Advances in Clinical Chemistry最新文献

Hemophilia A is an X-linked recessive bleeding disorder characterized by absent or ineffective coagulation factor VIII, a condition that could result in a severe and potentially life-threatening bleed. Although the current standard of care involves prophylactic replacement therapy of factor VIII, the development of neutralizing anti-factor VIII alloantibody inhibitors often complicates such therapeutic treatment. Emicizumab (Hemlibra®), a novel recombinant therapeutic agent for patients with hemophilia A, is a humanized asymmetric bispecific IgG4 monoclonal antibody designed to mimic activated factor VIII by bridging factor IXa and factor X thus effecting hemostasis. Importantly, this drug eliminates the need for factor VIII and complications associated with inhibitor generation. Emicizumab has been approved for use in several countries including the United States and Japan for prophylaxis of bleeding episodes in hemophilia A with and without FVIII inhibitors. Therapy is also approved in the European Union for routine prophylaxis of bleeds in hemophilia A with inhibitors or severe hemophilia A without inhibitors. Unfortunately, emicizumab therapy presents unique challenges for routine and specialty coagulation tests currently used to monitor hemophilia A. In this review, hemophilia A is presented, the biochemistry of factor VIII is discussed, and the impact of the therapeutic agent emicizumab is highlighted.

Cortisol, the main human glucocorticoid, is synthesized from cholesterol in the adrenal cortex and predominantly metabolized by the liver. Interpretation of quantitative results from the analysis of serum, urine and saliva is complicated by variation in circadian rhythm, response to stress as well as the presence of protein-bound and free forms. Interestingly, cortisol is the only hormone routinely measured in serum, urine, and saliva. Preanalytical and analytical challenges arise in each matrix and are further compounded by the use of various stimulation and suppression tests commonly employed in clinical practice. Although not yet included in clinical guidelines, measurement of cortisol in hair may be of interest in specific situations. Immunoassays are the most widely used methods in clinical laboratories to measure cortisol, but they are susceptible to interference from synthetic and endogenous steroids, generally producing a variable overestimation of true cortisol results, especially in urine. Analysis by mass spectrometry provides higher specificity and allows simultaneous measurement of multiple steroids including synthetic steroids, thus reducing diagnostic uncertainty. An integrated review of cortisol in various disease states is also addressed.

Cardiovascular disease (CVD) is prevalent in patients with chronic kidney disease (CKD) and it is responsible for approximately half of all CKD-related deaths. CVDs are the primary cause of death in hemodialysis patients due to major adverse cardiovascular events. Therefore, better approaches for differentiating chronic hemodialysis patients at higher cardiovascular risk will help physicians improve clinical outcomes. Hence, there is an urgent need to discover feasible and reliable cardiac biomarkers to improve diagnostic accuracy, reflect myocardial injury, and identify high-risk patients. Numerous biomarkers that have significant prognostic value with respect to adverse CVD outcomes in the setting of mild to severe CKD have been identified. Therefore, a better understanding of the positive clinical impact of cardiac biomarkers on CVD patient outcomes is an important step toward prevention and improving treatment in the future. In this review, we address the relationship between cardiovascular biomarkers and CKD treatment strategies to elucidate the underlying importance of these biomarkers to patient outcomes.

TRPV6 is a Transient Receptor Potential Vanilloid (TRPV) cation channel with high selectivity for Ca²⁺ ions. First identified in 1999 in a search for the gene which mediates intestinal Ca²⁺ absorption, its far more extensive repertoire as a guardian of intracellular Ca²⁺ has since become apparent. Studies on TRPV6-deficient mice demonstrated additional important roles in placental Ca²⁺ transport, fetal bone development and male fertility. The first reports of inherited deficiency in newborn babies appeared in 2018, revealing its physiological importance in humans. There is currently strong evidence that TRPV6 also contributes to the pathogenesis of some common cancers. The recently reported association of TRPV6 deficiency with non-alcoholic chronic pancreatitis suggests a role in normal pancreatic function. Over time and with greater awareness of TRPV6, other disease-associations are likely to emerge. Powerful analytical tools have provided invaluable insights into the structure and operation of TRPV6. Its roles in Ca²⁺ signaling and carcinogenesis, and the use of channel inhibitors in cancer treatment are being intensively investigated. This review first briefly describes the biochemistry and physiology of the channel, and analytical methods used to investigate these. The focus subsequently shifts to the clinical disorders associated with abnormal expression and the underlying pathophysiology. The aims of this review are to increase awareness of this channel, and to draw together findings from a wide range of sources which may help to formulate new ideas for further studies.

Chronic and heavy alcohol consumption is commonly observed in alcohol use disorder (AUD). AUD often leads to alcohol-associated organ injury, including alcohol-associated liver disease (ALD). Approximately 10-20% of patients with AUD progress to ALD. Progression of ALD from the development phase to more advanced states involve the interplay of several pathways, including nutritional alterations. Multiple pathologic processes have been identified in the progression and severity of ALD. However, there are major gaps in the characterization and understanding of the clinical presentation of early-stage ALD as assessed by clinical markers and laboratory measures. Several Institutions and Universities, including the University of Louisville, in collaboration with the National Institutes of Health, have published a series of manuscripts describing early-stage ALD over the past decade. Here, we comprehensively describe early-stage ALD using the liver injury and drinking history markers, and the laboratory biomarkers (with a focus on nutrition status) that are uniquely involved in the development and progression of early-stage ALD.

Diabetes mellitus is the ninth leading cause of mortality worldwide. It is a complex disease that manifests as chronic hyperglycemia. Glucose exposure causes biochemical changes at the proteome level as reflected in accumulation of glycated proteins. A prominent example is hemoglobin A1c (HbA1c), a glycated protein widely accepted as a diabetic indicator. Another emerging biomarker is glycated albumin which has demonstrated utility in situations where HbA1c cannot be used. Other proteins undergo glycation as well thus impacting cellular function, transport and immune response. Accordingly, these glycated counterparts may serve as predictors for diabetic complications and thus warrant further inquiry. Fortunately, modern proteomics has provided unique analytic capability to enable improved and more comprehensive exploration of glycating agents and glycated proteins. This review broadly covers topics from epidemiology of diabetes to modern analytical tools such as mass spectrometry to facilitate a better understanding of diabetes pathophysiology. This serves as an attempt to connect clinically relevant questions with findings of recent proteomic studies to suggest future avenues of diabetes research.

Growth differentiation factor-15 (GDF-15) is a GDF subfamily member with potential kidney protective functions. Its nephroprotective activity is associated with both inflammation downregulation and upregulation of nephroprotective factors with anti-inflammatory activity, such as Klotho in tubular cells. However, GDF-15 has diverse and partially opposing functions depending on the state of the cells and the microenvironment. Increased GDF-15 levels have been linked to an increased risk of incident chronic kidney disease and a faster decline in kidney function in various renal disorders, including diabetic nephropathy, IgA nephropathy, lupus nephritis, anti-glomerular basement membrane nephritis, primary membranous nephropathy, kidney transplantation, Fabry disease and amyloidosis. The mechanisms underlying these effects are not yet fully understood. In this review, we will summarize GDF-15's potential role as a biomarker for kidney function in the general population, as well as in some specific kidney diseases.

New psychoactive substances (NPS) are chemical compounds designed to mimic the action of existing illicit recreational drugs. Synthetic cannabinoids (SCs) are a subclass of NPS which bind to the cannabinoid receptors, CB1 and CB2, and mimic the action of cannabis. SCs have dominated recent NPS seizure reports worldwide. While urine is the most common matrix for drug-of-abuse testing, SCs undergo extensive Phase I and Phase II metabolism, resulting in almost undetectable parent compounds in urine samples. Therefore, the major urinary metabolites of SCs are usually investigated as surrogate biomarkers to identify their consumption. Since seized urine samples after consuming novel SCs may be unavailable in a timely manner, human hepatocytes, human liver microsomes and human transporter overexpressed cell lines are physiologically-relevant in vitro systems for performing metabolite identification, metabolic stability, reaction phenotyping and transporter experiments to establish the disposition of SC and its metabolites. Coupling these in vitro experiments with in vivo verification using limited authentic urine samples, such a two-pronged approach has proven to be effective in establishing urinary metabolites as biomarkers for rapidly emerging SCs.

Oxidative stress is the result of an imbalance between the formation of reactive oxygen species (ROS) and the levels of enzymatic and non-enzymatic antioxidants. The assessment of biological redox status is performed by the use of oxidative stress biomarkers. An oxidative stress biomarker is defined as any physical structure or process or chemical compound that can be assessed in a living being (in vivo) or in solid or fluid parts thereof (in vitro), the determination of which is a reproducible and reliable indicator of oxidative stress. The use of oxidative stress biomarkers allows early identification of the risk of developing diseases associated with this process and also opens up possibilities for new treatments. At the end of the last century, interest in oxidative stress biomarkers began to grow, due to evidence of the association between the generation of free radicals and various pathologies. Up to now, a significant number of studies have been carried out to identify and apply different oxidative stress biomarkers in clinical practice. Among the most important oxidative stress biomarkers, it can be mentioned the products of oxidative modifications of lipids, proteins, nucleic acids, and uric acid as well as the measurement of the total antioxidant capacity of fluids in the human body. In this review, we aim to present recent advances and current knowledge on the main biomarkers of oxidative stress, including the discovery of new biomarkers, with emphasis on the various reproductive complications associated with variations in oxidative stress levels.

Psoriasis is an inflammatory skin disease affecting over 8 million people in the US and Canada. Approximately, a quarter of psoriasis patients have an inflammatory arthritis termed psoriatic arthritis (PsA). Psoriatic disease encompassing both psoriasis and PsA is regarded as an immune-mediated inflammatory disease, exhibiting both autoimmune and autoinflammatory features. A review of the current literature on the presence and clinical significance of autoantibodies found in psoriatic disease are presented. The frequency of several autoantibodies in psoriasis and PsA patients as well as their clinical significance regarding disease diagnosis, disease activity and treatment response are reviewed. Additionally, the basic principles of antibody assays are presented, and the methods used for each study are analyzed. Despite historically described as a rheumatoid factor negative (seronegative) disease, an array of autoantibodies has been identified in patients with psoriatic disease. This points to an autoimmune component potentially playing a role in psoriatic disease; however, additional evidence is needed to determine the clinical utility of these autoantibodies.