for example, chronic renal failure as a result of diabetic nephropathy in patients with type 2 DM, occurrence of the brain infarction as a result of complicated hypertonic crisis in patients with hypertonic disease, HD);

– iatrogenic comorbidity is frequently considered as a type of complicated comorbidity, however, most scientists [19, 28, 33, 88] differentiate it as a separate type which occurs in case of forced adverse effect of a doctor to a patient, provided a beforehand defined danger of a medical procedure (for instance, glucocorticoid-induced osteoporosis in patients who undergo a long-term treatment with hormonal drugs, hepatitis as a result of TB chemoprophylaxis of lungs prescribed for “virage” of tuberculin sensitivity testing);

– unspecified – in case common pathogenic mechanisms of occurrence of disease, which form a certain combination, but their detection requires certain research to prove a researcher’s or clinician’s hypothesis (for example, erectile dysfunction as an early marker of generalized atherosclerosis, occurrence of erosion and ulcer lesions of the mucous membrane of upper part of gastrointestinal tract (GIT) in patients with vascular diseases;

– “random” – consistency of the combination of diseases is not proved at the onset, but soon it can be explained from clinical and scientific point of view (for example, a combination of ischemic heart disease (IHD) and GSD, a combination of acquired heart disease and psoriasis) [88].

According to Schaefer I. et al. (2010) [111] comorbid diseases can be divided into typical (diseases with common pathophysiological associations, in particular, common risk factors of occurrence) and random (abnormal, non-typical combination of diseases).

Various interpretations of comorbidity and its classification peculiarities proposed by other scientists are collected in the works by Krueger R. F., Markon K.E. (2006) [96] and Jakovljević M., Crnčević Ž. (2012) [88].

In Ukraine, the standards of comorbidity structure understating have been in force since the middle of XX c. until now, first of all in order to formulate a correct clinical diagnosis to a patient with comorbid diseases [25], requiring to differentiate primary and background diseases in the structure of diagnosis, and also its complications and concomitant lesions. If a patient suffers from several diseases, then one of them is primary. Without criticism of names and sense of definitions, we provide the definition, which are common in Ukraine:

1) primary disease is a nosological form which itself or as a result of complications requires priority treatment due to the highest danger for life and efficiency.  Primary disease is the one, which was the reason to ask for medical care or death of a patient. If a patient has several primary diseases, a notion of “combined primary diseases” (concurrent or combined) is used;

1.1) simultaneously present nosological forms in a patient, etiologically and pathogenetically interdepended, referring to the criteria of primary disease (for example, transmural myocardial infarction and massive pulmonary embolism caused by phlebothrombosis of lower extremities). In pathological practice, two or more diseases are named concurrent when observed in a single patient, and each of them could be a cause of death itself due to its complications;

1.2) combined diseases are etiologically and pathologically different diseases, each of which is not a cause of death, but due to the same time of occurrence and mutually burdening each other they lead to death (for example, operated osteoporotic hip fracture and hypostatic pneumonia);

2) background disease facilitates occurrence or adverse course of primary disease, increases its danger, and facilitates complications. This disease, as well as a primary, requires emergency treatment (for example, type 2 DM);

3) complications are pathogenetically associated with primary disease, syndromes and nosologies aggravating unfavorable course of disease, leading to acute deterioration of a patient’s condition (complicated comorbidity). In some cases, complications of primary disease, associated etiological and pathological factors are defined as combined diseases. In this case they belong to causal comorbidity;

4) concomitant diseases are nosological unites without etiological and pathological association with primary disease.

Modern interpretation of the problem of syntropy requires differentiating the following types of interplay of comorbid diseases: syntropy – mutual aggravation; neurotropy – random combination of diseases; dystropy – mutual repulsion.

The term “syntropy” was first used by Hurler G. (1919) [87] to characterize Hurler syndrome (former Pfaundler-Hurler disease) with the emphasis on the influence of genetic factors in pathogenesis of its occurrence (Puzyrev V. P.) [30]). In its turn, the term “syntropy” (as mutual aggravation) was used by German pediatricians Pfandler M. and von Seht L. [117] in 1921. They used it in case of simultaneous combination of two and more pathological conditions with common etiological and pathogenic mechanisms, which facilitate the occurrence of each other. Krylov A. A. [18] characterized syntropy as a type of polypathy, when diseases rather “stretch” one after another, seeking to merge or preparing soil for each other”. Pfandler M. and von Seht L. [117] stated that it was not only a nosological unit, but also a syndrome to be considered as a syntophy, since it is regarded as a random concomitancy of certain disorders (Puzyrev V. P., 2008) [31]).

The topicality of syntropy was proved by the analysis results and synthesis of information from around 30 000 medical histories of children since 1906 [117]. The scientists proposed syntropy index (S), which shows to which extent the observed number of diseases combination differ from the index level, which would be expected by chance and in case of great number of syntropy examples with a high S value. For example, “congenital heart defect – rheumatisms of the joints (S = 58.55), “psychopathy – enuresis” (S = 15.31), “hyperthyroidism – nephropathy” (S = 4,94) and “nephritis – exudative erythema” (S = 4,49) (Puzyrev V. P., 2008) [31].

Valderas J. M. et al. [71] state that nosological syntropy is a type of comorbidity and the result of the occurrence of determined disease combinations, and a peculiarity of this relation is synchrony (simultaneous occurrence of, at least, two diseases).

Puzyrev V. P. has recently specified the term “syntropy” defining it as a natural species-specific combination of two or more pathological conditions in a person and his/her close relatives, which are non-random and have evolutional and genetic basis [30, 31, 125].

This conception was checked and proved by modern complex statistical research methods [30, 31, 124]. Considerably bigger or considerably smaller frequency of mutual occurrence of certain diseases rather than expected by chance is demonstrated in the above-mentioned works. For today, the following syntropies are the following: Hurler syndrome [87], “Rhupus” syndrome, A. Caplan’s syndrome [54], combination of rheumatoid arthritis, systemic lupus erythematosus and chronic lymphocytic thyroiditis; systemic lupus erythematosus, rheumatoid arthritis and psoriasis, osteoarthrosis and atherosclerosis; IHD and HD; GSD and pancreatitis; DM and IHD; DM and osteoarthrosis and atherosclerosis (DNA methylation disorder); rheumatoid arthritis or psoriasis and atherosclerosis; other combinations of immune-dependent (autoimmune and allergic) diseases [65, 146], HD and chronic cholecystitis, chronic pancreatitis and COPD; COPD and IHD [71, 81, 97, 114, 115, 121, 123, 124, 132, 143]; the liver and kidney lesions in patients with leptospirosis, yellow fever, sarcoidosis, Reye syndrome, amyloidosis, unspecified ulcerative colitis (Bielousov Yu. V., 2012) [2]; DM, autoimmune thyroiditis and gluten enteropathy [140]; schizophrenia and bipolar disorder [123]; lipoprotein deficiency and myocardial infarction; ataxia-telangiectasia and breast cancer; A. Marfan syndrome and some neuropsychiatric diseases (autism, bipolar disorder, depression); asthma or psoriasis and fragility of X-chromosome [119]. The most widespread diseases influencing cardio-vascular system (IHD, type 2 DM, HD and hypercholesterinemia) in case of the combination in a single body form a so-called cardio-vascular continuum, which is also named “a syntropy of cardiovascular continuum” [30, 124, 140]. Generally, according to the information obtained during one of the phenotypic research, which was based on the results of data bases processing, which included 1.5 million medical records (description of both monogenic and multifactor diseases), the correlations for 161 diseases have been identified [123].

Syntropic comorbid diseases in young patients usually occur within a single system of organs. For example, a combination of pathological processes of gastroduodenal and hepatobiliary systems (gastritis, gastroduodenites and cholecystitis, geopatogenic gastropathies, peptic ulcer and pancreatitis), which are based on primary or more frequently secondary disorders of gastrointestinal hormones excretion and disregulative processes. As a rule, they do not aggravate each other. With age, a patient obtains a clinically described or with small number of symptoms and even hidden comorbidity within several systems based on common unspecified pathogenic links. The main cause of syntopic comorbidity in senior patients is atherosclerosis. Atherosclerosis of vessels leads to the occurrence of comorbidity on pathogenic principle: IHD, discirculatory atherosclerotic encephalopathy, AH, atherosclerosis of mesenteric arteries, intestinal ischemia etc. [11, 19, 28]. Around 96.0 % of the patients with cirrhosis can have glucose intolerance and 30.0 % can have DM clinically.

The term “interference” is frequently used along with the term “syntropy” (interferential diseases, interferential syntropies, interferential constellations), and there are several similar terms in the literature, but they are rather contradictory interpretations: a) occurrence of one disease under the influence of another (glomerulonephritis in patients with hepatitis C [44], B (Belousov Yu. V., 2012) [2], hepatorenal syndrome, hepatitis/liver cirrhosis and hyperkinetic circulation type) [2]; b) influence of a single disease on the course of the other one as processes occurring independently (occurrence of chronic pancreatitis and duodenum ulcer) [33]; c) interferential syntropies/interferential constellations – a disease occurring at the presence of the other and aggraviating its course [18] (bronchial asthma (BA) and metabolic syndrome or BA and obesity [8]). An example of such association in elderly and senior patients can be a combination of COPD hormonal dysfunction of glands of the endocrine system, in particular, hypophysis, thyroid gland and adrenal cortex, hepatorenal syndrome (kidney failure in patients with pyelonephritis as a result of liver diseases, in  case there is no other reason for kidney failure [2, 22, 41], hepatitis B or C and glomerulonephritis [2, 3, 18, 41, 45], hepatitis/cirrhosis and hyperkinetic circulation type with lowered myocardial contractility potential).

Considering the similarity in definitions of syntropy and interference, we state that it is possible to propose a generalized notion “syntropic diseases” dividing them into interferential and non-interferential syntropic diseases.

Neurotropy is a term recommended to be used in case of occurrence of randomly combined diseases independently from each other in a single body.

Dystropy (mutual repulsion – reverse comorbidity) – naturally rare or impossible combination of certain diseases in a single body, in case the presence of the one slows down the occurrence of the other one (contrassociations).

As examples of comorbid dystropies, some scholars [18, 132] propose a combination of pulmonary TB and mitral stenosis, type 1 DM and peptic ulcer disease, lymphoproliferative and myeloproliferative processes, others [112, 133] – combination of TB and BA, referring to epidemiological paradigm that the risk of atopic BA and its different manifestations occurrence during all the life is much lower than in persons who had TB in childhood. Despite all, it was found that in case of BA and TB, the thing that matters is a general genetic basis (genes of HLA system, interleukins and their receptor antagonists etc.) determined by functional significance of expression products of these genes in infectious-allergic process [60, 77, 98, 130]. There was no combination with pathogenetic reason for TB occurrence among the analyzed combinations of polymorphic types of genes. The obtained results testify that the influences of combinations of certain genotypes of genes are different in the occurrence of BA and TB. Thus, the study of molymorphic types of metabolism system in BA and TB is topical and requires further research due to their relation to clinical peculiarities of diseases course for better understating of interaction mechanism in the realization process of hereditary information in the whole body. Rzhetsky A. et al. (2007) [123] discovered a negative correlation between the possibility of occurrence in patient with aortic aneurysm and schizophrenia, breast cancer and bipolar disorders, and also the fact that patients with J. L. Down syndrome, J. Parkinson’s disease, schizophrenia, diabetes, anorexia nervosa, A. Alzheimer’s disease, multiple sclerosis and G. Huntington’s disease are “protected” from many types of cancer, including solid tumors, tumors caused by smoking, prostate cancer [139]. Recently, due to transcriptomics meta-analysis new molecular proofs of dystrophic connections between some disorders of central nervous system (CNS) and oncological diseases have been obtained [107]. The authors conducted transcriptomics analysis of three CNS diseases (A. Alzheimer’s, J. Parkinson’s and schizophrenia) and three types of cancer (the lungs, prostate, rectum). It was discovered that 74 genes are suppressed in case of these three CNS disorders and increase their activity in case of three abovementioned types of cancer. And, vice versa, expression of 19 genes intensifies simultaneously in case of aforementioned three CNS disorders and suppresses in case of aforementioned types of cancer [107].

Despite the widespread use of the term “dystropy” is this sense, it is essential to consider that, from the clinical point of view, there is a considerable difference in the tactics and strategy of the assistance to patient in case of rare combination of diseases or impossibility of combination of certain diseases. In our opinion, it is appropriate to distinguish dystropy as a rare combination of certain diseases in a single body (pulmonary TB and BA, pulmonary TB and mitral stenosis, type 1 DM and peptic ulcer [32], atopic dermatitis and type 1 DM [138]. Measles, hepatitis, asthma, TB in childhood prevents asthma and atopic dermatitis occurrence [112, 144], besides, plague and scurvy, malaria and sickle cell anemia are dystropic [18]. Considering these facts, we propose introducing a new term “atropy” – impossibility of diseases combination in a single body (lymphoproliferal and myeloproliferal processes, HD and vegetal vascular dystonia of hypotonic type, myxedema and thyrotoxic goiter, obesity and hypotrophy).

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