RU2692988C1 - Method for determining hepatic cirrhosis - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention refers to medicine, namely to hepatology, and can be used for screening of patients suspected of liver disease. To this end, ¹³C-metacetin respiratory test. If the cumulative dose value ¹³C the specified test at 30th minute <5.65 % hepatic cirrhosis is determined.

EFFECT: method enables non-invasive determination of hepatic cirrhosis, which enables eliminating the risk of developing complications.

1 cl, 1 tbl, 2 ex

Description

The invention relates to the field of medicine, namely hepatology, and can be used for screening patients with suspected liver disease and subject to further examination (puncture liver biopsy, screening for cancer, searching for etiological factors of liver cirrhosis (autoimmune diseases, diseases of the cardiovascular system, etc). according to the existing standard).

To date, the following research methods are used in clinical practice for chronic liver diseases (CKD):

1) Laboratory tests (biochemical blood test with assessment of cytolysis and cholestasis enzymes).

2) Instrumental methods: ultrasound examination of abdominal organs, fibrogastroduodenoscopy (FGDS) (assessment of the condition of veins, esophageal mucosa, gastric mucosa), computed tomography, magnetic resonance imaging.

3) Methods for assessing the degree of liver fibrosis (AF): puncture biopsy of the liver (PBP), including non-invasive (fibrotest, fibroelastometry).

4) Calculated prognostic indices: APRI, FIB-4, MELD, FibroFast, FibroIndex, FibroMeter, Hepascor.

PBP is a method that is considered a reference method for determining cirrhosis of the liver [1]. At present, the lifetime morphological study of liver tissue continues to be widely used. PBP allows you to confirm, clarify, and often change the clinical diagnosis. It should be noted that the method has a high specificity (81-99%) [2]. Unfortunately, this technique is invasive, can lead to the development of such complications as intra-abdominal bleeding (0.24%) [3], intrahepatic hematoma (2%) [4], pneumothorax (0.08%) [5], biliary peritonitis (0.04%) [6], death (0.01%) [7], local metastasis with targeted biopsy of malignant tumors (0.0005%) [8]. The reason for the refusal to carry out the FSN is also the patients' fear of the procedure, the fear of pain in the puncture site and the side effects on the anesthesia make up to one third of the patients refuse to perform the FSN. This leads to a delay in making a decision on the initiation of specific therapy and prolongation of hospitalization periods [9, 10]. In addition, there are strictly regulated requirements for the amount of material for PBP, the non-observance of which can lead to insufficiently correct conclusions: the length of the liver tissue column should be> 15 mm, and the number of portal paths - at least 6-8 [11, 12]. It should be emphasized that PBP does not provide information about liver function.

In recent years, non-invasive methods such as elastometry and fibrotests have become widespread in clinical practice. For the diagnosis of cirrhosis of the liver, elastometry and fibrotest testing are limited, so limiting factors for elastometry include body mass index ≥28 kg / m2, presence of ascites, cholestasis, venous stasis in the portal vein system, and insufficient operator experience, which requires technical improvement. method. The restriction to the implementation of fibrotests is acute hepatitis (of any etiology), extrahepatic cholestasis. In addition, the method cannot be considered reliable in chronic inflammatory connective tissue diseases (rheumatism, rheumatoid arthritis, systemic lupus erythematosus, scleroderma, etc.), hereditary hyperbilirubinemia, for example, Gilbert syndrome, hemolytic anemia. It should be noted that the sensitivity and specificity of these tests are high only when they are combined (elastometry + fibrotest) [13], since only in this case these diagnostic methods are able to provide a result that is informatively similar to that of PBP.

According to the closest technical essence, as a prototype we have chosen the method of puncture biopsy of the liver.

PBP is a liver tissue sampling, with its subsequent cytological and morphological description.

Liver biopsy is performed in the morning 1.5-2 hours after taking a light breakfast in order to reduce the volume of the gallbladder. One-time sets of Mengini needles or Tru-cut needles with a diameter of 16-18G are used. The biopsy is performed in the position of the patient lying on his back with the body bending to the left and dropping his right hand behind his head. Perkutorno determine the boundaries of hepatic dullness, after which an ultrasound is checked to clarify the localization of large vessels in the area of puncture. After treatment of the skin and layer-by-layer anesthesia, the skin is incised in the VII-IX intercostal space, along the upper edge of the lower rib, between the anterior and middle axillary lines. At the height of the exhalation, the puncture needle is passed through an incision, subcutaneous fatty tissue, intercostal muscles. The Menghini needle with rotational movement pierces the internal fascia of the intercostal muscles and simultaneously pushes out about 2.0 ml of physiological saline from the syringe to clean the needle from the side tissues. Depending on the type of needle used, the final stage has several modifications. After installing the Menghini needle, a vacuum is created on the surface of the liver with a piston of the syringe, and the needle itself is injected with an abrupt movement of 3-4 cm into the liver parenchyma and is immediately removed. Tru-cut needles are inserted into the liver parenchyma, after which the stem with the cutting window is released and the tissue is cut off. For larger liver size, puncture can be performed through the anterior abdominal wall below the edge of the costal arch. The frequency of complications with such access is less - 2.7%, than with intercostal one - 4.1% [14, 15]. After the biopsy, the patient is in bed for 8 hours. Dynamic control of hemodynamic parameters and clinical blood analysis is carried out. In some cases, liver biopsy is advisable to perform under the control of ultrasound (US), computed tomography (CT) or magnetic resonance imaging (MRI). This technique allows to avoid damage to adjacent organs, large vessels and focal lesions, localized in the projection of the biopsy. For biopsy, special needles with a notch are used, which is visible on the screen of an ultrasound device or a computer tomograph. Obtaining a tissue sample from a small area or the formation of a liver in the parenchyma requires coordinated actions by the operator and an assistant who directs the manipulations with an ultrasound or CT scan. Thus, this technique has specific indications.

Biopsy with local hemostasis. This technique is a type of blind percutaneous biopsy and was first described in 1984. Its purpose is to obtain a sample of liver tissue in patients with impaired blood coagulation, when there are no technical possibilities for a transjugular biopsy. Tru-cut needles are used with regular access. The final stage of manipulation is carried out as follows. At the height of the exhalation, the stylet and the cutting part of the needle are introduced into the liver tissue. After cutting the tissue sample, the stylet and the cutting part are disconnected and the latter together with the tissue sample is removed from the liver. A plastic cannula is brought into the stylet and, with its help, a hemostatic gel or gelatin is introduced into the puncture area with a syringe, which closes the tissue defect. The stylet is removed and the patient is allowed to breathe peacefully [16].

The disadvantage of the method chosen by us as a prototype, include:

- The method has high specificity (81-99%), but this technique is invasive, can lead to the development of such complications as intra-abdominal bleeding (0.24%), intrahepatic hematoma (2%), pneumothorax (0.08%), biliary peritonitis (0.04%), death (0.01%), local metastasis with targeted biopsy of malignant tumors (0.0005%).

- The reason for the restriction of PBP is the fear of patients before the procedure, forcing up to a third of patients to refuse to perform PBP. This leads to a slower decision on the initiation of specific therapy and an extension of the hospital stay.

- Sighting biopsy of the liver eliminates the possibility of its implementation on an outpatient basis, requires a mandatory stay of the patient in the hospital, which leads to the duration of the method.

- In addition, performing a liver biopsy requires highly qualified specialists: a surgeon and a morphologist. The results of this study are not reproducible, subjective, the results are interpreted by the morphologist.

The technical result of the invention is:

- the possibility of non-invasive determination of cirrhosis of the liver, and thus, eliminating the risk of complications inherent in the prototype method, such as intra-abdominal bleeding, intrahepatic hematoma, pneumothorax, biliary peritonitis, death, local metastasis with targeted biopsy of malignant tumors;

- reducing the time of the method and the possibility of its implementation on an outpatient basis;

- eliminating the need to attract highly qualified specialists to perform the method, as well as the exclusion of the subjectivity of the evaluation of the research results;

- an increase in patient compliance for examination in connection with the exclusion of the invasiveness of the study and, accordingly, with the exception of possible complications.

The technical result of the invention is achieved by the fact that the patient is subjected to a ¹³ C-methacetin breath test and, at a cumulative dose of ¹³ C of this test, liver cirrhosis is determined at 30 minutes <5.65%.

The method is as follows:

Perform ¹³ C-methacetin breath test.

The principle of the respiratory test is based on the evaluation of the determination of a metabolizable substrate in exhaled air. When the substrate methacetin, labeled ¹³ C, enters the body, it passes through the bloodstream, is metabolized in the liver (demethylation takes place) to form acetaminophen (paracetamol) and a volatile compound (formaldehyde), which is then excreted through the lungs in the form of ¹³ CO ₂ . The metabolic function of the liver is determined by the speed and volume of substrate elimination [17]. Metatsetin drug is administered orally with a fixed dosage of 75 mg per study in a dry form, dissolved in 200 ml of water. The first metabolic process to which the drug is subjected is O-demethylation - cleavage of the ¹³ C-methyl group labeled with an isotope, which occurs during the catalytic action of the enzymes of the cytochrome P450 liver system with formaldehyde synthesis. Further, the label is part of formic acid and bicarbonate ion and is discharged through the lungs in the form of ¹³ CO ₂ . Measuring the carbon isotopic composition in the carbon dioxide of exhaled air, information is obtained on the rate of hepatic metabolism. Exhaled air is sampled within 2 hours - before taking the drug, every 10 minutes in the first hour of the study and every 20 minutes during the second hour. The study is conducted on an infrared (IR) gas analyzer Iris, Germany. The results of each study are presented as dependencies of the exogenous carbon label (PDR) withdrawal rate on time and the total fraction of the derived label on time [18, 19]. Further, using the value of the cumulative dose of ¹³ C at the 30th minute of the specified test <5.65%, the presence of cirrhosis is determined

The essential distinguishing features of the proposed method and the causal link between them and the achieved result:

The patient is performed a ¹³ C-methacetin respiratory test and, using the values of the cumulative dose of ¹³ C at the 30th minute of the indicated test <5.65%, the presence of liver cirrhosis is determined.

The invention is based on the first established relationship between a decrease in the cumulative dose of ¹³ C on the 30th minute of the ¹³ C-methacetin breath test and the risk of cirrhosis in patients.

Using the proposed method, we examined 101 patients with chronic liver diseases (CKD), who had different degrees of liver fibrosis, including F4, that is, cirrhosis. Various clinical and laboratory methods were used, such as puncture biopsy (prototype), fibrotests and elastometry. The results of the proposed method, that is, the definition of cirrhosis consistent with the values of the above methods. The study involved 55 men, 46 women aged 21 to 77 years, the median age was 47 years. All patients were divided into groups depending on the degree of fibrosis, and also, subsequently, according to the degree of functional reserve reduction: group F0 = 26 people, F1 = 23 people, F2 = 23 people, F3 = 12 people, F4 = 17 people.

Results:

In our study, it was found that the differences in the ¹³ C-methacetin breath test were in all the groups studied, but when checking the differences between groups, it was determined that statistically significant differences between the f0-f1, f0-f2, f1-f2 groups was not, these data allowed to enlarge the group f1 and f2 to f1-2 for further work.

When comparing the f0 and f3 groups, statistically significant differences were identified for the following biochemical markers: ALT, ACT, ALP, albumin, MHO, CUM120, dob-40, dob-80, dob-100 (p <0.05)

When comparing f0 and f4, there were statistically significant differences in all indicators, including the methacetin test, except for: total protein, creatinine, indirect bilirubin.

When comparing the f1 and f3 groups, the differences were statistically significant in the following indicators: albumin, indirect bilirubin, dose / h-40, dob-40.

When comparing groups f1 and f4, statistically significant differences were found in all indicators of the methacetin test, as well as in the studied parameters, except for the level of blood platelets, total protein, creatinine.

When comparing the f2 and f3 groups, statistically significant differences were identified by the following indicators: albumin, MHO; there were no statistically significant differences in terms of the metacetin breath test.

When comparing groups f2 and f4, there were statistically significant differences in the following parameters: ALT, ACT, GGTP, alkaline phosphatase, bilirubin, MHO, as well as on all indicators of the methacetin breath test, except dose / h-80, dose / h120, dob-80, dob-120.

When comparing groups f3 and f4, there were statistically significant differences in the following parameters: GGTP, ALP, indirect bilirubin, CUM-30-120, dose / h 20-50, dob20, dob50

Further, using the logic tree method, threshold values of the cumulative dose were allocated in the first 30 minutes of the test. If CUM30 <5.65, the risk of cirrhosis increases by 23.3 times, based on these data, a scheme was developed to determine liver cirrhosis.

We give examples from clinical practice.

Example 1

Patient A., 55 years old, height - 165 cm, weight - 91.2 kg, BMI - 33.8 kg / m ² .

Diagnosis: Cirrhosis of the class A Child-Pugh, HCV-etiology, moderate activity. Antiviral therapy (simeprevir + pegylated interferon-a + ribavirin): recurrent viremia.

Concomitant diseases: type 2 diabetes, insulin-dependent. Glycated hemoglobin 11.6%.

It is noteworthy that in the presence of ultrasound signs of portal hypertension (portal vein - 14 mm), varicose veins of the esophagus were not detected. Class A (for Child-Pugh) - 6 points, MELD - 1 point. Cirrhosis is confirmed by liver biopsy.

The table presents the data of laboratory and instrumental examination of patient A. (Example 1).

Data ¹³ C-MDT patient A. presented in Appendix 1.

CUM30 = 4.3%, which is less than 5.65%, which confirms the presence of cirrhosis in this patient

Example 2

Patient S., 40 years old Height - 165 Weight - 75 BMI - 27.5 kg / m2 Fat content - 41.5%

Complaints: no

Anamnesis: In 2007, markers of HCV infection were first identified. Established chronic hepatitis C, genotype 1b. Viremia is low (2015).

Complete blood count (08/31/16): Hb - 133 WBC - 4.5 PLT - 198

B / x blood test (08/31/16): ALT - 22 ACT - 30 GGTP - 11 alkaline phosphatase - 49 croas - 69 urea - 5.7 a2-macroglobulin - 1.92

Fibrotest (08/31/16): F0 A0, confirmed by elastometry

Ultrasound (31.08.16): spleen - 10 × 4 cm, portal vein - 8 mm

Diagnosis: Chronic hepatitis C, genotype 1b, low viremia, minimal activity, F0 fibrosis stage (according to fibrotest data).

Data ¹³ C-MDT of the patient are presented in Appendix 2.

The cumulative dose of ¹³ C by the 30th minute of the test was 10.9%, which is more than 5.65, which confirms the absence of cirrhosis in this patient.

Therefore, using the proposed method, it is possible to diagnose cirrhosis of the liver with a high degree of accuracy. The duration of the proposed method of determining cirrhosis is 30 minutes. During the study, there was no refusal to conduct this test, since it is non-invasive, it is performed on an outpatient basis, does not require hospitalization, and also a large amount of time spent by the patient.

The results of the proposed method are comparable with the results of the method selected as a prototype, that is, it has comparable specificity.

Thus, the claimed method of determining cirrhosis of the liver, compared with the prototype, without reducing its specificity, allows you to:

- perform non-invasive determination of cirrhosis, and thus eliminate the risk of complications inherent in the prototype method, such as intra-abdominal bleeding, intrahepatic hematoma, pneumothorax, biliary peritonitis, death, local metastasis with targeted biopsy of malignant tumors;

- reduce the time of the method and perform it on an outpatient basis;

- eliminate the need for highly qualified specialists to perform the method, as well as the subjectivity of the evaluation of research results;

- to increase the compliance of patients with the examination in connection with the exclusion of the invasiveness of the study and, accordingly, with the exception of possible complications.

Bibliography:

1. Dienstag J.L. The role of liver biopsy in chronic hepatitis C. Hepatology. 2002; 36: 152-60.

2. Adeyi O., Fisher S.E., Guindi M. Liver allograft pathology: approach to the interpretation of needle biopsies with clinocopathological correlation. J. Clin. Pathol. 2010; 63 (1): 47-74.

3. McGill D.B., Rakela J., Zinsmeister A.R., Ott B.J. A 21-year experience with major biopsy after liver biopsy. Gastroenterology. 1990; 99: 1396-400.

4. Hederstorm E., Forsberg L., Floren C.H., Prytz H. Liver biopsy complications monitored by ultrasound. J. Hepatol. 1989; 8: 94-8.

5. Ultrasound diagnosis in abdominal vascular surgery / ed. G.I. Kuntsevich. Minsk: 000, "Cavalier Publishers". 1999

6. Yoshida J., Donahue P., Nyhus L.M. Hemobilia: review of the worldwide problem // Am. .one. Gastroenterol. 1987. Vol. 82. P. 448.

7. Sherlock S., Dooley D. Liver and biliary tract diseases. M .: Geotar medicine, 1999.

8. Ultrasound diagnosis in abdominal vascular surgery / ed. G.I. Kuntsevich. Minsk: 000, "Cavalier Publishers". 1999

9. Maida I., Nunez M., Jose Rios M., Martin-Carbonero L., Sotgiu G., Toro S., Rivas P., Barreiro P., Mura MS, Babudieri S., Garcia-Samaniego J., Gonzalez-Lahoz J., Soriano V. Severe liver disease associated with prolonged exposure to antiretroviral drugs. J. Acquir. Immune Defic. Syndr. 2006; 42 (2): 177-82.

10. Poynard, T., Cost effectiveness of pegylated interferon alpha 2b and ribavirin combination in chronic hepatitis C. Gut. 2003; 52: 1532.

11. Czaja A.J., Carpenter H.A. Sensitivity, specificity and predictability of biopsy interpretations in chronic hepatitis. Gastoenterology. 1993; 105 (6): 1824-32.

12. Fryer E., Wang L.M., Verrill C., Fleming K. How often do our liver core biopsies reach current definitions of adequacy? J. Clin. Pathol. 2013; 66 (12): 1087-89.

13. Vyalov S.S. Screening methods for detecting liver fibrosis; g. Archive of internal medicine №3 / 2012

14. Grant A., Neuberger J. Guidelines on the use of liver biopsy in clinical practice // Gut. - 1999. - Vol. 45 (suppl. 4). - P. 1-11.

15. Menghini G., Antonini R., Bruschelli P. Open one-second liver biopsy by a modified one-second technic // Am. J. Surg. - 1977. - N 133. - p. 383-384.

16. Riley S.A., Ellis W.R., Irving H.C. et al. Percutaneous liver biopsy with a needle tracker: a safe method for patients with impaired coagulation // Lancet. - 1984. - P. 436

Berlin, eingereichte Dissertation, vorgelegt von Berlin, 2015. 26 p17. Suha AA Analysis of Bacterium Physik der Freien

Berlin, eingereichte Dissertation, vorgelegt von Berlin, 2015. 26 p

18. Moody F.G., Rikkers L.F., Aldrete J.S. Estimation of the liver reserve. Ann. Surg. 1974; 180 (4): 592-98

19. Novruzbekov M.C., Donova L.V., Khodareva E.N., Androsova M.V., Zhao A.V., Nevmerzhitsky V.I. Prognostic criteria of liver failure after liver resection with its focal lesion. Annals of surgical hepatology. 2009; 14 (1): 41-8.

Appendix 1. Indicators ¹³ C-MDT of patient A. (Example 1)

Appendix 2. The results of ¹³ C-MDT patient C. (Example 2)

Claims (1)

The method of determining liver cirrhosis, which consists in a clinical and laboratory study, characterized in that the patient is performed ¹³ C-methacetin respiratory test and with a cumulative dose of ¹³ C of the specified test in 30th minute <5.65% determine liver cirrhosis.