Dr Alex Lawson is a Principal Clinical Scientist at the Birmingham Heartlands Hospital, UK. Dr Lawson is using inductively coupled plasma mass spectrometry (ICP-MS) in clinical science research. Sonia Nicholas, Associate Editor for SelectScience® spoke to Dr Lawson to find out more about his work.
SN: Alex can you give me a brief description of your job role at the hospital?
AL: I am a principal clinical scientist working in the fields of clinical and forensic toxicology. My main role entails the clinical interpretation of biochemical and toxicological information, and communicating pertinent results to requesting clinicians to aid care and guide any subsequent investigations. I also perform this role for the coroner. I am involved in a number of research and development projects with the aim of using chromatography and mass spectrometry to improve healthcare.
Using novel technology to enhance clinical care
SN: In which areas of clinical research are you working?
AL: The toxicology department at Heartlands Hospital is a fully UKAS accredited analytical and interpretative service. We run an extensive menu of established quantitative and screening tests using a variety of analytical techniques, which include the detection of novel psychoactive substances (NPS or so called ‘legal highs’), for the investigation of unexplained illnesses or for cause of death information.
Often we develop methods using novel technologies to answer a particular clinical question. An example of this is our clinical research work into resistant hypertension. Arterial hypertension is one of the most preventable causes of premature morbidity and mortality with resistant hypertension reported to be present in 5–30% of the total hypertensive population. Despite the poor prognosis, as many as 53% of those with resistant hypertension are reported to be non-adherent to their prescribed medication. We therefore developed an LC-MS/MS method to screen for a wide range of antihypertensive drug and analytes in urine1. The research test objective was to locate an adherence test, which is not only easy to administer, quick, inexpensive and reliable, but could also identify individuals with true resistance to antihypertensive drugs, to optimize their response. We are also actively researching the potential to monitor adherence to asthma and HIV medications in a similar fashion.
Another area where we have been using modern technology to improve clinical care is in our research work on cystic fibrosis (CF). Sweat chloride analysis is the gold standard test for diagnosis of CF. However, current methods (e.g. coulometry, colourimetry, and ISE) are time-consuming, costly and require large sample volumes relative to the minimum acceptable collection. We have developed a clinical research method for the measurement of sweat chloride and sodium using ICP-MS. Using this technology, we could obtain all of the information that we need from just 2 µL of sample, allowing duplicate measurement to be performed on all viable sweat samples, thereby reducing the number of repeat sweat tests for individuals in the future.
SN: When did you start using inductively coupled plasma mass spectrometry (ICP-MS) and why did you change from your existing technology?
AL: The Department of Toxicology at Birmingham Heartlands Hospital was founded in 2013 as an addition to the well-established department of clinical chemistry and immunology. Prior to this, we did not perform any trace element analysis. When our service laboratory was set up, we brought in an ICP-MS, the Thermo Scientific™ iCAP™ Q ICP-MS. We opted for ICP-MS technology, over other non-MS based methodologies for trace element analysis, for a number of reasons. Firstly, due to the sensitivity and specificity of ICP-MS instrumentation, only a small sample volume (typically 10 – 20 µL) and simple sample preparation (dilution with nitric acid / methanol) was required for the majority of analytes. Crucially, due to the flexibility of the MS-based analysis coupled with Kinetic Energy Discrimination (KED) modes on modern instruments, we could set up a large number of methods with minimal adjustment of instrumental settings (c.f. atomic absorption).
Although I didn’t have previous experience of ICP-MS, as a laboratory, we had a clinical background in the investigation and management of both trace element deficiencies and heavy metal poisoning. We also have a wealth of experience with a number of other mass spectrometry (MS) techniques including liquid chromatography tandem mass spectrometry (LC-MS/MS) and gas chromatography mass spectrometry (GC-MS). You do need to have some experience with basic MS in order to understand some of the technical limitations of ICP-MS, but other than that it is really quite straight forward to select the right isotope and the platform is user-friendly. We also had training and support from Thermo Fisher Scientific during the implementation. This meant that we were in a good position to implement new services.
SN: What is the most interesting forensics case/sample in which you’ve used ICP-MS to provide answers?
AL: The analysis of herbal medications (especially ayurvedic medicines) has been particularly interesting, with their use increasing in the UK, and with many manufacturers of these compounds unlicensed. At present we have a lots of media coverage about NPS but perhaps we should also be paying more attention to the heavy metal content (e.g. lead, mercury and arsenic) of some of these medications. This is especially relevant as some data suggests that mild elevations of compounds may have subtle effects on health (e.g. CVD), rather than the more classical toxidromes described previously. ICP-MS technologies are able to easily measure these slight elevations in elements, which may not have been so straightforward using other technologies.
Another advantage of how we have set up our ICP-MS, is that we carry out a survey scan, in addition to the three main analytical scans, on every sample. During this survey scan, the system scans very quickly through all elements in the periodic table. This untargeted approach is very helpful if we receive either a blood, urine or herbal donor sample in which heavy metal poisoning is suspected. As we run this survey scan on every sample, we can also retrospectively analyze data sets to see if a previously unsuspected element may be present in the sample of interest (e.g. silver).
The potential of ICP-MS technology
SN: In what areas does ICP-MS offer the most promise?
AL: The majority of our work is in the investigation and monitoring of trace element deficiencies and heavy metal poisonings. This type of analysis is well established using ICP-MS and other more traditional techniques (e.g. atomic absorption spectroscopy).
Regarding research, there have been several studies looking at a number of trace elements and their role in predicting disease. I think that due to the ubiquitous nature of some of the commonly measured trace elements in clinical laboratories (Zn, Cu), and their function as co-factors in large numbers of enzymes and proteins involved in certain key biochemical pathways, it is perhaps not surprising that these elements are predictive indicators for a number of disorders. It will be interesting to see if the measurement of these elements becomes routine in the biochemical workup of common conditions such as the measurement of Cu in cardiovascular disease risk due to its role in lipoprotein homeostasis, or Zn in individuals with T2DM in which it was shown to be low.
However, the utility of these elements as biomarkers for disease is somewhat complicated by the difficulty of interpretation of mild elevations (Cu) and decreases (Zn) due to processes such as inflammation and the use of serum as the matrix of measurement, which is not always a good indicator of whole body metal levels. The use of ICP-MS to allow accurate and precise measurement of these elements in future research studies will be important.
Also, the increased availability of ICP-MS instruments which are able to reliably measure low levels (e.g. nmol/L) of a number of elements, potentially means that some elements which have some postulated links to a number of diseases in both deficiency and excess states (a prime example is manganese), can be investigated easily in a large number of centres. More work is needed for some elements such as chromium, for which deficiency has been postulated to be involved in a number of diseases, but a putative reference range has not been established, and low level detection is complicated by environmental contamination.
SN: Do you have any advice for other laboratories looking to implement ICP-MS?
AL: My advice would be to sort out the plumbing and ventilation systems immediately, because this was where we had the most trouble. We are on the ground floor and so we needed to find a practical solution for de-fumigation and argon supply. After that, my advice is to make sure you have a good team around you, ideally including staff members with some MS experience. Once you figure these out, the possibilities are endless! We have found that our ICP-MS system has given us an almost ‘turn-key’ solution for the sensitive and specific analysis of a broad range of analytes with set-up of the system for new analysis proving straightforward and user friendly. It has been the versatility and sensitivity offered by ICP-MS technologies which has set it apart from more traditional methods.
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