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Коморбідний ендокринологічний пацієнт

Международный эндокринологический журнал Том 19, №2, 2023

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Вплив неалкогольного стеатогепатиту на функціональний стан нирок у пацієнтів із цукровим діабетом 2-го типу і діабетичною хворобою нирок

Вплив неалкогольного стеатогепатиту на функціональний стан нирок у пацієнтів із цукровим діабетом 2-го типу і діабетичною хворобою нирок

Авторы: Z.Ya. Кotsiubiichuk, O.S. Khukhlina, А.А. Аntoniv, O.Ye. Mandryk
Bukovinian State Medical University, Chernivtsi, Ukraine

Рубрики: Эндокринология

Разделы: Клинические исследования

Версия для печати


Резюме

Актуальність. Стеатоз печінки та неалкогольний стеатогепатит (НАСГ) вважаються найпоширенішими патологіями печінки, що в розвинених країнах спостерігаються в 20–30 % дорослого населення. У хворих на цукровий діабет (ЦД) часто виникають такі неспецифічні ураження нирок, як безсимптомна бактеріурія, пієлонефрит, карбункул нирки, абсцес нирки, туберкульоз нирки, папілярний некроз, що значно ускладнюють перебіг діабетичної нефропатії (ДН). На ДН припадає 40 % ускладнень при ЦД 1-го типу та 5–15 % при ЦД 2-го типу. Мета дослідження: встановити вплив неалкогольного стеатогепатиту на функціональний стан нирок у пацієнтів із цукровим діабетом 2-го типу і діабетичною хворобою нирок (ДХН). Матеріали та методи. Обстежено 160 осіб із НАСГ, коморбідним ЦД 2-го типу середньої тяжкості та ДХН I–IV стадій. Проведено проспективне дослідження, у якому взяли участь 160 пацієнтів і 30 практично здорових осіб. Зокрема, 25 хворих на НАСГ із ЦД 2-го типу (перша група), 20 пацієнтів із НАСГ та ожирінням І ступеня (друга група), 70 осіб із НАСГ І–IV стадії (третя група), із них 31 (44,3 %) пацієнт мав ДХН І–ІІ стадії (група 3а), 20 (28,6 %) — ІІІ стадії (група 3б), 19 (27,1 %) — ДХН ІV стадії (група 3в). Результати. У пацієнтів із НАСГ, ЦД 2-го типу та ДХН І–IV стадії гіпоальбумінурія була вірогідно вищою порівняно з показником в осіб із ЦД 2-го типу, ДХН І–IV стадії без НАСГ, що свідчить про вплив НАСГ на рівень альбумінурії; підвищення рівня креатиніну і сечовини в крові; зниження швидкості клубочкової фільтрації, що підтверджує негативний вплив НАСГ на перебіг ЦД 2-го типу з ДХН. За наявності НАСГ у пацієнтів із ДХН був вищий рівень альбумінурії, креатиніну в сечі, співвідношення альбумін/креатинін, ніж за його відсутності. Висновки. Показники функціонального стану нирок у хворих на НАСГ та ЦД 2-го типу змінювалися залежно від наявності ДХН та її стадії. Зі збільшенням стадії ДХН знижувався вміст альбуміну в крові, підвищувалися рівні креатиніну та сечовини. Результатом встановлених змін стало підвищення швидкості клубочкової фільтрації, що свідчить про феномен гіперфільтрації, притаманний початковим стадіям ДХН.

Background. Hepatic steatosis and nonalcoholic steatohepatitis (NASH) are considered the most common liver pathologies, which in developed countries is observed in 20–30 % of the adult population. Patients with diabetes mellitus (DM) often develop non-specific kidney lesions such as asymptomatic bacteriuria, pyelonephritis, kidney carbuncle, kidney abscess, kidney tuberculosis, necrotizing papillitis, or papillary necrosis, which significantly complicate the course of diabetic nephropathy (DN). DN accounts for 40 % of complications in type 1 DM and 5–15 % among patients with type 2 DM. The purpose of the study is to clarify the impact of non-alcoholic steatohepatitis on the renal functional status in patients with type 2 diabetes and diabetic kidney disease (DКD). Materials and methods. One hundred and sixty patients with NASH with comorbid type 2 DM of moderate severity and DКD stages I–IV were examined. A prospective study was conducted, which involved 160 patients and 30 practically healthy individuals. In particular, 25 patients with NASH and type 2 diabetes (group 1), 20 people with NASH and class I obesity (group 2), 70 patients with NASH stage I–IV (group 3), of whom 31 patients (44.3 %) had DКD stage I–II (group 3a), 20 (28.6 %) stage III (group 3b), 19 (27.1 %) had DKD stage IV (group 3c). Results. In patients with NASH, type 2 DM, and DKD stage I–IV, hypoalbuminemia was found to be probably higher compared to that of patients with type 2 DM, DКD stage I–IV and without NASH that indicates the influence of NASH on the level of albuminemia; higher blood level of creatinine and urea; lower glomerular filtration rate, which confirms the negative effect of NASH on the course of type 2 DM with DКD. In the presence of NASH, patients with DКD had a higher level of albuminuria, urinary creatinine, albumin-creatinine ratio than if it’s absent. Conclusions. Indicators of the renal functional state in patients with NASH and type 2 DM varied depending on the presence of DКD and its stage. As the stage of DКD increased, the content of albumin in the blood decreased, the levels of creatinine and urea increased. The result of the detected changes was an increase in glomerular filtration rate, which indicates the phenomenon of hyperfiltration, which is specific for the initial stages of DКD.


Ключевые слова

неалкогольний стеатогепатит; цукровий діабет 2-го типу; діабетична хвороба нирок; інсулінорезистентність

non-alcoholic steatohepatitis; type 2 diabetes; diabetic kidney disease; insulin resistance

doi: http://dx.doi.org/10.22141/2224-0721.19.2.2023.1253

Introduction

Hepatic steatosis and nonalcoholic steatohepatitis (NASH) are considered the most common liver pathology, which in developed countries is observed in 20–30 % of the adult population [1]. It has been proven that the most frequent cause of NASH is obesity and type 2 diabetes mellitus (DM) [2].
Diabetic nephropathy, a serious complication of DM, is one of the leading causes of end-stage renal disease in industrialized countries [3]. Since 2007, the National Kidney Foundation’s Kidney Disease Outcomes Quality Initiative has proposed using the term “diabetic kidney disease” instead of “diabetic nephropathy” [4]. Diabetic kidney disease (DKD) or diabetic nephropathy (DN) occurs according to the type of diffuse or focal glomerulosclerosis [5].
In addition, patients with DM often develop such non-specific kidney lesions as asymptomatic bacteriuria, pyelonephritis, kidney carbuncle, apostematous nephritis, kidney abscess, kidney tuberculosis, necrotic papillitis or papillary necrosis, which significantly complicate the course of DN [6, 7]. DN accounts for 40 % of complications in type 1 DM and 5–15 % among patients with type 2 DM [8].
The natural history of DN, typified by a progressive increase in albuminuria from normoalbuminuria to overt proteinuria, followed by a declining GFR, has changed profoundly; this is in part because of the effects of treatment. Remission or regression of microalbuminuria (incipient DN) is a common feature of both type 1 DM and type 2 DM, and is more common than progression to proteinuria. Moreover, a fall in glomerular filtration rate (GFR) has frequently been seen even in the absence of albuminuria, possibly because of predominant macro- and or microvascular and tubulo-interstitial lesions [9].
Histological changes in DN are identical in type 1 DM and type 2 DM. People with type 1 DM and type 2 DM have equivalent rates of proteinuria, azotaemia and ultimately end-stage kidney disease. The two types of DM show strong similarities in rate of renal functional deterioration and onset of co-morbid complications [10].
The purpose of the study is to establish the impact of non-alcoholic steatohepatitis on the renal functional status in patients with type 2 diabetes and diabetic kidney disease.

Material and methods

A prospective study was conducted, in which 160 patients and 30 practically healthy people (PНР) participated. In particular, 25 patients with NASH with type 2 DM (group 1), 20 patients with NASH and obesity of the first degree (group 2), 70 patients with NASH and stage I–IV (group 3), including 31 (44.3 %) patients with stage I–II stages (3a group), 20 (28.6 %) with stage III (group 3b), 19 (27.1 %) people with stage IV DKD (3c group).
The comparison groups consisted of 45 patients with type 2 DM with stage I–IV DKD without NASH (group 4), including 18 (40.0 %) with stage I–II DKD (group 4a), 14 (31.1 %) patients with stage III DKD (group 4b), 13 (28.9 %) people with IV stage DKD (group 4c), as well as 30 PHP of the appropriate age and sex (group 5). A comorbid disease in 82.6 % of patients with NASH was type 2 DM of moderate severity, obesity was a comorbid disease in 17.4 % of patients with NASH. 17.9 % of patients with type 2 DM have not comorbid DKD, and 82.1 % had DKD.
The diagnosis of NASH was established according to the unified clinical protocol approved by the Order of the Ministry of Health of Ukraine No. 826 of 06.11.2014, in the presence of criteria for excluding chronic diffuse liver disease of viral, hereditary, autoimmune, or medicinal origin as the cause of cytolytic, cholestatic, and mesenchymal-inflammatory syndromes, and as well as the results of ultrasonographic examination of the liver. The degree of hepatic steatosis and its nature were determined using the validated kit “SteatoTest”, “ASH” and “NASH-Test” (BioPredictive, France) in the Synevo laboratory. The stage of liver fibrosis was determined by using a set of markers for the quantitative biochemical assessment of fibrosis “FibroTest” (BioPredictive, France) in the Synevo laboratory.
Diagnosis of type 2 DM was carried out in accordance with the unified clinical protocol approved by Order of the Ministry of Health of Ukraine No. 1118 dated 21.12.2012. Diagnosis and treatment of chronic kidney disease (CKD) was carried out according to the recommendations of the clinical guidelines of the Institute of Nephrology of the National Academy of Sciences of Ukraine (2012). GFR was calculated using the GFR calculator of the Institute of Nephrology of the National Academy of Sciences of Ukraine using the average value of three calculated indicators: creatinine clearance according to the Cockcroft-Gault formula, MDRD and CKD EPI [11, 12].
Statistical analysis of the obtained results was carried out according to the type of research conducted and the types of numerical data that were obtained. The normality of the distribution was checked using the Lilliefors, Shapiro-Wilk tests and the method of direct visual evaluation of histograms of the distribution of eigenvalues. Quantitative measures that had a normal distribution are presented as mean (M) ± standard deviation (S). Discrete values are presented in the form of absolute and relative frequencies (percentage of observations to the total number of examinees). Parametric tests with Student’s t-test and Fisher’s F-test were used to compare data that had a normal distribution. In the case of non-normal distribution, the Mann-Whitney rank U-test was used, for multiple comparisons — the Wilcoxon T-test (in the case of research of dependent groups). To assess the degree of dependence between variables, Pearson’s correlation analysis was used in the case of a parametric distribution and Spearman’s rank correlation coefficient in the case of a distribution of indicators that probably differed from normal. Statistical and graphical analysis of the obtained results was carried out using software packages Statistica for Windows version 8.0 (Stat Soft Inc., USA), Microsoft Excel 2007 (Microsoft, USA).

Results

The analysis of indicators of the functional state of the kidneys in NASH patients with type 2 DM and without type 2 DM, as well as in NASH patients with obesity, indicates a normal blood albumin level, normal indicators of GFR and albuminuria (Table 1). At the same time, in patients with NASH, type 2 DM, and DKD I–IV grades significant decrease in the blood albumin level by 1.7 times was established, which was significantly different from the indicator of the content of albumin in the blood in patients with type 2 DM with DKD I–IV stage without comorbid NASH, which was 1.4 times lower than the indicator in PHP (p < 0.05) with the presence of a probable difference between groups (p < 0.05) (Table 1).
This fact indicates the influence of NASH on the level of albuminemia. The content of creatinine in the blood in these comparison groups changed unidirectionally, but also with a predominance in group 3 it increased by 1.7 times against 1.3 times in group 4 (p < 0.05) with the presence of a probable difference between the groups (p < 0.05) (Table 1). Similar changes were found in the groups of examined patients with regard to the content of urea in the blood in group 3 an increase by 3.4 times, and in group 4 — by 2.5 times (p < 0.05) with the presence of a probable difference between the groups (p < 0.05).
GFR as a whole in 3 and 4 comparison groups was reduced, respectively, by 1.8 versus 1.3 times (p < 0.05) with the presence of a probable difference (p < 0.05), which confirms negative effect of NASH on the course of type 2 DM with DKD.
Analysis of indicators of albumin content in urine showed their likely increase in groups 1, 3 and 4. In group 1, the indicator of albuminuria exceeded the reference values by 1.4 times (p < 0.05), in groups 3 and 4, the indicators of albuminuria probably increased by 8.3 and 5.5 times compared to the indicator in PHP. Creatinine content in urine was probably increased in patients of groups 3 and 4 — respectively 1.7 and 1.6 times (р < 0.05) compared to the indicator in PHP. An important marker is changes in the A/C ratio, which probably differed from the indicator in PHP in all comparison groups. Thus, in group 1, the indicator exceeded the data in PHP by 1.3 times (р < 0.05), in group 2, the coefficient exceeded the reference values by 1.2 times (р < 0.05), and in groups 3 and 4 the excess was 5.3 and 3.7 times, respectively (p < 0.05), with a probable difference between groups (p < 0.05).
Indicators of the functional state of the kidneys in patients with NASH, type 2 DM, depending on the presence of DKD and its stage are shown in Table 2. The analysis of indicators indicates that in the 3a group, the albumin content in the blood was reduced by 1.4 times, in the 3b group by 1.6 times, and in the 3c group by 1.7 times (p < 0.05) with the presence of a probable differences between 3a and 3c groups (р < 0.05). The content of creatinine in the blood also increased depending on the stage of DKD respectively in groups 3a, 3b, 3c — by 1.2, 1.4 and 2.6 times (p < 0.05) with the presence of a probable difference between groups 3a and 3c (p < 0.05). Similarly to the previous indicator, the content of urea in the blood increased depending on the stage of DKD — respectively in groups 3a, 3b, 3c — by 2.5, 3.1 and 4.4 times (р < 0.05) with the presence of a probable difference between 3a and 3c groups (p < 0.05). The result of the established changes was a 1.2-fold increase in GFR in patients of the 3a group (p < 0.05), which indicates the phenomenon of hyperfiltration, which is inherent in the initial stages of DKD. In patients of group 3b, a significant decrease in GFR was established by 1.8 times (p < 0.05), and in group 3 — by 3.8 times (p < 0.05) compared to the indicator in PHP (Table 2), which indicates the progression of DKD.
Analysis of albumin content in urine showed their significant increase in all subgroups of group 3. In group 3a, the indicator of albuminuria exceeded the reference values by 2.2 times (p < 0.05), in groups 3b and 3c, the indicators of albuminuria probably increased by 17.5 and 128.6 times compared to the indicator in PHP.
The content of creatinine in the urine was probably increased by 1.5, 1.8 and 1.9 times (p < 0.05), respectively, compared to the indicator in PHP (Table 2), since creatinine from primary urine is not absorbed and in connection with the increase in its content in the blood, it also increases in the urine. The calculation of the A/C ratio in patients of subgroup 3 of group indicates its growth depending on the stage of DKD: 1.7, 10.2 and 71.2 times, respectively (p < 0.05), with the presence of a probable difference between 3a and 3c groups (p < 0.05).
At the same time, comparing indicators of the functional state of kidneys in patients with type 2 DM depending on the presence of DKD and its stage without comorbid NASH, shown in Table 3, the following regularities were established. In the 4a group, the albumin content in the blood was reduced by 1.2 times (then by 1.4 times in the 3a group), in the 4b group by 1.4 times (against 1.6 times in the 3b group), and in the 4c group by 1.5 times (against 1.7 times in the 3rd subgroup) (p < 0.05). The content of creatinine in the blood increased depending on the stage of DKD — respectively in groups 4a, 4b, 4c — by 1.2, 1.3 and 1.5 times (р < 0.05). The content of urea in the blood increased depending on the stage of DKD — respectively, in groups 4a, 4b, 4c — by 2.3, 2.5 and 2.7 times (р < 0.05) with the presence of a probable difference with similar indicators in 3a, 3b and 3c groups (p < 0.05) (Table 3).
Thus, GFR in patients of the 4a group decreased by 1.2 times (p < 0.05), in patients of the 4b group, the GFR decreased by 1.3 times (p < 0.05), and in the 4c group — by 1.5 times (p < 0.05) in comparison with the indicator in PHP, which indicates the progression of DKD. However, the degree of decrease in GFR in patients of group 4 was probably lower than the degree of decrease in comparison group 3 (p < 0.05).
Analysis of albumin content in urine showed their significant increase in all subgroups of group 4. In group 4a, the indicator of albuminuria exceeded the reference values by 3.6 times (p < 0.05), in groups 4b and 4c, the indicators of albuminuria probably increased by 7.5 and 41.1 times compared to the indicator in PHP (Table 3).
Creatinine content in urine was probably increased by 1.2, 1.5 and 1.6 times (p < 0.05), respectively, compared to the indicator in PHP. The A/C ratio in patients of subgroups of group 4 indicates its increase depending on the stage of DKD: 3.3, 5.4 and 27.5 times, respectively (p < 0.05), with the presence of a probable difference between subgroups (p < 0.05).

Discussion

The incidence of non-alcoholic fatty liver disease and its more severe form, NASH, is rising [13, 14]. Patients with advanced fibrosis or cirrhosis from NASH are at increased risk of complications, including the development of hepatocellular carcinoma [15]. Additionally, NASH leads to poorer quality of life and significantly increases healthcare costs and resource utilization [16, 17]. NASH is prevalent but under-recognized in the primary care setting [18].
Certain high-risk populations, such as those with type 2 DM, are significantly more affected by NASH [19], but large-scale screening strategies are challenging to implement. Patients with type 2 DM have an increased risk of NASH, advanced fibrosis, and hepatocellular carcinoma compared to those without type 2 DM [20]. The development of NASH is thought to be multifactorial, of which metabolic syndrome and insulin resistance, as seen in type 2 DM, remain the cornerstone of its pathophysiologic mechanism [21]. In fact, the American Diabetes Association recommends evaluating NASH in all patients with type 2 DM [22].
Screening all patients with type 2 diabetes is challenging. Targeting screening protocols to those with complications from diabetes may be the way forward. We know those with elevated hemoglobin A1c (HbA1c) levels, for example, have an associated increase in liver fibrosis [23]. However, whether the presence of type 2 DM-related complications influences the degree of fibrosis, independent of HbA1c, is yet to be determined. More clearly defining which patients with type 2 DM are at higher risk of fibrosis from NASH can help narrow targets for screening and improve screening uptake in primary care practices.
Targeted liver fibrosis evaluation for those with type 2 DM who are at the highest risk of NASH may help narrow screening strategies. In this study, we demonstrate patients with type 2 DM complications, namely nephropathy are at increased risk of hepatic fibrosis and may represent a suitable screening target in primary care settings [24].
Our results suggest type 2 DM complications, defined by the presence of DN, are an important consideration when evaluating patients for NASH-related risk, particularly in resource-limited settings where more advanced diagnostic tools, such as liver biopsy, may not be available and where widespread implementation of screening may be challenging.

Conclusions

In patients with NASH, type 2 DM, and DKD stage I–IV, hypoalbuminemia was probably higher in the blood (by 1.7 times) compared to the rate in patients with DM2 with DKD stage I–IV without NASH (by 1.4 times), which indicates the influence of NASH on the level of albuminemia; higher content of creatinine and urea in the blood; lower GFR, which confirms the negative effect of NASH on the course of DM2 with DKD. In the presence of NASH, patients with DKD had a higher level of albuminuria; creatinine content in urine, A/C ratio (by 5.3 versus 3.7 times) than in its absence.
Indicators of the functional state of the kidneys in patients with NASH and DM2 varied depending on the presence of DKD and its stage. As the stage of DKD increased, the content of albumin in the blood decreased, the content of creatinine and urea in the blood increased. The result of the established changes was a 1.2-fold increase in GFR in patients of the 3a group, which indicates the phenomenon of hyperfiltration, which is inherent in the initial stages of DKD. In patients of groups 3b and 3c, a significant decrease in GFR by 1.8 and 3.8 times was found, which indicates the progression of DKD.
Creatinine content in urine and A/C ratio in patients with DKD with NASH exceeded the indicator in similar groups of patients with DKD without NASH, depending on the stage of DKD.
 
Received 09.01.2023
Revised 20.02.2023
Accepted 09.03.2023

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