RU2659955C1 - Method for diagnosing high gastroesophageal refluxes - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine and is intended for diagnosis of high gastroesophageal reflux (GER). From mouth area of the duct of the right parotid salivary gland, the saliva stimulated by the citric acid is collected from the patient, containing, as one of the components of the salivary gland secretion, and determine the level of final metabolites of nitric oxide (nitrite) in saliva. If level of final metabolites of nitric oxide in the saliva is less than 10.4 mcmol/l, conclusion is made that there are no high gastroesophageal refluxes. At values of 14.8–20.8 mcmol/l – patient has a weakly acidic nature of refluxate. At values of 10.5–14.7 mcmol/l – on presence of acidic nature of refluxate. At values of more than 20.9 mcmol/l – presence of a slightly alkaline nature of refluxate.

EFFECT: method allows to increase efficiency of differential diagnostics of gastroesophageal reflux disease.

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Description

The invention relates to medicine. namely, to dentistry and gastroenterology, and can be used to diagnose high gastroesophageal reflux (GER).

Gastroesophageal reflux disease (GERD) is a complex of characteristic symptoms with the presence of inflammatory changes in the mucous membrane of the esophagus, and sometimes upstream organs, resulting from repeated refluxes of the gastric and / or duodenal contents into the esophagus [1].

The specificity of the clinical manifestations of high gastroesophageal refluxes is determined by the peculiarities of their pathophysiology. This condition is a consequence of dysfunction of the upper esophageal sphincter against the background of episodes of transient relaxation of the lower esophageal sphincter, and therefore traditional methods of surgical correction of the lower esophageal sphincter with high GER are ineffective.

The following methods are known for the diagnosis of gastroesophageal reflux (GER).

1. X-ray diagnostics

The main place in the X-ray diagnosis of gastric-esophageal reflux and reflux esophagitis, hiatal hernia is occupied by polyposition fluoroscopy and radiography of the esophagus. When examining patients in the Trendelenburg position and in a horizontal position, GER are detected by the appearance of a radiopaque substance in the esophagus. In patients with clear clinical data on the presence of pathological refluxes and complications, X-ray examination gives positive results in 86% of cases [3]. The disadvantage of the X-ray diagnostic method for the diagnosis of GER is the unsafe effect of ionizing radiation on the body and the low sensitivity of the method in the absence of complications [2].

2. Endoscopic diagnosis of GER

An endoscopic method for examining the esophagus allows you to identify and establish the severity of reflux esophagitis, one of the main complications of GER. With esophagofibroscopy in most patients, it is possible to observe a yawning cardia and throwing of gastric contents into the esophagus. The frequency of GER detection during x-ray and endoscopic examination is approximately the same and amounts to 47-60%. The main area of application for esophagoscopy is the detection of esophagitis and the treatment of esophageal strictures associated with GER. The disadvantage of this method is its invasiveness, high cost [4] and a number of contraindications for conducting: severe cardiovascular failure; cerebrovascular accident; respiratory failure.

3. Measurement of pH in the lumen of the esophagus (daily monitoring of pH in the esophagus)

With daily intra-esophageal pH monitoring, episodes of reflux to the distal esophagus are revealed, as evidenced by a decrease in pH to 4 or less. The total number of refluxes is recorded, the number of episodes lasting more than 5 min, the duration of the largest episode, the average duration of reflux, the total study time during which the pH was below 4. The disadvantage of the methods for detecting GER by measuring the pH in the lumen of the esophagus is the need for x-ray or gauge control probe, the presence of only one electrode, the excessively high cost of equipment for daily monitoring of pH, the reluctance of some patients (18-30%) to participate in these research. The need for a daily nasogastric tube, which creates discomfort in the nasopharynx, as well as obstructing nasal breathing and eating, does not reveal damage to the esophagus, in 14-29% of cases it gives normal values in patients with endoscopically confirmed esophagitis.

4. Esophageal manometry

It allows you to determine the pressure of the lower esophageal sphincter, to solve the issue of surgical treatment of GERD [2].

The study of the lower esophageal sphincter is performed by introducing a water-perfusion catheter and a computer. Measurements are taken of the total length of the lower esophageal sphincter (normal 2-5 cm), the length of its abdominal part (normal 1-5 cm), the average level of basal pressure (normal 14.3-34.5 mm). Periods of transient relaxation that are not associated with swallowing are recorded (sphincter relaxation lasting more than 10 seconds), the ability of the sphincter to relax when swallowing is assessed [5]. The disadvantage of this method is the uncomfortability for the patient, the complexity and high cost.

5. Impedance diagnostics

The methodology for the study of gastroesophageal reflux by the impedance method is based on recording a decrease in the intraesophageal impedance during the reverse reflux of the stomach and duodenal contents into the esophagus [6]. This method allows you to determine the height of gastroesophageal reflux, the speed of esophageal clearance throughout the organ, the nature of the reflux (acidic, slightly acidic, slightly alkaline) and its aggressiveness, depending on pH and volume.

6. Bernstein test (perfusion of 0.1N hydrochloric acid solution in the esophagus)

If the result is positive, the test is accompanied by the development of a condition characteristic of the symptoms of GERD [2]. Limitations disadvantages: the development of symptoms of GERD during, which require relief; the difficulty of accurately installing the catheter in the lower third of the esophagus (x-ray control is required): the sensitivity of the test is not more than 50-70%.

The listed drawbacks of existing diagnostic methods require the development of new simple, informative, indirect methods for diagnosing GERD suitable for use in a clinic.

As a result of the patent information search, the following patents were selected for subsequent analysis.

There is a known method for the diagnosis of gastroesophageal reflux and the mpedansometric method, including determining the intragastric acidity using a probe, further installing its distal end 2-3 cm above the level of the esophageal-gastric junction and registering the intraesophageal impedance. The probe is inserted into the stomach. intragastric acidity is determined in the basal phase of secretion, after which the probe is removed from the stomach and placed in the esophagus, intra-esophageal impedance is recorded in eight zones throughout the esophagus and the time during which the impedance does not exceed 100 Ohms, the reflux aggressiveness (AR) is determined, taking into account the value of intragastric acidity, the rate of local esophageal clearance (CL) and the height of reflux (HR), and if AR> 10%, pathological gastroesophageal reflux is diagnosed, and if CL <10%, then determine impaired esophageal clearance (RF patent No. 2191537).

A known method for predicting the development of GERD. To do this, conduct esophageal manometry and measure the average respiratory pressure in the lower esophageal sphincter. By changing the latter, a low, medium, high or no risk of developing GERD is predicted (RF patent No. 2283020). The disadvantage of this method is the complexity of execution and high cost.

A known method for the diagnosis of gastroesophageal reflux disease, including the registration and analysis of fluctuations in the pH of the esophagus, as well as the number and strength of cough tremors, characterized in that both 24-hour esophageal pH metering and tussography are performed using an ICT-1 tussograph followed by a joint analysis of the obtained pH -grams and tussograms, and if a decrease in pH below 4 occurred simultaneously or within 5 minutes before a cough occurs, gastroesophageal reflux disease is diagnosed (RF patent No. 2257142). The disadvantage of this method is the high cost of the equipment, the complexity of the proposed method, and the fact that the method of esophageal manometry is invasive.

A known method for predicting the development and progression of reflux esophagitis, including endoscopic assessment of the degree of damage to the esophagus. In this case, the esophagus is stained with a solution of Congo red through a spray catheter with maximum air insufflation, the length of the stained portion of the esophagus h from the Z-line with the dye changed to blue-black in centimeters is measured, the coefficient of completeness of staining of the esophagus circumference is visually evaluated as 1 at full staining or ¾, 1/2, 1/4 with partial staining, and based on these data, the area of the esophagus S is calculated according to the formula: S = 2πrhK, where r = 1 cm and if the patient has no endoscopic signs of reflux esophagitis, but in the presence of pathological acid gastroesophageal reflux S> 3.14 cm ² , then a high risk of developing reflux esophagitis of the 1st degree is predicted, and with a value of S> 9.42 cm ² in a patient with a 1st degree of reflux esophagitis predict a high risk of progression with transformation into reflux esophagitis of the 2nd degree (RF patent 2512942).

As a prototype of the selected method for the diagnosis of chronic gastroduodenitis and functional dyspepsia in children (RF patent No. 2270610). This method of diagnosing high gastroesophageal reflux is to study the secretion of the salivary glands for the subsequent determination of the physiological and pathophysiological conditions of the body. The method allows to diagnose chronic gastroduodenitis and functional dyspepsia in children. The gas chromatographic method determines acetic, propionic and butyric acids in saliva and at a concentration of any of three acids: acetic acid is greater than 0.910 mmol / l, propionic acid is greater than 0.150 mmol / l, butyric acid is greater than 0.013 mmol / l, chronic gastroduodenitis is diagnosed, and at acid concentrations: acetic in the range of more than 0.010 to 0.910 mmol / l, propionic to 0.150 mmol / l, oil to 0.013 mmol / l, functional dyspepsia in children is diagnosed.

Reasons that prevent accurate diagnosis: the presence of hypertension (GB), coronary heart disease (CHD) in patients with concomitant hypertension, chronic obstructive pulmonary disease (COPD), bronchial asthma (BA) with traditional drug therapy, and the presence of stress ( this leads to an increase in blood pressure), type 1 diabetes mellitus (DM), cystic fibrosis, bleeding, septic shock, burn disease, systemic lupus erythematosus (SLE), the presence of any chronic inflammatory th process in the body; the need for a strict diet; smoking.

There may also be difficulties associated, for example, with complaints of dry mouth, since dry mouth can be associated with taking medications, the presence of stress. Complaints of scalding of the tongue may be associated with neurological symptoms.

The presence of various complications and approaches to the treatment of GERD dictates the need to differentiate the acidity of gastroesophageal refluxes. The proposed diagnostic method does not have the above disadvantages. Patient complaints in the presence of acid reflux or slightly acid may be the same.

Acid refluxes (acidity level <4 pH, determined using multichannel pH-impedance measurement of the esophagus) in patients with reflux disease is more common, easily amenable to standard treatment, represents reflux of aggressive acidic contents from the stomach into the esophagus, which has not been exposed to the esophagus for a long time neutralization; such refluxes often lead to the formation of ulcers, erosion and tumors of the esophagus.

Weak acid refluxes (esophagus acidity is from 4 to 7 pH, determined using multichannel pH-impedance measurement of the esophagus) in patients with reflux disease is difficult to diagnose, again difficult to treat (standard therapy with proton pump inhibitors does not help). These are refluxes, which are most likely the acidic contents of the stomach that are neutralized by food or the contents of the duodenum. They very rarely lead to the occurrence of erosion, ulcers and tumors of the esophagus (low percentage of occurrence), causing mostly mild inflammation.

Weakly alkaline or duodenogastric refluxes in patients with reflux disease (with an acid level> 4 pH, determined using multichannel pH-impendanceometry) contain pancreatic enzymes, bile acids, lysolecithin. These are the most aggressive and difficult to detect refluxes: they are not treated with standard therapy and almost always lead to malignancy of the esophagus.

The objective of the invention is the development of a diagnostic method that allows you to obtain reliable information about GERD, devoid of the above disadvantages.

The technical result is to increase the efficiency of differential diagnosis of gastroesophageal reflux disease, simplifying the method for diagnosing high GER, early identification of patients at risk for the development and progression of reflux esophagitis, Barrett's esophagus for the timely appointment of adequate therapy, developing a simple informational and non-invasive method for the primary diagnosis of disease organs of hepatopancreatogastroduodenal zone, especially their preclinical forms.

The technical result is achieved using the method for the diagnosis of high gastroesophageal refluxes by examining the secretion of the salivary glands for the subsequent determination of physiological and pathophysiological conditions of the body. From the mouth of the duct of the right parotid salivary gland, the patient's saliva stimulated by citric acid is collected containing nitric oxide as one of the components of the salivary gland secretion, the protein is freed from it, nitric oxide is converted into nitrite using the Griss reaction, and the level of the final metabolites of nitric oxide (nitrites) is determined ) in saliva; if the level of final metabolites of nitric oxide in saliva is less than 10.4 μmol / L, the absence of high gastroesophageal refluxes is judged, with values of 14.8-20.8 μmol / L, the patient has a slightly acidic character of reflux, with values of 10.5- 14.7 μmol / l - the presence of an acidic nature of the refluxate, with values of more than 20.9 μmol / l - the presence of a slightly alkaline nature of the refluxate.

The proposed diagnostic method can be used at a dental appointment, subject to a thorough history and the exclusion of another pathology for subsequent referral for examination and treatment by gastroenterologists. The proposed method can also help gastroenterologists, not only in the differential diagnosis of high GER, having different acidity, but also in choosing a certain type of treatment.

The proposed diagnostic method can be used as an additional diagnostic tool for GERD in gastroenterology. Indications for this study may be typical esophageal manifestations in patients (frequent heartburn, belching, vomiting, chest pain), as well as extra esophageal manifestations:

1. Dental symptoms (erosion of tooth enamel, caries, stomatitis, periodontitis, halitosis, a feeling of "coma" in the throat, a sense of "scalded" tongue, xerostomia, etc.);

2. otorhinolaryngological symptoms (hoarseness, cough, laryngitis, pharyngitis, otitis media, rhinitis, etc.);

3. bronchopulmonary symptoms (chronic bronchitis, pneumonia, hemoptysis, nocturnal breath holding, etc.);

4. chest pain not related to heart disease.

In the asymptomatic course of GERD, this research method may precede invasive instrumental studies conducted by gastroenterologists (intragastric pH meter, endoscopic pH meter, etc.). It can be used in the absence of pronounced endoscopic changes in patients with typical symptoms, as well as in the presence of contraindications for instrumental studies. The method can be used to assess the effectiveness of the treatment of this pathology, before and after surgery.

To determine nitric oxide, an indirect method is used, based on the determination of stable metabolites of nitric oxide (nitrites) in saliva from the right parotid gland. This method involves the reduction of nitrate to nitrite, the determination of which is carried out using the Griss reaction. The sensitivity limit of the method is 0.9 μmol / L, and the quantitative sensitivity is 2.1 μmol / L. The technique is characterized by the linearity of a large range of concentrations of NO ₂ - for the calibration curve.

As a result of the research, the authors obtained the following information, summarized in table. 1 and 2, where:

1. Dry mouth: none - normal; present (may accompany GERD).

2. Feeling sour in the mouth: absent (normal); present (may accompany GERD).

3. A feeling of bitterness in the mouth: absent (normal); present (may accompany GERD).

4. The feeling of “coma” in the throat and, or “scalding” of the tongue: absent (norm); present (may accompany GERD).

5. The level of nitric oxide in saliva from the right parotid salivary gland: 2.9; 6.6; 10.4 μmol / L - normal; 10.5; 12.6; 14.7 μmol / L - acid reflux; 14.8; 17.8; 20.8 μmol / L - slightly acid reflux; 20.9 μmol / L and higher - slightly alkaline reflux.

Research Methodology

The basis is the well-known and described technique [7].

The patient before the study adheres to a strict diet consisting of cereals and dairy products. Vegetables, fruits, meat, coffee, tea, alcohol, smoked meats, fish are excluded from the diet in order to exclude sources of nitrates from food. Smoking is prohibited 2 hours before the study. Before collecting saliva, the subjects carefully rinse their mouth with distilled water and spit 2-3 times. Saliva is collected from the right parotid salivary gland (due to the asynchronous operation of the salivary glands secreting a secret that is different in number and concentration of NO; since the secret from the sublingual and submandibular salivary gland is mixed and comes out more in volume, but contains a lower concentration of NO), placing special cotton hygroscopic swab from a Salivette centrifuge tube from Sarstedt (Germany), impregnated with citric acid, into the mouth of the duct of the right parotid salivary gland (in anticipation of the oral cavity, at the level of the upper right second molar), and asking investigated thoroughly sucked the swab for 10 minutes. Thus, stimulated saliva is used, as patients with GERD have a low salivation rate, and collect saliva in sufficient quantities (1-1.5 ml is needed for 10 minutes).

To prevent factors that could affect the composition and amount of secretion secreted, the subjects sat, breathed through their nose, did not talk. Saliva is always taken strictly at a specific time (08:58), corresponding to an increased concentration of nitric oxide in the secretion of the right parotid gland. Next, the saliva is centrifuged at a speed of 3500 rpm for 3.5 minutes The obtained centrifuged saliva is poured into eppendorfs and stored at a temperature of -30 ° C until measurement. Then the samples (0.4 ml) are thawed and deproteinized (freed from protein) by adding to them 0.8 ml of 0.5 M NaOH and 0.8 ml of 10% zinc sulfate solution to avoid clouding of the samples. After that, the protein content in the samples does not exceed 20-50 mg / l. The contents of the tube are mixed for 30 seconds and centrifuged for 15 minutes at 9000 rpm. Cadmium granules of 0.5 grams (mass fraction of granular cadmium> 99.96%) are added to the supernatant to reduce NO ₃ to NO ₂ . Preliminarily, cadmium granules are washed with bidistilled water. 1M HCl and again with double-distilled water until neutral. The parameters of the completeness of reduction of nitrate to nitrite with granules of cadmium added to the samples are determined by the concentration dependence of nitrite, verified by the Griss reaction. The return of NO ₃ added to the saliva samples under the action of cadmium granules was 96-105%. After that, an equal volume of Griss reagent (1% sulfanilamide, 0.1% naphthylenediamine, 2.5% phosphoric acid) is added to the supernatant (1.5 ml) and incubated for 10 minutes at room temperature. Measurement of the absorption of the solution is carried out on a spectrometer at a wavelength of 546 nm. The nitrite concentration is determined using the standard, which is used as sodium nitrite.

After taking measurements in the laboratory, it is necessary to evaluate the results obtained. If the level of the final metabolites of nitric oxide (nitrites) in the saliva obtained from the parotid salivary gland is less than 10.4 μmol / l, then we can judge the absence of pathology; at values from 10.5 to 14.7 μmol / l, it is possible to suspect the presence of a refractate in the studied acidic character; if the values are from 14.8 to 20.8 μmol / l, then the nature of the refluxate is slightly acidic, with values of more than 20.9 μmol / l - slightly alkaline.

Clinical example 1

Patient I., 30 years old. I went to the dental clinic complaining of a feeling of a “scalded” tongue, a feeling of “coma” in my throat, a plentiful plaque in my tongue, a feeling of sour in my mouth. The patient also complained of heartburn, pain in the epigastric region. The presence of GB, IHD, COPD, BA, type I diabetes. SLE denied the presence of bad habits. The results of using the method for the determination of nitrites in stimulated saliva from the right parotid salivary gland: 13.8 μmol / L. According to clinical signs and the concentration in the saliva and the concentration in the saliva of this patient, the final metabolites of nitric oxide (nitrites) are more than 10.5 μmol / L, but less than 14.7 μmol / L, the diagnosis is established: GERD with a predominance of acidic reflux. Additional examination: 24-hour pH-impedance measurement of the esophagus revealed a predominance of acidic high gastroesophageal refluxes in the upper third of the esophagus. The final diagnosis: GERD with a predominance of the acidic nature of the refluxate coincides with the diagnosis established by the claimed method.

Clinical example 2

Patient P., 38 years old. I turned to the dental clinic complaining of a feeling of a “scalded” tongue, a feeling of swelling of the lower lip, a plentiful plaque on the tongue, a feeling of bitterness and sour in the mouth, a feeling of accumulation of mucus in the throat. The patient also complained of severe heartburn. The presence of GB, IHD, COPD, BA, type I diabetes, SLE, denied the presence of bad habits. The results of using the method for determining nitrites in saliva from the right parotid salivary gland: 18.4 μmol / L. According to clinical signs and the concentration in the saliva of this patient, the final metabolites of nitric oxide (nitrites) are more than 14.8 μmol / L, but less than 20.8 μmol / L, the diagnosis was established: GERD with a predominance of slightly acidic nature of the reflux Additional examination: 24-hour pH impedasometry of the esophagus revealed a predominance of slightly acidic high gastroesophageal refluxes in the upper third of the esophagus. The final diagnosis: GERD with a predominance of slightly acidic nature of the refluxate coincides with the diagnosis established by the claimed method.

Clinical example 3

Patient P., 45 years old. I turned to the dental clinic complaining of a feeling of a “swollen” and “scalded” tongue, a feeling of “tickling” and “coma” in my throat, a profuse plaque in my tongue, a feeling of bitterness in my mouth. The patient also complained of pain in the epigastric region of a burning character, nausea and vomiting mixed with bile. The presence of GB, coronary heart disease, COPD, BA. Type I diabetes, SLE, the presence of bad habits denied. The results of using the method for the determination of nitrites in saliva from the right parotid salivary gland: 22.3 μmol / L. According to clinical signs and the concentration in the saliva of this patient of the final metabolites of nitric oxide (nitrites) more than 20.9 μmol / l, the diagnosis was established: GERD with a slightly alkaline nature of the reflux. Additional examination: 24-hour pH impedance measurement of the esophagus revealed a predominance of slightly alkaline high gastroesophageal refluxes in the upper third of the esophagus. The final diagnosis: GERD with a predominance of the slightly alkaline nature of the refluxate coincides with the diagnosis established by the claimed method.

But all the examples noted that the application of the proposed method allowed to increase the accuracy of diagnosis and timely prescribe effective treatment.

The use of this diagnosis in dentistry and gastroenterology will allow high gastroesophageal refluxes to be identified with a high degree of reliability with the possibility of differentiating the nature of the refluxate and the possibility for gastroenterologists to prescribe adequate treatment in a timely manner, which will significantly increase the effectiveness of treatment, prevent the progression of the disease and the occurrence of complications, and will help improve their quality of life .

Using the proposed method can improve the accuracy of diagnosis of high GER and timely prescribe treatment with double doses of proton pump inhibitors or ursolfac, which will also help eliminate the negative impact of the aggressive environment on the oral mucosa.

The claimed method is highly informative, easy to use, does not have any significant limitations and contraindications, is non-invasive and can be used to improve the efficiency of diagnosis and treatment of high GER.

Information sources

1. Timoshenko V.O. Gastroesophageal reflux disease: history, principles of diagnosis and treatment // Almanac of endoscopy. - 2002. - No. 1. - S. 126-1332.

2. Recommendations for the examination and treatment of patients with gastroesophageal reflux disease (a manual for doctors) / Ed. V.T. Ivashkina. - 2002. - 17 p.

3. Weinstein G.I. A new X-ray diagnostic technique for gastro-esophageal reflux and hiatal hernia. // Clinical medicine. 1964.4. 54-58.

4. Lymen I. Bilhari. Complications of gastroesophageal reflux disease // Russian Journal of Gastroenterology, Hematology, Coloproctology. 1998, 5, p. 69-76.

5. Chernova T.G., Kubyshkin V.A., Korpjak B.S., Azimov R.Kh. Functional research methods in the diagnosis of gastroesophageal reflux disease // Russian Gastroenterological Journal, 1999, 4, p. 16-26.

6. Golubev D.A., Mutalimov M.E. The study of the motor function of the stomach with the help of rheogastrography // The final conference of the military scientific society of cadets and students of the Military Academy of Sciences: Abstracts - Military Medical Academy SPb., 1999, p. 19) .

7. Chronobiological analysis of the content of nitric oxide in the secret of the human salivary glands. O.V. Myachina et al. Bulletin of Voronezh State University. Series: Chemistry, Biology Pharmaceuticals. 2006. No1. C 141-145.

• +, - more common

• -, + are less common

• * Reliability in relation to the control group (p <0.01)

Claims (1)

A method for diagnosing high gastroesophageal refluxes by examining a patient’s saliva secretion for subsequent determination of physiological and pathophysiological conditions of the body, characterized in that the patient’s saliva stimulated with citric acid and containing nitric oxide as a component of the salivary gland secretion are collected from the mouth of the duct of the right parotid salivary gland; from protein, using the Griss reaction, nitric oxide is converted to nitrite and the level of final metabolites of nitric oxide (nit rit) in saliva, if the level of end metabolites in saliva is less than 10.4 μmol / L, the absence of high gastroesophageal refluxes is judged, with values of 14.8-20.8 μmol / L, the patient has a slightly acidic character of reflux, with values 10.5-14.7 μmol / L - the presence of an acidic nature of the refluxate, with values of more than 20.9 μmol / L - the presence of a slightly alkaline nature of the refluxate.