VOC Biomarkers overview and potential

      Increasing interest is noticed in the potential of volatile organic compound (VOC) analysis as non-invasive diagnostic biomarker in clinical medical practice. Максимально системный анализ всех VOC выделяемых из человеческого тела впервые можно найти в статье [1]. 1840 VOCs have been assigned from breath (872), saliva (359), blood (154), milk (256), skin secretions (532) urine (279), and faeces (381). Some recent studies continue to report on the progress on VOC additional identification significantly increasing numbers[1].
      Как уже сказано, все VOC а также их комбинации и концентрация являются маркерами определенных состояние человека. Их присутствие/отсутствие является сигналом определенного заболевания либо состояния. На наш взгляд задача определения самого спектра VOC выделяемых из человека решена достаточно полно. С другой стороны, с точки зрения потенциального применения необходимо решить научную задачу построения связей между VOC и конкретными болезнями. Именно научные изыскания в этом направлении сняли одну из важнейших преград и позволилили разработке описываемой в данной работе иметь место [1,2].
      So, VOCs can be detected in exhaled breath, urine, fecal and sweat.
      First we provide an outline of exhaled breath VOC detection. Researchers below have been able to diagnose diseases such as cancer, liver disease, kidney failure using VOCs as biomarkers.
      Phillips and coworkers’ research on VOCs showed that 22 VOCs are breath markers of lung cancer [1].Methylated alkanes and selected alkanes have been shown to be able to distinguish lung cancer patients from healthy controls [37]. The rule of the lung cancer breath diagnosis is to check if a person’s breath contains more than 1 of the 11 VOCs with a concentration that is higher than the breath diagnostic cut-off [38].
      Liver disease is one of the most prominent extra-oral causes of bad breath. It was found that dimethyl sulfide, acetone, 2-pentanone and 2-butanone were significantly higher in alveolar air of liver disease patients [1]. Other researchers used gas chromatography to demonstrate that the levels of all sulfur-containing molecules were elevated in the breath of patients with cirrhosis, even outside liver coma [41].
      Acetone is an exhaled volatile organic compound that has been used as a marker of various diseases. In the human breath it is a biomarker for diabetes mellitus, especially in type 1 diabetes mellitus [19]. It is derived from oxidation of non-esterified fatty acids, which results in acetyl-CoA and ultimately acetoacetate through spontaneous decarboxylation or enzymatic conversion. [42]. Acetone levels in breath have also been used for detection and monitoring of abnormal concentrations of blood beta-hydroxybutyrate levels in diabetes mellitus [43]. Reghetton and the team proved strong correlation between blood and exhale breath level of acetone. Moreover, it is also reported that acetone is also emitted from the skin and urine and its concentrations correlate with breath acetone and blood beta-hydroxybutyrate [44,46]. Thus acetone is proved to be one of the vital biomarkers to be detected as diabetes biomarker.
      Thus, a huge amount of studies have focused on VOC analysis in exhaled breath, aiming at the identification of disease-specific VOC profiles. However, recently, an increasing number of studies have evaluated the usability of VOC present in the headspace of feces and urine in the diagnostic work-up of a wide range of gastrointestinal diseases. The detection process is non-invasive, high-throughput and low-cost.
      Promising results have been demonstrated particularly in those diseases in which microbiota alterations are considered to play a significant etiological role, such as colorectal carcinoma, inflammatory bowel disease, irritable bowel syndrome, celiac disease and infectious bowel diseases. In addition, fecal and urine VOC analysis proven to have potential as a diagnostic biomarker for extra-intestinal diseases, including bronchopulmonary dysplasia and sepsis. Most studies on application of fecal VOC analysis in infectious disease have focused on Clostridium difficile [1,2,3]. Other studies include detection of Campylobacter jejuni, cholera, giardiasis and rotavirus [1]. Al-Kateb and colleagues studied fecal VOC profiles of samples of 53 children from Malawi, comprising 27 rotavirus positive and 26 stool samples of children with unspecified gastrointestinal problems, by means of GC-MS. In particular, two VOCs were found with a higher frequency[25].
      Bond et al. compared fecal VOCs from 16 adult patients infected with Giardia lamblia with 17 controls with diarrhea without Giardia lamblia by means of GC-MS. The two groups could be separated based on five different VOCs[26].
      Colorectal cancer (CRC) is one of the most prevalent malignancies in the industrialized world and is an important cause of cancer-related mortality [41,42]. Between 70% and 90% of CRC originates from adenomatous polyps, and early detection and removal of these precancerous adenomas significantly decrease CRC incidence and mortality [43]. Therefore, current CRC screening aims for early detection of CRC, and those adenomas with a high risk of malignant transformation (advanced adenomas) [44]. In screening tests, individuals with a positive fecal immunological test (FIT) are referred for colonoscopy (gold standard). However, performance of this test is suboptimal, results in a substantial number of false positive tests, and as a consequence, unneeded colonoscopies. Because of these limitations, an unmet need exists for a more sensitive and specific test to select only high risk individuals for colonoscopy. VOCs originating from breath, feces, blood and urine are increasingly considered as potential noninvasive biomarkers for CRC and advanced adenomas. Few studies demonstrated that classification based on VOC profiles was possible with good sensitivity and specificity [49,50].
      In 2009, Garner et al. conducted a pilot case-control study analyzing fecal VOCs of six NEC and seven control infants by means of GC-MS [24]. Necrotizing enterocolitis , or NEC, is the most common and serious intestinal disease among premature babies. It happens when tissue in the small or large intestine is injured or inflamed. This can lead to death of intestinal tissue and, in some cases, a hole in the intestinal wall. Fecal samples of different time points prior to clinical manifestation of NEC were analyzed. The number of different extracted VOCs became more numerous as the infant matures, while this trend was absent in NEC cases. So it was possible to discriminate fecal VOC profiles of NEC cases from controls up to three days prior to clinical onset of NEC [14]. So this studies underline the potential of fecal VOC analysis in early detection of infants who develop NEC, as a non-invasive, low-cost and user friendly diagnostic mean. Furthermore, in clinical practice, it is yet found difficult to diagnose NEC at an early stage, whereas early diagnosis is correlated with a better outcome.
      Many authors reports on detection of urine VOC markers of breast cancer which is the most common cancer detected in women[1,2] Urine contains VOCs that are products of metabolic pathways and detection may serve as a reliable screening source of biomarkers for breast cancer [1]. This studies are considered to be as important as one can imagine due to absence of screening test for breast cancer at the moment.
      Wang and the team provided studies on idiopathic membranous nephropathy (iMN). Six urinary VOCs were isolated from patients with iMN using GC/MS and revealed potential for developing a non-invasive method for the detection of iMN[1].
      Mazzone and the team reports the potential of colorimetric sensor array signature of VOC in the urine headspace to be capable of distinguishing lung cancer. [1]
      Investigation of urine screening VOC analysis could be also important for metabolic control. Several studies reveals the VOC presents versus metabolic conditions of children and adults [1,2].
      Summary:
      This review gives a glimpse of what has been achieved to date and what might be possible in the future through the use of VOC detection. Various sensing (eNose, MS, bio-sensors, chemical sensors) continue to open up new possibilities for real-time, accurate and fast detection allowing earlier detection of diseases and evaluations of patient conditions before symptoms appear. A significant amount of VOCs outgoing from human body are strongly interlinked with a bunch of diseases like cancer, liver disease, kidney failure, gastrointestinal diseases etc.