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UDC 616.36-002.8+616-073/616.36-003.826 DOI: 10.22141/2308-2097.51.3.2017.112634
Yu.M. Stepanov1, N.V. Nedzvetskaya1, V.B. Yagmur1, D.V. Popok1, L.M. Shendrik2 1State Institution "Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine", Dnipro, Ukraine
2State Institution "Dnipropetrovsk Medical Academy of Ministry of Health of Ukraine", Dnipro, Ukraine
Fibroscan and non-invasive indices for the diagnosis of nonalcoholic fatty liver disease
For cite: Hastroenterolohiya. 2017;51:183-7. doi: 10.22141/2308-2097.51.3.2017.112634
Abstract. Background. Non-alcoholic fatty liver disease (NAFLD), an independent nosological entity, is characterized by fat accumulation in hepatocytes not associated with alcohol abuse, and includes a wide spectrum of disorders: from fatty liver, non-alcoholic steatohepatitis to fibrosis with possible outcome in liver cirrhosis. Given the prevalence of this disease, the deterioration of the quality of life of patients, increased mortality from complications, there is a growing interest in developing techniques for accurate and timely assessment of fibrosis. Objective: comparative characteristics of the results of transient elastometry (FibroScan) and non-invasive laboratory indices in the determination of fibrotic transformation of the liver in patients with non-alcoholic fatty liver disease. Materials and methods. The study included patients with NAFLD, who underwent diagnostics and treatment in the department of liver and pancreas of the SI "Institute of Gastroenterology of the NAMS of Ukraine". Results. We have examined 42 patients with NAFLD, among which 18 (45 %) men and 24 (55 %) women. All patients underwent calculation of non-invasive markers of liver fibrosis: aspartate aminotransferase to platelet ratio index (APRI), fibrosis-4 index, aspartate aminotransferase/alanine aminotransferase ratio, the measurement of liver stiffness using the FibroScan apparatus. Conclusions. Our results are consistent with most studies indicating that the most effective non-invasive index is APRI. The combination of transient elasto-graphy (FibroScan) and the APRI index may provide a more effective approach to the diagnosis of liver fibrosis in patients with NAFLD.
Keywords: non-alcoholic fatty liver disease; liver fibrosis; non-invasive diagnostic methods; transient elastography
Орипнальш досл^ження Original Researches ■ < ■ 1 ГАСТРОЕНТЕРОЛОПЯ GASTROENTEROLOGY
Патолопя печшки i жовчовив^дноУ системи / Pathology of Liver and Biliary Excretion System
Introduction
Nonalcoholic fatty liver disease is a condition of excess fat in the hepatic parenchyma in the absence of significant alcohol consumption. The boundary value is 5 % fatty inclusions according to the morphological study, or 5.6 % according to the results of magnetic resonance spectrosco-py [1]. NFLD is a worldwide problem with prevalence according to various studies from 12.5 % to 51 %. The scope of these indicators is due to the presence of various risk factors and depends on the methods of diagnosis [1—4]. The spectrum of pathology included in the concept of NFLD consists of simple steatosis, steatohepatitis with the possibility of progression to cirrhosis of the liver and even hepatocellular carcinoma. Recently, there is an understanding that NFLD is a hepatic embodiment of the metabolic syndrome and is closely related to insulin resistance, the risk of car-
diovascular pathology and the development of diabetes mel-litus. Rapid progression of fibrosis is a significant problem, although it occurs in a small number of patients with fatty disease. A gold standard for isolating a group of patients at risk of disease progression and to determine the degree of fibrosis is still considered a morphological study, although liver biopsy is associated with certain inconveniences and life-threatening complications [5].
In the last decade, alternative methods of noninvasive or minimally invasive determination of the degree of fibrosis with various liver pathologies, including NFLD, are actively developing. Among them, the evaluation of various indices calculated on the basis of blood values — the ratio of activity of aspartate aminotransferase (AST) to the number of platelets (APRI), the ratio of aspartate aminotransferase to alanine aminotransferase (AST/ALT), commercial integral
© «Gastroenterology», 2017 © «Гастроентеролопя», 2017
© Publisher Zaslavsky O.Yu., 2017 © Видавець Заславський О.Ю., 2017
For correspondence: Yu. Stepanov, MD, PhD, Professor, State Institution "Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine", Slobozhanskii Avenue, 96, Dnipro, 49074, Ukraine; e-mail: gastrodnepr@i.ua
Для кореспонденцп': Степанов Юрш Миронович, доктор медичних наук, професор, ДУ «1нститут гастроентерологп' НАМН Укра'ши», пр. Сло-божанський, 96, м. Дшпро, 49074, Украина; e-mail: gastrodnepr@i.ua
indices — NAFLD fibrosis score (NFS), Fibrosis 4 calculator (FIB-4) [1]. In the diagnosis of NFLD, imaging methods are becoming increasingly important. Ultrasound, computer and magnetic resonance imaging, magnetic resonance spectroscopy, and transient elastography are used. Computed tomography is used in a limited way because of both the radiation load and lack of sensitivity.
Transient elastography (TE) measures the propagation velocity of transverse waves at a depth of 25—65 mm and is converted to a liver stiffness index (LSM). The resistance of deformation, which depends on the rigidity of the liver, is expressed by the Young's modulus in kilopascals (kPa). The TE uses the formula E = 3pV2, which is based on Hooke's law, where E is Young's modulus, p is the density (presumably 1000 kg/m3) and V is the velocity of propagation of transverse waves [6].
The advantages of TE are simple, non-invasive, as well as high clinical significance. Restrictions on the use of the method are the presence of ascites in the patient, excessively developed fatty tissue, narrow intercostal spaces. The effectiveness of TE in patients with viral hepatitis has already been confirmed by a large number of studies [7, 8]. At the same time, the diagnostic capabilities of the method in patients with NFLD have not been adequately described.
The purpose. Comparative characteristics of the results of transient elastometry (FibroScan) and noninvasive laboratory indices in the determination of fibrous liver transformation in patients with NFLD.
Materials and methods
The study included patients with NFLD who underwent examination and treatment in the Department of Liver and Pancreatic Diseases at the Institute of Gastroenterology of the National Academy of Medical Sciences of Ukraine. The diagnosis was based on ultrasound examination of the abdominal and evaluation of the activity of liver enzymes. Patients with a different liver disease, including viral, drug, autoimmune and alcoholic hepatitis, were excluded from the study.
The activity of ALT and AST in blood serum was determined by the colorimetric dinitrophenylhydrazed Reitman-Frenkel method. The laboratory reference range of ALT and AST was up to 40 U/l, and the normal platelet count was 150-450 g/l.
The liver stiffness measurement (LSM) was performed on a FibroScan 502 Touch F 60156 machine, the company Echosens (France). The impact of the sensor pin was applied to the right intercostal space at the level of the anterior or middle axillaries line and was directed to the right lobe of the liver. Using ultrasonic M- and A-mode, the shear wave propagation velocity and the controlled ultrasonic attenuation parameter were estimated through a standard 4 cm section. The final result was expressed in kPa and was the median value of 10 individual actual measurements. The studies, which resulted in 10 valid measurements with a valid level of at least 60 % and an interquartile range of no more than 30 % of the median stiffness values, were considered successful. The results were evaluated as follows: F 0 — 0-5.9 kPa, F 1 — 6-6.9 kPa, F 2 — 7-9 kPa, F 3 — 9.1-10.3 kPa, F 4 — 10.4 kPa and more.
The AST/ALT ratio was calculated for each patient.
APRI was calculated by dividing the AST level [U/L], expressed as the number of times above the upper limit of normal [ULN], by platelet count [GL]:
APRI = (AST [UL] x 100) / (AST [ULN] x x platelet count [GL]).
FIB-4 was calculated using the formula:
FIB-4 = (age [years] x AST [U/L]) / (platelet count [G/L] x x 4ALT [U/L]).
The statistical analysis was carried out with the Statis-tica for Windows 6.0. Since most of the data had a normal distribution, parametric statistics were used — mean (M) and standard deviation (SD). Correlation analysis was used to reveal the interrelations between different values of the investigated indicators. To determine the significance of the differences between the integral indices of fibrosis of AST/ALT, APRI and FIB-4 in patients with minimal (F 0-1), moderate (F 2-3) and severe (F 4) fibrosis, the Student's t-test was applied. The difference was considered significant when p < 0.05.
Results
42 patients with NFLD were examined, including 18 (45 %) men and 24 (55 %) women; the average age of patients was 44.9 ± 1.6 years.
There were no significant differences in age, platelet count, ALT and AST activity between men and women. The results of a biochemical blood test and platelet count are shown in Table 1.
The average liver stiffness index was (9.10 ± 1.33) kPa and in most patients there was no fibrosis (F0 — 31 %) or fibrosis was moderately expressed (F1/2 — 45.3 %). In male patients, the stiffness index was higher than in women, but this difference was not significant (11.7 (SD: 12.7) compared with 7.1 (SD: 2.22), respectively, p = 0.091). According to TE, the patients were divided into 3 groups: 1 — with minimal fibrosis (F 0-1), 2 — with moderate fibrosis (F 2-3) and 3 — with severe liver fibrosis.
Correlation analysis revealed a positive relationship between ALT level and liver stiffness (r = 0.32 and 0.47 for p = 0.003 and 0.002 for Kendall and Spearman correlations, respectively), as well as AST level and liver stiffness (r = 0.39 and 0.55 at p = 0.0002 and 0.0001 for Kendall and Spearman correlations, respectively). There was also a positive correlation between APRI and transient elastometry (r = 0.33 and 0.49 for p = 0.002 and 0.001 for Kendall and Spearman correlations, respectively). There was a significant difference in the APRI score between patients with moderate
Table 1 — Platelet and hepatic enzyme indices in the examined patients
Lab.test M ± SD Normal range
Platelets, g/l 252.47 ± 66.82 150-450
Serum ALT, U/L 68.54 ± 56.81 < 40
Serum AST, U/L 46.98 ± 32.74 < 40
to severe (F 2—3/F 4), and initial and severe (F 0—1/F 4) fibrosis (Table 3).
A weak correlation between FC, APRI, FIB-4 and AST/ALT ratio can be explained by the small number of patients examined, which necessitates continuation of this study, as well as further monitoring of patients at the stages of NFLD development.
Discussion
The pathophysiology of a specific disease lies at the heart of the development of biomarkers, reflecting the different stages of the development of this disease. In the case of NFLD, there are two potential targets for researchers. The first is the introduction of markers in practice, by which one could distinguish simple steatosis from steato-hepatitis — a state with a more serious prognosis. The second goal is to identify the stage of fibrosis. Most prospective cohort studies of patients with NFLD showed that the prognosis is determined by the stage and level of progression of fibrosis even more than by the presence of necrotic inflammation. Clinical significance is the possibility of differentiation between absence or minimal fibrosis (F 0—1), significant fibrosis (F 2), severe fibrosis (F 3) and cirrhosis (F 4) [9].
F.C. Kruger, C.R. Daniels, M. Kidd and colleagues evaluated the results of 111 patients with histologically proven fatty liver disease. Biopsy specimens were described according to the NASH clinical research network (CRN) criteria. Groups with steatosis, steatohepatitis with absent or moderate fibrosis and with severe fibrosis were identified. The sensitivity and specificity of APRI with NFS and ALT/ AST ratio were compared. The APRI value was significantly
Table 2 — Distribution of different degrees
of fibrosis in the examined patients according to transient elastometry
The stage of fibrosis (kPa) N (%)
F 0 (< 5.9) 13 (31)
F 1 (6-6.9) 7 (16.7)
F 2 (7.0-9.0) 12 (28.6)
F 3 (9.1-10.3) 3 (7)
F 4 (> 10.4) 7 (16.7)
All patients 42 (100)
Tab^ 3 — Integral indicators of liver fibrosis and the reliability of differences between them in patients, distributed depending on the TE
Tests Group 1 (N = 20) Group 2 (N = 15) Group 3 (N = 7)
LSM, kPa 5.13 ± 1.36* 8.30 ± 0.82* 22.14 ± 15.96
FIB-4 0.98 ± 0.69 1.08 ± 0.33 1.60 ± 1.10
APRI 0.37 ± 0.24 0.44 ± 0.21* 0.998 ± 0.550
AST/ALT 0.78 ± 0.28 0.71 ± 0.20 0.96 ± 0.45
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5 10 15 20 25 30 35 40 45 50 LSM, kPa |-1 | r = - 0.12; p = 0.471
Figure 1 — Correlation between the FibroScan (liver sriffness, kPa) and the AST/ALT ratio
Figure 2 — Correlation between the FibroScan (liver sriffness, kPa) and the APRI
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Figure 3 — Correlation between the FibroScan (liver sriffness, kPa) and the FIB-4
higher with severe fibrosis. So the optimal cut-off point was 0.98 with a sensitivity of 75 % and a specificity of 86 %. The NFS for steatohepatitis was significantly lower in the group with severe fibrosis. Positive predictive value was 54 % for APRI, while for NFS it was 34 %. The negative predictive value was 93 % for APRI and 94 % for NFS. Analysis of the data showed that for the diagnosis of severe fibrosis APRI is more preferable than NFS and ALT/AST [10].
A group of American scientists retrospectively analyzed a database of 514 adult patients with NFLD, assessing the diagnostic accuracy of FIB-4, comparing it with seven other non-invasive markers. The authors concluded that FIB-4 is superior to other fibrosis indices in patients with NFLD, but there is still a need to develop more sensitive non-invasive markers [11].
English scientists S. McPherson, S.F Stewart, E. Henderson et al. compared morphology data of 145 Newcastle Hospitals Fatty Liver Clinic patients over a 6-year period. The FIB-4 scale had the best diagnostic accuracy for severe fibrosis — AUROC = 0.86, the AST/ALT ratio (AUROC = 0.83), NFS (AUROC = 0.81), and the AST/ platelet ratio (AUROC = 0.67). AST/ALT, FIB-4 and NFS had a negative predictive value above 90 %. The positive prognostic value was moderate. To exclude severe hepatic fibrosis, biopsies can potentially be avoided in 69 % of patients with AST/ALT, 62 % with FIB-4, 52 % with NFS [12].
The French P. Cales, F. Laine, J. Boursier compared the NFLD-specific certified FibroMeter and NFS tests with the non-specific APRI test. The data of 235 patients with fatty liver disease of two clinical centers were evaluated. The highest accuracy was 91 % with a marked fibrosis in FibroMeter, whose AUROC was 0.94, which was significantly higher than in NFS (0.884, p = 0.008) and APRI (0.866, p < 0.001). Using threshold values of 90% predictive value, liver biopsy could be avoided in most patients: FibroMeter — 97.4 %, NFS: 86.8 % (p < 0.001) and APRI: 80.0% (p < 0.001) [13].
Conclusions
In our study, the standard with which we compared the minimally invasive markers of fibrosis was transient elas-tometry. According to the results of many years of clinical practice, TE measurement by FibroScan is a safe method allowing to determine the degree of fibrosis with high accuracy. The results of our work are consistent with most studies, according to which the most effective of minimally invasive indices is APRI. With its help, it is possible to differentiate the stage of fibrosis with high accuracy (from moderate — F 2-3 to severe F 4), but its use is limited in the diagnosis of initial fibrosis (F 1). The combination of transient elastometry (FibroScan) and the APRI index can provide a more efficient approach in the diagnosis of liver fibrosis in patients with NFLD. Thus, the use of TE with FibroScan in combination with the APRI index allows early diagnosis of fibrosis as an alternative to puncture liver biopsy.
Conflicts of interests. Authors declare the absence of any conflicts of interests that might be construed to influence the results or interpretation of their manuscript.
References
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2. Chalasani N, Younossi Z, Lavine JE, et al. The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroen-terological Association. Hepatology. 2012 Jun;55(6):2005-23. doi: 10.1002/hep.25762.
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4. Li H, Wang YJ, Tan K, et al. Prevalence and risk factors of fatty liver disease in Chengdu, Southwest China. Hepatobiliary. Hepatobiliary Pancreat Dis Int. 2009 Aug;8(4):377-82. PMID: 19666406.
5. Machado MV, Cortez-Pinto H. Non-invasive diagnosis of non-alcoholic fatty liver disease. A critical appraisal. J Hepatol. 2013May;58(5):1007-19. doi: 10.1016/j.jhep.2012.11.021.
6. Friedrich-Rust M, Romen D, Vermehren J, et al. Acoustic radiation force impulse-imaging and transient elastogra-phy for non-invasive assessment of liver fibrosis and steatosis in NAFLD. Eur J Radiol. 2012 Mar;81(3):e325-31. doi: 10.1016/j. ejrad.2011.10.029.
7. Ying HY, Lu LG, Jing DD, Ni XS. Accuracy of transient elastography in the assessment of chronic hepatitis C-related liver cirrhosis. Clin Invest Med. 2016 Oct 14;39(5):E150-E160. PMID: 27805898.
8. Cales P, Boursier J, Lebigot J, et al. Liver fibrosis diagnosis by blood test and elastography in chronic hepatitis C: agreement or combination? Aliment Pharmacol Ther. 2017 Apr;45(7):991-1003. doi: 10.1111/apt.13954.
9. Fitzpatrick E, Dhawan A. Noninvasive biomarkers in nonalcoholic fatty liver disease: Current status and a glimpse of the future. World J Gastroenterol. 2014 Aug 21;20(31):10851-63. doi: 10.3748/wjg.v20.i31.10851.
10. Kruger FC, Daniels CR, Kidd M, et al. APRI: a simple bedside marker for advanced fibrosis that can avoid liver biopsy in patients with NAFLD/NASH. S Afr Med J. 2011 Jun 27;101(7):477-80. PMID: 21920102.
11. Shah AG, Lydecker A, Murray K, et al. Nash Clinical Research Network. Comparison of noninvasive markers of fibrosis in patients with nonalcoholic fatty liver disease. Clin Gastroenterol Hepatol. 20090ct;7(10):1104-12. doi: 10.1016/j.cgh.2009.05.033.
12. McPherson S, Stewart SF, Henderson E, Burt AD, Day CP. Simple non-invasive fibrosis scoring systems can reliably exclude advanced fibrosis in patients with non-alcoholic fatty liver disease. Gut. 2010Sep;59(9):1265-9. doi: 10.1136/gut.2010.216077.
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Received 12.06.2017 ■
Степанов Ю.М.1, Недзвецька Н.В.1, Ягмур В.Б.1, Попок Д.В.1, ШендрикЛ.М.2
1ДУ «1нститут гастроентерологП НАМН Украни», м. Днпро, Украна
2ДУ «Днпропетровська медична академя МОЗ Украни», м. Днпро, Украна
FibroScan i нешвазивш шдекси в ^агностищ неалкогольноУ жировоУ хвороби печiнки
Резюме. Актуальшсть. Неалкогольна жирова хвороба печш-ки (НЖХП) е самост1йною нозолопчною одиницею, характе-ризуеться накопиченням жиру в гепатоцитах, не пов'язаним 3i зловживанням алкоголем, i включае широкий спектр пору-шень — вщ жирово'! дистрофи печшки, неалкогольного стеа-тогепатиту до ф1брозу з можливим переходом у цироз печш-ки. З огляду на поширешсть ще'1 патологи, попршення якосй життя хворих, збiльшення смертносп вщ ускладнень зростае штерес до розробки метод1в для точно'! й своечасно'1 оц1нки ф1брозу. Мета: пор1вняльна характеристика результат1в тран-з1ентно'1 еластометрН (FibroScan) i нешвазивних лабораторних шдекс1в у визначенш ф1брозно'1 трансформацН печшки у хворих 1з неалкогольною жировою хворобою печшки. Mamepiaau та методи. У досладження включеш пашенти з НЖХП, яш проходили обстеження й л1кування у вщдшенш захворювань
печшки та пщшлунково'! залози ДУ «1нститут гастроентерологП НАМН Украши». Обстежеш 42 пашенти з НЖХП, серед яких 18 (45 %) чоловтв i 24 (55 %) жшки. Ус1м пащентам було виконано розрахунок нешвазивних маркер1в ф1брозу печ1нки: APRI, FIB-4, сшввщношення аланшамшотрансферази/ас-партатам1нотрансферази, проведено вим1рювання жорсткосп печшки за допомогою апарату FibroScan. Результати нашо'1 роботи узгоджуються з бшьшктю дослiIджень, згiIдно з яки-ми найбшьш ефективним з малошвазивних шдекс1в е APRI. Висновки. Поеднання транз1ентно'1 еластометри (FibroScan) з шдексом APRI може забезпечити б1льш ефективний пщхщ до д1агностики ф1брозу печшки у хворих з НЖХП. K™40Bi слова: неалкогольна жирова хвороба печшки; ф1-броз печшки; нешвазивш методи д1агностики; транз1ентна еластометр1я
Степанов Ю.М.1, Недзвецкая Н.В.1, Ягмур В.Б.1, Попок Д.В.1, Шендрик Л.М.2
1ГУ «Институт гастроэнтерологии НАМН Украины», г. Днепр, Украина
2ГУ «Днепропетровская медицинская академия МЗ Украины», г. Днепр, Украина
FibroScan и неинвазивные индексы в диагностике неалкогольной жировой болезни печени
Резюме. Актуальность. Неалкогольная жировая болезнь печени (НЖБП) является самостоятельной нозологической единицей, характеризуется накоплением жира в гепатоци-тах, не связанным со злоупотреблением алкоголем, и включает широкий спектр нарушений — от жировой дистрофии печени, неалкогольного стеатогепатита до фиброза с возможным исходом в цирроз печени. С учетом распространенности этой патологии, ухудшения качества жизни больных, увеличения смертности от осложнений растет интерес к разработке методов для точной и своевременной оценки фиброза. Цель: сравнительная характеристика результатов транзи-ентной эластометрии (FibroScan) и неинвазивных лабораторных индексов в определении фиброзной трансформации печени у больных с НЖБП. Материалы и методы. В исследование включены пациенты с НЖБП, которые проходили обследование и лечение в отделении заболеваний печени
и поджелудочной железы ГУ «Институт гастроэнтерологии НАМН Украины». Обследовано 42 пациента с НЖБП, среди которых 18 (45 %) мужчин и 24 (55 %) женщины. Всем пациентам был выполнен расчет неинвазивных маркеров фиброза печени: APRI, FIB-4, соотношение аланинаминотран-сферазы/аспартатаминотрансферазы, проведено измерение жесткости печени при помощи аппарата FibroScan. Результаты нашей работы согласуются с большинством исследований, согласно которым наиболее эффективным из ма-лоинвазивных индексов является APRI. Выводы. Сочетание транзиентной эластометрии (FibroScan) с индексом APRI может обеспечить более эффективный подход в диагностике фиброза печени у больных с НЖБП.
Ключевые слова: неалкогольная жировая болезнь печени; фиброз печени; неинвазивные методы диагностики; транзи-ентная эластография
