GB2524587A - Method and apparatus for non-invasive detection of inflammation of a visceral organ - Google Patents

Abstract

A method for determining the presence or absence of inflammation in a subjects visceral organ is disclosed. The method comprising: obtaining a measurement of relaxometry data of the subjects visceral organ for extracellular fluid (T1); obtaining an iron content for the visceral organ; if iron overload is indicated from the obtained iron content for the visceral organ, correcting the measurement of extracellular fluid for the subjects visceral organ; comparing the corrected measurement for extracellular fluid with a threshold; and determining solely from the comparison, the presence or absence of inflammation in the subjects visceral organ. Also claimed is a method for determining the presence or absence of inflammation in a childs visceral organ, the method comprising: obtaining a measurement of relaxometry data of the childs visceral organ for extracellular fluid (T1); comparing the measurement for extracellular fluid with a threshold; and determining solely from the comparison, the presence or absence of inflammation in the childs visceral organ.

Description

METHOD AND APPARATUS FOR NON-INVASIVE DETECTION OF INFLAMMATION OF A VISCERAL

ORGAN

Technical Field

100011 The field of this invention relates generally to a method and apparatus for the non-invasive detection of inflammation of a visceral organ, and in particular for detecting inflammation utilising an iron corrected spin lattice (Ti) relaxation time.

Background

10002] Liver disease is currently the fifth most common cause of mortality for both men and women. However, whilst mortality rates for the other four major causes of death are falling, the trend for mortality through liver disease is rising in both sexes, at is what is deemed by the medical professionals as an alarming rate. The current childhood obesity epidemic, increasing alcohol misuse and viral hepatitis are all contributing to this increase. A problem with liver disease is that often symptoms of the disease are not apparent until the disease reaches an advanced stage, i.e. fibrosis or cirrhosis.

10003] The current accepted practice, or gold standard', for diagnosing liver disease is an ultrasound-guided liver biopsy. This procedure has a small but significant complication risk (for example 1:1000 result in severe bleeding for the patient, especially in coagulopathic patients). Further, only around 0.002% of the liver is examined, and there is great intra and inter-observer variability in historical interpretation. It is known that severe liver disease in children, in particular, is difficult to diagnose, with 49% of cases of paediatric liver failure in a prospective trial showing an indeterminate cause (see J Pediatr. 2006 May;148(5):652-658).

100041 There are few non-invasive diagnostic alternatives for detecting liver disease. For example, methods described in W02013/085i49 and W020i3/088151 by the inventors of the present application, relate to performing multi-parametric magnetic resonance (MR) diagnosis for liver disease and disease of visceral organs.

10005] In the 1990s, some groups identified elevated Ti in the livers of patients with cirrhosis (Thomsen, et al. Prolonged Ti in patients with liver cirrhosis: An in vivo MRI study. Magn Reson Imaging.

1990; 8:599-604 and Keevil, et al. Non-invasive assessment of diffuse liver disease by in vivo measurement of proton nuclear magnetic resonance relaxation times at 0.08 T. Br J Radiol. 1994; 67:1084-1087), but this did not gain widespread acceptance, perhaps in part because of conflicting experimental data (Goldberg, et al. Hepatic cirrhosis: magnetic resonance imaging. Radiology. i984; 153:737-9; Chamuleau, et al. Is the magnetic resonance imaging proton spin-lattice relaxation time a reliable non-invasive parameter of developing liver fibrosis? Hepatology. 1988; 8:217-21; Aisen, et al. Detection of liver fibrosis with magnetic cross-relaxation. Magn Reson Med. 1994; 31:551-6), and a lack of easily applied in-vivo Ti-mapping methods.

100061 More recently, with the development of robust, single breath-hold Ti mapping techniques (Piechnik, et al. Shortened Modified Look-Locker Inversion recovery (ShMOLLI) for clinical myocardial Ti-mapping at 1.5 and 3 T within a 9 heartbeat breathhold. J Cardiovasc Magn Reson. 2010 12:69), interest in Ti-mapping of the liver in patients with cirrhosis has increased again (Heye, et al. MR relaxometry of the liver: significant elevation of Ti relaxation time in patients with liver cirrhosis. Eur Radiol. 2012; 22:1224-32 and Kim, et al. Quantitative evaluation of liver cirrhosis using Ti relaxation time with 3 tesla MRI before and after oxygen inhalation. J Magn Reson Imaging. 2012; 36:405-10). However, these studies have excluded patients with iron overload. One study (Henninger, et al. Evaluation of MR imaging with Ti and T2* mapping for the determination of hepatic iron overload. Eur Radiol. 2012; 22:2478-86) has addressed the additional information that can be gained by combining T2* and Ti measurements, but only qualitatively (presence/absence of iron overload or fibrosis).

100071 A potential problem with the above mentioned techniques is that they are only applicable to quantify the extent of scar tissue or fat that has already formed in a patient's liver. There is a great clinical need for a test that can identify early inflammation in liver disease, especially in suspected steatohepatitis. At present, this can only be determined by measuring the Non-alcoholic Fatty Liver Disease Activity Score (NAS). However, this process requires a costly, invasive liver biopsy, and expert reporting, and even then is subject to considerable inter-observer variation.

100081 Thus, the abovementioned measurements are only able to confirm the presence of liver fibrosis utilising non-invasive methods, after it has developed over time. Furthermore, in order to detect liver inflammation, prior to the onset of chronic fibrosis, a liver biopsy followed by a measurement of a NAS value is required, which is invasive and undesirable, not least because the interpretation of the NAS measurement and surrounding factors requires an experienced professional and can be somewhat subjective.

Summary of the Invention

100091 Accordingly, the invention seeks to mitigate, alleviate or eliminate one or more of the above mentioned disadvantages singly or in any combination.

100101 In a first aspect of the invention, a method for determining the presence or absence of inflammation in a subject's visceral organ is disclosed. The method comprises: obtaining a measurement of relaxometry data of the subject's visceral organ for extracellular fluid; obtaining an iron content for the visceral organ; if iron overload is indicated from the obtained iron content for the visceral organ, correcting the measurement of extracellular fluid for the subject's visceral organ; comparing the corrected measurement for extracellular fluid with a threshold value; and determining solely from the comparison, the presence or absence of inflammation in the subject's visceial organ.

100111 In this mannel, validation in the studies is that the coriected measurement of extracellular fluid for the subject's visceral organ (cTl) correlates extremely well with the previous use of NAS scores in determining inflammation, without the preiequisite of mandating a biopsy to obtain a NAS score.

100121 In an optional embodiment, the method may further complise measuring one or more characteristic relaxation time(s) in the visceral organ by medical imaging to obtain the measurement of relaxometry data.

10013] In an optional embodiment, the method may further comprise using at least one of Ti mapping to obtain the measurement of the subject's visceral organ for extracellular fluid and using T2* imaging to obtain the measurement for iron content.

10014] In an optional embodiment, the method may further comprise automated identifying a particular legion of inteiest in the visceral organ that is free of vessels before measurements are performed.

10015] In an optional embodiment, the method may further comprise using Ti mapping comprises using a modified Look Locker inversion (MOLLI) recovery pulse sequence or a shortened modified Look Locker inversion recovery (Sh-MOLLI) sequence.

10016] In an optional embodiment, the method may further comprise measuring iron content using one or more of: T2 mapping, T2* mapping, measuring one or more blood biomarkers, or MR spectroscopy.

10017] In an optional embodiment, the visceral organ may be one of: liver, pancreas or the kidney.

10018] In an optional embodiment, the subject may be a child.

10019] In an optional embodiment, inflammation in the subject's liver may be deemed present if the coFrected measuFement for extracellulaF fluid in a liver is at OF above SSOms.

10020] In a second aspect of the invention, a system for determining inflammation is disclosed.

The system complises: at least one computing device; at least one database; and at least one application executable in the computing device, wheiein the at least one application is operable to: receive MR data; obtain a measurement of relaxometry data of a subject's visceial organ foi extracellulai fluid; obtain an iron content for the visceral organ, determine if iron overload is indicated from the obtained iron content and if iron overload is indicated correct the measurement for extracellular fluid; compare the corrected measurement for extracellular fluid with a threshold value; and determine solely from the comparison the presence or absence of inflammation.

100211 In an optional embodiment, the at least one application may be operable to flag the received MR data if inflammation is deemed present.

100221 In an optional embodiment, the at least one application may be operable to access the at least one database to obtain medical information of a subject ielating to the flagged MR data.

100231 In an optional embodiment, the obtained medical information may comprise histoiical information on the subject complising one or more of: dietary infoimation, hereditary information, previous ailments, information on alcohol consumption, and presence of viral hepatitis infection.

100241 In an optional embodiment, the histoiical information on the subject may complise an indication of one or more of: non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), high hepatic lipid content (HLC), hepatic fibrosis, a disease associated with hepatic fibrosis, hepatitis, a condition associated with iron overload, autoimmune hepatitis, primaly biliary cirihosis, primaly sclerosing cholangitis, viial hepatitis, chionic hepatitis, drug-induced hepatitis, haemochiomatosis, thallassaemia, alcoholic hepatitis, alcoholic liver ciirhosis, portal hypertension, vascular liver disease, idiopathic hepatic fibrosis, saicoidosis, hepatic cysts, or hemangiomas, pancreatic disease, pancreatic tumouis, pancreatitis, glomerulonephritis.

100251 In an optional embodiment, the MR data may be provided by a medical imaging device comprising a magnetic iesonance (MR) scannel.

100261 According to a third aspect of the invention, a method for deteimining a presence or absence of inflammation in a child's visceral organ is disclosed. The method complises: obtaining a measurement of relaxometry data of the child's visceral organ for extracellular fluid; comparing the measurement for extracellular fluid with a threshold; and determining solely from the comparison, the presence or absence of inflammation in the child's visceral organ.

100271 According to a fourth aspect of the invention, a system for determining inflammation in a child is disclosed. The system complising: at least one computing device; at least one database; and at least one application executable in the computing device, wherein the at least one application is operable to: obtain a measurement of relaxometry data of the child's visceral organ for extracellulai fluid; compare the measuiement foi extracellular fluid with a thieshold; and determine solely from the compalison, the presence or absence of inflammation in the child's visceral organ.

Brief Description of the Drawings

100281 Further details, aspects and embodiments of the invention will be described, by way of example only, with reference to the drawings. In the drawings, like reference numbers are used to identify like or functionally similar elements. Elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale.

100291 FIG. 1 illustrates a two-compartment model. Please could you provide a redrawn diagram for this FIG, as we are not sure how you wish it to be changed.

100301 FIG. 2 illustrates flow chart for performing imaging assessment of a liver.

100311 FIG. 3 illustrates a block diagram of an apparatus for determining inflammation in a visceral organ.

100321 FIG. 4 illustrates a flow chart of an operation of aspects of FIG. 3.

100331 Skilled artisans will appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions and/or relative positioning of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of various embodiments of the present invention. Also, common but well-understood elements that are useful or necessary in a commercially feasible embodiment are often not depicted in order to facilitate a less obstructed view of these various embodiments of the present invention. It will further be appreciated that certain actions and/or steps may be described or depicted in a particular order of occurrence while those skilled in the art will understand that such specificity with respect to sequence is not actually required. It will also be understood that the terms and expressions used herein have the ordinary technical meaning as is accorded to such terms and expressions by persons skilled in the technical field as set forth above except where different specific meanings have otherwise been set forth herein.

Detailed Description

100341 The following description relates to detecting inflammation in visceral organs, which may be a flag to various diseases in the visceral organs, and for clarity and simplicity has been directed towards detecting inflammation in a liver. However, this is purely for ease of explanation and should not be seen as limiting the application. It is envisaged that aspects of the invention are applicable to any applicable visceral organs, which, in this application are limited to the pancreas, kidney and liver.

100351 In examples of the invention, references to multi parametric data relates to, for example, Ti mapping to obtain measurements for a subject's visceral organ for extracellular fluid, and, for example, T2 mapping or T2* mapping to obtain the measurement for iron content.

10036] In some examples, measurements relating to Ti and T2* may be regarded as bio-markers, and not necessarily exact replications of aspects of the visceral organs in question.

10037] It should be noted that there are many methods of determining iron content, with T2 and T2* are envisaged as being suitable, with the details described being specific examples of suitable methods. Therefore, we should note that by referring to T2* in detail, we are simply providing one of many known methods to determine iron content for a subject, and this should not be seen as limiting.

100381 The inventors of the present application have considered the aforementioned findings, and additionally and advantageously recognized through further investigation that there may be a need for non-invasive detection of flags to various liver diseases, for example liver fibrosis, cirrhosis, viral hepatitis and alcoholic and non-alcoholic forms of fatty liver disease, as well as other diseases in other visceral organs of a subject's body.

10039] Further, the inventors of the present application have additionally and advantageously recognized that there may be a need for non-invasive detection of flags to diseases in other visceral organs of a subject's body, for example the pancreas and kidney. Furthermore, the inventors of the present application have additionally and advantageously recognized that there may also be a need for non-invasive detection of flags to diseases in visceral organs of mammalian subjects, including in particular a human subject.

10040] visceral organThus, the inventors of the present application have recognized that in some examples, it may be advantageous to be able to identify flags to liver disease. For example, it may be advantageous to be able to flag a patient's liver that may have developed/be developing characteristics of liver disease, before it has fully developed.

10041] Furthermore the inventors of the present application have recognized that in some examples, it may be advantageous to be able to identify inflammation in a subject's visceral organ, which may be a flag to future diseases, for example fibrosis. For example, identifying inflammation in a subject's liver may be a flag to the onset of fibrosis. Thereafter, the inventors of this application have recognized that, in some examples, it may be advantageous to be able to identify inflammation in visceral organs, for example the kidney, liver and pancreas, in order to predict and potentially prevent the onset of future disease in these visceral organs.

10042] Medical imaging, for example magnetic resonance imaging (MRI), can be used to measure tissue characteristics that can, in combination, help determine the presence and severity of diseases in visceral organs such as liver disease, including in particular, liver fibrosis.

10043] MRI can be a powerful tool in the diagnosis of diseased visceral organs. In recent years the use of relaxometry, i.e. the measurement of the characteristic relaxation times in liver tissue, has become more widespread, due to the sensitivity of T2 and T2* to iron accumulation in the liver (St Pierre, et al. Non-invasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood. 2005; 105:855-61 and Wood, et al. MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood.

2005; 106:1460-5).

100441 Using MR relaxometry to measure one or more characteristic time (or times) in the liver tissue, for example, using Ti mapping of the liver, can reliably show differences in extracellular fluid (ECF) content. Higher Ti relaxation time(s) determined from Ti mapping of the liver for extracellular fluid measurement is an indication of fibrosis in the liver. A higher Ti relaxation time can indicate a higher degree of hepatic fibrosis or active hepatitis. For example, it has been observed by the inventors that liver Ti values from transverse liver Ti maps were elevated in patients with normal liver iron, and that these were correlated with the known Ishak score, thereby indicating a relationship between Ti values and the presence of extracellular fluid and liver fibrosis. High Ti values correlated with the presence of liver fibrosis. Thus, in liver tissue with normal iron content, Ti mapping of the organ can reliably show differences in extracellular fluid content and thereby allow quantification of the degree of liver fibrosis, for example by defining Ti ranges corresponding to normal, mild 0-2), moderate (3-4) or severe (5-6) fibrosis on the Ishak scale.

100451 Elevated liver iron, or iron overload, can alter the Ti relaxation time and its measurement. Mild iron overload is relatively common in the general population, and higher still in patients with suspected liver disease. The most important causes of iron overload are hereditary hemochromatosis (HHC), which is a highly prevalent genetic disease with autosomal dominant heritability, transfusion iron overload, and chronic liver disease. Iron overload tends to lower Ti relaxation time and, through its effects on T2 and T2*, also affect the precision of its measurement using a particular sequence and, thereby, cause the measured Ti relaxation time to under-report, for example, extracellular fluid measurement. Iron overload commonly causes liver cirrhosis if left untreated, so the two commonly co-exist.

100461 In accordance with the inventors detailed investigation and analysis, normal iron was considered to be in the range of ii -i.7micrograms per milligram of dry weight liver. Furthermore, in accordance with the inventors detailed investigation and analysis, iron correction was taken to begin at approximately 1.3. However, for the purposes of this description and claims, the definition and range of normal iron content is envisaged as encompassing any suitable range that is appropriate to the subject and measurements being taken, piimaiily as these ranges and values are highly debated and because normal people don't have dry weight ilon biopsies. Dry weight liver is livei that has had water removed from it and, as such, is variable.

100471 Measuiing iron content allows correcting for under-ieporting by Ti values when ilon overload is present. Foi example, in livei tissue with excess iron content, T2* mapping can deteimine the degree of ilon overload. Iron oveiload of the liver is toxic and causes fibiosis, and causes a reduced T2* value. The Ti value can be coirected in patients with reduced T2* to still enable assessment for fibiosis.

10048] It is known that other methods can be used to measure iron content, besides T2* mapping. Suitable methods also include T2 mapping (see St Pierre et al., Non-invasive measurement and imaging of liver iron concentiations using proton magnetic resonance. Blood. 2005; 105:855-61, which is incorporated by refeience as if fully set forth herein), as well as measuring one or more blood biomaFkers, such as ferritin, transferrin, transferFin saturation, hepcidin, soluble tFansferrin FeceptoF (sTfR) index (sTfR / log feriitin). MR spectroscopy can also be used to measure iron content and, thus, ilon overload. Foi example, the width of the 1H MRS spectra can indicate higher than normal iron loads.

Accuiate quantification of the impact of iron on the measurement of Ti in the liver can provide for rapid non-invasive diagnosis of the type and/or severity of liver fibrosis regardless of livei ilon content. To enable a more quantitative approach to the impact of iron on the measurement of Ti in the liver, we provide a novel multiple compartment biophysical model of the microscopic environment of the watei in the liver.

10050] In some examples of the invention, it has been noted that iron overload may also occur in the pancreas. Iron correction is known to be needed in a significant number of liver patients (for example 20-40% of discovered cases). With the pancleas, Haemosiderosis, 01 bronze diabetes', is characterized by (i) Liver iron, leading to disease, (ii) Diabetes, which MAY be due to pancreatic ilon (iii) Skin iron, leading to very rapid tanning (hence bronze). It is very difficult to deteimine the normal range for pancieatic iron as the organ self-digests. However, in accordance with examples of the invention, the inventors have determined that Ti mapping alone show pancreatic disease, which in some examples may be optimized further by iron correction.

10051] The presence of paramagnetic iron-containing compounds in the body causes local, micioscopic magnetic field variations. These field inhomogeneities not only cause more rapid decoherence of magnetization in the transverse plane, but also increase the spectral weight at the Larmor frequency, thus reducing the Ti relaxation time. Measured Ti is also affected by the partial volume of different tissues within an imaging voxel, for example, a high proportion of free fluid in a voxel will lead to a longer Ti. These competing effects can limit the use of Ti-mapping alone, in order to quantify either extracellular fluid (ECF) or iron.

100521 In an example of a two-compartment model, shown in Fig 1, Please could you provide a redrawn FIG. 1, as we are not sure what elements you wish to change? compartments correspond to intra-and extra-cellular fluid, the proportions of which can be varied. The quantity of iron in the cells can also be varied, corresponding to different hepatic iron contents. Other compartments could also be included, for example fat. The magnetic resonance behaviour of the water in these compartments is modelled using knowledge of the field strength of the MR relaxometry, and exact details of a Ti-mapping pulse sequence, which could be, for example, any of inversion recovery, saturation recovery or variable flip angle Ti-mapping method. The model can be, for example, a full Bloch simulation. The output of this model is dependent on the measured Ti on the different variables, for example extracellular fluid fraction and iron in the case of one two-compartment model. If the iron has been independently measured, for example using T2* mapping, it is then possible to assess the extracellular fluid fraction given the hepatic iron content and measured Ti, and hence correct the measured Ti for an individual patient, as if the patient's iron levels were normal.

10053] One example embodiment of the present invention for performing magnetic resonance (MR) diagnosis of a liver is illustrated in FIG. 2, which depicts a flowchart 100 for performing imaging assessment of a liver taking into effect the presence of iron in the liver on MR relaxometry measurements, for example, Ti measurements.

10054] MR relaxometry data iiO is obtained of a subject's liver. In some examples, the relaxometry data may be for extracellular fluid in the liver tissues. A subject may be a mammalian subject, including in particular examples, a human subject. The relaxometry data may include the details of a Ti mapping sequence used i20. Included in this example of MR relaxometry data is a measured T2* iSO and measured Ti i40, in the form of maps or values determined from larger regions of interest in the tissue.

100551 In some examples of the invention a particular region of interest may be identified in the visceral organ that is free of vessels before measurements are performed.

100561 the retUInec ptisurenerIs na be automated, 100571 In some examples, hepatic iron content can be determined 140 from the measured T2*.

A non-limiting example of how hepatic iron content (HIC) can be determined is provided below.

Alternatively, in some examples, T2 mapping may be used. In some examples, another method may be to measure dry weight iron from a separate liver biopsy, where a normal liver typically has less than 3 mmols per 1 OOg of liver tissue.

100581 In some examples, a measurement 150 of the subject's liver for extracellular fluid (ECF) for a given Ti measurement sequence may be simulated. For example, a multiple compartment biophysical model of the microscopic environment of water in the liver may be employed. At least two compartments can be adopted, one corresponding to intra-cellular fluid and one to extra-cellular fluid, the proportions of which can be varied. Additionally, the quantity of iron in the cells can also be varied in the simulation. The magnetic resonance behaviour of the water in the compartments can then be modelled using, for example, the relaxation characteristics of water in the different compartments, equations such as Bloch equations, knowledge of the pulse sequence employed to obtain the relaxometry data 110, the method used to calculate the Ti map, and the biophysical model adopted, to simulate a Ti measurement. The impact of the variable fraction of extra-cellular fluid and iron content on the relaxation characteristics of water in the different compartments may be determined from published literature and input into the system or method. This allows a determination of the impact of both the variable fraction of extra-cellular fluid and iron content in the liver on the measured Ti relaxation time.

[0059] The simulated measurements of relaxation time for various proportions or fractions of extracellular fluid and hepatic iron content can then be stored for look up 170 and comparison to actual relaxation time measurements obtained. For example, the measured Ti i40 can be combined with the measured hepatic iron content 160 to find the extracellular fluid fraction used in the simulation which produces that measured Ti in the presence of that iron content. This extracellular fluid fraction can be compared to the normal extracellular fluid fraction, for example 25%, to determine the presence of inflammation/fibrosis in the liver. In addition, this value of extracellular fluid can be used, for example using the simulated Ti measurement 150, to determine the Ti that would have been measured if the patient's hepatic iron content had been normal 180, to produce an "iron-corrected Ti".

100601 In some examples, the effect of applying the above examples in-vivo with the resulting MRI measurements of disease being correlated with results of biopsy in homogeneous liver disease were investigated. In this example, Ti measurements used the Sh-MOLLI (Piechnik et al., Shortened Modified Look-Locker Inversion recovery (Sh-MOLLI) for clinical myocardial Ti-mapping at 1.5 and 3 T within a 9 heartbeat breathhold. J Cardiovasc Magn Reson. 2010 12:69) Ti-mapping method at 3T, on a Siemens Trio. However, it is envisaged that in other examples the invention is equally applicable to other Ti-mapping techniques, for example other inversion recovery, saturation recovery or variable flip angle methods. It is also applicable to other field strengths and scanner makes and models. -10-

10061] In some examples, the investigation split the liver into two components, liver parenchyma (hepatocytes with varying levels of iron) and extracellular fluid (serum albumin), assumed to be mixed on a sub-voxel level. This is shown schematically in FIG. 1.

10062] Relaxation times were based on literature values as follows.

10063] Liver Parenchyma: 10064] At 1.5T, transverse relaxivities (in s) of liver tissue as a function of hepatic iron content (HIC, measured in mg Fe/g dry weight) are given by St Pierre et al., Non-invasive measurement and imaging of liver iron concentrations using proton magnetic resonance. Blood. 2005; 105:855-61 and Wood et al., MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood. 2005; 106:1460-5: 10065] R2(1.5T) = 6.88+26.O6x(HIC)°701-0.438x(HIC) 1.402, 100661 R2*(i.5T) = (HIC-0.202)/0.0254.

10067] To convert these to relaxivities of liver at 3T (Ghugre et al. Multi-field behaviour of Relaxivity in an Iron-rich environment. Proc Intl Soc Mag Reson Med. 2008; 16:644): 10068] R2(3T) = R2(i.ST)xl.47-2.2 10069] R2*(3T) = 2xR2(i.ST)-35.

100701 The dependence of longitudinal relaxivity of liver tissue on HIC at 1.5T is given by Ghugre et al., Mechanisms of tissue-iron relaxivity: nuclear magnetic resonance studies of human liver biopsy specimens. Magn Reson Med. 2005; 54:1185-93, as: 10071] Ri = Ri0 + O.O29XHlCwet weight Ri0 + 0.029x4.1xHIC, 10072] here: the scaling factor between dry weight and wet weight HIC is given in Ghugre et al., Mechanisms of tissue-iron relaxivity: nuclear magnetic resonance studies of human liver biopsy specimens. Magn Reson Med. 2005; 54:1185-93.

100731 Ri0 was the only free parameter in the model, and was set at 0.6361s, such that for normal ECF fraction (25%) and normal HIC (1.2 mg/g) the modelled measured Ti was Si9ms, close to the normal value for hepatic Ti at ST (as measured on 50 healthy volunteers using the same Sh-MOLLI protocol). The dependence of Ri on iron concentration was assumed to be the same at 1.5 and ST. This was based on the low field-sensitivity of ferritin Ri (Vymazal et al., Ti and T2 of ferritin at different field strengths: Effect on MRI. Magn Reson Med. 1992; 27:367-74), reported limited effect of haemosiderin on Ti (Versluis et al., Detection of cerebral microbleeds: Physical principles, technical aspects and new -ii -developments. In: Cerebral Microbleeds ed. Werring DJ. Cambridge University Press. 2011; ppl 3-21) and low field-dependence of Ti measurements in brain iron-overload (Vymazal et al., The relation between brain iron and NMR relaxation times: An in vitro study. Magn Reson Med. 1996; 35:56-61) (caused by a mixture offerritin and haemosiderin).Extracellular Fluid: 100741 The Ri for plasma at 3T of 0.44/s was used. See, Rohrer et al., Comparison of magnetic properties of MRI contrast media solutions at different magnetic field strengths. Invest Radiol. 2005; 40:715-24.

10075] The same transverse relaxation times were used for extracellular fluid (ECF) as for liver parenchyma. Water molecules in the cellular environment traverse a distance of several tens of microns even over a typical T2. Koenig et al., Relaxometry of tissue. NMR Encycl. 1996; 6:4108-20. For a normal hepatic iron concentration of 1.2 mg/g2 iron is typically distributed on length scales of 2 pm.

Ghugre et al., Relaxivity-iron calibration in hepatic iron overload: Probing underlying biophysical mechanisms using a Monte Carlo model. Magn Reson Med. 2011; 65:837-47. Thus the water in ECF will tend to sample the non-local field inhomogeneities due to iron accumulations (Fig. 5) and the T2 and T2* of these protons will be correspondingly reduced.

[0076] Simulations: [0077] The relaxation times from above were used in full Bloch simulations of the Sh-MOLLI (Piechnik et al., Shortened Modified Look-Locker Inversion recovery (Sh-MOLLI) for clinical myocardial Ti-mapping at 1.5 and 3 T within a 9 heartbeat breathhold. J Cardiovasc Magn Reson. 2010 12:69) sequence, implemented in Matlab. This sequence is used as an example, but the method can be generally applied to any Ti-mapping sequence. The two components were simulated separately, for hepatic iron concentrations ranging from 1-5 mg/g. The complex signal amplitudes were combined with the fraction of ECF ranging from 0 to 100%. The magnitude and phase were calculated and then fitted using the Sh-MOLLI reconstruction algorithm (Piechnik et al., Shortened Modified Look-Locker Inversion recovery (Sh-MOLLI) for clinical myocardial Ti-mapping at 1.5 and 3 Twithin a 9 heartbeat breathhold. J Cardiovasc Magn Reson. 2010 12:69), implemented in IDL. This produced a predicted measured Ti value for each combination of iron and ECF concentrations. There was some variation in the validation data in the precise acquisition parameters (particularly the number of phase encode lines) used, so parameters from a number of patient scans were simulated and then an average taken.

[0078] MRI data acquisition: [0079] Using a Siemens Verio ST MR scanner, Ti maps were acquired using an ECG-gated Sh-MOLLI sequence on a transverse slice through the liver, pancreas and/or kidney using the following acquisition parameters: TR 2.i4ms, TE i.O7ms, flip angle 35°, matrix size i92x144t, field-of-view 36Ommx27Ommt, slice thickness 6mm and a GRAPPA acceleration factor of 2. The dagger (t) denotes variable acquisition parameters. T2* maps for the same slice were calculated from an ECG-gated multi-echo RE-spoiled gradient-echo sequence the following parameters: TR 26.Sms, TE = 2.46, 7.38, 12.30, 17.22 and 22.i4ms (water and fat in phase), flip angle 20, matrix size 192x144t, field-of-view 36Ommx27Ommt, slice thickness 3mm, and a GRAPPA acceleration factor of 2. Again, the dagger (t) denotes variable acquisition parameters. The T2* maps were calculated using a linear fit to the log-transformed reconstructed pixel values. In some examples of the invention, it should be noted that the transverse slice through the liver, pancreas and/or kidney may not all be in the same anatomical slice.

100801 In some examples, the transverse slice may be, say, around 5-10mm in size.

100811 In some other examples, the pancreas and liver may be in the same anatomical slice.

100821 Correcting Ti: 10083] Two regions of interest (ROls), matched as closely as possible on the two maps and avoiding large vessels, were drawn on the Ti and T2* map for each patient. One ROI was placed laterally (aiming to match the approximate location of transcutaneous liver biopsy) and one medially. The mean Ti and T2* over each ROI was calculated. For this analysis, the two measurements of each relaxation time were averaged before being used to correct the Ti.

10084] The matrix of predicted measured Ti was used as a look-up table, as follows. For each patient the hepatic iron content was calculated using the relation (Wood et al., MRI R2 and R2* mapping accurately estimates hepatic iron concentration in transfusion-dependent thalassemia and sickle cell disease patients. Blood. 2005; i061460-5 and Ghugre etal., Multi-field behaviour of Relaxivity in an Iron-rich environment. Proc Intl Soc Mag Reson Med. 2008; i6:644): 10085] HIC = (0.202+0.0254*(R2*+35)/2).

10086] The measured Ti was then compared to the predicted measured Ti for that measured iron content. This Ti was associated with a particular ECF fraction, which could be used as a proxy for fibrosis or used to calculate the Ti which we predict would be measured if the patient had normal liver iron (i.2mg/g), known as the corrected Ti'. The process is shown schematically in FIG. 5.

10087] It should be emphasized that the above-described embodiments are merely examples of possible implementations. A similar process could be used for other Ti-mapping methods and different MR field strengths, for example, i.5 Tesla. Many variations and modifications may be made to the above-described embodiments without departing from the principles of the present disclosure. All such modifications and variations are intended to be included herein within the scope of this disclosure and protected by the following claims.

-i3 - 100881 Up to this point in the application, it has been determined that the correction of Ti, from hereon in deemed cTi', can improve the rank correlation between Ti and Ishak score, which is a biopsy measure of liver fibrosis. Therefore, utilising cTi can be shown to confirm the presence of liver disease in a subject, without the need for an invasive liver biopsy.

100891 Further, it has been realized that utilising cTi to assess the degree of fibrosis, combined with an accurate quantification of HLC, can allow for further confirmation of diseases such as various forms of fatty liver disease.

100901 Notably, after significant investigation and in accordance with example embodiments of the invention, it can be shown that cTi (in some examples in isolation) may be additionally and advantageously utilized to detect inflammation in visceral organs of a subject, prior to the onset of scarring, wherein scarring could be fibrosis/cirrhosis, for example.

100911 Further, in some example embodiments of the invention, it has been shown that cTi values can correlate well with corresponding NAS scores of biopsy findings. Therefore, in some examples, a threshold cTl value can be determined from NAS scores, potentially allowing a calculated cTl value to be utilised to determine inflammation, without the need for invasive measurements.

10092] For example, referring to FIG. 3, two diagrams illustrate how cTl scores can relate to hepatocyte ballooning 300 and NAS scores 350 in liver tissue.

100931 Hepatocyte ballooning is part of the NAFLD activity score NAS, which is a scoring system designed by the Non-alcoholic Steatohepatitis (NASH) Clinical Research Network (CRN) to encompass the spectrum of NAFLD and evaluate historical changes, wherein steatosis ranges from 0-3, lobular inflammation ranges from 0-3, and hepatocyte ballooning ranges from 0-2.

100941 Referring to 350, a number of subjects were measured utilising aspects of the invention relating to ECF and iron content, and compared to respective biopsy findings. Based on the NAS scoring system, the biopsy findings were scored according to NAS, and grouped into the following: No inflammation' 352 (NAS score of 0-2') , Indeterminate inflammation' 353 (NAS score of 3-4') and Definite Inflammation' (NAS score greater than 4') 354.

100951 It was found that when the determined cTl values were compared to the biopsy findings, that cTi was able to distinguish between biopsy results with no inflammation 352 and biopsy results with definite inflammation 354.

10096] Therefore, it was found that there was a clear correlation between cTi and NAS scores.

10097] As a result, for samples relating to the liver, a cTl threshold value 360 of around 850ms could be utilised to determine patients that may have inflamed livers, without having to perform invasive testing. Furthermore, it has been determined that a NAS score of between, say, 820-850ms may be regarded as indeterminate' and a NAS score of less than S2Oms would be determined as no inflammation.

100981 Therefore, in some examples, utilising a value of cTl of around S5Oms may detect inflammation in a liver, which may be due to NASH rather than NAFLD. Therefore, in some examples, cTl values may be able to distinguish between patients with NASH and NAFLD.

100991 Further, in some examples, cTl values of around 850ms may detect inflammation in the liver, which may be a precursor to fibrosis, for example.

1001001 In some examples, similar measurements to those performed above may have been performed for the pancreas and kidneys.

1001011 Thus, in some examples, a value of less than 850ms may suggest inflammation is unlikely in the pancreas, and a value of greater that 950ms may suggest inflammation is likely in the pancreas.

100102] In some examples, a correction factor of 2% may be applied to measurements for the liver and the pancreas. In some examples, a correction factor of 5% may be applied to measurements for the kidneys.

1001031 Thus, in some other examples, a value of less than l400ms may suggest inflammation is unlikely in the kidneys, and a value of greater than 1650ms may suggest that inflammation is likely in the kidneys.

1001041 Although examples of the invention have been described with respect to a threshold value of around 850ms identifying inflammation in the liver, with a threshold value of around 820-850ms being regarded as indeterminate' (both plus or minus a suitable margin of say 2% dependent upon many factors, such as equipment being used, measurement tolerances, etc.), it is noteworthy that the threshold values may change with respect to different magnet manufacturers and field strengths being employed.

Notwithstanding the above, it is reiterated that the principle that disease (as compared to pure inflammation) provides a higher measurement.

1001051 Hepatocyte ballooning is a key feature of liver cell inflammation, and referring to 300, it may be shown that cTl scores can determine hepatocyte ballooning.

1001061 For example, liver biopsy results for hepatocyte ballooning were compared with calculated cTl values for a range of subjects. Healthy subjects 302 had no evidence of liver disease on their biopsy slides, absent 304 patients had no evidence of hepatocyte ballooning on biopsy slides, -15-however the cTl score suggests the onset of inflammation, and present 306 patients were confirmed as having hepatocyte ballooning visible on their biopsy slides.

1001071 Therefore, it can be shown that calculated cTl values can be utilised to detect hepatocyte ballooning in patients, without requiring invasive measurements. As hepatocyte ballooning is a key feature of liver cell inflammation, it can be shown that cTl can be utilised to show inflammation in subjects.

1001081 Therefore, in some examples, comparing cTl values with a table of NAS scores, may allow inflammation to be determined in patients, without the need for invasive measurement techniques, wherein inflammation may be a pre cursor to later diseases such as fibrosis and cirrhosis, for example.

1001091 Using the techniques herein before described, it was recognised that children that had taken part in the study did not have liver fibrosis, as they were too young for fibrosis to have developed.

However, studies carried out by the inventors of this application advantageously discovered that similar cTl results could be determined in children up to 18 years old, where the results had previously only been determined in adults who had been diagnosed with liver fibrosis, for example due to alcohol intake.

Therefore, in some examples, cTl results may be advantageously utilised to deteimine inflammation in children, priorto the onset of overt liver failure and metabolic syndrome.

1001101 Furthermore, in some examples, the inventors performed studies on children, where the studies did not include a determination of ilon overload. Most children with disease have fatty liver, and do not have much iron. In these studies, the inventors deteimined that, for a child, an un-corrected Ti measurement may be used to identify inflammation, even when the child may not necessarily have elevated iron levels.

1001111 Thus, in this context, a system and method for determining a presence or absence of inflammation in a child's visceral organ has been illustrated. The method comprises: obtaining a measurement of relaxometry data of the child's visceral organ for extracellular fluid; comparing the measurement for extracellular fluid with a threshold; and determining solely from the comparison, , a presence or absence of inflammation in the child's visceral organ.

1001121 Referring to FIG. 4, a study was undertaken on a number of obese and lean boys, wherein their HLC scores were compared to Ti maps. In this example, the NAS score determined patients with fatty liver disease (NASc5) from those with active steatohepatitis (NAS»=5). From this study, it was found that Ti maps appear to quantify ECF in obese boys and lean boys, wherein a high ECF suggests high NAS.

1001131 From this study, it was found that Ti maps could distinguish between boys with simple fatty liver disease and those with NASH (circled in black).

100114] Multiparametric MR can quantify hepatic steatosis, which increases with obesity, in adults and children. Importantly, some obese children have evidence of liver disease as severe as adults with biopsy-proven severe steatohepatitis, in the absence of diabetes. This suggests that NASH occurs early in the development of the Metabolic Syndrome.

100115] Measurement of extracellular fluid content with cTl, validated in adults, can distinguish children with NASH from children with simple steatosis.

100116] Multiparametric MR studies are tradable in children with suspected liver disease.

Analysable quantitative data were obtained from all children and adults. In the absence of validated tools for the paediatric population, this is a safe, attractive method for further clinical development.

1001171 Therefore, the inventors of this application considered these findings and advantageously determined that following a calculation of cTl, it is possible to detect inflammation in visceral organs, not just inflammation in diseased organs due to, for example, scarring or viral contributors, solely from the calculated cTl value.

100118] Further, the inventors of this application considered these finding and advantageously determined that following a calculation of cTl, it is possible to distinguish between subjects that have NASH and NAFLD. For example, subjeds with NASH had higher cTl that those with NAFLD, suggesting that subjects with steatohepatitis have greater ECF than patients with simple steatosis.

100119] Thus, in some examples, it was determined that cTl values could be utilised solely to detect inflammation in both adults and children. As a result, patients with relatively high cTl levels could be flagged as likely candidates to have NASH, or to later develop fibrosis, for example.

100120] Referring to FIG. 5, there is illustrated a typical computing system 500 that may be employed to implement software related aspects of the invention, for example algorithm 510 in order to determine an inflammation score in a visceral organ for a subject, based on obtained MR data. Example computing system 500 comprises, inter alia, a processor 502, memory 504, a number of input/output interfaces 506, a display 508, a communications interface 506 and algorithm 510. Further, the computing system 500 may be operably coupled to a number of databases, which may be internal databases 512 or external databases 514, and which may be operable to store medical information relating to patients/subjects.

100121] The processor 502 may initially receive magnetic resonance (MR) data, and confirm that it is in a correct format, for example in a DICOM (digital imaging and communications in medicine) format.

In some other examples, the MR data may have been provided by a medical imaging device, for example -17-an MRI scanner 501, which may have provided the MR data directly to the processor 502. In some other examples, the MR data may have been stored in memory 504 or one in one of databases 512, 514.

1001221 In some examples, the MR data may be data corresponding to a visceral organ, for

example a liver.

1001231 Subsequently, the processor 502 may be operable to determine whether a Ti map of a subject's visceral organ, for example the liver, is present. In some examples, the Ti map of the subject's visceral organ may be analysed by the processor 502 and calculations/measurements performed, e.g. comparing to one or more threshold levels, to confirm that it is of sufficient quality.

1001241 Subsequently, some or all of the MR data may then be transmitted to the algorithm 510, or in some other examples, the algorithm 510 may be loaded into the processor 502.

1001251 A region of interest may then be input by an operator, for example via communications interface 506 of the computing system 500, or the computing system 500 may determine a region of interest based on received MR data.

1001261 The algorithm 510 may then be operable to determine a Ti value of the region of interest identified. In some examples, the region of interest may be liver tissue, which may be free of major blood and biliary vessels. In some other examples, the region of interest may be pancreas tissue or kidney tissue, which may also be free of vessels.

1001271 Subsequently, the processor 502 may obtain a value of iron content for the region of interest. In some examples, the value of iron may be obtained from a previous measurement, which may have been stored in databases 512, 514. In some other examples, the algorithm 510 may be operable to determine real-time iron content based on received MR data.

100128] In some examples, a value of iron content for the region of interest may be obtained/determined from spectroscopy, T2 mapping or T2* mapping.

1001291 The algorithm 510 may then be operable to determine a corrected Ti value of the region of interest based on MR data and determined iron content, which may be based on previously discussed methods related to FIG. 2. In some examples, if the algorithm 510 determines that the iron content for the region of interest is within normal levels, the algorithm may not output a corrected Ti value.

1001301 In some other examples, if the algorithm 510 determines that the iron content for the region of interest is not within normal levels, e.g. it is lower or higher than expected normal levels, the algorithm may output a corrected Ti value.

-is - 1001311 The algorithm 510 may then be operable to output a determined cTl value to the processor 502. The processor may then be operable to output the determined cTl value via display 508, in order to notify the operator of the determined cTl value.

100132] In some other examples, the processor 502 may be operable to receive the determined cTl value, and subsequently compare the determined cTl value to a look up table', which may relate to NAS values, stored, for example, in memory 504 or databases 512, 514.

100133] In some examples, the look up table' may comprise a number of threshold values for various visceral organs, wherein a calculated cTl value is compared with one or more threshold values to determine inflammation. In some examples, the look up table may resemble an example look up table as illustrated in Table 2 below. In some other examples, the look up table may vary depending on the type of visceral organ being measured.

100134] In this example, the magnetic resonance system that was used to take measurements comprised a 3 Tesla Siemens scanner. However, it is envisaged that similar 1.5 Tesla systems, for example, Toshiba, GE and Phillips may be utilised to validate or characterise the results.

100135] In some examples relating to liver and pancreas data, a 2% margin has been added to take into account any measurement errors and tolerances. Referring to kidney data, a 5% margin has been added to take into account any measurement errors and tolerances.

T1/cTl value for liver Determination <820ms Inflammation unlikely >8SOms Inflammation likely T1/cTl value for pancreas c8SOms Inflammation unlikely >950ms Inflammation likely T1/cTl value for kidney <l400ms Inflammation unlikely >1650ms Inflammation likely

Table. 2 -19-

1001361 It has been found from various studies by the inventors of this application that a Ti value around 850ms or above, for liver, appears to represent a reasonably good indicator that inflammation is prese nt.

1001371 Alternative ways of interpreting the Ti value in the context of a patient's iron load are possible. These include, for example: 100138] A correction factor based on blood biomarkers, such as ferritin, transferrin, transferrin saturation, hepcidin, soluble transferrin receptor (sTfR) index (sTfR / log ferritin).

100139] A correction factor based on patient history of transfusion, age, disease and genotype.

1001401 Directly correcting the measured Ti value using an empirical relation such as Ti corrected = Ti measured + 420 -(20 x T2* measured).

1001411 Using a two-compartment model for the liver, consisting of liver parenchyma and a variable proportion of extracellular fluid, with higher fractions of ECE corresponding to a more fibrotic liver.

The dependence of Ri, R2 and R2* of liver parenchyma on iron concentration at 3T was based on data from previous studies. The Ri value for ECF was 0.44/s. R2 and R2* values for ECF were the same as those for the liver parenchyma, based on the large distance (relative to the length scale of the hepatic iron distribution) traversed by water molecules during T2 relaxation. Bloch simulations were used to calculate the combined signal from the two compartments during the ShMOLLI readouts and then the measured Ti calculated using the ShMOLLI algorithm. A look-up table was used to correct the measured Ti for a given HIC to the Ti,which would have been measured in the case of normal HIC.

1001421 Using the width of the iH MRS spectra to determine the effect of iron on the Ti signal -normal liver with normal iron load yields narrow spectral peaks, whereas higher iron loads have broader spectral peaks 1001431 In some examples, the processor 502 may compare the value of Ti or cTi determined from the algorithm 5i0, or obtained from memory 504 or databases 5i2,3i4, and determine an MR inflammation score therefrom.

1001441 In some examples, if the processor 502 determines that the MR inflammation score is above SSOms, the processor 502 may associate or flag' the processed MR data to the operator of computer system 500. In some other examples, the processor 502 may be operable to highlight or generate a notification based on the processed MR data, and associated this with the subject of the MR data.

1001451 Therefore, in some examples, of the invention, the computer system 500 may be operable to determine inflammation based on MR data of a subject's visceral organ, and subsequently -20 -flag' inflammation of the subject's visceral organ to allow a medical practitioner to further investigate particular reasons for the inflammation.

1001461 In some other examples, the processor may be operable to extract personal information of a subject with a flagged MR inflammation score from databases 512, 514, and submit this information with a flagged MR inflammation score to the operator of the computer system 500, orto memory 504, for further investigation. In some examples, the personal information may be related to hereditary information, dietary information, or information from a general practitioner, for example.

1001471 Therefore, in some examples, the processor 502 may be operable to provide additional information with a flagged MR inflammation score to allow a medical practitioner to diagnose a particular type of disease before it has developed. For example, a flagged inflammation score in a subject, who is additionally identified as a child, may allow a medical practitioner to diagnose the start of a form of steatohepatits. In another example, a flagged inflammation score in a subject, who additionally is identified as an alcoholic adult, may allow a medical practitioner to diagnose the start of a form of alcohol [elated fatty liver disease.

1001481 Therefore, by providing a computer system that can determine inflammation in a subject, before the subject has necessarily developed a diseased visceral organ, may allow the prevention or treatment of the disease, which may otherwise go untreated until symptoms of the disease, such as scarring, can be identified.

1001491 In some examples, the computer system 500 illustrated in FIG. 5, may be embodied, for example, as a magnetic resonance apparatus, which may include a processing module or logic for performing conditional data processing, and may be implemented either oft-line or directly in a magnetic resonance apparatus. For such embodiments, the computer system 500 may be implemented as a multi-channel, multi-coil system with advanced parallel image processing capabilities, and direct implementation makes it possible to generate immediate Ti maps available for viewing immediately after image acquisition, thereby allowing re-acquisition on-the-spot if necessary. Examples of apparatus in which the Ti mapping sequences, such as the MOLLI and Sh-MOLLI sequences, may be implemented are described in U.S. Patent Nos. 5,993,398 and No. 6,245,027 and U.S. Patent Application Publication No. 2011/0181285, which are incorporated by reference as if fully set forth herein.

1001501 In some examples, information may be stored in other elements, for example, a media drive and/or a removable storage interface. The media drive may include a drive or other mechanism to support fixed or removable storage media, such as a hard disk drive, a floppy disk drive, a magnetic tape drive, an optical disk drive, a compact disc (CD) or digital video drive (DVD) read or write drive (R or R, -21 -or other removable or fixed media drive. As these examples illustrate, the storage media may include a computer-readable storage medium having particular computer software or data stored therein.

1001511 Further, in some examples, information storage system may be implemented within a type of cloud storage'. For example, information may be stored in virtualised pools of storage, which may be hosted by a third party, wherein information can be stored as files or data objects.

1001521 In one example, a tangible non-transitory computer program product comprises executable program code operable for determining an MR inflammation score for a subject, based on obtained MR data, in accordance with some aspects of the invention.

1001531 In some examples of the invention, as discussed above, it may not be necessary to perform a corrected Ti operation. For example, from studies and significant analysis performed by the inventors of this application, it was found that children may not necessarily have elevated iron levels.

Therefore, in some examples, it may be possible to detect inflammation in children based on an un-corrected Ti value.

1001541 In some other examples, however, where children may have iron loading conditions, for example thalassaemia, it may be necessary to determine a corrected Ti value.

1001551 Therefore, in some examples and based on the above, it may be advantageous to determine a general health of a subject, for example a child, before implementing a correction of a determined Ti value.

1001561 In some other examples, by determining that children, as well as adults, are prone to inflammation in visceral organs, in particular the liver, it has been shown that inflammation, a flag to various diseases, can be utilised as a measure to flag the potential risk of these diseases to, for example, a medical practitioner.

1001571 Further, in some examples, the inventors of the application have additionally and advantageously realised from further studies that children may be too young to develop fibrosis.

Therefore, a high MR inflammation level may predict the start of other forms of disease, for example viral hepatitis or fatty liver disease.

1001581 In some examples, a flagged MR inflammation score, coupled with a relevant subject's medical history, may allow a medical practitioner, for example, to predict whether the detected inflammation is a flag to a visceral disease, for example fibrosis, cirrhosis, viral hepatitis (A-E), alcohol related diseases, non-alcoholic fatty liver disease (NAFLD) or Non-alcoholic steatohepatitis (NASH), which obviously depend on the particular visceral organ in question.

-22 - 1001601 Referring to FIG. 6, a flow chart 600 illustrating aspects of the invention is shown, for example an operation of apparatus 500 from FIG. 5.

1001611 Initially, at 602, the process commences and, at 604, MR data may be received, which may be subsequently analysed to confirm whether or not it is in a correct format, for example a DICOM format. The MR data may have been provided directly from a medical imaging device, for example an MRI scanner, or from a memory, which may have stored previously generated MR data. Therefore, in some examples, analysis of MR data may be performed in real time.

1001621 Subsequently, at 606, a determination is made as to whether a Ti map is present in the received MR data, and whether (or not) it is of sufficient quality. If it is determined that either the Ti map is not present, or that it is not of sufficient quality, a notification 608 is transmitted to re-provide the MR data. If it is determined that the Ti map is present and of sufficient quality, the process transitions to 6i0, wherein a region of interest may be received and analysed. If it is determined at 610 that a region of interest has been identified or a region of interest has been received, the procedure transitions to 612, otherwise the procedure waits for a region of interest to be identified.

1001631 At 612, the process may determine whether (or not) the region of interest is free from vessels, for example major blood and biliary vessels. If it is determined that the region of interest is not free from vessels, the process may flag this and require a further region of interest to be identified at 614, otherwise the process determines a Ti value for the MR data in the region of interest, prior to the process transitioning to 6i6, wherein a value of iron content for the region of interest is obtained.

1001641 In some examples, the value of iron content may be determined in realtime, or obtained from a previously determined value.

1001651 If it is determined at 6i8 that the iron content is within normal levels, the process may transition to 620, otherwise the process may calculate a corrected, cTl, value at 622 as though it had determined normal iron levels and output to 620.

1001661 At 620, the process may then compare the determined Ti value from 6i8 or cTi value from 622 with values, e.g. one or more threshold values, from a look up table comprising associated inflammation values, and output the associated inflammation value(s) to a display.

1001671 In some examples, if it is determined at 624 that the Ti or cTi value is above a threshold, say of 850ms, the procedure may determine, solely from the Ti or cT2 value, that inflammation is present in the sampled MR data. As a result, in some examples, the procedure may flag 626 this result and store it in a memory for further investigation. -23 -

100168] Further, in some examples, the procedure may obtain relevant medical information relating to the subject's MR data, to allow a medical practitioner to potentially diagnose the reason for detected inflammation.

100169] In some examples, detected inflammation may be a precursor to fibrosis or other diseases, which have not yet developed.

100170] Therefore, in some examples, the procedure illustrated in FIG. 6, may be operable to determine inflammation based on a subject's MR data, and, therefore, predict a possibility of disease if the detected inflammation is not treated or investigated further.

100171] It should be noted that various features disclosed in examples of the invention may be combined together, even if they are taken from different, discrete, examples of the invention.

100172] It will be further appreciated that, for clarity purposes, the described embodiments of the invention with reference to different functional units and processors may be modified or re-configured with any suitable distribution of functionality between different functional units or processors is possible, without detracting from the invention. For example, functionality illustrated to be performed by separate processors may be performed by the same processor. Hence, references to specific functional units are only to be seen as references to suitable means for providing the described functionality, rather than indicative of a strict logical or physical structure or organization.

100173] Aspects of the invention may be implemented in any suitable form including hardware, software, firmware or any combination of these. The invention may optionally be implemented, at least partly, as computer software running on one or more data processors and/or digital signal processors. For example, the software may reside on non-transitory computer program product comprising executable program code to allow an MR inflammation score for a subject to be determined, based on obtained MR data.

100174] Thus, the elements and components of an example embodiment of the invention may be physically, functionally and logically implemented in any suitable way. Indeed, the functionality may be implemented in a single unit, in a plurality of units or as part of other functional units.

100175] Those skilled in the art will recognize that the functional blocks and/or logic elements herein described may be implemented in an integrated circuit for incorporation into one or more of the apparatus units. For example, the integrated circuit may be suitable for determining an MR inflammation score for a subject, based on obtained MR data.

100176] Furthermore, it is intended that boundaries between logic blocks are merely illustrative and that alternative embodiments may merge logic blocks or circuit elements or impose an alternate -24 -composition of functionality upon various logic blocks or circuit elements. It is further intended that the architectures depicted herein are merely exemplary, and that in fact many other architectures can be implemented that achieve the same functionality.

1001771 Although the present invention has been described in connection with some example embodiments, it is not intended to be limited to the specific foim set forth herein. Rathei, the scope of the present invention is limited only by the accompanying claims. Additionally, although a feature may appear to be described in connection with particular embodiments, one skilled in the art would recognize that various featuies of the described embodiments may be combined in accordance with the invention.

In the claims, the term comprising' does not exclude the presence of other elements or steps.

1001781 Furthermore, although individually listed, a plurality of means, elements or method steps may be implemented by, for example, a single unit or processor. Additionally, although individual features may be included in different claims, these may possibly be advantageously combined, and the inclusion in different claims does not imply that a combination of features is not feasible and/or advantageous. Also, the inclusion of a feature in one category of claims does not imply a limitation to this category, but rather indicates that the featuie is equally applicable to other claim categories, as appropiiate.

1001791 Furthermore, the order of features in the claims does not imply any specific order in which the features must be performed and in paiticulai the order of individual steps in a method claim does not imply that the steps must be perfoimed in this ordei. Rather, the steps may be performed in any suitable order. In addition, singular references do not exclude a plurality. Thus, references to a, an', fiist', second', etc. do not preclude a plurality. -25 -

Claims (18)

1. We claim: 1. A method for determining the presence or absence of inflammation in a subject's visceral organ, the method comprising: obtaining a measurement of relaxometry data of the subject's visceral organ for extracellular fluid; obtaining an iron content for the visceral organ; and if iron overload is indicated from the obtained iron content for the visceral organ, correcting the measurement of extracellular fluid for the subjects visceral organ; comparing the corrected measurement for extracellular fluid with a threshold; and determining solely from the comparison, the presence or absence of inflammation in the subject's visceral organ.
2. 2. The method of Claim 1, further comprising measuring one or more characteristic relaxation time(s) in the visceral organ by medical imaging to obtain the measurement of relaxometry data.
3. 3. The method of Claim 1 or 2, further comprising at least one of: using Ti mapping to obtain the measurement of the subject's visceral organ for extracellular fluid and using T2* imaging to obtain the measurement for iron content.
4. 4. The method of any preceding Claim, further comprising automated identifying a particular region of interest in the visceral organ that is free of vessels before measurements.
5. 5. The method of Claim 3 or Claim 4, wherein using Ti mapping comprises using a modified Look Locker inversion (MOLLI) recovery pulse sequence or a shortened modified Look Locker inversion recovery (Sh-MOLLI) sequence.
6. 6. The method of Claim 3, wherein the subject's visceral organ is measured for iron content using one or more of: T2 mapping, T2* mapping, measuring one or more blood biomarkers, or MR spectroscopy.
7. 7. The method of any preceding Claim, wherein the visceral organ is one of: liver, pancreas or the kidney.
8. 8. The method of any preceding Claim, wherein the subject is a child.

   -26 -
9. 9. The method of any preceding Claim, wherein inflammation in the subject's liver is deemed present if the corrected measurement for extracellular fluid is above SSOms, or potentially present if the corrected measurement for extracellular fluid is between S2Oms and 850ms.
10. 10. A system, comprising: at least one computing device; at least one database; and at least one application executable in the computing device, wherein the at least one application is operable to: obtain a measurement of relaxometry data of a subject's visceral organ for extracellular fluid; obtain an iron content for the visceral organ; determine if iron overload is indicated from the obtained iron content and if iron overload is indicated correct the measurement for extracellular fluid; compare the corrected measurement for extracellular fluid with a threshold; and determine solely from the comparison the presence or absence of inflammation.
11. 11. The system of claim 10, wherein inflammation in the subjects visceral organ is deemed present if the corrected measurement for extracellular fluid is at or above S5Oms.
12. 12. The system of Claim 10 or 11, wherein the at least one application is operable to flag the received MR data if inflammation is deemed present.
13. 13. The system of Claim 12, wherein the at least one application is operable to access the at least one database to obtain medical information of a subject relating to the flagged MR data.
14. 14. The system of claim 13, wherein the obtained medical information comprises historical information on the subject comprising one or more of: dietary information, hereditary information, previous ailments, information on alcohol consumption, and presence of viral hepatitis infection.
15. 15. The system of claim 14, wherein the historical information on the subject comprises an indication of one or more of: non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), high hepatic lipid content (HLC), hepatic fibrosis, a disease associated with hepatic fibrosis, hepatitis, a condition associated with iron overload, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, viral hepatitis, chronic hepatitis, drug-induced hepatitis, -27 -haemochromatosis, thallassaemia, alcoholic hepatitis, alcoholic liver cirrhosis, portal hypertension, vascular liver disease, idiopathic hepatic fibrosis, sarcoidosis, hepatic cysts, or hemangiomas, pancreatic disease, pancreatic tumours, pancreatitis, glomerulonephritis.
16. 16. The system of Claim 10, wherein MR data is provided by a medical imaging device comprising a magnetic resonance (MR) scanner.
17. 17. A method for determining a presence or absence of inflammation in a child's visceral organ, the method comprising: obtaining a measurement of relaxometry data of the child's visceral organ for extracellular fluid; comparing the measurement for extracellular fluid with a threshold; and determining solely from the comparison, the presence or absence of inflammation in the child's visceral organ.
18. 18. A system, comprising: at least one computing device; at least one database; and at least one application executable in the computing device, wherein the at least one application is operable to: obtain a measurement of relaxometry data of the child's visceral organ for extracellular fluid; compare the measurement for extracellular fluid with a threshold; and determine solely from the comparison, the presence or absence of inflammation in the child's visceral organ. -28 -Amendments to the claims have been filed as follows We claim: 1. A method for determining the presence or absence of inflammation in a subject's visceral organ, the method comprising: obtaining a measurement of Ti relaxometry data representative of extracellular fluid content for the subject's visceral organ obtaining an iron content for the visceral organ; and if iron overload is indicated from the obtained iron content for the visceral organ, correcting the measurement of Ti relaxometry data representative of extracellular fluid content for the subject's visceral organ; comparing the corrected measurement of Ti relaxometry data with a threshold; and determining solely from the comparison, the presence or absence of inflammation in the subject's visceral organ.2. The method of Claim i, further comprising measuring one or more characteristic relaxation LI') time(s) in the visceral organ by medical imaging to obtain the measurement of Ti relaxometry data.o 3. The method of Claim i or 2, further comprising using T2* imaging to obtain the measurement for iron content.C4. The method of any preceding Claim, further comprising automated identifying a particular region of interest in the visceral organ that is free of vessels before measurements.5. The method of Claim 3 or Claim 4, wherein obtaining a measurement of Ti relaxometry data of the subject's visceral organ representative of extracellular fluid content comprises using a modified Look Locker inversion (MOLLI) recovery pulse sequence or a shortened modified Look Locker inversion recovery (Sh-MOLLI) sequence.6. The method of Claim 3, wherein the subject's visceral organ is measured for iron content using one or more of: T2 mapping, T2* mapping, measuring one or more blood biomarkers, or MR spectroscopy.7. The method of any preceding Claim, wherein the visceral organ is one of: liver, pancreas or the kidney.8. The method of any preceding Claim, wherein the subject is a child.9. The method of any preceding Claim, wherein inflammation in the subject's liver is deemed present if the corrected measurement of Ti relaxometry data representative of extracellular fluid content is above 8SOms, or potentially present if the corrected measurement for extracellular fluid is between 820ms and B5Oms.10. A system, comprising at least one computing device arranged to: obtain a measurement of Ti relaxometry data of a subject's visceral organ representative of extracellular fluid content; obtain an iron content for the visceral organ; determine if iron overload is indicated from the obtained iron content and if iron overload is indicated correct the measurement of Ti relaxometry data representative of extracellular fluid content; compare the corrected measurement ofTi relaxometry data with a threshold; I_f) and determine solely from the comparison the presence or absence of inflammation.o 11. The system of claim 10, wherein inflammation in the subjects visceral organ is deemed present if the corrected measurement Ti relaxometry data representative of extracellular fluid content is at C or above 850ms.12. The system of Claim 10 or ii, wherein the at least one computing device is operable to flag the received MR data if inflammation is deemed present.13. The system of Claim 12, wherein the at least one computing device is operable to access the at least one database to obtain medical information of a subject relating to the flagged MR data.14. The system of claim 13, wherein the obtained medical information comprises historical information on the subject comprising one or more of: dietary information, hereditary information, previous ailments, information on alcohol consumption, and presence of viral hepatitis infection.15. The system of claim 14, wherein the historical information on the subject comprises an indication of one or more of: non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), high hepatic lipid content (HLC), hepatic fibrosis, a disease associated with hepatic fibrosis, hepatitis, a condition associated with iron overload, autoimmune hepatitis, primary biliary cirrhosis, primary scierosing cholangitis, viral hepatitis, chronic hepatitis, drug-induced hepatitis, haemochromatosis, thallassaemia, alcoholic hepatitis, alcoholic liver cirrhosis, portal hypertension, vascular liver disease, idiopathic hepatic fibrosis, sarcoidosis, hepatic cysts, or hemangiomas, pancreatic disease, pancreatic tumours, pancreatitis, glomerulonephritis.16. The system of Claim 10, wherein MR data is provided by a medical imaging device comprising a magnetic resonance (MR) scanner.17. A method for determining a presence or absence of inflammation in a child's visceral organ, the method comprising: obtaining a measurement of Ti relaxometry data representative of extracellular fluid content for the child's visceral organ comparing the measurement of Ti relaxometry data representative of extracellular fluid content with a threshold; and determining solely from the comparison, the presence or absence of inflammation in the LI) child's visceral organ.18. A system, comprising at least one computing device arranged to: C) obtain a measurement of Ti relaxornetry data representative of extracellular fluid content 0 for a child's visceral organ; 0 compare the measurement of Ti relaxometry data representative of extracellular fluid C) content with a threshold; and determine solely from the comparison, the presence or absence of inflammation in the child's visceral organ.