RU2667471C1 - Method of differential diagnostics of anemia - Google Patents

Abstract

FIELD: medicine.

SUBSTANCE: invention relates to medicine, namely to diagnosis of anemia, and discloses a method for screening a blood test to determine the direction of the diagnostic search for anemia. Method is characterized by evaluating the MCH or color index, thereby differentiating iron-deficient, sideroachrestic, iron-redistributive anemia, thalassemia, B12-deficient or folic acid-deficient anemia; evaluate the level of reticulocytes, which differentiates acute blood loss, hemolysis, restoration of previously damaged erythropoiesis and tumor metastasis in the bone marrow, B12 deficiency, folic deficiency, aplastic anemia.

EFFECT: declared method of differential diagnostics of anemia using a two-stage algorithm is highly informative, accurate and reliable, allows you to quickly and without financial costs determine the most likely and, conversely, the unlikely directions of diagnostic search for anemia.

1 cl, 3 tbl, 3 ex, 2 dwg

Description

The invention relates to medicine, namely to therapy, and can be used for differential diagnosis of anemia.

Normally, the hemoglobin content in the blood is 120-140 g / l in women and 130-160 g / l in men. This indicator depends on the age and gender of the patient (highest on the first day after birth). A decrease in hemoglobin below 110 g / l in an adult is called anemia.

According to the WHO, 1.62 billion people worldwide have anemia, which corresponds to 24.8% of the population. The highest prevalence is observed in preschool children (47.4%), and the lowest prevalence of anemia is observed in males (12.7%).

About 1 million 360 thousand cases of anemia are registered annually among the population of the Russian Federation, of which more than 50% are in children from 0-17 years old.

Over the past fifteen years, the incidence of the adult population has increased 2.5 times, and children 3.7 times.

Analysis of the dynamics of cases of anemia per 100,000 people, according to official data from the Ministry of Health of the Russian Federation, clearly shows an increase in the number of patients.

Of all the anemia, 80% are iron deficiency anemia (IDA).

The age groups in which anemia is more common are women of childbearing age, pregnant women and adolescents 12-17 years old. In old age, gender differences gradually disappear, and even a predominance of men with iron deficiency is noted. According to official statistics from the Russian Ministry of Health, 34.4% of women who gave birth had anemia in 1995, and 43.9% in 2000. In certain population groups, the frequency of occurrence of iron deficiency states reaches 50% and even 70-80%.

Such a high frequency of occurrence of IDA often leads doctors astray - diagnosing the iron deficiency nature of any anemia, which in about 1/5 of the cases leads to incorrect diagnosis and, as a result, to incorrect treatment (according to our own data, based on testing of primary health care doctors undergoing training in continuing education courses in our department).

The aim of our study was to develop an algorithm that allows you to quickly and correctly diagnose the different nature of anemia without the use of additional equipment and without increasing costs in the face of a severe lack of time in real medical practice.

There are no analogues of a two-stage algorithm. Recommendations on the value of deviations from the norm of all indicators of a general blood test are widespread (and often not the same).

A known method for the diagnosis of anemia in diabetic angiopathies (RF Patent No. 2216274, published April 20, 2003), including determining the concentration of hemoglobin, the number of red blood cells, red blood cells, reticulocytes, serum iron, iron-binding ability of serum, characterized in that it determines the metabolic stress indicators: hyperglycemia, glycated hemoglobin, lipid peroxidation products, indicators of endogenous intoxication syndrome, establish pathogenetic criteria for anemia, such as lower a decrease in the number of red blood cells due to an increase in red blood cell count, determined by the concentration of EEG above 0.36 g / dl,% hemolysis above 0.32% and a decrease in the osmotic resistance of red blood cells, a decrease in the average volume of red blood cells below 80 fl, an increase in the number of microcytes, a change in the index of deformability of red blood cells more 0.42 conv. units, an increase in the number of reticulocytes over 11%, reveals the differential criteria for anemia with DA and with a decrease in the diameter of red blood cells less than 7.0 μm3, an increase in anisocytosis more than 8.5%, an increase in the proportion of microcytes more than 20%, a decrease in the proportion of discocytes less than 60% an increase in the number of echinocytes and irreversible prehemolized forms of more than 22%, a combination of elevated or normal concentrations of interleukin 1 and ferritin with a normal level of serum iron, anemia is diagnosed with DA.

The disadvantage of this method is the need to determine a large number of specific parameters, the availability of special equipment and laboratories.

A known method for diagnosing iron deficiency anemia (RF patent No. 2301023, published 02.10.2007), based on the measurement of clinical blood parameters, characterized in that the diagnosed individual determines the amount of hemoglobin, the percentage of oxyhemoglobin, the number of red blood cells, the number of leukocytes, the number of lymphocytes, the sedimentation rate red blood cells and normalized deviations of these parameters from the average parameters of a group of healthy individuals form a factor diagram diagnosed by statements of the above normalized deviations of parameters into factorial expressions with weight loads previously obtained for a group of healthy individuals when processing the same parameters by factor analysis, and the presence of a disease is judged by the deviation of the factor diagram of the diagnosed individual from the factor diagrams determined for the group of healthy individuals, the initial degree of the disease or pre-pathological condition is diagnosed if the factor values are outside the range from 0 to 2 by a factor that fills such parameters as the number of red blood cells and the percentage of oxyhemoglobin, mild anemia is diagnosed with a deviation of values for this factor from 2 to 10, mild anemia is diagnosed with a deviation of this factor from 10 to 15, severe anemia is diagnosed with a deviation there are more than 15 values for this factor.

The disadvantages of this method is the impossibility of its use for other types of anemia (for example, iron-saturated, iron redistribution, etc.). In addition, the percent determination of oxyhemoglobin is not a routine laboratory method and is not used in most laboratories. The calculation of the average parameters of a group of healthy volunteers obviously carries a high risk of error, since in small groups the individual characteristics of each organism can play a decisive role. In addition, a survey of a group of healthy volunteers involves additional financial costs.

A known method for the differential diagnosis of anemia in pregnant women (RF patent No. 2407011, published December 20, 2010) by immunochemical study of biological fluids, characterized in that the blood serum of pregnant women determine the level of hepcidin by enzyme-linked immunosorbent assay, with hepcidin level more than 245 ng / ml determine anemia chronic diseases, with hepcidin level less than 230 ng / ml - iron deficiency anemia.

The disadvantage of this method is the limited use of it - only in pregnant women, as well as the lack of a routine determination of hepcidin level in clinical laboratories.

A known method for the differential diagnosis of iron deficiency anemia and anemia of chronic diseases (patent RU 2566282 C1, published October 20, 2015), including the study of blood serum using enzyme-linked immunosorbent assay, characterized in that it determines the level of hepcidin-25 and with an increase in its value more than 11.8 ng / ml diagnose anemia of chronic diseases, and if it decreases below 4.33 ng / ml, iron deficiency anemia is diagnosed.

The disadvantage of this method is that the determination of hepcidin-25 is not performed in most laboratories.

The closest we adopted for the prototype is a method for the differential diagnosis of anemia in children (RF patent No. 2538722, published January 10, 2015), which includes determining the parameters of iron metabolism, characterized in that the hematological analyzer determines the hemogram parameters and red blood indices, such as : hemoglobin (HB) and hemoglobin of reticulocytes (Ret-He), and in the blood serum the level of the soluble transferrin receptor (p-TGF), erythropoietin of serum (EPO) is determined, the obtained indices are compared with the reference interval and with values: HB <120 g / l, p-TGF <25 nMU / ml, Ret-He> 29 pg, EPO ≤21 mIU / ml conclude anemia against inflammation (AB), with values: HB < 120 g / l, r-TGF> 25 nMU / ml, Ret-He <29 pg, EPO> 50 mIU / ml conclude iron deficiency anemia (IDA), and at intermediate values falling into the intervals characterizing IDA or AB, talk about a combined version of AB + IDA.

The disadvantage of this method is its use only in pediatric practice, the inability to detect other anemia, as well as additional financial costs for determining the levels of soluble serum transferrin receptor and erythropoietin.

The task to which the invention is directed is the differential diagnosis of the nature of anemia, allowing on the basis of a general blood test (OAK) to determine the genesis of the disease.

The problem is solved in that the method of differential diagnosis of anemia is carried out in the form of a two-stage algorithm, based on indicators of a general blood test: 1st screening - according to the level of MSH or color indicator, 2nd screening - according to the level of reticulocytes, when detecting the level of MSH or color an indicator above the norm is diagnosed with B12- or folic acid deficiency anemia, if an MSN level or a color indicator below the norm is detected, iron deficiency anemia, thalassemia, iron-saturated or iron-redistributing anemia; when a level of reticulocytes is detected above the norm, blood loss, hemolysis, restoration of previously damaged erythropoiesis or tumor metastases in the bone marrow are diagnosed, if a level of reticulocytes is found below the norm - B12 or folio-deficiency anemia or aplastic anemia.

The technical result provided by the given set of features is to increase the accuracy of the differential diagnosis of anemia, cost-effectiveness (without additional financial costs), reducing the time of the study.

These specific features of the invention, such as a two-stage algorithm based on indicators of a general blood test: 1st screening according to the level of SIT, or color indicator, 2nd screening according to the level of reticulocytes, allow primary health care doctors and narrow specialists in detecting anemia the patient can quickly determine the priority areas for further diagnostic search (therefore, to cut off the least probable causes of these changes and not spend time and money on them), which allows you to get this particular conc ode results, such as improving the accuracy of differential diagnosis, which does not require additional financial costs at a minimum study time.

A detailed description of the method and examples of its clinical implementation

Patients who turn to primary care physicians - general practitioners (family doctors) and general practitioners (as well as many specialist specialists) are usually prescribed a general blood test (OAK). The claimed invention is intended to help a practitioner quickly and without additional financial costs to determine the nature of anemia and the subsequent priority areas of the diagnostic search. Given that when anemia is detected in OAK, it is very important to determine its genesis, we recommend a two-stage screening: stage 1 - by the value of the color indicator (color index (CP), or SIT - the average hemoglobin content in red blood cells). It depends on whether a hemisphere analyzer is available in the laboratory or if OAK is done manually under a microscope. 2nd stage - according to the level of reticulocytes. To perform the 2nd stage of screening, it is necessary to program the count of reticulocytes in the list of items when programming all hemanalysers (regardless of the type of medical institution).

The color index (CPU) is the ratio of the amount of hemoglobin multiplied by 3 to the first three digits of red blood cells (normally 0.85-1.05).

The average erythrocyte hemoglobin content (MCH) represents the amount of hemoglobin within a single red blood cell. It is calculated by dividing hemoglobin by the number of red blood cells. The indicated parameter is measured in picograms. The norm of SIT is the same for men, women, children: 27.0-33.3 pg.

SIT is an analogue of a color indicator.

The color indicator is equal to SIT multiplied by 0.03.

Traditionally, hemosanalysers determine SIT. If there is no hemanalyzer in the laboratory and a general blood test is performed, the color indicator is manually calculated. In our study, we used OAK patients performed on various types of hemanalysers and OAK patients performed manually.

The 1st stage of the screening we are conducting - determining the nature of anemia depending on the saturation of red blood cells with hemoglobin (i.e., from CPU or MCH), is illustrated in FIG. 1 and table 1.

The meaning of our screening is to cut off the least probable causes and not waste time and money on them. With information about a small number of the most probable reasons, it is much easier to conduct further examination and establish a diagnosis (based on complaints, medical history, physical, laboratory and instrumental examinations). And then prescribe treatment taking into account the personal characteristics of the patient (for example, individual intolerance to drugs, etc.).

At the second stage of the diagnostic search, we propose to analyze the level of reticulocytes. This stage is illustrated in FIG. 2 and table 2).

Reticulocytes are immature red blood cells that have nuclear residues. The content of reticulocytes in the blood allows us to judge the regenerative activity of the bone marrow.

The rate of reticulocytes for adults is 0.2-1.2% (G.I. Kozinets, V.M. Pogorelov, O.A. Diaghileva, I.N. Naumova. // Blood. Clinical analysis. Diagnosis of anemia and leukemia. Interpretation results M., Medicine XXI, 2006; Lugovskaya S.A., Morozova V.T., Pochtar M.E., Dolgov V.V. // Laboratory hematology. M., "Triad", 2006; Lugovskaya S. A., Pochtar M.E. // Reticulocytes. M., 2006.).

Reticulocytosis - an increase in the number of reticulocytes is more than normal. The cause of reticulocytosis is increased production of red blood cells in the bone marrow or their entry into the bloodstream from a depot in case of urgent need.

Reticulopenia - a decrease in the number of reticulocytes of less than 0.2%. The cause of reticulopenia is inhibition of erythropoiesis (the formation of red blood cells in the bone marrow).

The performance of the proposed method is confirmed by the following clinical examples:

Example 1

Patient L., 45 years old. In OAK, hemoglobin is 87 g / l, CP 0.67, reticulocytes 4.0. According to the first stage of screening, a decrease in the color index can occur with iron deficiency anemia, iron redistributive anemia, siderohrestichnoe (iron-saturated anemia) and with thalassemia. According to the second stage of screening, an increase in reticulocytes may indicate the presence of acute hemolysis, acute blood loss, tumor metastases in the bone marrow, or restoration of previously damaged erythropoiesis (treatment of deficient anemia with a pathogenetic drug). As a result of a joint analysis of the 1st and 2nd stages of screening, the following options are possible :.

1. Iron deficiency anemia, against which there is acute blood loss or treatment with iron preparations (approximately the first 2-14 days from the start of treatment) - the most likely diagnosis is by frequency of occurrence. Diagnostic criteria are clinical signs of sideropenic syndrome and laboratory criteria for iron deficiency (serum iron, ferritin, transferrin saturation coefficient of iron is reduced, and OZHSS is increased). It is also necessary to question the patient about taking iron preparations and / or signs of obvious blood loss.

2. Iron redistribution anemia, against which there is acute blood loss. Diagnostic criteria are a high iron content in the body (serum iron, ferritin, a high transferrin saturation coefficient with iron, and OGSS is reduced), as well as the presence of clinical and laboratory signs of an active inflammatory (infectious or non-infectious) process, less often tumors of different localization. It is also necessary to question the patient for signs of obvious blood loss.

3. Sideroahrestichnoe (iron-saturated anemia), against which there is acute blood loss. Diagnostic criteria are a high iron content in the body (serum iron, ferritin, high transferrin saturation coefficient of iron, and OGSS is reduced), signs of hemosiderosis of internal organs (clinical signs of damage to the liver, myocardium, insular apparatus, adrenal glands, as well as biopsy data of the skin, liver) , a positive result of the treatment of anemia with pyridoxine or pyridoxalphosphate (mainly in men with the pyridoxine-sensitive variant). It is also necessary to question the patient for signs of obvious blood loss.

4. Tumor metastases in the bone marrow, possibly with the development of iron deficiency due to the consumption of iron by the tumor. To clarify the diagnosis, it is necessary to collect complaints and anamnesis, ESR, and, if necessary, oncoscreens.

5. The combination of iron-redistributing or siderohrestichny (iron-saturated) anemia with tumor metastases in the bone marrow (to clarify the diagnosis - see paragraphs 2, 3, 4).

6. Thalassemia - to clarify, it is enough to collect an anamnesis (the diagnosis is usually established in childhood, there is a hereditary nature of the disease).

Understand everything and always should only the attending physician in each case.

Example 2

Patient N., 37 years old. In OAK, hemoglobin is 62 g / l, CP 1.16, reticulocytes 0.05%.

According to the first stage of screening, an increase in the color index can occur with B12 and / or folic acid deficiency anemia. According to the second stage of screening, a decrease in the level of reticulocytes is also characteristic of B12 and / or folic acid deficiency anemia or aplastic anemia.

As a result of a joint analysis of the 1st and 2nd stages of screening, the following options are possible:

1. B12-deficient anemia.

2. Folic deficiency anemia.

For the differential diagnosis of B12-deficient anemia from folic acid deficiency anemia, it is possible to perform 1) sternal puncture with staining of the bone marrow smear with alizarin red: with B12-deficiency megaloblasts are colored red, with folic deficiency they are not stained. 2) More cost-effective and gentle for the patient is to determine the level of vitamin B12 and folic acid in the blood serum.

Example 3

Patient Z., 19 years old. In OAK, hemoglobin 104 g / l, CP 0.95, reticulocytes 1.5%.

According to the first stage of the screening, the normal color index for anemia eliminates situations associated with an increase in the color index (B12-deficient anemia and / or folic acid deficiency anemia) and a decrease in the color index (iron deficiency anemia, iron-redistributing anemia, sidereal (anemia-saturated) anemia). Accordingly, the probable causes of anemia in this patient may be acute blood loss (not leading to the development of iron deficiency), hemolysis (except for thalassemia, which is characterized by a decrease in color index), aplastic anemia.

According to the second stage of screening, an increase in the number of reticulocytes occurs with bleeding, hemolysis, tumor metastases in the bone marrow, restoration of previously damaged erythropoiesis (that is, treatment of deficient anemia with a pathogenetic drug).

As a result of a joint analysis of the 1st and 2nd stages of screening, the following options are possible:

1. Bleeding. To clarify the diagnosis, a collection of complaints and an anamnesis is necessary, possibly an analysis of feces for occult blood and / or a general urinalysis, targeted follow-up examination (for example, endoscopy).

2. Acute hemolysis. To clarify the diagnosis, it is necessary to collect complaints and anamnesis, if necessary, determine the level of serum bilirubin (total and free) and / or hemosiderin in the urine.

The claimed method examined 1012 with various pathologies.

The results showed that the use of this algorithm is highly efficient (provided there are no laboratory errors). With minimal time (you just need to remember or open the algorithm and compare with the patient’s OAK), the doctor immediately rejects the unlikely causes of deviations from the MCH norm and / or the level of reticulocytes and determines the subsequent directions of the diagnostic search. Finances for carrying out this algorithm are not spent, but, on the contrary, are saved due to the lack of additional appointments for unnecessary analyzes. Considering how much research you need to do in all areas of the diagnostic search, it’s much less and faster if, with the help of our two-stage screening, you cut off the unnecessary and further examine it for the most probable reasons.

Moreover, some of these reasons, doctors often simply do not know (for example, iron-redistributing anemia or reticulocytosis as a result of tumor metastases in the bone marrow). The patient spends time on an inadequate examination or treatment, and the real disease progresses at this time. Moreover, the identification of inconsistencies using this algorithm allows you to identify patients who need to recheck a general blood test due to a suspected laboratory error.

For patients with no anemia (hemoglobin is normal or below normal, but above 110 g / l for adults), this algorithm can be used to detect deviations from the normal color indicator (or MCH) - in this case, the same two stages of the algorithm are performed in direct order .

If abnormalities in the level of reticulocytes are detected in the absence of anemia in the patient, this algorithm can be applied in the reverse order (step 2 precedes step 1).

In total, according to the proposed algorithm, an analysis of the indicators of a general blood test was performed for 1012 patients with anemia, who sought outpatient care from a cardiologist or gastroenterologist at the clinic for 2012-2016. All patients underwent a general blood test (with reticulocyte counting) on different models of hemispheres (with the calculation of SIT) or manually (with the subsequent calculation of the color index by a consulting doctor).

The data are summarized in table 3, which provides information on the detected incidence rate of anemia of various origins. For all groups, hemoglobin and reticulocyte level parameters, as well as a color indicator, are given. For patients who underwent a general blood test on a hemisphere analyzer with the calculation of SIT, for the convenience of comparison, we performed the calculation of the color index (CP).

Note: in columns 2 and 3, the numbers in bold give a total of 100% (1012 patients). Figures from the same columns that are not highlighted in bold refer to the same patients (for example, the patient has iron deficiency anemia - is included in the numbers in bold. The same patient is recovering previously damaged erythropoiesis during iron therapy - is included in the numbers without oily discharge).

The claimed method of differential diagnosis of anemia using a two-stage algorithm is highly informative, accurate and reliable, allows you to quickly and without financial costs determine the most likely and, conversely, unlikely directions for a diagnostic search for anemia, in combination with availability and simplicity, can be used as a method of differential diagnosis of anemia in time-deficit conditions in real clinical practice. The above allows you to simplify and speed up the examination of patients with minimal effort and money, as well as to avoid unreasonable prescription of drugs.

Claims (7)

A method for screening a blood test to determine the direction of a diagnostic search for anemia, characterized in that an MSN or a color indicator is evaluated, resulting in in the case of a decrease in SIT below 27.0 pg or a color indicator below 0.85, differentiate iron deficiency, iron-saturated, iron redistribution anemia or thalassemia, in the case of an increase in SIT above 33.3 pg or a color indicator above 1.05, differentiate B12-deficient or folio-deficiency anemia, and also evaluate the level of reticulocytes, as a result of which in the case of an increase in the level of reticulocytes of more than 1.2%, they differentiate between acute blood loss, hemolysis, restoration of previously damaged erythropoiesis and tumor metastases in the bone marrow, in the event of a decrease in the level of reticulocytes below 0.2%, they differentiate B12-deficient, folic acid deficiency, aplastic anemia, and based on the analysis of the above indicators, the direction of the diagnostic search is determined when anemia is detected.

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