PRACA ORYGINALNA

ORIGINAL ARTICLE

Comorbidity severity index as a new tool for assessment of co-existing diseases in patients with non-alcoholic fatty liver disease at the carbohydrate metabolism disorder background and concomitant subclinical hypothyroidism

Snizhana V. Feysa, Ivan V. Chopei

Uzhhorod National University, Uzhhorod, Ukraine

Abstract

Introduction: Non-alcoholic fatty liver disease (NAFLD) is the most common disease which is characterized by comorbidity. However, no comorbidity index for its assessment has been described yet.

The aim of this study was to develop a new index for evaluation of comorbidity in patients with NAFLD.

Materials and methods: 226 patients with NAFLD and associated carbohydrate metabolism disorders were examined. Besides, 60 persons with subclinical hypothyroidism, 30 patients with type 2 diabetes mellitus (T2-DM) and 30 NAFLD patients were examined. 30 healthy persons formed the control group. Clinical diagnoses were based on the laboratory tests and liver sonography. A new index of comorbidity has been used. Calculation of comorbidity severity index (ComSI) includes the possible presence of NAFLD, thyroid disorders, abdominal obesity, dyslipidemia, anemia, chronic complications of T2-DM, aggravated anamnesis.

Results: The contradiction in the calculation of the well-known comorbidity indices values (CIRS – Cumulative illness rating scale, CCI – Charlson’s comorbidity index, Kaplan-Feinstein index) was shown. So, their limited suitability for using in patients with carbohydrate metabolism disorders who have NAFLD was detected. According to our results an increasing of patients’ age is associated with the increasing of concomitant diseases number and with deteriorating of the patients’ general condition, which is reflected in an increasing of the ComSI value. The increasing of concomitant diseases number is associated not only with the higher ComSI, but also with the number of persons with a severe comorbidity according the ComSI value. Instead, the persons without comorbidity (groups 6, 7, 8) were marked as the patients with mild or moderate disease according the ComSI.

Conclusions:The new ComSI index can be used to evaluate the severity of comorbidity in patients with NAFLD.

KEY WORDS: non-alcoholic fatty liver disease, comorbidity severity index, ComSI, severity course evaluation

Wiad Lek 2019, 72, 4, 650-653

Introduction

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver condition worldwide [1]. In the general population, the prevalence of NAFLD has been reported to widely range from 6.3% to 51% related to the different population/ethnicity evaluated as well as to the diagnostic methods used to measure the amount of intrahepatic fat content [2-4]. The prevalence of NAFLD among patients with carbohydrate metabolism disorders (type 2 diabetes mellitus – T2-DM; pre-diabetes – PD) is more than 75% [5]. NAFLD as a liver manifestation of metabolic syndrome (MS) is related to insulin resistance and associated with co-existing cardiovascular diseases, chronic kidney diseases, T2-DM, obesity. Approximately 90% of patients with NAFLD have more than one component of MS and about one-third of patients meet the criteria of MS [6]. That is why the NAFLD is a typical example of comorbidity.

Comorbidity has been defined as the “existence or occurrence of any additional entity during the clinical course of a patient who has the index disease under study”. Comorbidity (multimorbidity) is considered to be one of the important problems of modern medicine, since the combination of diseases that compete in its diagnostic and prognostic significance requires the appointment of many (often incompatible) drugs [7]. This fact leads to polypharmacy and, due to the possibility of interactions between drugs, often changes the response to therapy, reducing the results of treatment [8].

The use of different comorbidity indices was proposed for standardization of the combined diseases researches. 12 methods of comorbidity estimation [9] have been described, each of which has its advantages and disadvantages. The most popular and well-known among them are Cumulative illness rating scale (CIRS), Kaplan-Feinstein index, Charlson comorbidity index (CCI), multimorbidity index (MMI). However, there is no perfect index that can measure comorbidity. The Medline database (English-language segment) does not contain information about using of comorbidity indices to determine the severity of the NAFLD patients’ condition. The Kaplan-Feinstein index, which is designed to evaluate the comorbidity in patients with T2-DM, also does not include the possible presence of NAFLD which is very often combined with T2-DM. Such disorders as possible thyroid disorder, hyperglycemia (PD), dyslipidemia, anemia, hyperuricemia, which aggravate patient’s condition and decrease the effectiveness of treatment are also not taken into account.

The wideworld prevalence of NAFLD and its frequent combination with hypothyroidism [10], including subclinical ones, as well as the absence of comorbidity indices that take into account the presence of these diseases, necessitate the development of a new tool for assessing the health status of such patients.

The aim

The aim: to develop a new method for evaluating comorbidity in patients suffering from NAFLD, by improving the Kaplan-Feinstein scale, adapting it to a greater number of possible comorbid states.

Materials and methods

This study is a part of common scientific theme of Therapy and Family Medicine Department «Optimization of prevention and treatment of obesity and diabetes mellitus in cases of Helicobacter pylori associated diseases». The article is also a part of scientific research work for obtaining a Doctor of Medicine degree “Non-alcoholic fatty liver disease and concomitant subclinical hyperthyroidism”. The study was carried out in accordance with the requirements of the Helsinki Declaration. The Ethical Committee of the Therapy and Family Medicine Department approved the study protocol, and informed consent was obtained from the participants.

226 patients with NAFLD and carbohydrate metabolism disorders were examined. Diagnosis of T2-DM or PD were confirmed according to the criteria of American Association of Clinical Endocrinologists and American College of Endocrinology (ACE / ACE) (2015 р.) [11]. Criteria of pre-diabetes include the following: increasing fasting plasma glucose to 5.6-6.9 mmol/l; impaired glucose tolerance: fasting plasma glucose level ≤ 7.0 mmol/l, 2-hour postprandial glucose level (random plasma glucose) 7.8 – 11.0 mmol/l, HbA1C 5.7 – 6.4 %. The diagnosis of NAFLD [3] was based on the results of abdominal ultrasonography, after excluding heavy alcohol consumption, and viral, or other liver diseases. NAFLD patients were subjected to a full assessment of medical history, physical examination, abdominal ultrasonography as well as routine laboratory tests. Assessment of thyroid function was performed using the following: thyroid stimulating hormone (TSH), free serum tri-iodothyronin (FT3) and free serum thyroxine (FT4) were measured by the method of immuno-chemoluminescence using automatic laboratory system Roche Hitachi Сobas e411 (Switzerland, Japan). The following interpretation of TSH was used: level of TSH from 0.4 to 4.0 mU/l describes normal thyroid function, i.e. euthyroidism; level of TSH more than 4 mU/l is considered to be a clinical manifestation of hypothyroidism; level of TSH from 4.01 to 10.0 mU/l detects subclinical hypothyroidism (SH); increase of TSH more than 10 mU/l shows manifestative (overt) hypothyroidism (OH).

According to the thyroid function all the patients were divided into some clinical groups. The first group consisted of 32 patients with NAFLD, T2-DM and concomitant subclinical hypothyroidism (NAFLD+T2-DM+SH), the second group included 40 patients with NAFLD at the background of pre-diabetes and concomitant SH (NAFLD+PD+SH). The 73 patients with NAFLD, T2-DM and normal thyroid function belonged to the third group (NAFLD+T2-DM+Euthyroid), and 55 patients with NAFLD at the background of pre-diabetes and normal thyroid function were included into the forth group (NAFLD+PD+Euthyroid). The fifth group consisted of 26 patients with NAFLD at the background of T2-DM or PD and concomitant overt hypothyroidism (NAFLD+T2-DM/DM+OH). The 60 persons with SH formed the sixth group. The seventh group consisted of 30 euthyroid patients suffering from T2-DM without NAFLD, the 8th group was formed by NAFLD patients without T2-DM or PD. The control group consisted of 30 almost healthy persons (without NAFLD, T2-DM or PD), there were no statistically significant difference between the patients and the controls regarding age and sex.

The Kaplan-Feinstein index and a new Comorbidity Severity Index (ComSI) were calculated for each examined patient. To calculate ComSI, the Kaplan-Feinstein index was used after its supplementing by the following pathological conditions: NAFLD; thyroid gland disorders (hypothyroidism, including subclinical; hyperthyroidism); abdominal obesity (waist circumference over 80 cm in women and more than 94 cm in men and / or body mass index greater than 30); dyslipidemia; anemia; diabetic microangiopathy (retinopathy, nephropathy); diabetic neuropathy; presence of acute cerebrovascular accident and / or acute myocardial infarction, pulmonary artery thromboembolism in the anamnesis; allergic diseases; connective tissue disease (systemic diseases).

METHODIC OF CALCULATING ComSI

To calculate the index, we should evaluate the severity of all diseases and pathological conditions in the patient according the following score: “0” – no disease, “1” – disease at the preclinical stage, subclinical condition or mild course, “2” – moderate disease compensated or subcompensated by medication, “3” is a serious illness in the stage of sub- or decompensation despite the treatment by medications in accordance with the current protocols. After that we should add all the points and evaluate the course severity of the comorbidity according to the obtained index value. Index value less than 10 points indicates mild course of comorbidity and needs to lifestyle modification and glycemic control. Index value from 11 to 20 points indicates moderate course of comorbidity and needs treatment by using medications for diseases which are marked as 2 or 3 point (dominated pathology). Index value from 21 to 35 points indicates severe comorbidity and more than 36 describes very severe course of comorbidity. In these cases, all prescribings should be reviewed in order to avoid polypharmacy, drug interactions and the possible side effects development. Correction of treatment should be done according to cardiovascular risk level.

STATISTICAL ANALYSIS

The statistical analysis was made using «Statistica 10.0» after making of database in tables Excel.

Results and discussion

The age of the patients that were included in the study varied from 35 to 73 (57.8 ± 4.1) years. As the age increased, the number of comorbid diseases increased and the general condition deteriorated. As an example of the ComSi index application, we describe here its calculation for a patient V., aged 46. The patient has the following diseases: arterial hypertension (2 points), heart and vascular diseases (2 points), diseases of the central and peripheral nervous system (1 point), respiratory system diseases (1 point), kidneys problems (2 points), digestive system diseases (2 points), abdominal obesity (3 points), dyslipidemia (2 points), anemia (1 point), subclinical hypothyroidism (1 point) and exacerbation of chronic sinusitis and tonsillitis (marked as 2 points in the row “different”). The total value of the index is 21 points, indicating a severe clinical course of comorbid pathology. The treatment of the patient was revised: the main attention was paid to the abdominal obesity treatment, the recommendations for the elimination of modified cardiovascular risk factors were made, and medical treatment with taking into account possible risk of side effects development and drug interactions was recommended.

The calculation of other comorbidity indices was carried out for the same patient V., 46 years old. His CIRS index was 17 and pointed to moderate comorbidity. The calculation of the Kaplan-Feinstein index gave 14 points, indicating the patient’s mild comorbidity. Concomitant hypothyroidism, II degree of obesity and dyslipidemia are serious pathological conditions in case when patient suffer from subcompensated diabetes mellitus and non-alcoholic steatohepatosis. However, during calculating of Kaplan-Feinstein index, these factors have been indicated only as 1 point (as “different”), resulting in a comorbidity of this patient was assessment as “light” or “mild” with a value of index 14. At the same time, the Charlson Index has been calculated as 5 points, corresponding to severe comorbidity, indicating a 21% 10-year survival rate for such patients.

The course severity of comorbidity (according to ComSI) for patients who were included in our study is illustrated by the Table I.

As can be seen from Table I, with the increase of the number of concomitant diseases, not only the value of ComSI was increasing, but the number of persons with a severe course of comorbidity was increasing too. Instead, in groups 6, 7, 8, where there was no combination of the studied diseases, the index value in majority cases indicated a mild or moderate course of comorbidity

The analyzed example of assessing the state of severity by calculating various comorbidity indexes showed contradictory data. Analyzing the comorbid status of the patient V., 46 years old, by using of the most known international comorbidity scales, we obtained fundamentally different results. Their ambiguity hinders the objective assessment of the patient’s condition severity and complicates the prescribing of rational pharmacotherapy. The new index of comorbidity assessment, proposed by us, not only assesses the severity of the condition, but can also be used to determine the further tactics of patient management. The advantages of the ComSI index are the following: index can be used for persons with diabetes, because it takes into account the possible presence of T2-DM chronic complications (microangiopathy, neuropathy), NAFLD, hypothyroidism (including subclinical), anemia (tissue hypoxia worsens the condition of the patient), dyslipidemia (a factor of cardiovascular risk), and also gives the doctor the opportunity to review the treatment management of a comorbid patient taking into account all the factors of comorbidity.

Conclusions

Considering the prevalence of non-alcoholic fatty liver disease in patients with diabetes mellitus, the severity of complications and high cardiovascular risk of comorbid patients, taking into account the disadvantages of existing methods for assessing the severity of the disease and the benefits of the proposed method, it is advisable to implement the new comorbidity index, which is unique for such a contingent of patients, into practice.

References

1. Bellentani S. The epidemiology of non-alcoholic fatty liver disease. Liver Int. 2017;37(1):81-84. Doi: 10.1111/liv.13299.

2. Buzzetti E, Pinzani M, Tsochatzis EA. The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). J Metabol. 2016;65(8):1038–1048. Doi:10.1016/j.metabol. 2015.12.012.

3. Clinical Practice Guidelines for the management of non-alcoholic fatty liver disease. Clinical recommendations of EASL-EASD-EASO. J Hepatol. 2016;64(6):1388-1402. Doi: 10.1016/j.jhep.2015.11.004.

4. Perazzo H, Dufour JF. The therapeutic landscape of non-alcoholic steatohepatitis. Liver Int. 2017;37(5):634-647. Doi: 10.1111/liv.13270.

5. Hazlehurst JM, Woods C, Marjot T et al. Non-alcoholic fatty liver disease and diabetes. J Metabol. 2016;65(8):1096–1108. Doi:10.1016/j.metabol.2016.01.001.

6. Ballestri S. Nonalcoholic fatty liver disease is associated with an almost two-fold increased risk of incident type 2 diabetes and metabolic syndrome. Evidence from a systematic review and meta-analysis. J Gastroenterol Hepatol. 2016;31(5):936–944. Doi: 10.1111/jgh.13264.

7. Campbell-Scherer D. Multimorbidity: a challenge for evidence-based medicine. Evid Based Med. 2010;15:165-166.

8. Patel P JHayward KLRudra R et al. Multimorbidity and polypharmacy in diabetic patients with NAFLD: Implications for disease severity and management. Med Baltimore. 2017;96(26):e6761. Doi: 10.1097/MD.0000000000006761.

9. Fawad Aslam, Nasim Ahmed Khan. Tools for the assessment of comorbidity burden in rheumatoid arthritis. Front Med (Lausanne) 2018;5:39. Doi: 10.3389/fmed.2018.00039.

10. Arafat Kassem, Farag Khalil, Mokhtar Ragab Ramadan, et al. Association and impact of non-alcoholic fatty liver disease on thyroid function. Int. J Curr Res Med Sci. 2017;3(7): 94-107. DOI: http://dx.doi.org/10.22192/ijcrms. 2017.03.07.016.

11. Handelsman Y, Bloomgarden ZT, Grunberger G et al. American association of clinical endocrinologists and american college of endocrinology–clinical practice guidelines for developing a diabetes mellitus comprehensive care plan–2015. Endocr Pract. 2015;21(1):1-87. Doi: 10.4158/EP15672.GL.

Authors’ contributions:

According to the order of the Authorship.

Conflict of interest:

The Authors declare no conflict of interest.

CORRESPONDING AUTHOR

Snizhana V. Feysa

Uzhhorod National University

Sobranecka, 148, 88017, Uzhhorod, Ukraine

tel: +380505600847

e-mail: snizhana.feysa@uzhnu.edu.ua

Received: 10.02.2019

Accepted: 05.04.2019

Table I. The course severity of comorbidity (according to ComSI) for patients of different clinical groups

Clinical groups of patients

n

Mean

ComSI

Mild severity (ComSI ≤10)

(n; %)

Moderate severity

(ComSI 11-20)

(n; %)

Severe comorbidity (ComSI 21-35)

(n; %)

Very severe comorbidity

(ComSI ≥36)

(n; %)

Group 1

(NAFLD+T2-DM+ SH)

32

27,7±3,1

1 (3,125%)

11 (34,375%)

18 (56,25%)

2 (6,25%)

Group 2

(NAFLD+PD + SH)

40

21,4±2,8

6 (15%)

19 (47,5%)

14 (35%)

1 (2,5%)

Group 3

(NAFLD+T2-DM)

73

21,8±2,1

7 (9,59%)

34 (46,58%)

30 (41,1%)

2 (2,74%)

Group 4

(NAFLD+PD)

55

17,5±2.6

8 (14,5%)

40 (72,7%)

7 (12,7%)

0

Group 5

(NAFLD+T2-DM/PD+OH)

26

23,5±3,1

0

12 (46,15%)

12 (46,15%)

2 (7,7%)

Group 6 (SH)

60

5,2±1,3

55 (91,7%)

5 (8,3%)

0

0

Group 7 (T2-DM)

30

14,3±2,7

11 (36,7%)

18 (60%)

1 (3,3%)

0

Group 8 (NAFLD)

30

9,7±1,3

23 (76,7%)

7 (23,3%)

0

0

Control group

of healthy persons

30

2,3±0,2

30 (100%)

0

0

0

Total account

376

Note: n – number of people in the group