CN114010221A - System and method for determining parameters related to the health condition of the liver of a subject - Google Patents
System and method for determining parameters related to the health condition of the liver of a subject Download PDFInfo
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Abstract
A system (1) and method for determining a parameter related to the health condition of the liver of a subject, the system comprising an elastography device (2), a blood test reader (3) and an associated blood test disposable (10), the disposable comprising capillaries for taking capillary blood samples from the subject and comprising reagents suitable for detecting at least one liver enzyme in the blood samples, the blood test reader being operatively connected to the elastography device, and a control and processing system (4) configured to control the elastography device and the blood test reader and to determine the parameter related to the health condition of the liver of the subject by taking into account the value of at least one mechanical parameter measured by the elastography device and the concentration value of at least one liver enzyme.
Description
Technical Field
The disclosed technology relates to a system and method for determining a parameter related to the health of the liver of a subject, in particular based on liver stiffness measurements and liver enzyme concentrations in the blood of the subject.
Background
Liver stiffness, measured by vibration-controlled transient elastography, has proven to be an effective tool for diagnosing chronic liver disease (e.g. fibrosis). For example, Sandrin et al, 11/12 2003, published in Ultrasound in Medicine and Biology, Vol 29, "Transient elastography: a new non-invasive method for assessing liver fibrosis", indicates that liver stiffness is closely related to liver fibrosis. However, liver stiffness is also affected by other factors, such as inflammation and congestion.
Interestingly, liver inflammation can be assessed by measuring the concentration of one or more liver enzymes in the blood (since liver inflammation typically results in high levels of these enzymes). Thus, knowing the concentration of one or more Liver enzymes in the blood allows a better interpretation of the measured values of Liver stiffness and enables reliable information on possible inflammation/hyperemia and possible fibrosis/cirrhosis to be obtained, as shown in the article "Liver stiffness: a novel parameter for the diagnosis of Liver disease" published by S.Muller and L.Sandrin in 2010 in the Heastic Medicine: Evidence and Research (Liver Medicine: Evidence and Research) Vol.2, pp.49-67.
In order to take these two parameters into account and acquire (serological and mechanical), the value of a reference parameter may be calculated in determining the parameters related to the health condition of the liver of the subject, the reference parameter value depending on both the liver stiffness and the concentration(s) of liver enzyme(s), and the reference parameter value being specifically designed to allow identification of different health conditions of the liver of the subject. Such baseline parameters are sometimes denoted in medical publications as "scores". For example, The "Fibroscan-AST (FAST) score, published by P.Newscale et al on The Lancet, Gastroenterology and Hepatology (lancets, Gastroenterology and Hepatology) Vol.5, No. 4, pp.362-373, on Vol.2020 and 04, for The non-invasive identification of patients with non-alcoholic steatohepatitis with significant activity and fibrosis, a prospective and global validation study" gave such a parameter named "FAST" which takes into account The basal hardness "referred to as The" hardness of liver ", The parameters of controlled attenuation in liver transaminase (CAP), and The" CAP "concentration. The reference parameter is calculated according to the following formula F1 (where AST is expressed in IU/L):
in any case, to detect and characterize a possible liver disease in a subject by considering both liver stiffness and the concentration of one or more liver enzymes, both parameters must first be measured.
Liver stiffness is typically measured by vibration-controlled transient elastography. Such measurements are completely non-invasive and are typically performed in a medical imaging laboratory environment. And, to determine the concentration of one or more liver enzymes in the subject's blood, a health care professional trained in biological sample collection will collect a sample of venous blood with a syringe and send the sample to a biomedical analysis laboratory where the blood sample is analyzed. Once the liver hardness value and one or more liver enzyme concentration values are all available, parameters related to the health of the subject's liver may be evaluated (e.g., by calculating the reference parameters given above).
There are several disadvantages to this approach.
First, such venous blood based serological analysis and liver stiffness measurements have distinct requirements in terms of the examiner and the environment. Thus, the two inspections are typically performed at different places or environments (and therefore at different times), which complicates the overall process, makes it more costly, and increases the likelihood of errors in communicating the inspection portion results.
Furthermore, in this process, the blood analysis results are not immediately available and a complete diagnosis can only be obtained a posteriori. Thus, when the combined test results (both physical and serological) ultimately indicate the possible presence of liver disease (e.g., corresponding to abnormally high values of FAST parameters), the healthcare professional is no longer able to repeat one or both tests for diagnosis, which may increase the false positive detection rate.
And this independence of blood analysis from hardness and/or ultrasound attenuation measurements can lead to systematic analysis of the subject's blood, which is not useful in some cases. For example, it is assumed that regardless of the concentration of liver enzymes in the blood of the subject (as described in the muller and sandrin articles cited above), the negative predictive value of liver stiffness (NPV) is very good, with very low liver stiffness (typically less than 6 to 7kPa), indicating that the subject examined is unlikely to suffer from any fibrosis. Therefore, in this case, the subject blood test is usually performed as a useless resource consumption.
The collection of venous blood enables a large quantity of blood to be obtained for use, whereby a fine and accurate blood analysis can be performed. But in turn it increases the delay (and possibly travel time) between blood sample collection and analysis. It has been shown that such delays vary significantly from hospital to hospital or medical testing center to medical testing center, and even vary greatly from day to day in the same hospital or medical testing center. Also, once a sample is taken, the chemical activity of liver enzymes in the blood sample will be significantly reduced over time. Thus, for a given blood sample, the actual measured concentration of a given liver enzyme (in other words, the apparent concentration of such enzyme) will vary greatly with the delay between collection and analysis. Thus, the variability of the delay in acquiring the analysis can lead to variability in the liver enzyme results themselves, which is one of the reasons for displaying normal values along with the measured values.
Furthermore, during this measurement, blood sample collection and liver stiffness measurements can be made at very different times. Since the concentration of liver enzymes in the blood of a subject may change over time due to circadian rhythms and other changes, lack of coordination may also affect the reproducibility of the final diagnosis.
In this context, a blood test device called a Point of Care (POC) device is known that is capable of analyzing a blood sample in situ without sending and transporting the sample to a central laboratory for testing. Some of these POC devices, such as the Piccolo Xpress model by Abaxis (Piccolo Xpress is a registered trademark), provide results accurate enough to allow further benchmarking and scoring calculations. With this device, to test a subject's blood, the subject would take a blood sample of approximately 100 microliters, which would then be injected into the disc-shaped disposable using a micropipette. The disposable is then inserted into a blood test reader where it is rotated to separate the blood sample using centrifugal force, thereby separating the cellular components of the blood from the other blood components. The sample is then reacted with reagents contained in the disposable and suitable for optically detecting various blood components, such as liver enzymes.
By using such POC devices, the above process can be improved as an alternative to sending the blood sample to a central laboratory for testing.
But such POC devices require quite a bit of blood (about 0.1 mL). The problem of collecting such blood samples is therefore exactly the same as that of collecting venous blood, and such collection usually requires the intervention of a medical professional (in any case it is very difficult to inject the collected blood sample into the disposable).
In any case, even if such POC device is used for detection of liver enzyme concentration in blood of a subject, serological and hardness measurements will still be separated from each other, and the results of the process will thus still be affected by the above-mentioned variations and fluctuations.
Thus, there is a need to further improve such processes for determining parameters related to the health condition of the liver of a subject based on both serology and hardness measurements. In particular, there is a need to further improve the reproducibility thereof, so as to allow better control of the inspection conditions and processes, and to simplify them and reduce the associated costs.
Disclosure of Invention
To address at least part of the above issues, the disclosed technology is a system and method for determining a parameter related to the health of a liver of a subject:
-wherein the blood test reader is operatively connected to the elastography device to allow cooperation of these devices, e.g. coexistence operation of these devices, an
-wherein the blood test disposable associated with the blood test reader is configured to enable simple and convenient collection of a capillary blood sample, even for non-professional persons.
More specifically, the disclosed technology relates to a system for determining a parameter related to the health of a liver of a subject, the system comprising:
an elastography device configured to measure at least one mechanical parameter related to shear wave propagation in the liver,
-a blood test reader and a blood test disposable associated with the blood test reader, the blood test disposable being configured to receive a capillary blood sample and to be inserted into the blood test reader, and the blood test reader being configured to determine a concentration of at least one liver enzyme in the blood sample, wherein:
-said blood test disposable comprises:
a capillary for taking a blood sample from a finger, and
-a reagent suitable for detecting at least one liver enzyme in a blood sample, wherein
-the blood test reader is operatively connected to an elastography device, an
-a control and processing system comprising at least one processor and a memory programmed to perform the steps of:
a step S1 of acquiring a value of at least one mechanical parameter measured by the elastography device,
-a step S2 of obtaining a concentration value of at least one liver enzyme in a blood sample collected from the subject measured by a blood test reader, and
-a step S3 of considering the value of the at least one mechanical parameter and the concentration value of the at least one liver enzyme to determine a parameter related to the health condition of the liver of the subject, said parameter related to the health condition being the health or disease stage determined in the different stages of a given health condition classification, or a reference parameter considering both the value of the at least one mechanical parameter and the concentration value of the at least one liver enzyme, or being represented by both the health or disease stage and the value of the reference parameter, and outputting data representative of said parameter related to the health condition.
The control and processing system is configured to control the elastography device and the blood test reader. In particular, it may be configured to control the elastography device and the blood test reader in the following manner: the measurement of the at least one mechanical parameter and the measurement of the concentration value are carried out according to a predefined time sequence (for example within a given time range) and/or according to a predefined conditional measurement procedure (as shown in fig. 11 to 15).
The collection of blood samples (especially small capillary blood samples) by means of capillaries can be easily achieved, even by personnel other than the medical professional trained in the collection of biological samples. Furthermore, since the capillary tube is integrated with the disposable, it is not necessary to carefully inject the collected blood sample into the prior art disc-shaped disposable as described above.
Thanks to the special structure of the blood testing disposable, specialized medical staff trained to collect biological samples and environments suitable for biological sample collection are no longer required. Thanks to this particular disposable (and the associated reader), the entire examination procedure can thus be performed in a single examination environment (with less stringent hygiene than in a conventional biological sample collection environment) by a single operator (e.g., a medical professional trained in medical imaging examinations, rather than two different medical professionals with different specialties), or even by the subject of examination himself. This simplifies the overall procedure and, more importantly, as mentioned above, it greatly helps to achieve co-existence (concomitant) measurements of liver hardness and liver enzyme levels, thereby significantly improving the repeatability and reliability of the procedure.
Applicants emphasize that taking a small amount of capillary blood to measure liver enzyme concentration is a rather unusual approach in view of determining parameters related to the health condition of the liver of a subject, in particular by calculating reference parameters.
Indeed, determining parameters related to the health of the liver of a subject and calculating reference parameters requires accurate measurement of such concentrations, which is made very difficult by the relatively low concentration of such enzymes in the blood. This is why venous blood samples, which allow extensive blood analysis, are usually taken and used for such measurements.
Surprisingly, however, it turned out that liver enzyme concentrations can be determined quite accurately from a limited amount of capillary blood samples, and the accuracy of the results thus obtained is in fact suitable for such liver diagnostics. In fact, the use of this collection method enables the blood analysis to be started immediately after collection, thus avoiding the decrease in hepatic enzymatic chemical activity (decrease in apparent concentration) that normally occurs between collection and analysis in venous blood analysis methods. Thus, for capillary blood samples, the relative accuracy of the measurement may be less, but the enzymatic activity higher, than for venous blood samples, which ultimately results in a measurement accuracy suitable for determining a parameter related to the liver health of the subject.
It will be appreciated that the expression "liver enzyme concentration" may give the apparent concentration of such an enzyme, as determined using a given detection reaction or series of reactions, or the chemical activity of the liver enzyme in question. In this context, the expressions "enzyme concentration", "enzyme chemical activity" or "enzyme activity" will be used indifferently.
To allow accurate determination of the activity of one or more liver enzymes from small amounts of capillary blood, the inventors developed a specially designed blood test disposable and reader. In particular, to reduce the amount of blood needed to perform the analysis, a specific blood test disposable configured to allow only liver enzyme activity to be determined has been developed (rather than using a general blood test disposable configured to detect multiple different types of enzymes or blood components). This particular blood test disposable may be specifically configured to allow only AST and/or ALT activity to be measured.
Furthermore, as mentioned above, the fact that the blood test reader and the elastography device are operatively connected to each other allows the two devices to cooperate, in particular to operate simultaneously (more generally to operate the two devices according to a predefined time sequence or a predefined condition measurement procedure). Also, as detailed hereinabove, by implementing the elastography measurement and the corresponding blood test simultaneously or within a given limited time frame, the repeatability and reliability of the finally obtained health-related parameters or other results are significantly improved. In some embodiments, the parameter relating to the health condition of the subject's liver may be the health condition itself (which may directly indicate whether the liver is considered healthy for such criteria), or it may be an intermediate parameter that is combined with other information relating to the health condition of the subject's liver or to the subject itself to characterize his liver condition.
In particular, thanks to this relationship, the control and processing system may control the elastography device and the blood test reader such that they start the elastography measurement process and the blood test process comprising the blood sample collection and analysis, respectively, within a single time frame, which facilitates the acquisition of the co-existing measurements (i.e. simultaneous or nearly simultaneous measurements). In particular, the control and processing system may be programmed so that the time range has a duration of at most 30 minutes.
In one embodiment, for example, the elastography device may be configured to prompt an operator to complete an elastography measurement of a mechanical parameter at the beginning of the measurement process in question. Also, the blood test reader may be further configured to prompt the operator to collect a capillary blood sample from the subject at the beginning of the measurement process triggered by the control and processing system. The prompt may be communicated to the operator in various ways, such as by displaying a message on a screen, by turning on an indicator light, or by turning on a blood test disposable dispenser.
The control and processing system may also be programmed to transmit a prompt at the beginning of the measurement process in question to prompt the operator to take a capillary blood sample from the subject within a given time and complete the elastography measurement (such prompt may be achieved by displaying a timer or time bar, for example).
Once elastography and liver enzyme measurements are complete, the control and processing system may also be programmed to check whether they are performed concurrently. For this purpose, the control unit may be programmed to test whether a time interval between the moment of measurement of the at least one mechanical parameter and the moment of measurement of the concentration of the at least one liver enzyme in the blood sample exceeds a given duration threshold. Also, when the two measurements are not performed concurrently, the control and processing system may be programmed to output an error message to indicate that the process of determining the parameter related to the health condition of the liver of the subject failed or that the parameter related to the health condition of the liver of the subject may be unreliable.
Furthermore, because the blood reader and the elastography device are operatively connected to each other (rather than working independently of each other), the system is capable of performing diagnostic procedures and workflow wherein the two devices interact with each other to dynamically adjust the procedure based on the measurements.
As an example, in one embodiment, the control and processing system may be programmed to perform the following operations:
-performing step S10, controlling the elastography device such that the elastography device starts an elastography measurement process, followed by
-performing step S1, followed by
-if the value of at least one mechanical parameter acquired in step S1 satisfies a given criterion:
-performing step S3' of determining a parameter related to the health condition of the liver of the subject by taking into account the value of the at least one mechanical parameter, irrespective of the concentration of the at least one liver enzyme in the blood of the subject, and outputting data representative of said parameter, while simultaneously
-if the value of the at least one mechanical parameter does not satisfy the criterion:
-performing step S20, controlling the operator interface such that the interface transmits information indicating that a blood test is recommended for the liver health assessment of the subject, and/or information prompting the operator to take a capillary blood sample from the subject and to start an analytical sampling of the blood, followed by step S20
-performing step S2, followed by
-performing step S3.
Thanks to these features, the blood test is only performed if a decision that a parameter related to the health condition of the liver of the subject is expected to be significantly improved, thereby saving time and resources.
In particular, the control and processing system may be programmed to control the blood test reader such that the blood test is started only if the value of the at least one mechanical parameter acquired in step S1 indicates that the liver stiffness of the subject is above a given threshold value (e.g. above 5-6 kPa).
More generally, the control and processing system may be programmed to determine that the value of the at least one mechanical parameter does not meet the criterion (and thus to advise a blood test) when it exceeds a threshold value corresponding to a limit between an average value at which the liver does not suffer a health impairment and a value at which the liver may suffer a health impairment.
In other embodiments, the system for determining a parameter related to the health of the liver of a subject may be configured to initiate a measurement process of one or more liver enzymes followed by initiation of an elastography measurement process (rather than beginning with an elastography measurement to determine whether a liver enzyme measurement is useful).
Even with blood test disposables and readers optimized to allow rapid determination of liver enzyme concentration, such determination is not immediate and typically takes several minutes (which is necessary for the detection reagents to react with liver enzymes). It would therefore be very beneficial if the liver enzyme measurement process was first started as early as possible and the time required for the analysis of the blood sample was used for the elastography measurement. In fact, proceeding in this order reduces the time required to complete the entire inspection procedure.
In this last embodiment, in particular, the control and processing system can be programmed to perform the following operations:
-performing step S20', controlling the operator interface such that the interface conveys information prompting the operator to take a capillary blood sample from the subject and to start analyzing the blood sample, and then, upon insertion of the blood test disposable into the blood test reader,
-executing S10, controlling the elastography device such that the elastography device starts an elastography measurement process, followed by
Performing steps S1 and S2, and then,
-performing step S3.
Further, in some embodiments:
-in the memory of the control and processing system, different calculation formulas are associated with different value ranges of the at least one mechanical parameter, each calculation formula corresponding to a given reference parameter for the evaluation of the health of the liver and each calculation formula being capable of calculating a corresponding reference parameter from the at least one mechanical parameter and from the at least one liver enzyme concentration in the blood sample,
-said control and processing system is programmed to select one of the reference parameters by comparing the value of at least one mechanical parameter previously measured on the subject's liver with the value ranges respectively associated with the different reference parameters, and
-the control and processing system is programmed to calculate in step S3 the value of the selected reference parameter according to the calculation formula associated with the previously selected reference parameter.
Now, with respect to the blood test disposable and the associated blood test reader, in one embodiment the blood test disposable is configured such that the blood sample collected through the capillary tube has a volume of at most 60 microliters, or even at most 40 or 30 microliters.
The amount of capillary blood that can be collected from one finger prick is typically 10 to 20 microliters. Thus, the blood sample mentioned above may be collected by performing a limited number of finger pricks or even a single prick. Thus, the inconvenience caused to the object is very limited (in particular, pricking all fingers of the object is avoided). If it turns out that liver enzyme measurements should be performed again, another blood sample of this type can be taken again.
In some embodiments, the capillary tube is secured (e.g., non-removably secured) to a portion of the disposable.
In particular, the blood test disposable may comprise:
-a cartridge (cartridge) containing a reagent, and
-a removable plug, which plug is removable,
-the capillary is fixed on a removable plug, or on a cartridge, the plug and cartridge being configured such that:
the plug can be removed from the box and then reinserted on the box, and made to stand
When the plug is inserted into the cartridge, the capillary is located inside the disposable and the blood sample collected by the capillary is brought into contact with the reagent.
Thus, in order to collect a blood sample, an operator (who may itself be the subject of examination) pricks the skin of at least one finger of the subject (e.g. with a lancet). The operator also removes the plug from the cartridge and then collects the drop (or drops) of capillary blood thus obtained with the capillary tube. The operator then reinserts the plug onto the box. The capillary is therefore kept inside the disposable for most of the time, which prevents possible contamination of the capillary or of the capillary once the blood sample has been taken. Furthermore, thanks to this structure, the collected blood sample can be mixed with the reagent in a reproducible manner, consistently and easily, and careful injection of the blood sample into the disposable of the prior art is avoided.
According to an optional feature of the system described above, the plug is configured such that insertion thereof onto the cartridge causes a pressure increase which pushes the blood sample collected by the capillary tube into the fluidic circuit. Furthermore, the cartridge may comprise a fluidic circuit arranged to bring at least a portion of the blood sample into contact with the reagent. Also, the plug may be configured to place the capillary in fluid communication with the fluid circuit when the plug is inserted on the cartridge body.
In one embodiment of the system presented above:
-the at least one liver enzyme is one of: aspartate aminotransferase (hereinafter referred to as "AST"), alanine aminotransferase (hereinafter referred to as "ALT"), gamma-glutamyltransferase (hereinafter referred to as "GGT"),
-said reagent is adapted to optically detect said at least one liver enzyme,
-the blood test disposable is configured such that at least a part of the blood sample is mixed with the reagent in the first reaction zone, and
the blood test reader comprises at least a light source and a light sensor for determining the concentration of at least one liver enzyme in the blood sample by means of light reflectance and/or transmittance measurements performed at the first reaction zone.
The blood testing disposable may comprise a filter membrane arranged to filter red blood cells from a blood sample collected from a subject to obtain a plasma sample, and configured to contact at least a portion of the plasma sample with a reagent.
The filtration by means of such membranes may not be as thorough as other filtration methods (e.g. centrifugation) and it results in a plasma sample rather than a serum sample, but is sufficiently efficient for subsequent liver enzyme detection and is faster and results in less volume loss than existing methods (such volume loss is typically less than 60% of the initial volume of the collected blood sample), where it is very beneficial due to the smaller volume of the collected capillary blood sample and the object of the disclosed technique is to reduce the time required to determine parameters related to the health of the liver of the subject.
In one embodiment of the system presented above:
-said at least one liver enzyme is AST or ALT,
-said agents comprise alpha-ketoglutaric acid, and L-aspartic acid or L-alanine, respectively, and
-the blood test disposable comprises the following catalysts: pyruvate oxidase and peroxidase, and an indicator that becomes colored upon reaction with a series of reaction set products produced upon mixing at least one liver enzyme with a reagent.
In particular, the indicator may comprise a MAOS Trinder reagent and the blood test disposable may comprise a liquid buffer and may be configured such that the buffer is mixed with the reagent when the blood test disposable is inserted into a blood test reader, the buffer being an aqueous solution containing TRIS (hydroxymethyl) aminomethane (hereinafter referred to as TRIS).
In particular, the concentration of TRIS in the buffer may be 0.05 to 1 mol/l, or may even be 0.1 to 0.5 mol/l.
By using the indicator and the buffer, a fast and accurate determination of the concentration of at least one liver enzyme in the collected blood sample is allowed. In practice, with this system, measurements are typically taken 10 minutes or less (typically 5 minutes) after blood collection, and the measurement accuracy is better than 20%, typically around 10% or even lower.
MAOS Trinder reagent indicated N-ethyl-N- (2-hydroxy-3-sulfopropyl) -3, 5-dimethylaniline sodium salt. And TRIS (hydroxymethyl) aminomethane (TRIS) indicates 2-amino-2-hydroxymethylpropane-1, 3-diol.
In one embodiment, the reagent is contained in a dry test pad and the catalyst and indicator are contained in a dry test substrate (substrate) distinct from the pad, the substrate and pad being disposed in the first reaction zone, whereby at least a portion of the plasma sample, possibly mixed with a buffer, wets the test pad and substrate pad (substrate pad), thereby allowing for liver enzyme detection.
The liquid buffer mentioned above may also comprise phosphate and/or have a pH between 6.5 and 8, which is advantageous for liver enzyme detection as described above.
In one embodiment:
-the blood test disposable comprises a catalyst active on-board control (on board control) comprising:
dry control substrate comprising oxaloacetate, and
-a dry control pad (dry control pad) comprising a catalyst and an indicator, said control pad being different from said control substrate,
-the blood test disposable is configured to allow the liquid to saturate the control substrate and control pad upon insertion of the blood test disposable into a blood test reader or upon receiving a blood sample in the blood test disposable.
In particular, oxaloacetate reacts to produce hydrogen peroxide if pyruvate oxidase and peroxidase are present. Next, the MAOS is oxidized by hydrogen peroxide and thereby becomes colored, which is optically detected by a blood test reader, thereby confirming the integrity and activity of the catalysts (pyruvate oxidase and peroxidase). Thus, such a plate-loaded control improves the reliability of the system (especially when low liver enzyme concentrations are measured, the control will confirm that the results are not due to insufficient catalyst).
It may be noted that pyruvate oxidase and peroxidase allow the detection of AST or ALT (when combined with alpha-ketoglutarate and L-aspartate, or with alpha-ketoglutarate and L-alanine, respectively). Thus, the integrity of a disposable configured to detect AST (in the first reaction zone) and ALT (in the second detection zone) can be assessed in a reasonably complete manner by a single on-board control as set forth above (rather than requiring two different controls), which simplifies the construction of the disposable and the amount of liquid required for its operation.
The liquid that saturates the control substrate and control pad can be a liquid buffer contained in a frangible bubble when the blood test disposable is inserted into the blood test reader. The frangible bubble can be configured to rupture and inject buffer into the control pad and substrate upon insertion of the blood test disposable into the blood test reader. It would be highly beneficial to be able to reduce the amount of blood required for liver enzyme measurements by using such a buffer to achieve this integrity control, rather than using a plasma sample drawn from a collected blood sample.
In some embodiments, the system is further configured to allow determination of the platelet count in the blood sample or another blood sample taken from the subject, and the control and processing system may be programmed to determine the parameter related to the health condition by taking into account the platelet count in step S3.
In some embodiments of the system:
the elastography device is further configured to perform measurements on ultrasound attenuation parameters in the liver, and
-said control and processing system is further programmed to perform the following operations:
-acquiring in step S1 values of ultrasound attenuation parameters measured by the elastography device, and
-determining a parameter related to the health condition of the liver of the subject by taking into account the value of the ultrasound attenuation parameter in step S3.
In particular, the control and processing system may be programmed to calculate a reference parameter representative of the health of the liver of the subject by taking into account the value of the at least one mechanical parameter, the value of the ultrasound attenuation parameter and the value of the concentration of the at least one liver enzyme in step S3.
The at least one mechanical parameter associated with the propagation of shear waves in the liver may be liver stiffness, the ultrasound attenuation parameter may be an ultrasound attenuation coefficient per unit length, and the at least one liver enzyme may be AST. Also, the control and processing system may be programmed to calculate a reference parameter equal to or proportional to the exponent of X divided by the exponent of 1 plus X, X being the linear combination of the logarithm of liver stiffness and the third power of the ultrasound attenuation coefficient, minus one correction term (all correction terms above AST concentration are small). As an example, above the concentration of AST, the correction term may be proportional to 1. In particular, the reference parameter may be according to equation F1 (which corresponds to-1.65 +1.07 xln LSM ═ X]+2.66×10-8×CAP363.3/AST) calculated FAST parameters given above)
By using such reference parameters, particularly when AST concentration and liver hardness measurements are performed concurrently, it allows a very reliable differentiation between healthy liver conditions and poor/diseased liver conditions of the subject.
It is to be understood that the different embodiments presented above may be combined according to all technically possible combinations in accordance with the disclosed technology.
The disclosed technology also provides a method for determining a parameter related to the health condition of a liver of a subject by a system comprising:
an elastography device configured to measure at least one mechanical parameter related to shear wave propagation in the liver,
-a blood test reader and a blood test disposable associated with the blood test reader, the blood test disposable being configured to receive a capillary blood sample and to be inserted into the blood test reader, the blood test reader being configured to determine a concentration of at least one liver enzyme in the blood sample, wherein:
-said blood test disposable comprises:
a capillary for taking a blood sample from a finger, and
-a reagent adapted to detect at least one liver enzyme in a blood sample, and wherein
-the blood test reader is operatively connected to an elastography device, an
-a control and processing system comprising at least one processor and a memory, said method comprising the steps of:
a step S100 of measuring a value of a mechanical parameter of a liver of the subject under examination using an elastography device,
a step S1, in which the control and processing system acquires values of at least one mechanical parameter measured by the elastography device,
a step S200 of taking a capillary blood sample from the subject by means of the capillary tube, followed by introducing the blood test disposable into a blood test reader,
a step S2, the control and processing system obtaining a concentration value of at least one liver enzyme in a blood sample collected from a subject measured by the blood test reader,
-a step S3, the control and processing system determining a parameter related to the health condition of the liver of the subject by taking into account the value of the at least one mechanical parameter and the concentration value of the at least one liver enzyme, the parameter related to the health condition being a health or disease stage determined from different stages of a given health condition classification, or a reference parameter taking into account the value of the at least one mechanical parameter and the concentration value of the at least one liver enzyme, or being represented by the values of the health or disease stage and the reference parameter, and outputting data representative of the parameter related to the health condition.
In the method, a control and processing system controls the elastography device and the blood test reader. In particular, the control and processing system may control the elastography device and the blood test reader by: wherein the measurement of the at least one mechanical parameter and the measurement of the concentration value are performed according to a predefined time sequence (e.g. within a given time range) and/or according to a predefined conditional measurement procedure (as shown in fig. 11 to 15).
In particular, steps S100 and S200 may be performed within a single time range having a maximum preset duration. The maximum duration may be 30 minutes, or 15 minutes or even 10 minutes.
In the above method, if steps S100 and S200 are not performed within a single time range having a maximum duration, the control and processing system may output an error message.
The features of the different embodiments of the system described above may also be applied to the method for determining a parameter related to the health condition of the liver of a subject just presented.
Drawings
Other features and benefits of the disclosed technology will become apparent from the description given below, by way of example and not limitation, with reference to the accompanying drawings, in which:
fig. 1A schematically illustrates a first embodiment of a system for determining a parameter related to the health of a liver of a subject in accordance with the disclosed technique.
FIG. 1B depicts the system of FIG. 1A in a more pictorial manner.
Fig. 2 schematically illustrates a second embodiment of a system for determining a parameter related to the health of a liver of a subject according to the disclosed technique.
Fig. 3 schematically illustrates a third embodiment of a system for determining a parameter related to the health of a liver of a subject in accordance with the disclosed technique.
FIG. 4 is a schematic perspective view of a blood testing disposable that may be equipped with any of the systems of FIGS. 1A-3.
Fig. 5 and 6 are schematic bottom and top views of the blood testing disposable of fig. 4.
FIG. 7 is a schematic side view of a test pad of the blood testing disposable of FIG. 4.
FIG. 8 is a schematic side view of an on-board control of the blood testing disposable of FIG. 4.
Figure 9 shows the chemical reactions involved in the detection of liver enzymes in the blood test disposable of figure 4.
FIG. 10 is a flow chart depicting the different steps of liver enzyme detection.
Fig. 11 and 12 depict steps of a first embodiment of a method for determining a parameter related to the health of a liver of a subject, which may be implemented by the system of any of fig. 1A-3, in accordance with the disclosed technique.
Fig. 13 schematically depicts how different reference parameters may be selected and calculated in the method of fig. 11 to determine parameters related to the health of the liver of a subject.
Fig. 14 shows in more detail the calculation and test sequence performed in an implementation example of the method in fig. 11.
Fig. 15 depicts steps of a second embodiment of a method for determining a parameter related to the health of a liver of a subject in accordance with the disclosed technology, which may be implemented by any of the systems of fig. 1A-3.
Detailed Description
FIGS. 1A, 2 and 3 respectively depict a system 1 for determining a parameter related to the health of a liver of a subject; 1'; 1 ";
in each of these embodiments, the system 1; 1'; 1' comprises:
an elastography device 2; 2'; 2 "configured to measure at least one mechanical parameter related to the propagation of shear waves in the liver, such as liver stiffness, and
a blood test reader 3 and a blood test disposable 10 associated with the blood test reader 3 for determining the concentration of at least one liver enzyme in a blood sample taken from a subject under examination.
A system 1; 1'; 1 "also comprises a control and processing system 4; 4'; 4 "for controlling the elastography device 2 while examining the object (e.g. according to the examination process depicted in fig. 11 or 15); 2'; 2 "and a blood test reader 3.
A control and processing system 4 comprising at least a processor and a memory; 4'; 4 "is programmed to determine a parameter related to the health of the liver of the subject by considering all two of:
by the elastography device 2; 2'; 2 "a value of at least one mechanical parameter measured during the examination of the object; and
the concentration value of at least one liver enzyme measured by the blood test reader 3 during the examination.
A system 1; 1'; 1 "(depicted in fig. 1A, 2 and 3, respectively) the main differences between these three embodiments relate to the control and processing system 4; 4'; 4' in system 1; 1'; 1' internal distribution. For example, for fig. 1A, the control and processing system 4 is housed in the same housing 6 as the elastography device 2, and it is actually implemented in the form of a control unit of the elastography device 2. In contrast, for fig. 2, control and processing system 4 ' is a distinct electronic device located outside housing 6 ' of elastography device 2 ' and blood test reader 3. And in fig. 3, part of the control and processing system 4 "is implemented by means of a non-localized remote computing resource 7 (for example a" cloud ").
In summary, system 1; 1'; 1 "have many common features. Therefore, the same or corresponding elements of these different embodiments may be described only once and may be identified by the same reference numerals/numbers.
In each of these embodiments, the blood test reader 3 is operatively connected to the elastography device 2; 2'; 2". Such a connection can be made directly without an intermediate system. It can also be realized by means of an intermediate device as in the case of fig. 2, wherein the elastography device 2 'is operatively connected to the blood test reader 3 via a control and processing system 4'.
In summary, the elastography device 2; 2'; 2 "and blood test reader 3 allows the two devices to cooperate, e.g. co-exist operation.
As an example, the connection 9 may be used to transmit commands or execution requests from the elastography device 2 to the blood test reader 3. In this case, the elastography device 2 and the blood test reader 3 may be programmed to operate according to a master-slave mode, wherein the elastography device 2 is the master device and issues commands to the blood test reader 3, which executes the commands and in response sends confirmation data, measurement results, data related to the liver enzyme measurement process and/or data representative of the status of the blood test reader 3.
The connection between the elastography device 2 ' and the blood test reader 3 may also allow transmission of commands or execution requests to the blood test reader which are not directly determined by the elastography device 2 ' but are determined based on data transmitted by the elastography device 2 ', such as liver stiffness measurements or status data. In particular, these commands or requests may be determined by the control and processing system 4 'based on data received from the elastography device 2', and therefore the control and processing system 4 'plays a positive role in the connection of the elastography device 2' with the blood test reader 3 (therefore, the connection is a kind of compound and active connection). Instead, the elastography device 2 'may receive commands or execution requests determined on the basis of data received from the blood test reader 3 (by the control and processing system 4').
An elastography device 2; 2'; 2 "and blood test reader 3 may be implemented by a wired or wireless link according to USB, firewire, bluetooth, 6LoWPAN, ZigBee, Z-Wave, Sigfox or other protocols.
As described above, the elastography device 2; 2'; 2 "and blood test reader 3 allows the two devices to operate in cooperation, e.g. in coexistence. And, the control and processing system 4; 4'; 4 "may be programmed as described herein to control the elastography device and the blood test reader such that they perform the elastography measurement process and the liver enzyme measurement process, respectively, in a coordinated, in particular co-existing, manner, which may be achieved by the above-mentioned connections.
As mentioned in the summary section above, by enabling concurrent measurement of a mechanical parameter (e.g. liver stiffness) and at least one liver enzyme concentration, a more reliable and repeatable determination of a parameter related to the health of the liver of a subject may be achieved.
A particular blood test disposable 10 for measuring the concentration of at least one liver enzyme in the blood of a subject and a reader 3 participate in this improvement. They do allow for accurate, rapid in situ determination of the concentration of at least one liver enzyme in a subject's blood from very limited capillary blood collected from the subject. The fact that these characteristics, in particular the volume of blood to be collected, is small, simplifies the whole process and greatly facilitates the realization of co-existing measurements regarding liver stiffness and liver enzyme levels.
The system 1 will now be described in more detail with reference to fig. 1A to 3; 1'; 1 "in the general structure. In the system 1; 1'; 1 "and the reader 3 will be described further with reference to fig. 4 to 10. Two different embodiments of methods for determining a parameter related to the health condition of the liver of a subject will be described next with reference to fig. 11 and 15, respectively. Each of these two methods may be performed by the system 1 as described above; 1'; 1 "in any of the three embodiments. And, these systems 1; 1'; 1 "of any one of the control and processing systems 4; 4'; 4 "may be programmed to perform one or the other of these methods.
In the system 1 of fig. 1A and 1B, the control and processing system 4 is part of the elastography device 2 and serves as a control unit for the elastography device 2 (in addition, it controls the blood test reader 3).
As mentioned above, the elastography device 2 is configured to measure at least one mechanical parameter related to the propagation of shear waves in the liver. Here, the mechanical parameter is a quantity related to the liver stiffness, such as the propagation velocity Vs of the shear wave, the shear modulus of the liver tissue or its young's modulus E. Here, this parameter is designated as liver hardness or LSM ("liver hardness measurement"). In other embodiments, however, the mechanical parameter may be a quantity related to low frequency (e.g., below 500Hz) shear wave attenuation in tissue, such as viscosity.
As an example, the elastography device 2 may be configured to measure at least one mechanical parameter by transient elastography.
Here, the elastography device 2 is also configured to measure ultrasound attenuation parameters in the liver, more precisely ultrasound attenuation coefficients per unit length, referred to as controlled attenuation parameters or "CAP". The ultrasound attenuation coefficient represents the attenuation of high-frequency ultrasound waves in the organ under examination (these ultrasound waves usually have a center frequency of several megahertz-for example 2 to 5 MHz).
The elastography device 2 includes an elastography module 21, the elastography module 21 being configured to drive a probe 22 and to receive signals acquired by the probe 22.
The probe 22 includes at least one vibrator for generating shear waves and an ultrasound transducer for transmitting ultrasound transmissions and receiving corresponding echo signals to track how the liver of the subject is moved by the shear waves generated by the vibrator. During the liver stiffness measurement, the probe 22 is pressed against the subject's skin.
The elastography module 21 comprises an ultrasound front end containing electronics modules for generating ultrasound signals to be transmitted and for acquiring and pre-processing ultrasound echo signals received by the ultrasound transducer of the probe 22. The elastography module 21 also includes a motion actuator servo-controller for driving the vibrators of the probe 22.
The elastography module 21 may also comprise dedicated logic circuits (for example FPGA, ASIC-application specific integrated circuit, or other kinds of programmable microcircuits) for processing the acquired echo signals to obtain values of the mechanical parameters to be measured (for example liver stiffness). The dedicated logic circuit may also be included in the control and processing system 4 instead of the elastography module 21.
The control and processing system 4 is connected to the elastography module 21 and to an operator interface 5, for example a display screen. In the above-described measurement of mechanical parameters, the elastography module 21 and the operator interface 5 are controlled by the control and processing system 4. For example, the control and processing system 4 controls the operator interface 5 such that it displays guidance information to assist the operator in positioning the probe in front of the subject's liver, and displays the measurements (e.g., elastogram and finally obtained stiffness value) once they have been acquired.
As already mentioned, the control and processing system 4 comprises at least a processor and a memory coupled to the processor. More generally, it comprises circuitry for processing data and for transmitting and receiving data. The memory includes a physical non-transitory (non-volatile) memory module for storing machine executable instructions executed by the processor for performing the functions of the control and processing system 4. It may also include RAM memory for storing signal data and instructions during system operation.
In the system 1 of fig. 1A, the control and processing system 4 and the elastography module 21 are housed in the housing 6 of the elastography device 2. The operator interface 5 may be integrated into the housing 6 or may be implemented as a different remote device. The elastography device 2 and the blood test reader 3 may be located in the same room or may be separated from each other by a distance of less than 15 meters to avoid transferring the subject or blood sample from one place to another, thereby avoiding transfer times or errors.
As already mentioned, the control and processing system 4 is also operatively connected to the blood test reader 3 via a connection 9 as described above. Also, the control and processing system 4 is not only programmed to monitor the elastography device 2 to perform measurement processes with respect to the above-mentioned mechanical parameters. It is also programmed to control the blood test reader 3 so as to trigger the liver enzyme measurement process in a coordinated (e.g. co-existing) manner with the mechanical parameter measurement. For example, the control and processing system 4 may be programmed to start the liver enzyme measurement process according to the first obtained liver hardness value (the liver enzyme measurement process is started immediately or nearly immediately after the hardness value is obtained). It may also be programmed to start the liver enzyme measurement process and the mechanical parameter measurement process almost in parallel with only a short delay between the respective start points (e.g. less than 5 minutes or less than 15 minutes).
The control and processing system 4 can also be programmed to check posteriorly, once these measurement processes have been completed, whether the time interval between the moment of measurement of the above-mentioned mechanical parameter and the moment of measurement of the concentration of one or more hepatic enzymes in the subject sample is below a given duration threshold. If the time gap is above the duration threshold, the control and processing system 4 may output an error message indicating that the parameter associated with determining the health condition of the liver of the subject failed, or that the parameter may be unreliable and/or it may skip determining or communicating the health condition.
In any case, as already mentioned, the control and processing system 4 is programmed to determine the parameter related to the health of the liver of the subject by taking into account the above-mentioned mechanical parameter values measured by the elastography device 2 and the concentration values of the one or more liver enzymes measured by the blood test reader 3 (although this determination process may or may not be performed depending on certain conditions, for example based on preliminary hardness measurements).
In describing the methods of fig. 11 and 15, different methods of determining a parameter related to the health of the liver of a subject based on these two measurements (and possibly other measurements as well) will be described.
More specifically, the control and processing system 4 of the system 1 of fig. 1A may be programmed to control the blood test reader 3 and the elastography device 2 according to the method of fig. 11 or according to the method of fig. 15. In particular, the control and processing system 4 may be programmed to perform steps S10, S1, S20, S2 of the method of fig. 11, followed by step S3 (or alternatively step S3'). Or steps S20, S10, S1, S2 of the method of fig. 15 are performed, followed by step S3.
The system 1 ' of fig. 2 is similar to the system of fig. 1A, but in this second embodiment, the control and processing system 4 ' is independent of the elastography device 2 '.
The elastography device 2' includes the elastography module 21 and the probe 22 described above. The elastography module 21 is housed in a different housing 6 'independent from the housing 41' of the control and processing system 4 ', the control and processing system 4' being connected to the elastography module 21. An operator interface 5 '(such as the operator interface 5 described above) is connected to the control and processing system 4'.
In this second embodiment, the control and processing system 4 'may be a personal computer (e.g., a laptop or tablet computer) or an electronic logic circuit or system (having one or more processors and one or more memories) of a smartphone operably connected to both the elastography device 2' and the blood test reader 3.
The blood test reader 3 and the disposable 10 are identical to those of the system 1 of fig. 1A, and the blood test reader 3 is connected to the control and processing system 4', just as in the system 1 of fig. 1A.
An additional optional connection (not depicted in fig. 2) may also connect the elastography device 2 '(more specifically the elastography module 21) directly to the blood test reader 3 (not via the control and processing system 4').
The system 1 "of fig. 3 is similar to the system of fig. 1A, but in this third embodiment, part of the control and processing system 4" is implemented by means of a non-localized remote computing resource 7 (e.g., a "cloud").
In this third embodiment, the control and processing system 4 "comprises:
a first part 41 configured to control the elastography device 2' and the blood test reader 3 and to monitor the measurement process, an
A second part 42 configured to determine parameters related to the health condition of the liver of the subject, in particular by calculating reference parameters (scores).
The first part 41 is implemented locally. More specifically, it is integrated into the elastography device 2 "and housed in the housing 6 of the elastography device 2". In contrast, the second part 42 of the control and processing system (e.g. the non-localized computing services and databases) is remote and implemented by remote and possibly distributed computing resources 7 (remote meaning that at least a part of the elastography devices of these resources are at least 1 km apart).
The first and second parts 41 and 42 of the control and processing system 4 "are operatively connected to each other and can therefore exchange data and instructions. The blood test reader 3 can also be directly connected to the second remote part 42 of the control and processing system 4 "without the first part 41 (housed in the elastography device), which then allows direct transmission of the liver enzyme measurements to the second part 42 of the control and processing system 4" more specifically dedicated to data processing and calculation.
The second part 42 of the control and processing system 4 "may be programmed to transmit data representing a parameter related to the health of the liver of the subject, after determining the data, to:
a first part 41 of the control and processing system 4 ", so as to transmit the parameter to the operator through the operator interface 5, and/or
A remote device 8, such as a personal computer or a smartphone, and/or
-a remote database for storage.
The third embodiment of the system 1 "is identical or at least similar to the first embodiment, except for the differences described above. In particular, the elastography device 2 "comprises an elastography module 21 (which is connected to the probe 22) and a first part 41 (control part) of the control and processing system 4" in the same housing 6. The first part 41 of the control and processing system 4 "is connected to the blood test reader 3 (which may be the same as those in fig. 1A and 2) via a connection 9.
The blood testing disposable 10 of the system 1 of fig. 1A will now be described in more detail with reference to fig. 4 to 10. As mentioned above, the blood test disposable 10 can be used indifferently with the system 1 described above; 1'; 1 "in any of the three embodiments.
The blood testing disposable 10 includes a capillary tube 13 for collecting a blood sample from a subject. For this purpose, the skin of one finger or two or three fingers of the subject may be punctured (e.g., with the aid of a blood lancet). Subsequently, one or more drops of blood of the thus obtained capillary vessel are collected by the capillary tube. Here, the capillary 13 is fixed, more precisely non-detachably fixed, to a part of the blood test disposable (which is not a detachable and exchangeable component).
As shown in fig. 5, the blood test disposable 10 includes two distinct parts, namely:
a cartridge 11 containing reagents suitable for detecting at least one liver enzyme, and
removable plug 12 (in fig. 5, plug 12 is depicted as being separate from case 11).
The plug 12 and the housing 11 are configured such that the plug 12 can be removed from the housing 11 and then reinserted into the housing 11.
To this end, the plug 12 and the box 11 can be provided with male and female fastening elements, respectively (or vice versa), for example ribs (on the plug) and grooves (on the box) with complementary shapes, or elastic teeth or clips and corresponding grooves or holes.
Here, the plug 12 is a cap-like member detachably fixed to an end face 121 of the case, that is, a back face thereof (the front face of the case is a face which is first introduced into the reader 3 when the disposable 10 is introduced into the reader 3).
A capillary tube 13 projects from the plug 12 to allow blood to be collected from a subject. The capillary 13 also extends inside the plug 12 so as to provide a receiving volume large enough to receive between 20 and 50 microliters (e.g. 25 ± 10 microliters) of a blood sample.
When the plug 12 is inserted into the box 11 (as in fig. 6), the outer portion 130 of the capillary 13 (i.e., the portion of the capillary 13 protruding the plug 12) will enter the box 11. The capillary 13 then extends completely inside the blood test disposable 10 (in other words, the capillary 13 is then completely accommodated inside the blood test disposable 10).
To take a blood sample, the operator (who may himself be the subject under examination) punctures the skin of at least one finger of the subject (e.g. with a lancet). The operator also removes the plug 12 from the cartridge 11 and then collects one or more drops of capillary blood thus obtained with the end 131 of the capillary 13. Next, once the capillary 13 (and possibly the reservoir) is filled with capillary blood, the operator reinserts the plug 12 onto the cartridge 11. To collect a suitable volume of blood, that is to say here to fill the capillary 13, the operator can prick more than one finger of the subject, for example 2 or 3 fingers.
The blood test disposable 10 is configured such that the blood sample thus collected through the capillary 13 is brought into contact with the reagent contained in the cartridge 11.
In the embodiment depicted in the figures, the blood sample collected by means of the capillary 13 flows out of the capillary through the same end 131 as the capillary used for collecting the blood sample (so as to flow into the cartridge and mix with the reagent). And here, the plug 12 is configured such that its insertion into the cartridge 11 causes an increase in pressure, thereby pushing the blood sample contained in the capillary tube toward the cartridge 11 inside the cartridge 11. For this purpose, as an example, the plug 12 may have a deformable body that is squeezed when the operator pushes the plug 12 to push it onto the cartridge.
Once the blood sample exits the capillary tube 13, it may be contacted with the above-mentioned reagents and, more generally, transported via a fluidic circuit (e.g., a microfluidic circuit) containing one or more conduits and/or connections, respectively, to different parts of the cartridge for enzymatic detection and control. The blood sample may also reach these reagents directly, or by infiltrating and passing through one or more membranes or substrates (rather than through tubing or other circuitry).
As shown in fig. 6, when the plug 12 is inserted into the case 11, the output end 131 of the capillary 13 is positioned just above the filter membrane 110. The filter membrane 110 is adapted to filter a sample of red blood cells from the blood in order to obtain a sample of plasma.
Thus, after the blood sample passes through the filter membrane 110, a portion of the blood sample (which actually becomes more like a plasma sample due to filtration) reaches and wets the first detection pad 111. And another portion of the filtered blood sample reaches and wets the second test pad 112.
When the reagent contained in the first detection pad 111 contacts the AST, the reagent produces a product (here, hydrogen peroxide) that reacts with the indicator (here, the MAOS Trinder reagent) as a result of one or more chemical reactions, wherein the indicator becomes colored in the presence of the product. Thus, thanks to such a reaction or reactions, the indicator becomes colored in the presence of AST, which allows liver enzyme detection.
The color change of the indicator is optically detected by the blood test reader 3, and the blood test reader 3 is configured to measure the light reflectance, more specifically the diffuse light reflectance of the first reaction zone Z1. For this purpose, the blood test reader 3 is equipped with a light source and a light detector. Here, the light source (e.g., a light emitting diode) has an emission spectrum suitable for detecting a color change of the indicator even without spectral filtering of the light reflected by the first reaction zone Z1 of the blood test disposable 10. For example, if the indicator in colored form selectively absorbs yellow light, the light source may emit primarily yellow light (in other words, the emission spectrum of the light source may at least partially overlap with the absorption spectrum of the indicator in colored form).
It may be noted that the expression "light reflectivity" refers to any quantity representing the intensity or spectral intensity or power of light reflected by an object or surface, compared to the power or intensity or spectral intensity used to illuminate the object or surface. In particular, the expression "light reflectance" may refer to the reflectance, reflectance coefficient, spectral reflectance or incident reflected luminous intensity ratio of light whose spectrum is mainly comprised within a given limited wavelength range. Also, the light reflectance of the region Z1 can measure or estimate the light reflectance of the region Z1 by comparing the luminous intensity of the light reflected by the region with the luminous intensity of the light reflected by another reference region (serving as a "blank region").
The blood test reader 3 is calibrated and programmed to determine the AST concentration in the blood sample collected from the subject from the light reflectance measurements described above.
Likewise, when the reagent contained in the second test pad 112 contacts the ALT, the reagent produces a product (also hydrogen peroxide) that reacts with the indicator (also MAOS Trinder reagent) as a result of one or more chemical reactions, wherein the indicator becomes colored in the presence of the product.
The reagent species and chemical reactions involved in such an enzymatic assay will now be described in more detail with reference to FIG. 9.
The first detection pad 111 (for AST detection) comprises L-aspartic acid and α -ketoglutaric acid. When the portion of the filtered blood sample containing the AST is contacted with the pad, L-aspartic acid and α -ketoglutaric acid react together and the AST acts as a catalyst (fig. 9). The first reaction R1 produces oxaloacetate, which then decomposes into pyruvate and carbon dioxide in reaction R2.
The first detection pad 111 also contains catalysts, pyruvate oxidase and peroxidase. In a reaction process called R3, the pyruvic acid produced by reaction R2 reacts with phosphate, oxygen and water contained in the filtered blood sample (possibly mixed with a buffer) to produce acetyl phosphate, carbon dioxide and hydrogen peroxide. Reaction R3 is catalyzed by pyruvate oxidase.
Here, the indicator contained in the first detection pad 111 becomes colored when oxidized. Thus, in the presence of hydrogen peroxide generated by reaction R3, the indicator oxidizes and becomes colored during reaction R4. Reaction R4 is catalyzed by peroxidase. By way of example, the indicator may be the MAOS Trinder reagent (the detailed formula of which is given above). In fact, the indicator proved to allow sensitive and reliable enzyme concentration measurements. In this case, the emission spectrum of the light source used to detect the state change of the MAOS may contain predominantly orange light (with spectral bands predominantly around 610 nm wavelength), or it may be filtered, so that reflectance measurements are made predominantly in the wavelength range around 610 nm wavelength (e.g. predominantly between 550 and 650 nm).
Here, the first detection pad 111 includes two different sub-pads, an upper pad containing reagents (L-aspartic acid and α -ketoglutaric acid) and a lower pad containing catalysts (pyruvate oxidase and peroxidase) and indicators (MAOS). The lower gasket is positioned below the upper gasket. The filtered blood sample (i.e., the plasma sample) first reaches the upper reagent pad, and then, once pyruvic acid is produced, flows or otherwise migrates to the lower catalyst and indicator pad. The upper pad may be implemented in the form of a substrate (which covers a wider area than the lower pad) extending over the lower pad. However, in some embodiments, the reagent, catalyst, and indicator may be mixed in a single dry test pad, rather than separated from each other (for better preservation), or they may be distributed in different pads in a different manner than described above.
Second test pad 112 (for ALT testing) includes L-alanine (instead of L-aspartic acid) and α -ketoglutaric acid. It also includes the same catalysts and indicators (i.e., pyruvate oxidase and peroxidase) and MAOS Trinder reagent as in the first test pad 111. Here, similar to the first detection pad, the second detection pad 112 includes an upper pad containing reagents (L-alanine and α -ketoglutarate) and a lower pad 111 containing a catalyst (pyruvate oxidase and peroxidase) and an indicator (MAOS).
When the second detection pad 112 is wetted by a portion of the filtered blood sample, the reaction that occurs in the second detection pad 112 proceeds as follows. First, L-alanine and alpha-ketoglutarate react together, and ALT functions as a catalyst (reaction R5). This reaction R5 produces pyruvate and glutamate. Next, in the same reaction as reaction R3 described above (involving AST detection), pyruvic acid reacts with phosphate, oxygen and water contained in the filtered blood sample (which may be mixed with a buffer) to produce acetyl phosphate, carbon dioxide and hydrogen peroxide. Then, in the same reaction as the reaction R4 described above, the hydrogen peroxide generated by the reaction R3 oxidizes the indicator, which becomes colored.
Optionally, as schematically depicted in fig. 10, the blood testing disposable 10 may further comprise a hemolysis check optical port (in fig. 10, this optional component is identified by reference numeral 122) positioned between the filter membrane and the first reaction zone along the path followed by the filtered blood sample. The optical port may be implemented in the form of a window followed by a channel for the filtered blood sample. To check whether the blood sample is significantly hemolyzed, the blood test reader may then be configured to measure the light reflectance and/or transmittance in a wavelength range suitable for detecting hemoglobin, here checking the light reflectance at the hemolysis check optical port. As an example, this light reflectance may be measured in a wavelength range predominantly around 410 nanometers (e.g., predominantly between 390 and 430 nanometers). Such a light reflectivity measurement can be realized by means of light-emitting diodes emitting blue light and by means of light detectors, for example photodiodes.
The blood test reader 3 can be programmed to test from said reflectance and/or transmittance measurements whether the filtered blood sample significantly absorbs light in the above-mentioned wavelength range, which indicates that it is significantly hemolyzed, for example by testing whether the light reflectance at the hemolysis check port exceeds a given threshold. And, when it exceeds the threshold, the blood test reader may issue an error message indicating that the liver enzyme concentration measurement failed. The error message may be transmitted by the blood test reader so that the operator may be directly aware of the error (e.g., by emitting an audible beep, by illuminating a particular indicator light, or by displaying the error message on a display screen of the blood test reader). The blood test reader can also be configured to transmit the error message to the control and processing system 4. In any event, when the blood test reader 3 determines that the filtered blood sample has significantly absorbed light in the above wavelength range, it will inhibit transmission of liver enzyme concentration measurements (without transmitting or otherwise outputting the results of these measurements). In fact, a high absorption in the above wavelength range indicates that the blood sample is significantly hemolyzed, which significantly changes its color and thus may lead to errors in liver enzyme measurement (since liver enzymes are detected by means of colored indicators). The reliability of the liver enzyme measurement is thus improved thanks to the haemolysis check port of the blood test reader 10 and the associated detection system of the blood test reader 3.
The blood test disposable 10 also includes an active on-board control of the catalyst 119 (fig. 5 and 8) described above. The activity control is based on the same colorimetric detection scheme as the liver enzyme detection, i.e. reactions R3 and R4 described above. To check the activity and integrity of the catalysts and indicators involved in these detection reactions, the on-board controls 119 included oxaloacetate predicted to be detected by these catalysts and indicators (see reactions R2 through R4).
In particular, the on-board controls 119 include:
a dry control substrate 116 comprising oxaloacetate, and
a dry control pad 117 containing the above-described catalysts (i.e. pyruvate oxidase and peroxidase) and an indicator (here MAOS).
The control substrate 116 and control pad 117 are different from each other so that the oxaloacetate and catalyst/indicator do not mix together (and therefore do not react with each other) during storage of the disposable 10. Here, the control pad 117 is located below the control substrate 116.
The cassette 11 further comprises a frangible bubble 114 configured to break upon insertion of the blood test disposable 10 into the blood test reader 3. Frangible bubble 114 is fluidly connected to an on-board control 119 (here via supply tube 115). A supply tube 115 extends from the frangible bubble 114 to the output end of the tube located directly above the control substrate 116 (on the other side of the control substrate than the control pad 117). When the frangible bubble 114 ruptures as a result of the disposable 10 being inserted into the reader 3, the buffer fluid will flow into the supply tube 115 to reach the on-board control where it will wet the control substrate 116 and then the control pad 117, thereby mixing the oxaloacetate of the control substrate 116 with the catalyst and indicator of the control pad 117. Then, unless the catalyst or indicator is defective, reactions R2 to R4 will occur and the color of the indicator will change. This color change is detected optically by the blood test reader 3.
To more reliably and sensitively detect this color change, the on-board control 119 includes a reference pad 118, the color of the reference pad 18 does not change in the presence of oxaloacetate, and is used to record a "blank" reference value of light reflectance. When the color of the indicator has not changed, the light reflectance properties of the reference pad 118 are close to, e.g., within 20% or even within 10% (at least within the visible range or a portion of the visible range) of the light reflectance properties of the control pad 117. As an example, reference pad 118 can be identical to control pad 117 except that reference pad 118 is free of the catalysts (pyruvate oxidase and peroxidase) and/or indicators described above.
The liquid buffer (initially contained in frangible bubble 114) is an aqueous solution containing phosphate. Its pH may be between 6 and 8, or even between 6.5 and 7.5. It may comprise TRIS at a concentration of between 0.05 and 1 mol/l, or even between 0.1 and 0.5 mol/l.
The cartridge 11 may be configured such that the buffer solution not only flows through the control substrate 116 after the frangible bubble is ruptured, but also reaches the detection zone where the plasma sample is mixed with the reagents and catalyst, which in turn will be mixed with the plasma sample. This treatment is very beneficial because the type of buffer described above (TRIS buffer with the concentrations and pH values described above) helps to detect AST and ALT quickly and accurately when mixed with a plasma sample. In particular, the cartridge may comprise a permeable membrane 123 for separating:
the front of the box containing the breakable bulb 114 and the onboard contrast 119,
the rear of the box containing the detection pads 111 and 112, through which the capillary 13 penetrates when the plug 12 is inserted on the box 11.
FIG. 10 summarizes in flow chart form the different steps involved in liver enzyme detection and control of catalyst and indicator activity.
The blood test disposable 10 and associated reader 3 described above are specifically configured to detect AST and ALT.
Furthermore, in other embodiments (not depicted in the figures), the blood test disposable and the reader may be configured to measure only the chemical activity of one of the two enzymes (but not both), such as AST alone. Or they may be configured to measure the chemical activity of another liver enzyme (e.g., GGT), or AST and GGT or AST, ALT and GGT.
In some embodiments, in addition to AST (and ALT) chemical activity, the blood test disposables and readers may also be configured to measure platelet counts in the collected blood sample. To measure platelet count, a portion of the blood sample collected by the capillary tube may remain unfiltered, and a longer cartridge may be used leaving some space for the platelet measurement component between the capillary output and the filter membrane.
In some embodiments, in addition to the blood test reader 3 and associated disposable 10 (which is configured to determine AST/ALT concentration in the subject's blood), the system may also include a point-of-care device configured to determine platelet concentration in a blood sample collected from the subject.
Fig. 11 depicts in flow chart form a first embodiment of a method for determining a parameter related to the health of a liver of a subject. Fig. 12 depicts in a simplified but more visual and illustrative manner the same method as in fig. 11.
In the method, the control and processing system 4 controls the elastography device 2 and the blood examination reader 3 so as to first measure mechanical parameters (in steps S10 to S1). Next, depending on the value of the mechanical parameter thus measured, a blood sample is taken from the subject and the liver enzyme concentration is measured (in steps S20 to S2), or the measurement of the liver enzyme concentration is not performed. In this first embodiment, the blood test is only performed if it is expected that the parameters relating to the health of the liver of the subject will be improved.
In fig. 11, the different steps of the method are depicted over time t. In the figure, the direction in which the time t elapses corresponds to the vertically downward direction. Each of the steps discussed is vertically aligned with the entity performing the step discussed. For example, step S1 is performed by the control and processing system 4, while step S100 is performed by the operator 100.
The method begins at step S10. In step S10, the control and processing system 4 controls the elastography device 2, in particular the elastography module 21, so that it starts an elastography measurement process.
In response, in step S11, the elastography module 21 generates a signal (in particular an ultrasound signal) adapted to probe the body part of the subject on which the probe 22 is placed, in order to guide the operator 100 and to assist the operator 100 in placing the probe 22 in front of the liver of the subject. At step S12, the operator interface 5 transmits (here by displaying the operator 100) the guidance information thus obtained (e.g., a-mode ultrasound image) and other information useful for elastography measurements (e.g., contact force applied at the tip of the probe 22) to the operator 100. At step S12, operator interface 5 may prompt the operator to perform an elastography measurement.
Next, in step S100, the operator 100 triggers an elastography measurement, here a transient elastography measurement. More precisely, the operator 100 triggers the emission of low frequency transient elastic waves (e.g. shear waves) and ultrasound beams, which are transmitted in order to track how the elastic waves move the tissue of the object. In step S13, the elastography module 21 acquires and processes the received response signals in order to determine the value of the above-mentioned mechanical parameter (e.g. liver stiffness). This transient elastography measurement may be repeated multiple times. Furthermore, in step S13, a CAP value is to be determined (based on the ultrasound echo signals acquired during the transient elastography measurement and/or based on other ultrasound echo signals (e.g. other ultrasound echo signals acquired in the interval between two consecutive transient elastography measurements)).
The values of the mechanical parameters and thus the measured CAP values are then transmitted to the control and processing system 4, which control and processing system 4 acquires these values in step S1.
Next, in step STThe control and processing system 4 tests whether the values of the mechanical parameters satisfy a given calibration.
Here, when the value of the mechanical parameter (e.g., liver hardness) acquired in step S1 exceeds a threshold value that reads the boundary between the average value at which the english liver does not suffer from health damage and the value at which the liver may suffer from health damage, the control and processing system 4 determines that the value does not satisfy the criterion.
For example, when the mechanical parameter is Young's modulus E, the threshold may be in the range of 6-7 kPa. In fact, Young's modulus values below 6-7 kPa, regardless of liver enzyme concentration in the blood of the subject, indicate that the subject being examined is less likely to suffer from liver fibrosis.
When the above criteria are satisfied, the control and processing system 4 executes S3'. In step S3', regardless of the concentration of liver enzymes (i.e., AST, ALT or GGT) in the blood of the subject, the control and processing system 4 determines a parameter related to the health of the liver of the subject by considering the value of at least one mechanical parameter. And when this criterion is met, neither a blood sample is taken from the subject nor analyzed.
Conversely, if the above criteria are not met, then at step STThereafter, the control and processing system 4 will start the liver enzyme measurement process in step S20. In particular, in step S20, control and processing system 4 controls operator interface 5 such that operator interface 5 transmits information indicating a recommendation to make liver enzyme concentration measurements and/or prompts operator 100 to collect data from a subjectA capillary blood sample and information that initiates analysis of the blood sample.
Next, in step S200, the operator 100 collects a capillary blood sample from the subject directly using the capillary tube 13 fixed to the blood testing disposable 10. Next, the operator introduces the blood test disposable 10 containing the blood sample into the blood test reader 3.
At step S23, the blood test reader 3 determines the concentration of at least one liver enzyme in the blood sample. Here, the blood test reader 3 specifically determines the concentration of AST and ALT using the above colorimetric detection method implemented in the blood test disposable 10.
Next, the blood test disposable 3 transmits the one or more values of the liver enzyme concentration measured in step S23 to the control and processing system 4, wherein the control and processing system 4 acquires the one or more values at step S2.
Next, in step S3, the control and processing system 4 determines a parameter related to the health condition of the subject by taking into account at least the value of the mechanical parameter acquired in step S1 and the at least one liver enzyme concentration value acquired in step S2. The control and processing system 4 then outputs data representative of the parameters thus determined. These data may be transmitted to the operator 100 via the operator interface 5, as an example. They may also be sent to a storage device or system, such as a personal electronic health card (for storing the data in this microcircuit card) or a non-localized/distributed health data storage system.
In the method of fig. 11, the operation of the elastography device 2 and the operation of the blood test apparatus 3 are obviously coordinated (since liver enzyme measurements are initiated after mechanical parameter measurements based on mechanical parameter values). Also, the operation of the elastography device 2 and the operation of the blood test device 3 are co-existing, that is to say they occur within a given limited time frame.
More specifically, it is apparent that in the method of FIG. 11, the start-up time lag T between the beginning of step S10 and the beginning of step S20SIs limited (due to the programming of the control and processing system). In practice, for the period of timeThe main part corresponds to a measurement step S100, during which step S100 the operator performs the operations required to detect the hardness of the liver of the subject (probe positioning, measurement triggering, possibly repeated elastography measurements). In practice, TSTypically between 2 and 5 minutes, and typically less than 10 minutes (or at least less than 20 minutes).
Further, in the method of fig. 11, a time lag T between the time of measurement of the mechanical parameter (at step S100) and the time of measurement of the liver enzyme concentration (at the end of step S23)mAs such, is limited. In practice, the main part of the period corresponds to:
the operations performed by the operator 100 (capillary blood sampling, insertion of the blood test disposable 10 into the blood test reader, which usually takes 1-3 minutes), and
the time required to complete the chemical reaction test, here, generally less than 5 minutes (or at least less than 10 minutes) thanks to the specific features of the abovementioned blood test disposable 10.
Thus, in practice, TmTypically between 6 and 15 minutes (typically less than 30 minutes).
Thus, the total time T required to perform the entire method of FIG. 11TTypically between 7 and 30 minutes, most often between 10 and 20 minutes (in any case less than 1 hour).
The process for determining the health condition-related parameter performed in step S3 will now be described in more detail.
The parameter relating to the health condition determined in step S3 may be in the form of information indicating whether the liver of the subject is likely to be healthy or, conversely, likely to be damaged by a given disease (e.g. fibrosis or steatosis) or inflammation.
The health related parameter determined in step S3 may also indicate in a more gradual manner whether the subject' S liver is likely to be healthy, for example in the form of a disease stage. By way of example, the disease stages may be the widely used fibrosis stages F0 to F4 (F0: no fibrosis; F1: mild fibrosis; F2: moderate fibrosis; F3: severe fibrosis; F4: most severe fibrosis/cirrhosis).
The health-related parameter determined in step S3 may relate to fibrosis, but may also relate to fatty liver (CAP values prove to be very useful for fatty liver) and/or liver inflammation (in this regard, liver enzyme concentration values provide very useful information).
At step S3, the parameters related to the health condition of the liver of the subject may be determined by:
-calculating a value ("score") of a reference parameter depending at least on the mechanical parameter and on the liver enzyme concentration as described above, followed by
Comparing the value of the reference parameter thus obtained with one or more threshold values (for example with a negative predictive value and a positive predictive value), and
-determining a parameter related to the health condition of the liver of the subject from the result of the one or more comparisons in question.
Also, in some embodiments, different disease stages may be associated with different value ranges of the baseline parameter, respectively.
The health related parameter determined in step S3 may also take the form of a value of a reference parameter which depends at least on the mechanical parameter and the concentration of liver enzymes as described above and which represents the fact that the liver of the subject is healthier or less healthy.
In other words, this health-related parameter may be an intermediate baseline parameter value that is beneficial to the healthcare professional in diagnosing the subject's liver, rather than corresponding to the final diagnosis itself.
The above-mentioned reference parameter may be the above-mentioned "FAST" parameter, which is calculated according to the above formula F1, as an example. As described above, the reference parameter depends on liver stiffness LSM (i.e., young's modulus E), CAP, and the concentration of AST in the blood of the subject.
For a reference parameter, more generally a parameter related to the health of the liver of a subject, the parameter may also be determined by taking into account the ALT concentration in the blood of the subject. Thus, the reference parameter in question may depend on liver stiffness LSM, optional CAP, AST concentration in the subject's blood and ALT concentration in the subject's blood.
Also, other characteristics of the subject's blood, such as platelet concentration, may be considered in determining parameters related to the health of the subject's liver.
Other clinical parameters related to the subject may also be considered when calculating the above-mentioned baseline parameters (score), such as age and gender (the score calculation formula may include such additional clinical parameters).
For example, the parameters related to the health condition of the liver of the subject may be determined by considering: AST concentration, ALT concentration, and platelet concentration in the subject's blood, age of the subject, and liver hardness LSM.
To this end, in one embodiment, the control and processing system 4 may:
-calculating the value of the "FIB-4" reference parameter, followed by
-determining a parameter related to the health condition of the subject based on the FIB-4 value and the LSM value obtained in step S1.
FIB-4 reference parameters are defined in the abstract of the following article: sterling R.K. et al, "Development of a simple non-invasive index to predict significant fibrosis patients with HIV/HCV co-infection" (Development of a simple non-invasive index for predicting significant fibrosis patients with HIV/HCV co-infection), published in Hepatology 2006, volume 43, 1317-1325.
In such embodiments, the FIB-4 value may be used, as an example, to confirm the health condition determined first based on the LSM value, or conversely to invalidate the health condition determined based on the LSM value.
FIB-4 values can also be used to refine preliminary health conditions determined based on LSM values, particularly to help decide between one health condition and another if the LSM values fall within the LSM "grey range" between negative and positive predictive values.
The FIB-4 value may also be considered by calculating a composite score as a function of both the FIB-4 value and the LSM value.
In step S3, as shown in fig. 13, the process of determining the parameters related to the health condition of the subject may involve different reference parameters (different scores). This is advantageous because, depending on the health condition to be determined, a given reference parameter may be better suited than another reference parameter for inferring information related to the health condition of the liver of the subject.
For example, if reference parameters based on logistic regression are used, each of these reference parameters can make a binary decision. For example, a first reference parameter may allow a determination of whether a subject's liver is impaired by F4 fibrosis, while a second reference parameter may allow a determination of whether the subject's stage of fibrosis is F0-F1 or higher. Thus, by using a reference parameter selected among different reference parameters, a finer or more sophisticated determination of the parameter related to the health condition of the liver of the subject may be achieved, depending on the health condition to be determined and/or depending on such a pre-characterization of the liver condition of the subject. Since the health or physical condition of the subject is not known in advance, it is more appropriate that the reference parameter be selected based on preliminary results including the mechanical parameter value (e.g., liver stiffness) and/or the ultrasound attenuation parameter acquired in step S1.
To this end, in some embodiments:
in the memory of the control and processing system 4, different calculation formulas are associated with different value ranges of at least one mechanical parameter, each calculation formula corresponding to a given reference parameter for the assessment of liver health and each calculation formula being able to calculate a corresponding reference parameter from at least one mechanical parameter and from at least one liver enzyme concentration in the blood sample,
the control and processing system 4 is programmed to select one of the different reference parameters by comparing the value of at least one mechanical parameter previously measured on the subject's liver with the value ranges associated with these different reference parameters, respectively, and
the control and processing system 4 is programmed to calculate in step S3 the value of the selected reference parameter according to the calculation formula associated with the previously selected reference parameter.
Such a way of determining a parameter related to the health condition of a subject is illustrated in fig. 13 by way of example.
In this example, a first reference parameter, called score a, is selected when the young's modulus E of the subject's liver is below a given threshold (here the given threshold is equal to 6.1 kPa). Next, the value of the score a is calculated by considering the value of young's modulus E and the concentration values of AST and ALT in the blood of the subject. When the value of the score a is lower than the first threshold t1, the control and processing system 4 determines that the stage of liver fibrosis in the subject is F0 or F1. And, when the value of the score a is higher than the second threshold t2, the control and processing system 4 determines that the subject liver fibrosis stage is F2, F3 or F4 (between F2 and F4). When the value of score a falls between t1 and t2 ("gray region"), the control and processing system 4 outputs data indicating that no parameter associated with the liver health of the subject can be determined.
In contrast, when the young's modulus E of the subject liver is higher than the above threshold (threshold equal to 6.1kPa), a second reference parameter, called score b, is selected. Next, the value of the score b is calculated by considering the value of young's modulus E and the concentration values of AST and ALT in the blood of the subject. When the value of the score b is lower than the third threshold t3, the control and processing system 4 determines that the stage of liver fibrosis of the subject is F0 or F1. And, when the value of the score b is higher than the fourth threshold t4, the control and processing system 4 determines that the stage of liver fibrosis of the subject is F2, F3 or F4. And, when the value of score b falls between t3 and t4 ("gray region"), the control and processing system 4 outputs data indicating that the parameter related to the liver health of the subject cannot be determined.
FIG. 14 shows a calculation and test sequence performed in a specific implementation example of the method in FIG. 11. In this example, the method for determining a parameter related to the health condition of the liver of a subject is in particular for determining whether the liver fibrosis stage of the subject is F4, or lower (F0 to F3). Thus, step STThe threshold value for the Young's modulus E referred to in (1) is relatively high, for example equal to 10.9 kPa.
When the Young' S modulus E is less than 10.9kPa, at step STThereafter, the control and processing system 4 performs a step S3' in which it directly determines, without further calculations (in this particular example), that the stage of liver fibrosis of the subject is comprised between F0 and F3 (equal to F0, F1, F2 or F3).
In contrast, if the Young' S modulus E is greater than 10.9kPa, then at step STThereafter, the control and processing system 4 initiates liver enzyme measurement (steps S20 to S2). Next, in step S3, a score value is calculated by taking into account the young modulus E and the concentration values of AST and ALT. When the score value is lower than the threshold t 1', the control and processing system 4 determines that the liver fibrosis stage of the subject is between F0 and F3. When the score is higher than the threshold t 2', the control and processing system 4 determines that the liver fibrosis stage of the subject is F4. Otherwise, the control and processing system 4 outputs data indicating that no parameters related to the health condition of the liver of the subject ("gray regions") can be determined.
Fig. 15 schematically depicts a second embodiment of a method for determining a parameter related to the health of the liver of a subject in accordance with the disclosed technique.
In this figure, the method is depicted in a flow chart of a form similar to that of fig. 11 (in particular, the direction in which time t elapses corresponds to the vertically downward direction).
In this second embodiment, the liver enzyme measurement process and the mechanical parameter measurement process are initiated almost in parallel with a short delay T between their respective onsetsS'. First, the liver enzyme measurement process is started (step S20'). Next, once a blood sample is collected from the subject (at step S200), and once the blood testing disposable 10 is introduced into the reader 3 (beginning at step S23), the mechanical parameter measurement process is initiated without delay (at step S10).
Thus, the time required to detect the occurrence of a chemical reaction (typically between 5 and 10 minutes) is used to measure the above-mentioned mechanical parameters in parallel. Doing so allows reducing the total time T required for determining a parameter related to the health condition of the liver of the subjectT’。
Thus, the method of FIG. 15 begins at step S20 ', during step S20', the control and processing system 4 initiates a liver enzyme measurement process. In particular, in step S20', the control and processing system 4 controls the operator interface 5 such that the operator interface 5 transmits information prompting the operator 100 to collect a capillary blood sample from the subject and begin analysis of the blood sample. In step S22, the operator interface 5 transmits the information to the operator 100 (here, by displaying the information). Next, in step S200, the operator collects a capillary blood sample from the subject, and introduces the blood testing disposable 10 containing the blood sample into the blood testing reader 3 (the same as in the method of fig. 11). Next, execution of step S23 for analyzing the blood sample is started. At the beginning of step S23, after the blood test disposable 10 has been inserted into the blood test reader 3, the blood test reader 3 transmits information to the control and processing system 4 indicating that the blood test disposable 10 has been inserted into the blood test reader 3. The control and processing system 4 receives this information at step S24. Once information is received confirming that analysis of the blood sample has begun, the control and processing system 4 initiates a mechanical parameter measurement process at step S10. Here, the measurement process includes steps S10, S11, S12, S100, S13, and S1, which have been described with reference to fig. 11.
In the execution of steps S10 to S1, the chemical analysis on the blood sample is continued, and finally such that respective values of AST concentration and ALT concentration in the subject' S blood are determined at the end of step S23. These values are then transmitted to the control and processing system 4, and the control and processing system 4 acquires these values in step S2. Next, step S3 will be performed as described above with reference to fig. 11.
In the method of FIG. 12, time TS' generally between 1 and 5 minutes. And the total time T between the start of the liver enzyme measurement (i.e. step S200) and the end of all measurements (whether serological or mechanical, here corresponding to the end of step S23 or the end of step S13, depending on which step was the latest to end)m' generally 4 to 10 minutes. And is required for carrying out the methodTotal time T ofT' (this time is less than the total time T required to perform the method of FIG. 11)T) Typically between 5 and 20 minutes, most often between 7 and 15 minutes (and in any case less than 1 hour).
Claims (21)
1. A system (1; 1'; 1 ") for determining a parameter related to the health condition of a liver of a subject, the system comprising:
an elastography device (2; 2') configured to measure at least one mechanical parameter related to shear wave propagation in the liver,
-a blood test reader (3) and a blood test disposable (10) associated with the blood test reader (3), the blood test disposable being configured to receive a capillary blood sample and to be inserted into the blood test reader (3), and the blood test reader (3) being configured to determine a concentration of at least one liver enzyme in the blood sample, wherein:
-said blood test disposable (10) comprising:
-a capillary tube (13) for taking the blood sample from a finger, and
-a reagent adapted for detecting said at least one liver enzyme in said blood sample, and wherein
-the blood test reader (3) is operatively connected to an elastography device (2; 2'), and
-a control and processing system (4; 4'; 4 ") comprising at least a processor and a memory programmed to perform the steps of:
a step S1 of acquiring a value of the at least one mechanical parameter measured by the elastography device (2; 2'),
-a step S2 of obtaining a concentration value of the at least one liver enzyme in a blood sample collected from the subject measured by the blood test reader (3), and
a step S3 of determining a parameter related to the health condition of the liver of the subject by taking into account both the value of the at least one mechanical parameter and the concentration value of the at least one liver enzyme, the parameter related to the health condition being a health or disease stage determined from different stages (F1, F2, F3, F4) of a given health condition classification, or a reference parameter taking into account both the value of the at least one mechanical parameter and the concentration value of the at least one liver enzyme, or being represented by values of the health or disease stage and of the reference parameter, and outputting data representative of the parameter related to the health condition,
the control and processing system (4; 4 ') is configured to control the elastography device (2; 2') and the blood test reader (3) in the following manner: wherein the measurement of the at least one mechanical parameter and the measurement of the concentration value are performed according to a predefined time sequence or according to a predefined conditional measurement procedure.
2. The system (1; 1 '; 1 ") as defined in claim 1, wherein the control and processing system (4; 4'; 4") is programmed to control the elastography device (2; 2 '; 2 ") and the blood test reader (3) such that the elastography device (2; 2'; 2") and the blood test reader (3) start an elastography measurement process and a blood test process comprising the acquisition and analysis of the blood sample, respectively, in a single time frame.
3. The system (1; 1 '; 1 ") as claimed in claim 2, wherein the control and processing system (4; 4'; 4") is programmed so that the time range has a duration (T) of at most 30 minutesS；TS’)。
4. The system (1; 1'; 1 ") of any one of claims 1 to 3, wherein the blood test disposable (10) is configured such that the blood sample collected via the capillary tube (13) has a volume of at most 60 microliters.
5. The system (1; 1 '; 1 ") according to any one of claims 1 to 4, wherein said control and processing system (4; 4'; 4") is programmed to perform the following steps:
-S10, controlling the elastography device (2; 2'), so that the elastography device starts an elastography measurement process, followed by
Said step S1, then
-if the value of said at least one mechanical parameter acquired in step S1 satisfies a given criterion:
-a step S3' of determining a parameter related to the health condition of the liver of the subject by taking into account the value of the at least one mechanical parameter, irrespective of the concentration of the at least one liver enzyme in the blood of the subject, and outputting data representative of said parameter, while simultaneously
-if the value of the at least one mechanical parameter does not satisfy the criterion:
-a step S20 of controlling an operator interface (5; 5') such that said interface transmits information indicative of a recommendation to perform a blood test for a liver health assessment of a subject and/or information prompting an operator (100) to take a capillary blood sample from a subject and initiate an analysis on said blood sample, followed by
Said step S2, followed by
-said step S3.
6. The system (1; 1 '; 1 ") according to claim 5, wherein said control and processing system (4; 4'; 4") is programmed to determine that the value of said at least one mechanical parameter does not satisfy said criterion when it exceeds a threshold value, said threshold value corresponding to a limit between an average value at which the liver does not suffer from health damage and a value at which the liver is likely to suffer from health damage.
7. The system (1; 1 '; 1 ") according to any one of claims 1 to 4, wherein said control and processing system (4; 4'; 4") is programmed to perform the following steps:
-a step S20 'of controlling the operator interface (5; 5') so that it transmits information prompting the operator (100) to take a capillary blood sample from the subject and to start analyzing said blood sample, and then, once said blood test disposable (10) is inserted into said blood test reader (3),
-a step S10 of controlling the elastography device (2; 2') such that it starts an elastography measurement process, followed by
-said step S1 and said step S2, and then
-said step S3.
8. The system (1; 1'; 1 ") of any one of claims 1 to 7, wherein:
-in the memory of the control and processing system (4; 4') different calculation formulae are associated to different ranges of values of the at least one mechanical parameter, each calculation formula corresponding to a given reference parameter for the assessment of liver health and each calculation formula being able to calculate a respective reference parameter from the at least one mechanical parameter and the concentration of the at least one liver enzyme in the blood sample,
-said control and processing system (4; 4') is programmed to select one of said reference parameters by comparing the value of said at least one mechanical parameter previously measured on the liver of the subject with a range of values respectively associated with different reference parameters, and
-said control and processing system (4; 4') is programmed to calculate, in said step S3, the value of said reference parameter according to a calculation formula associated with a previously selected reference parameter.
9. The system (1; 1'; 1 ") according to any one of claims 1 to 8, wherein said capillary tube (13) is fixed to a portion (12) of said disposable (10).
10. The system (1; 1'; 1 ") as defined in claim 9, wherein said blood test disposable (10) comprises:
-a cartridge (11) containing said reagent, and
-a removable plug (12),
-the capillary (13) is fixed to the removable plug (12) or to the cartridge, the plug (12) and the cartridge (11) being configured such that:
-said plug (12) being removable from said box (11) and then reinserted on said box, and enabling
-when the plug (12) is inserted onto the cartridge (11), the capillary (13) is inside the disposable (10) and the blood sample taken by the capillary is in contact with the reagent.
11. The system (1; 1'; 1 ") as claimed in any one of claims 1 to 10, wherein
The at least one liver enzyme is one of: aspartate Aminotransferase (AST), alanine Aminotransferase (ALT), gamma-glutamyl transferase (GGT),
said reagent being adapted to optically detect said at least one liver enzyme,
the blood test disposable (10) is configured such that at least a portion of the blood sample is mixed with the reagent in a first reaction zone (Z1),
the blood test reader (3) comprises at least one light source and a light sensor for determining the concentration of the at least one liver enzyme in the blood sample by taking light reflectance and/or transmittance measurements at the first reaction zone (Z1).
12. The system (1; 1'; 1 ") of any one of claims 1 to 11, wherein the blood testing disposable (10) comprises a filter membrane (110), the filter membrane (110) being arranged to filter red blood cells from a blood sample taken from a subject to obtain a plasma sample, and being configured to bring at least a portion of the plasma sample into contact with the reagent.
13. The system (1; 1'; 1 ") of any one of claims 1 to 12, wherein:
-said at least one liver enzyme is AST or ALT,
-said agents comprise alpha-ketoglutaric acid, and L-aspartic acid or L-alanine, respectively,
-the blood test disposable (10) comprises the following catalysts: pyruvate oxidase and peroxidase, and comprising an indicator, wherein the indicator becomes colored when reacted with a product of a series of reactions that occur when the indicator is mixed with the at least one liver enzyme and the reagent.
14. The system (1; 1'; 1 ") of claim 13, wherein:
-the blood test disposable (10) comprises an onboard control (119) of the catalytic activity,
the on-board controls (119) comprise:
-a dry control substrate (116) comprising oxaloacetate, and
-a dry control pad (117) comprising the catalyst and the indicator, the dry control pad (117) being different from the control substrate (116),
the blood test disposable (10) is configured to allow liquid to saturate the control substrate (116) and the control pad (117) when the blood test disposable (10) is inserted into the blood test reader (3) or when the blood sample is received in the blood test disposable (10).
15. The system (1; 1'; 1 ") according to claim 14, wherein the liquid is a liquid buffer contained in a frangible bubble (114), the frangible bubble (114) being configured to break upon insertion of the blood test disposable (10) into the blood test reader (3).
16. The system (1; 1 '; 1 ") of any one of claims 1 to 15, further configured to allow determining a platelet count in the blood sample or in another blood sample taken from the subject, and wherein the control and processing system (4; 4'; 4") is programmed to determine the parameter related to the health condition of the liver of the subject by taking into account the platelet count in said step S3.
17. A method of determining a parameter related to the health condition of a liver of a subject by means of a system (1; 1 '), said system (1; 1') comprising:
an elastography device (2; 2') configured to measure at least one mechanical parameter related to shear wave propagation in the liver,
-a blood test reader (3) and a blood test disposable (10) associated with the blood test reader (3), the blood test disposable being configured to receive a capillary blood sample and to be inserted into the blood test reader (3), the blood test reader being configured to determine a concentration of at least one liver enzyme in the blood sample, wherein:
-said blood test disposable (10) comprising:
-a capillary tube (13) for taking the blood sample from a finger, and
-a reagent adapted for detecting said at least one liver enzyme in said blood sample, and wherein
-the blood test reader (3) is operatively connected to the elastography device (2; 2'), and
-a control and processing system (4; 4'; 4 ") comprising at least a processor and a memory, said method comprising the steps of:
a step S100 of measuring a value of said at least one mechanical parameter of the liver of the subject under examination using said elastography device (2; 2'),
a step S1 of acquiring, by means of said control and processing system (4; 4'), the value of said at least one mechanical parameter measured by said elastography device,
a step S200 of taking a capillary blood sample from a subject through the capillary tube (13) and then introducing the blood test disposable (10) into the blood test reader (3),
-a step S2 of obtaining, by means of the control and processing system (4; 4'), a concentration value of said at least one liver enzyme in a blood sample collected from the subject measured by the blood test reader (3), and
a step S3, the control and processing system determining a parameter related to the health condition of the liver of the subject by taking into account the value of at least one mechanical parameter and the concentration value of at least one liver enzyme, the parameter related to the health condition being a health or disease stage determined from different stages of a given health condition classification, or a reference parameter taking into account both the value of at least one mechanical parameter and the concentration value of at least one liver enzyme, or being represented by the health or disease stage and the value of the reference parameter, and outputting data representative of the parameter related to the health condition,
the control and processing system (4; 4 ') controls the elastography device (2; 2') and the blood test reader (3) by: wherein the measurement of the at least one mechanical parameter and the measurement of the concentration value are performed according to a predefined time sequence and/or according to a predefined conditional measurement procedure.
18. The method of claim 17, wherein the steps S100 and S200 are performed with a maximum preset duration (T)m；Tm') is performed within a single time frame.
19. The method of claim 17, wherein the step S100 and the step S200 are not in a state of having a maximum preset duration (T)m；Tm') when executed within a single time frame, the control and processing system outputs an error message.
20. The method of any one of claims 17 to 19, wherein said steps S100 and S1 are performed first, followed by the steps of:
-if the value of said at least one mechanical parameter acquired in said step S1 satisfies a given criterion:
-step S3 ', the control and processing system (4; 4') determining a parameter related to the health condition of the liver of the subject, by taking into account the value of the at least one mechanical parameter, irrespective of the concentration of the at least one liver enzyme in the blood of the subject, and outputting data representative of said parameter, while simultaneously
-if the value of the at least one mechanical parameter does not satisfy the criterion:
-a step S20, in which the control and processing system (4; 4 ') controls an operator interface (5; 5') so that it transmits information indicating that a blood test is recommended for the liver health assessment of a subject, and/or information prompting an operator (100) to take a capillary blood sample from a subject and initiate an analysis on said blood sample, followed by
Said step S200 and said step S2, followed by
-said step S3.
21. The method according to claim 20, wherein the control and processing system (4; 4'; 4 ") determines that the value of the at least one mechanical parameter does not satisfy the criterion when it exceeds a threshold value, which corresponds to a limit between an average value at which the liver does not suffer from health damage and a value at which the liver may suffer from health damage.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US16/929,749 US20220015737A1 (en) | 2020-07-15 | 2020-07-15 | System and method for determining a health condition of the liver of a subject |
| EP20305804.5A EP3939514A1 (en) | 2020-07-15 | 2020-07-15 | System and method for determining a health condition of the liver of a subject |
| US16/929,749 | 2020-07-15 | ||
| EP20305804.5 | 2020-07-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN114010221A true CN114010221A (en) | 2022-02-08 |
Family
ID=80034368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110801424.8A Pending CN114010221A (en) | 2020-07-15 | 2021-07-15 | System and method for determining parameters related to the health condition of the liver of a subject |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP2022019626A (en) |
| KR (1) | KR20220009356A (en) |
| CN (1) | CN114010221A (en) |
| AU (1) | AU2021205042A1 (en) |
-
2021
- 2021-07-13 JP JP2021115491A patent/JP2022019626A/en active Pending
- 2021-07-14 AU AU2021205042A patent/AU2021205042A1/en active Pending
- 2021-07-15 KR KR1020210093063A patent/KR20220009356A/en unknown
- 2021-07-15 CN CN202110801424.8A patent/CN114010221A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| KR20220009356A (en) | 2022-01-24 |
| JP2022019626A (en) | 2022-01-27 |
| AU2021205042A1 (en) | 2022-02-03 |
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