Stable Isotope Histamine Diagnosis via LC-MS/MS Pathway Differentiation
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Solution Overview
Problem
Current diagnostic methods for histamine intolerance syndrome cannot differentiate between impaired histamine degradation pathways, making it difficult to determine the origin and cause of the condition, and thus, provide inadequate treatment options.
Innovation Solution
A method involving the administration of stable isotope-labelled histamine, followed by hydrophilic interaction chromatography and mass spectrometry (LC-MS/MS) to determine histamine inactivation activity in bodily fluids, allowing for the calculation of histamine inactivation pathways and identification of impaired routes, and optionally, immunological determination of diamine oxidase (DAO) activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Measurement precision
If conventional diagnostic methods measuring serum DAO activity are used, then the diagnosis process is simple and quick, but the measurement precision is insufficient to differentiate between impaired DAO and HNMT pathways
Solution Approach 1:
The patent segments the histamine degradation pathway into two distinct measurement components: DAO pathway (measuring imidazole acetic acid) and HNMT pathway (measuring methylimidazole acetic acid). By separately quantifying the activities of these two enzymatic pathways using stable isotope-labelled histamine and LC-MS/MS analysis, the method achieves precise differentiation between DAO and HNMT impairments, resolving the limitation of conventional single-parameter DAO measurements
Solution Approach 2:
The patent changes the measurement parameter from a single serum DAO activity value to a dual-parameter system measuring both imidazole acetic acid (DAO pathway) and methylimidazole acetic acid (HNMT pathway) concentrations. This parameter expansion enables differential diagnosis by comparing the relative contributions of each pathway to total histamine degradation, allowing identification of pathway-specific impairments
2Measurement precision
If stable isotope-labelled histamine administration followed by LC-MS/MS analysis is used, then the measurement precision and pathway differentiation capability are improved, but the device complexity and cost increase
Solution Approach 1:
The patent introduces stable isotope-labelled histamine as an intermediary substance to trace and differentiate between DAO and HNMT pathways. The labelled histamine serves as a controlled substrate that, when metabolized through each pathway, produces distinct labelled metabolites (labelled imidazole acetic acid via DAO, labelled methylimidazole acetic acid via HNMT). This intermediary approach enables precise pathway tracking and quantification using LC-MS/MS detection
Solution Approach 2:
The patent adds a dimensional layer to the diagnostic approach by incorporating stable isotope labelling (mass spectral dimension) to distinguish between pathway-specific metabolites. The LC-MS/MS system detects and quantifies metabolites based on their mass-to-charge ratios, creating a new measurement dimension that allows simultaneous assessment of both DAO and HNMT activities with high specificity, transforming a single-dimensional DAO activity measurement into a multi-dimensional pathway analysis
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
Enables a more accurate diagnosis of histamine intolerance by distinguishing between DAO and HNMT inactivation pathways, providing a basis for more efficient treatment by reflecting the physiological situation and combined routes of histamine inactivation.
Implementation Method 1
administering a preparation, solution, or suspension containing a known amount of histamine, labelled by a stable isotope
Implementation Method 2
determining the amounts of isotopically labelled histamine, methyl histamine and imidazole acetic acid in said sample using hydrophilic interaction chromatography and mass spectrometry
Implementation Method 3
determining the amounts of isotopically labelled histamine, methyl histamine and imidazole acetic acid in said sample using hydrophilic interaction chromatography and mass spectrometry
Implementation Method 4
enzymatic degradation to imidazole-4-acetaldehyde by secreted copper-containing (AOC1) diamine oxidase (DAO; EC 1.4.3.22), which is followed by a second enzymatic step mediated by mammalian aldehyde dehydrogenases (ADH; EC 1.2.1.3)
Implementation Method 5
enzymatic degradation by histamine N-methyltransferase (HNMT; EC 2.1.1.8) into 1-methylhistamine
Implementation Method 6
histamine N-methyltransferase (HNMT; EC 2.1.1.8) into 1-methylhistamine
Data Source
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AI summary
A method for diagnosing histamine intolerance syndrome in a patient suspected of suffering from insufficient histamine inactivation activity. The diagnostic procedure involves spiking or administering of histamine labelled with a stable isotope. Samples (usually serum, plasma, urine) are taken after one or more predetermined periods of time and an aprotic solvent is added to remove proteins and organic salts. The amounts of isotopically labelled histamine in the samples and, if applicable, one or more isotopically labelled inactivation products of histamine are determined by hydrophilic interaction chromatography and mass spectrometry. The histamine inactivation activity can then be determined from the amounts and ratios of isotopically labelled histamine, imidazole acetic acid, and methylhistamine, and optionally methylimidazole acetic acid. Diagnosis is based on the comparison with the histamine inactivation found in healthy individuals.