D-3-Hydroxybutyrate & Diabetic Ketoacidosis
D-3-Hydroxybutyrate & Diabetic Ketoacidosis
Diabetic Ketoacidosis is characterised by an accumulation of ketone bodies in response to insulin deficiency, most commonly occurring in T1DM patients, but is becoming increasingly prevalent among sufferers of T2DM.
Diabetic ketoacidosis is associated with symptoms such as polyuria, polydipsia, fever, vomiting, abdominal pain and fatigue with the most severe cases resulting in disastrous consequences such as cerebral oedema and death.
D-3-Hydroxybutyrate is considered to be the predominant ketone bodies associated with diabetic ketoacidosis and novel methods of detection utilise this biomarker to provide robust and accurate quantification of ketone bodies and aid in confident diagnosis of diabetic ketoacidosis.
This guide discusses the physiological and pathological processes associated with diabetic ketoacidosis and the relevant biomarkers, the complications associated with this condition and classic and novel detection methods.
To download this guide, simply click the image at the top of this post!
For more information on this assay visit https://www.randox.com/d-3-hydroxybutyrate-ranbut/
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Determining bilirubin concentration in paediatric facilities – Vanadate Oxidation Method
The quantification of bilirubin has a wide range of diagnostic utility. In paediatric settings, bilirubin concentrations are commonly used to identify cases of bilirubin encephalopathy or kernicterus.
Historically, bilirubin quantification has been achieved through various techniques derived from the diazo method, first described by Van der Bergh and Muller in 1918. New technologies and novel methods, like the Vanadate Oxidation method, have emerged and have been shown to display superior diagnostic power, driven by its lower sensitivity to interference caused by haemolysis and lipemia when compared with other methods.
This week, we present our educational guide, ‘Determining bilirubin concentrations in paediatric facilities’ which details the key points relating to bilirubin quantification, along with descriptions and comparisons of the methods mentioned above.
To download this guide, simply click the image at the top of this post!
For more information on our Vanadate Oxidation Bilirubin assay visit: www.randox.com/bilirubin
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The Importance of Maintaining Regular Dietary Patterns to reduce CVD risk
Cardiovascular disease (CVD) is the leading cause of mortality worldwide. An estimated 17.9 million people died from some form of CVD in 2019, accounting for 32% of all-cause mortality that year1. Associations between diet and risk of cardiovascular complications have long been established, largely relating to alterations in lipid profiles.
For as long as anyone can remember, breakfast has been considered the most important meal of the day. Previous studies2 have shown an association between skipping breakfast and increased CVD risk prompting recommendations that up to 30% of one’s daily energy intake should be consumed during the first meal of the day. It has been reported that over 25% of adults skip breakfast. These individuals are often socioeconomically disadvantaged, shift workers, individuals who work particularly long hours, those who suffer from depression or those with poor health literacy2. Another study3 showed that skipping breakfast, when compared with consuming a high-energy breakfast, was associated with a 1.6x and 2.6x higher probability of non-coronary and general atherosclerosis respectively, when all other CVD risk factor had been controlled. This suggests a close relationship between eating breakfast and reducing CVD risk, however, the mechanisms and magnitude of this relationship are poorly understood.
Small, dense low-density lipoprotein cholesterol (sdLDL-C) is a smaller form of LDL-C which boasts greater propensity for uptake by arterial tissue, increased proteoglycan binding, and increased susceptibility for oxidation4. sdLDL-C concentration is strongly associated with CVD risk, yet once again, the mechanisms of this association remain enigmatic. It is thought that all of the metabolic changes associated with alterations in sdLDL-C concentration collectively contribute to the increased risk of CVD, with the main drivers being its propensity for uptake by arterial tissues and its long circulatory stability4
Skipping breakfast and sdLDL-C
A recent study investigated the relationship between skipping breakfast and the effects on lipid parameters5. In a cohort of around 28’000 people from the Japanese population, this study looked at the several markers, including sdLDL-C, to develop an understanding of the importance of regular dietary patterns for reducing the risk of CVD.
The study participants were divided into two main categories: breakfast eaters and breakfast skippers. These categories were further subdivided to differentiate men and women, over and under 55 years old, and those who eat staple products (rice, pasta, bread, etc.) and those who did not. The participants contributed blood samples which were tested for several cardiovascular biomarkers: Creatinine, Liver ALT, Total Cholesterol, Triglycerides, direct LDL-C, HDL-C and sdLDL-C.
They found that around 26% of men and 16.9% of women skipped breakfast regularly. Of these, most were considered young and had significant increases in concentration of triglycerides, LDL-C and sdLDL-C compared with those who ate breakfast almost every day.
Table 1. Median concentration of triglycerides, LDL-C, and sdLDL-C for breakfast skippers and eaters5
| Analyte | Breakfast Skippers (mg/dL) | Breakfast Eaters (mg/dL) |
| Triglycerides | 103 | 93 |
| LDL-C | 124 | 122 |
| sdLDL-C | 34.7 | 32 |
This investigation also revealed that in this cohort, 20% of men and 27.3% of women did not regularly consume staple foods as part of their diet and had higher median sdLDL-C concentration.
Table 2. Median concentration of sdLDL-C in men and women who eat or skip staple food products in their diet5
| Gender | Staple Skippers (mg/dL) | Staple Eaters (mg/dL) |
| Men | 34.1 | 31.6 |
| Women | 25.8 | 24.7 |
The data from this study supports the finding that individuals who skipped breakfast had higher sdLDL-C concentrations than those who ate breakfast consistently. Skipping breakfast can therefore be associated with troublesome lipid parameters in both genders and all age groups in the Japanese population. This study suggests that eating breakfast every day is crucial to maintain beneficial lipid parameters and reduce the risk of developing CVD.
The data also show that individuals who skipped staple foods in their meals presented with higher concentrations of sdLDL-C and a higher sdLDL-C/LDL-C ratio, in men and postmenopausal women, when compared with those who included staple foods in their meals. It is becoming increasingly common to remove staple foods from one’s diet due to their high carbohydrate content and the prevalence of low-carbohydrate diets. This data exhibits the importance of maintaining a nutritionally balanced diet to help reduce the risk of developing CVD.
As the first large scale study of its kind, this analysis provides clear insight into the increased risk of CVD associated with not only skipping breakfast, but failing to maintain a nutritionally balanced diet. The major limitation of this analysis is that it only includes individuals from the Japanese population and the same affects may not be seen in populations from other ethnicities. Therefore, further in-depth analysis is required to confirm these findings in other ethnicities
Randox sdLDL-C Assay
The Randox sdLDL-C assay employs the clearance method which displays good correlation with the gold standard in sdLDL-C quantification, giving laboratories increased confidence in their results first time, every time. Supplied as liquid ready-to-use reagents, this this test can be applied to a wide range of clinical chemistry analysers, producing results in as little as 10 minutes. Relevant controls and calibrators are also available from Randox as part of the Acusera range.
Randox sdLDL-C Assay Key Features
- Direct, automated test for convenience and efficiency.
- Rapid analysis results can be produced in as little as ten minutes, facilitating faster patient diagnosis and treatment plan implementation.
- Liquid ready-to-use reagents for convenience and ease of use.
- Applications available detailing instrument specific settings for a wide range of clinical chemistry analysers.
- sdLDL-C controls and calibrator available.
References
- World Health Organization. Cardiovascular Diseases. World Health Organization. Published June 11, 2021. https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds)
- Ofori-Asenso R, Owen AJ, Liew D. Skipping Breakfast and the Risk of Cardiovascular Disease and Death: A Systematic Review of Prospective Cohort Studies in Primary Prevention Settings. Journal of Cardiovascular Development and Disease. 2019;6(3):30. doi:https://doi.org/10.3390/jcdd6030030
- Uzhova I, Fuster V, Fernández-Ortiz A, et al. The Importance of Breakfast in Atherosclerosis Disease. Journal of the American College of Cardiology. 2017;70(15):1833-1842. doi:https://doi.org/10.1016/j.jacc.2017.08.027
- Rizvi AA, Stoian AP, Janez A, Rizzo M. Lipoproteins and cardiovascular disease: An update on the clinical significance of atherogenic small, dense LDL and new therapeutical options. Biomedicines. 2021;9:1579. doi:https://doi.org/10.3390/biomedicines9111579
- Arimoto M, Yamamoto Y, Imaoka W, et al. Small dense low-density lipoprotein cholesterol levels in breakfast skippers and staple food skippers. Journal of Atherosclerosis and Thrombosis. 2023;30. doi:https://doi.org/10.5551/jat.64024
For more information on our sdLDL-C assay or any of our other products, please contact us at: marketing@randox.com
Featured Reagent – Cystatin C
Featured Reagent | Cystatin C
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Kidney Disease
Kidney disease is a huge global health crisis, increasing healthcare costs, mortality and morbidity rates. The global prevalence of chronic kidney disease (CKD) has continued to rise during a short lifespan. In 2016, 1 in 10, equivalent to 10 percent of the global population were identified with having CKD with the highest prevalence’s reported in Europe, the Middle East, East Asia and Latin America, estimated at 12 per cent and the lowest in South Asia, estimated at 7 percent1.
The early risk assessment of renal function is vital. In 1990, CKD was ranked the 27th leading cause of death in the Global Burden of Disease study2, rising to 18th 3 in 2010, 13th in 20132 and 12th by 2015. From 2005-2015, the overall CKD mortality rate has risen by 31.7 percent, accounting for 1.1 million deaths globally in 20154.
Inadequacies of Traditional CKD Biomarkers
The most commonly used screening test for renal impairment is creatinine. When testing for CKD using creatinine, certain factors must be taken into consideration, including: age, gender, ethnicity, and muscle mass. As such, black men and black women will present with higher creatinine levels compared to white men and white women respectively5.
Serum creatinine is not an adequate screening test for renal impairment in the elderly (65 years of age and over) due to their decreased muscle mass. As such, patients are misdiagnosed, thus, patients with severe renal failure are receiving suboptimal care6.
The main disadvantage of using creatinine to screen for renal impairment is that up to 50 percent of renal function can be lost before significant creatinine levels become detectable as creatinine is insensitive to small changes in the glomerular filtration rate (GFR). Consequently, treatment is not provided at the appropriate time which can be fatal, thus, an earlier and more sensitive biomarker for renal function is vital7.
Biological Significance
Cystatin C is a small (13 kDa) cysteine proteinase inhibitor, produced by all nucleated cells at a constant rate. Cystatin C travels through the bloodstream to the kidneys where it is freely filtered by the glomerular membrane, resorbed and fully catabolised by the proximal renal tubes. Consequently, cystatin C is the ideal biomarker of GFR function8.
Clinical Significance of Cystatin C
The National Institute for Health and Care Excellence (NICE) (2014) guidelines recommend cystatin C testing due to its higher specificity for significant disease outcomes than those based on creatinine. As such, eGFR cystatin C measurements will significantly reduce the number of misdiagnosed patients, thus reducing the overall CKD burden9.
In 2017, a systematic literature search found 3,500 investigations into cystatin C as a marker of GFR. The study concluded that eGFRcystatinc was a significantly more superior than eGFRcreatinine10.
Benefits of Cystatin C
The Randox cystatin C assay utilises the latex enhanced immunoturbidimetric method offering numerous key features:
A niche product from Randox meaning that Randox are one of the only manufacturers to provide the cystatin C test in an automated biochemistry format
An automated assay which removes the inconvenience and time consumption associated with traditional ELISA testing
Applications are available detailing instrument-specific settings for the convenient use of the Randox cystatin C assay on a wide range of biochemistry analysers
Liquid ready-to-use reagents for convenience and ease-of-use
Latex enhanced immunoturbidimetric method delivering high performance
Extensive measuring range for the detection of clinically important results
Complementary controls and calibrators available offering a complete testing package
Limited interference from Bilirubin, Haemoglobin, Intralipid® and Triglycerides
Cystatin C does not suffer from a ‘blind area’ like creatinine due to cystatin C’s sensitivity to small changes in GFR enabling the early detection renal impairment
An exceptional correlation coefficient of r=1.00 when compared against standard methods
References
[1] Bello, AK, et al. Global Kidney Health Atlas: A report by the Internal Society of Nephrology on the current state of organization and structures for kidney care across the globe. Brussels : Internal Society of Nephrology, 2017.
[2] Bikbov, Boris. Chronic kidney disease: impact on the global burden of mortality and morbidity. The Lancet. [Online] 2015. http://www.thelancet.com/campaigns/kidney/updates/chronic-kidney-disease-impact-on-global-burden-of-mortality-and-morbidity.
[3] National Kidney Foundation. Global Facts: About Kidney Disease. National Kidney Foundation. [Online] National Kidney Foundation, 2015. https://www.kidney.org/kidneydisease/global-facts-about-kidney-disease#_ENREF_1.
[4] Neuen, Brendon Lange, et al. Chronic kidney disease and the global NCDs agenda. s.l. : BMJ Global Health, 2017.
[5] Lascano, Martin E and Poggio, Emilio D. Kidney Function Assessment by Creatinine-Based Estimation Equations. Cleveland Clinic. [Online] August 2010. [Cited: May 16, 2018.] http://www.clevelandclinicmeded.com/medicalpubs/diseasemanagement/nephrology/kidney-function/.
[6] Swedko, Peter J, et al. Serum Creatinine Is an Inadequate Screening Test for Renal Failure in Elderly Patients. Research Gate. [Online] February 2003. [Cited: May 6, 2018.] https://www.researchgate.net/publication/8243393_Serum_Creatinine_Is_an_Inadequate_Screening_Test_for_Renal_Failure_in_Elderly_Patients.
[7] Mishra, Umashankar. New technique developed to detect chronic kidney disease. Business Line. [Online] May 07, 2018. [Cited: May 17, 2018.] https://www.thehindubusinessline.com/news/science/new-technique-to-detect-chronic-kidney-disease/article23803316.ece.
[8] Chew, Janice SC, et al. Cystatin C-A Paradigm of Evidence Based Laboratory Medicine. NCBI. [Online] May 29, 2008. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2533150/.
[9] National Institute for Health and Care Excellence. Chronic kidney disease in adults: assessment and management: 2 Implementation: getting started. NICE. [Online] January 2015. [Cited: April 19, 2018.] https://www.nice.org.uk/guidance/cg182/chapter/implementation-getting-started.
[10] Grubb, Anders. Cystatin C is Indispensable for Evaluation of Kidney Disease. NCBI. [Online] December 28, 2017. [Cited: April 19, 2018.] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746836/.
MORE FEATURED REAGENTS
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Cardiac Testing Panel
Regular cardiovascular disease (CVD) screening is vital to ensure that cardiac risk factors are detected in the earliest stages 1. Early CVD diagnosis aids in reducing the risk of a secondary cardiovascular event through ensuring early intervention and effective treatment plan implementation, thus aiding in the prevention of premature deaths. Early risk assessment is imperative in those with the greatest risk of CVD. This is evaluated through the identification of one or more risk factors including: hypertension, diabetes or hyperlipidaemia 2, 3. It is believed by 2030, almost 23.6 million people will die from CVD, mainly coronary heart disease (CHD) and cerebrovascular disease (CVA), and this is projected to remain the leading causes of death. This provides further confirmation that early diagnosis is vital to prevent and reduce the number of deaths attributed to CVD 3.
Randox offers an extensive range of 21 third party cardiac & lipid testing assays which includes superior performance and unique tests, which are internationally recognised as being of the highest quality; producing accurate and precise results.
Niche Tests
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Randox offers a range of niche tests including: Adiponectin, H-FABP and sdLDL-C. This means that Randox are one of the only manufacturers to offer these tests in an automated biochemistry format.
Superior Performance Tests
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Randox offers numerous cardiac & lipid testing assays that utilise a superior methodology, providing more accurate results. For example, the Randox Lp(a) test is one of the only methodologies on the market that detects the non-variable part of the Lp(a) molecule and therefore suffers from minimal size related bias.
Strong Correlation with Standard Methods
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The Randox cardiac & lipid testing assays display strong correlations when compared against standard methods, offering trust and confidence in results.
Wide Measuring Ranges
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The Randox cardiac & lipid testing assays can comfortably detect levels outside of the healthy range for the accurate detection of abnormal levels, offering peace of mind in patient samples.
Applications Available
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Applications are available detailing instrument-specific settings for the convenient use of the Randox cardiac & lipid testing assays on a wide range of clinical chemistry analysers.
The in vitro diagnostics market is continuously adapting to the changes in laboratory testing. Consequently, Randox have continued to reinvest in R&D to produce a variety of cardiac & lipid testing assays, including superior performance & unique tests, offering laboratories choice, quality and innovation.
The Randox Reagents range of cardiac & lipid testing assays encompasses superior performance & unique tests enabling laboratories to expand their routine test menus without expanding their labs. Not only does Randox Reagents provide confidence in patient results, the outstanding assay development in combination with superior performance methodologies contribute to the uncompromised quality offered by Randox Reagents. Moreover, laboratories can benefit from advanced assay testing with Randox Reagents.
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Adiponectin has been identified as having pleiotropic functions widely associated with anti-atherogenic, anti-diabetic, cardioprotective and anti-inflammatory effects. Adiponectin levels inversely correlate with insulin levels, BMI, triglyceride levels, insulin resistance (IR), glucose, and most importantly, visceral fat accumulation 4.
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A niche product from Randox, H-FABP is a highly sensitive and early risk marker of acute coronary syndrome, detectable as early as 30 minutes following the onset of an ischaemic episode. The implementation of a combined H-FABP high sensitivity troponin algorithm at an emergency department could aid in the identification of non-AMI patients on arrival, with the potential to reduce hospital admission by 36.8% 5.
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Hyperhomocysteinemia can cause inflammation of the endothelium. Failure to lower homocysteine levels can cause further inflammation of the arteries, veins, and capillaries causing atherosclerosis. Women with elevated levels of homocysteine have a 3-fold increased risk of CVD, whereas men have a 2-fold increased risk 6.
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A unique product from Randox, Lp(a) has proven to have a causal role in the pathogenesis of atherosclerotic and thrombotic vascular diseases 7. The Randox Lp(a) assay is one of the only methodologies on the market that detects the non-variable part of the Lp(a) molecule and therefore suffers minimal size related bias.
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A niche product from Randox, sdLDL-C, a subtype of LDL cholesterol, can more readily permeate the inner arterial wall. Research indicates that individuals with a predominance of sdLDL-C have a 3-fold increased risk of myocardial infarction 8.
Current Challenges
A combination of lifestyle factors can lead to a gradual build-up of fatty material (atheroma) in the arterial wall. The widespread accumulation of atheroma’s, otherwise known as atherosclerosis, can lead CHD. The disease develops gradually over many years, however as the symptoms are scarce, patients are unaware of the disease until chest pain onset. Pain and discomfort may arise if the arteries become so narrow that a limited amount of oxygenated blood can reach the heart (angina). If the problem persists and a piece of the atheroma breaks away a clot can form. If the clot blocks the coronary artery, the oxygen supply to the heart will be stopped resulting in myocardial infarction (heart attack). Continuous development of CHD causes the heart to weaken which can lead to heart failure 9.
Cerebrovascular disease includes a range of conditions that affect the flow of blood through the brain. This change in blood flow can lead to a temporary or permanent impairment of a patient’s brain function. The most common type of cerebrovascular disease is stroke. There are three main types of stroke; transient ischaemic attack, ischaemic stroke and haemorrhagic stroke, however an estimated 87% of strokes are ischaemic. An ischaemic stroke occurs when a blood clot prevents blood flow to the brain. An ischaemic stroke can be embolic, where the blood clot travels from another part of the body to the brain, or thrombotic, where the clot forms in the blood vessel in your brain 10.
PAD is a circulatory problem where narrowing of the arteries reduces the blood flow to the limbs. It can also be a sign of widespread accumulation of fatty deposits in the arteries, otherwise known as atherosclerosis. This could mean that there is reduced blood flow to the heart, brain and legs. The symptoms associated with PAD are mild or non-existent however in some cases patients can experience claudication symptoms. Claudication symptoms involve painful cramping in the hips, thighs or calf muscles triggered after completing certain activities such as walking. The location of pain depends on the position of the narrowed artery; however, the calf is most common. Other signs include leg numbness, a change in leg colour, shiny skin and weak pulse in the legs or feet. The pain of claudication can disappear after a few minutes rest, however, if the disease is left to progress the pain may occur when at rest and can become intense enough to disrupt sleep 11.
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References
[1] National Health Service (NHS). Cardiovascular disease. [Online] September 17, 2018. [Cited: November 30, 2018.] https://www.nhs.uk/conditions/cardiovascular-disease/.
[2] National Institute for Health and Care Excellence (NICE). Cardiovascular disease risk assessment and prevention. [Online] no date. [Cited: November 30, 2018.] https://bnf.nice.org.uk/treatment-summary/cardiovascular-disease-risk-assessment-and-prevention.html.
[3] World Health Organization (WHO). Cardiovascular diseases (CVDs). [Online] May 17, 2017. [Cited: November 30, 2018.] http://www.who.int/en/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds).
[4] New Insight into Adiponectin Role in Obesity and Obesity-Related Diseases. Nigro, Ersilia, et al. Napoli : BioMed Research International, 2014, Vol. 2014.
[5] Navarro CO, Kurth MJ, Lamont JV, Menown IB, Ruddock MW, Fitzgerald SP et al. Diagnostic Performance of a Combination Biomarker Algorithm for Rule-Out of Acute Myocardial Infarction at Time of Presentation to the Emergency Department, Using Heart-Type Fatty Acid-Binding Protein and High-Sensitivity Troponin T tests. Journal of Clinical & Experimental Cardiology 2018, Vol. 9
[6] Role of homocysteine in the development of cardiovascular disease. Ganguly, P and Alam, SF. 6, Riyadh, Kingdom : Nutrition Journal, 2015, Vol. 14.
[7] Lipoprotein(a). von Eckardstein, Arnold. 20, s.l. : European Heart Journal, 2017, Vol. 38.
[8] Austin. MA, et at, “Low-density lipoprotein subclass patterns and risk of MI”. JAMA 260, 1917, 1988
[9] Bupa. Coronary Heart Disease. Bupa. [Online] Bupa Health. [Cited: November 30, 2018.] https://www.bupa.co.uk/health-information/heart-blood-circulation/coronary-heart-disease.
[10] Nall, Rachel. What are the different types of stroke? Healthline. [Online] Healthline, May 24, 2018. [Cited: November 2018, 2018.] https://www.healthline.com/health/stroke-types.
[11] Mayo Clinic. Mayo Clinic.org. Peripheral artery disease (PAD). [Online] Mayo Clinic. [Cited: November 30, 2018.] https://www.mayoclinic.org/diseases-conditions/peripheral-artery-disease/symptoms-causes/syc-20350557.
Total Bile Acids: The Value of Fifth Generation Tests
Bile acids are water-soluble, amphipathic end products of cholesterol metabolism and are involved in liver, biliary and intestinal diseases. They are formed in the liver and are absorbed in the small intestine before being excreted. The fundamental role of bile acids is to aid in the digestion and absorption of fats and fat-soluble vitamins in the small intestine.1
Intrahepatic Cholestasis of Pregnancy
Intrahepatic cholestasis of pregnancy (ICP) is a pregnancy-specific liver disorder. It can be indicated by pruritus, jaundice, elevated total bile acids and/or serum transaminases and usually affects women during the second and third trimester of pregnancy.2,3
Intrahepatic Cholestasis of pregnancy or Obstetric Cholestasis is a condition that restricts the flow of bile through the gallbladder resulting in a build-up of bile acids in the liver.3 Due to the build-up, bile acids leak into the bloodstream where they are detected at concerning levels. It is an extremely serious complication of pregnancy that can lead to the increased risk of premature birth or even stillbirth, as such it is vital that women with the disease are monitored carefully.
In healthy pregnancies, there is very little increase in total bile acid levels although a slight increase is likely to be seen in the third trimester. Measurement of total bile acids in serum is thought to be the most suitable method of diagnosing and monitoring ICP.6
According to several reports total bile acid levels in ICP can reach as high as 100 times the upper limit of a normal pregnancy. It has been reported that a doubling in maternal serum bile acids, results in a 200% increased risk of stillbirth with total bile acids thought to trigger the onset of preterm labour. Additionally, bile acids can affect the foetal cardiovascular system as it has been found that there are often cardiac rhythm disturbances in the foetus due to the elevated bile acids in circulation.5
Although it is a rare condition, with only 0.3-0.5% of women likely to develop ICP, it can have extreme risks and so it is important to properly diagnose and monitor the condition.6 ICP increases the risk of meconium staining of the amniotic fluid and is reported to be a sign of foetal distress. This complication is found in 16-58% of all ICP cases, worryingly 100% of cases have resulted in foetal death. The frequency of this condition is found to be greater in pregnancies with higher levels of serum total bile acids.
Risk factors
There are several risk factors associated with ICP such as a family history of ICP, use of oral contraceptives, assisted reproduction techniques and multiple gestation. Genetic influence accounts for approximately 15% of ICP cases. Dietary selenium is a contributing environmental factor as serum selenium levels often decrease throughout pregnancy. Further to this, incidences of ICP rise in the winter months, most likely due to the fact selenium levels are naturally less during these months.7,8
Total Bile Acids
In addition to ICP, bile acid levels are also measured in the diagnosis of other liver disorders. The bile acids test in an extremely sensitive indicator of liver function, capable of detecting changes in hepatic function before clinical symptoms arise, thus providing valuable information that standard liver function tests cannot. As a result of its high sensitivity, bile acids can be used to assess liver function in transplant patients, allowing monitoring of the transplant success and of antirejection therapy. The bile acids test is most beneficial when used in conjunction with standard liver function tests such as ALT and AST which are markers of liver damage rather than liver function.
Measurement of Total Bile Acids
The enzyme cycling method, also known as the Fifth Generation Bile Acids test, is a method that allows for signal amplification through cycled regeneration reactions as can be seen in Figure 1. In the presence of Thio-NAD, the enzyme 3-α hydroxysteroid dehydrogenase (3-α HSD) converts bile acids to 3-keto steroids and Thio-NADH. The reaction is reversible and 3-α HSD can convert 3-keto steroids and Thio-NADH to bile acids and Thio-NAD. In the presence of excess NADH, the enzyme cycling occurs efficiently and the rate of formation of Thio-NADH is determined by measuring specific change of absorbance at 405 nm and is proportional to the amount of total bile acids in the sample. The analysing capability of the fifth generation total bile acids assay is far beyond the performance of conventional bile acid tests.10,11
Figure 1: The assay principle⁹
Inadequacies of Traditional Bile Acids Assays
Determining the cause and extent of liver damage is important in guiding treatment decisions and preventing disease progression. Standard liver function tests include; ALT, AST, ALP, GGT and Bilirubin. The measurement of TBA is most beneficial in conjunction with these standard liver tests and offers unrivalled sensitivity allowing identification of early stage liver dysfunction. There are several commercial methods available for the detection and measurement of TBA in serum. Traditional TBA tests based on the enzymatic method use nitrotetrazolium blue (NBT) to form a formazan dye. The reaction is measured at 546nm and the intensity of the colour is proportional to the concentration of bile acids.
Newer methods such as the enzyme cycling method or fifth generation methods offer many advantages including greater sensitivity, liquid reagents, small sample volumes and reduced instrument contamination from formazan dye. Additionally, the fifth generation assay does not suffer from interference from lipaemic or haemolytic samples. Both lipemia and haemolysis are common in new-borns and pregnant women, so this further supports that the fifth generation test is more sensitive for these sample types.12
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References
[1] The continuing importance of bile acids in liver and intestinal disease. A.f., Hofmann. 1999, Arch Intern Med, pp. 2647-2658.
[2] Diagnostic and Therapeutic Profiles of Serum Bile Acids in Women with Intrahepatic Cholestasis of Pregnancy – A Pseudo-Targeted Metabolomics Study. Cui, Yue. Xu, Biao. Zhang, Xiaoqing. He, Yifan. Shao, Yong. Ding, Min. s.l. : Clinica Chimica, 2018, Vol. 483.
[3] Randox Laboratories. Bile Acids Test for Obstetric Cholestasis – A serious complication of pregnancy. 2012.
[4] British Liver Trust (2019) Facts about Liver Disease, Available at: https://www.britishlivertrust.org.uk/about-us/media-centre/facts-about-liver-disease/ (Accessed: 18th June 2019).
[5] .Geenes, Victoria. Williamson, Catherine. 17, s.l. : World J Gastroenterol, 2009, Vol. 15.
[6] Howland, Genevieve. Cholestasis of Pregnancy: Why You Can’t Ditch the Itch. Mama Natural. [Online] December 22, 2018. [Cited: February 19, 2019.] https://www.mamanatural.com/cholestasis-of-pregnancy/.
[7] Bile Acid Levels and Risk of Adverse Perinatal Outcomes in Intrahepatic Cholestasis of Pregnancy: A Meta-Analysis. Cui, Donghua, et al.
[8] Intrahepatic Cholestasis of Pregnancy. Chivers, Sian. Williamson, Catherine. 7, 2018, Vol. 28.
[9] Masoud, N; Neill, S.H. Serum bile acids as a sensitive biological marker for evaluating hepatic effects of organic solvents. Available from URL: https://www.ncbi.nlm.nih.gov/pubmed/23885947 [Accessed 1 November 2018]
[10] Microassay of Serum Bile Acids by an Enzymatic Cycling Method. Komiyama, Y, et al. 10, s.l. : Chemical and Pharmaceutical Bulletin, 1982, Vol. 30.
[11] Evaluation of a Colorimetric Enzymatic Procedure for Determining the Total Bile Acids in the Blood. Agape, V, et al. 3, s.l. : Minerva Gastroenterologica e Dietologica, 1989, Vol. 35.
[12] Total Bile Acids Test & Clinical Diagnosis. Diazyme. 2019.
Superior Performance & Unique Tests
Superior Performance & Niche Reagents
Randox offer a range of high performance, unique and niche reagents that are designed to enhance your laboratory testing capabilities.
Our impressive portfolio of high performance & unique tests together with our standard assays sets us apart in the in vitro diagnostics market. Our superior performance reagents and methodologies deliver highly accurate and specific results, that can facilitate earlier diagnosis of disease states with confidence and precision.
Benefits of High Performance Reagents
Reduce Costs
We can help create cost-savings for your laboratory through excellent stability, eliminating the requirement for costly test re-runs. Our quality reagents also come in a range of different kit sizes to reduce waste and for your convenience.
Confidence in Patient Results
Our traceability of material and extremely tight manufacturing tolerances ensure uniformity across our reagent batches. All of our assays are validated against gold-standard methods.
Applications Available
Applications are available detailing instrument-specific settings for the convenient use of the Randox superior performance & unique assays on a wide variety of clinical chemistry analysers.
Superior Performance Offering
Randox offer an extensive range of 115 assays across routine and niche tests, and cover over 100 disease makers. Our high performance assays deliver superior methodologies, more accurate and specific results compared to traditional methods.
Reduce Labour
Reduce valuable time spent running tests. Randox reagents come in liquid ready-to-use formats and various kit sizes for convenient easy-fit. Barcode scanning capabilities for seamless programming.
Unique Offering
Our range of unique assays means that Randox are one of the only manufacturers to offer these tests in an automated biochemistry format.
The in vitro diagnostics market is continuously adapting to the changes in laboratory testing. Consequently, Randox have continued to reinvest in R&D to produce superior performance & unique tests offering laboratories choice, quality and innovation.
The Randox Lp(a) assay is calibrated in nmol/l and traceable to the WHO/IFCC reference material (IFCC SRM 2B) and provides an acceptable bias compared with the Northwest Lipid Metabolism Diabetes Research Laboratory (NLMDRKL) gold standard. A five-point calibrator with accuracy-based assigned target values (in nmol/l) is available, accurately reflecting the heterogeneity of the apo(a) isoforms.
The Randox bile acids test utilises an advanced enzyme cycling method which displays outstanding sensitivity and precision when compared to traditional enzymatic based tests. The Randox 5th Generation Bile Acids test is particularly useful in paediatrics where traditional bile acids tests are affected by haemolytic and lipaemic samples.
A superior assay from Randox, the vanadate oxidation method offers several advantages over the diazo method, including less interference by haemolysis and lipaemia, which is particularly evident for infant and neonatal populations.
The Randox Fructosamine assay utilises the enzymatic method which offers improved specificity and reliability compared to conventional NBT-based methods. The Randox enzymatic method does not suffer from non-specific interferences unlike other commercially available fructosamine assays.
Soluble transferrin receptor (sTfR) is a marker of iron status. In iron deficiency anaemia, sTfR levels are significantly increased, however remain normal in the anaemia of inflammation. Consequently, sTfR measurement is useful in the differential diagnosis of microcytic anaemia.
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Featured Reagent – G6PDH
Featured Reagent | G6PDH
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Glucose-6-phosphate dehydorgenase (G6PDH/G6PD) deficiency is an x-linked and sex-linked metabolic disorder, commonly affecting men more so than women1. The G6PDH enzyme is critical for the proper functioning of red blood cells (RBC’s). Depleated levels of G6PDH can cause the premature destruction of RBC’s (haemolysis). If the bone marrow cannot compensate for the reduction in RBC’s, heamolyic anaemia can develop. It is important to note that a deficiency in the G6PDH enzyme is not enough to promote the onset of haemolysis, but rather additional factors are required to promote the onset of symptoms2.
Some of the common side effects of G6PDH deficiency include: paleness, dark urine, yellowing of the skin and whites of the eyes, a rapid heart rate and shortness of breath. Common triggers for the development of haemolytic anaemia in those who are G6PDH deficient include: bacterial and viral infections, certain drugs (medications and antibiotics to treat malaria), and favism (inhaling the pollen from fava plants and ingesting fava beans)3
G6PDH deficiency has been recognised as a significant cause of mild to severe jaundice in newborns. It has been noted that those with this disorder commonly will not experience any signs or symptoms making them unaware that they have the condition3.
Haemolytic Anaemia
Haemolytic anaemia is an umbrella term used to describe the premature destruction of red blood cells (RBC’s). This disorder encompasses numerous conditions including: autoantibodies, medications, underlying malignancy, bone marrow failure, infection and heredity conditions including sickle cell disease or haemoglobinopathies4 5.
The severity of haemolytic anaemia depends on whether the onset of haemolysis is gradual or rapid and on the extent of RBC destruction. Patients with mild haemolysis can be asymptomatic whereas the anaemia in severe haemolysis can be life-threatening and can cause angina and cardiopulmonary decompensation. Haemolytic anaemia is an intravascular phenomenon meaning that this type of haemolysis occurs within the blood vessels and is caused by the following conditions: prosthetic cardiac valves, glucose-6-phosphate dehydrogenase (G6PDH) deficiency, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation, transfusion of ABO incompatible blood and paroxysmal nocturnal haemoglobinuria (PNH)6.
Heredity disorders can also cause haemolysis due to the erythrocyte membrane and haemoglobin abnormalities, and enzymatic defects. Some hereditary disorders include: G6PDH deficiency, hereditary spherocytosis and sickle cell anaemia6.
Glucose-6-phosphate dehydrogenase (G6PDH) is a cytosolic enzyme located on the X-chromosome found in bodily cells. G6PDH is involved in the normal processing of carbohydrates and plays a critical role in RBC, protecting them from damage and premature destruction. The two main products of G6PDH are ribose-5-phosphate which is important for DNA, the chemical cousin of RNA. The chemical reaction produces NADPH which protects bodily cells from reactive oxygen species1.
Benefits of the G6PDH Assay
A niche assay from Randox meaning that Randox are one of the only manufacturers to offer a G6PDH assay in an automated biochemistry format.
Superior stability of 4 weeks upon reconstitution and stored at +2°C to +8°C. Many other commercially available assays offer only 5 days stability, leading to product wastage.
Minimal interference as the sample pre-wash step included in the Randox G6PDH testing method serves to purify the sample, leading to no known interferences being observed.
Excellent correlation coefficient of r=0.99 when compared against other commercially available methods.
Lyophilised reagent for enhanced stability.
UV method
G6PDH controls offering a complete testing package.
Applications available detailing instrument-specific settings for the convenient use of the Randox G6PDH assay on a wide range of clinical chemistry analsyers.
References
[1] Croom, Edward. Progress in Molecular Biology and Translational Science. 2012. ISBN 9780124158139 / ISSN 1877-1173.
[2] National Organization for Rare Disorders. Glucose-6-Phosphate Dehydrogenase Deficiency. [Online] no date. [Cited: January 31, 2019.] https://rarediseases.org/rare-diseases/glucose-6-phosphate-dehydrogenase-deficiency.
[3] U.S. National Library of Medicine. Glucose-6-phosphate dehydrogenase deficiency. [Online] May 2017. [Cited: January 30, 2019.] https://ghr.nlm.nih.gov/condition/glucose-6-phosphate-dehydrogenase-deficiency.
[4] National Heart, Lung, and Blood Institute. Hemolytic Anemia. [Online] no date. [Cited: January 28, 2019.] https://www.nhlbi.nih.gov/health-topics/hemolytic-anemia.
[5] BMJ Publishing Group. Hemolytic anemia. BMJ Best Practice. [Online] March 2018. [Cited: January 28, 2019.] https://bestpractice.bmj.com/topics/en-us/98.
[6] Schick, Paul. Hemolytic Anemia. Medscape. [Online] December 29, 2018. [Cited: Janaury 28, 2018.] https://emedicine.medscape.com/article/201066-overview.
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Niche Reagents – Zinc, Copper & Aldolase
Reagents | Zinc, Copper & Aldolase
Advancing Routine Testing with Randox Reagents
Randox offer an extensive range of 115 third party diagnostic reagents which are internationally recognised as being of the highest quality; producing accurate and precise results. Continually reinvesting in R&D, Randox continue to offer the opportunity to expand your test menu without expanding your lab. Not only does Randox offer superior performance assays, but also niche assays, meaning that Randox are one of the only manufacturers to offer the test in an automated biochemistry format.
Zinc
A niche assay from Randox meaning that Randox are one of the only manufacturers to offer a clinical chemistry zinc assay
Strong correlation with standard methods as the Randox zinc assay showed a correlation coefficient of r=0.9946 when compared against standard methods
A measuring range of 11.3 – 159 µmol/l for the comfortable and accurate detection of abnormal levels
Liquid ready-to-use reagents for convenience and ease-of-use
Stable to expiry date when stored at +15 to +25°C
Applications are available detailing instrument-specific settings for the convenient use of the Randox zinc assay on a wide range of clinical chemistry analysers
An essential trace metal and the only metal present in all enzyme classes, zinc is the second most abundant micronutrient in humans after iron. Zinc is required for a healthy immune system, a healthy growth rate during pregnancy, childhood and adolescence, wound health and synthesizing DNA. Zinc can modulate brain excitability and is vital in the synaptic plasticity of the brain which is thought to contribute towards memory and learning. Zinc has also been identified as a neurotoxin which suggests that zinc homeostasis is involved in the normal functioning of the central nervous system and the brain 1.
Zinc deficiency is identified as a malnutrition problem worldwide, especially in areas of high cereal intake and low animal food intake. However, other factors may contribute to low zinc levels including: the bioavailability of zinc, chronic illnesses such as diabetes, malignancy, hepatic disease and sickle cell disease. Higher zinc requirements have been identified in infants, children, adolescents, and pregnant and lactating women compared to adults. During periods of growth, zinc deficiency can result in growth failure. The most common organs affected by zinc deficiency clinically include: central nervous system, gastrointestinal, epidermal, skeletal, immune, and reproductive systems 2 3.
Copper
A niche assay from Randox meaning that Randox are one of the only manufacturers to offer a clinical chemistry copper assay
Exceptional correlation with standard methods as the Randox copper assay showed a correlation coefficient of r=0.99 when compared against standard methods
A wide measuring range of 6.6 – 86 µmol/l for the comfortable and accurate detection of abnormal levels
Lyophilised reagents for enhanced stability
Excellent stability of 2 weeks when stored at +2 to +8°C
Applications are available detailing instrument-specific settings for the convenient use of the Randox copper assay on a wide range of clinical chemistry analysers
An essential trace metal, copper is the third most abundant micronutrient in humans after iron and zinc. Copper is mainly found in the brain, liver, kidneys, heart and skeletal muscle with the highest quantities found in the liver and muscles. It aids in some of the key bodily functions including: the production of red blood cells, the maintenance of nerve cells and the immune system, the formation of collagen to absorb iron for energy production, and the formation of melanin, bone and connective tissue. Ceruloplasmin is the protein responsible for the transportation of copper around the body 4.
There are various health problems that can cause abnormal copper levels, however deficiency is less likely than toxicity because a normal diet contains plenty of copper including: organic meats, beans and wholegrains. Deficiency is more likely to occur in those who are malnourished, more likely children.
Deficiency more commonly occurs in premature babies, resulting in bone abnormalities and fractures. Menkes Disease is a rare inherited genetic disorder of copper metabolism and is characterised by sparse and kinky hair as children with this disorder are unable to absorb enough copper 5.
Toxicity can be caused by consuming too many dietary supplements high in copper, from drinking contaminated water, or from fungicides containing copper sulphates. Wilson disease is a rare inherited disorder that prohibits the liver from safely storing and excreting copper resulting in it seeping out of the liver and building up in the eyes, liver, kidneys and brain causing nerve damage, and if untreated, it can be fatal 6.
Aldolase
A niche assay from Randox meaning that Randox are one of the only manufacturers to offer a clinical chemistry aldolase assay
Excellent correlation coefficient of r=0.9917 when compared against other commercially available methods
A wide measuring range of 1.73 – 106 µmol/l for the comfortable and accurate detection of abnormal levels
Lyophilised reagents for enhanced stability
UV Method
Applications are available detailing instrument-specific settings for the convenient use of the Randox aldolase assay on a wide range of clinical chemistry analysers
There are three types of Aldolase enzymes that can be can be found throughout the body: A, B and C. It is responsible for converting glucose into energy.
A is primarily contained within the muscle and erythrocytes, whereas B is contained within the liver, enterocytes and kidney, and A and C can be found within the brain. Despite the Aldolase enzyme existing throughout the body, the highest concentration levels of it can be found in the liver and the skeletal muscle, although testing this enzyme is routinely used for skeletal muscle damage 7.
Elevated levels of type A aldolase in the blood can be found in patients with damage to the skeletal muscle as the result of a trauma which includes dermatpmyositis, infectious mononucleosis, muscular dystrophy, myocardial infarction, hepatic cancer due to the damaged cells triggering the release of A into the blood. On the other hand, the concentration levels of A in the blood remain normal in situations where weakness is caused as the result of a neurological disease such as multiple sclerosis. Measuring A concentration levels in the blood can therefore be used to determine the root cause of muscle weakness, whether muscle trauma or neurological myopathy, in patients 7.
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References
[1] Osredkar, Josko and Sustar, Natasa. Copper and Zinc, Biological Role and Significance of Copper/Zinc Imbalance. 1, s.l. : Journal of Clinical Toxicology, 2011, Vol. 3.
[2] Jockers, Dr. David. How To Test Zinc Levels At Home. DrJockers.com. [Online] 2019. [Cited: November 28, 2018.] https://drjockers.com/test-zinc-levels-home/..
[3] Roohani, Nazanin, et al. Zinc and its importance for human health: An integrative review. National Center for Biotechnology Information. [Online] J Res Med Sci, February 18, 2013. [Cited: November 28, 2018.] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724376/..
[4] Nordqvist, Joseph. What are the health benefits of zinc? Medical News Today. [Online] December 5, 2017. [Cited: November 28, 2018.] https://www.medicalnewstoday.com/articles/263176.php.
[5] Macfarlane, Susan. Understanding Nutrient Ratios: Zinc/Copper. Susan Macfarlane. [Online] October 29, 2017. [Cited: November 28, 2018.] https://susanmacfarlanenutrition.com/understanding-nutrient-ratios-zinccopper/.
[6] National Center for Advancing Translational Sciences. Menkes disease. National Center for Advancing Translational Sciences. [Online] Genetic and Rare Disease Information Center, April 7, 2017. [Cited: November 30, 2018.] https://rarediseases.info.nih.gov/diseases/1521/menkes-disease.
[7] Berridge, Brian R, Van Vleet, John F and Herman, Eugene. Chapter 46 – Cardiac, Vascular, and Skeletal Muscle Systems. 2013.
Featured Reagent – Copper & Zinc
Featured Reagents | Copper & Zinc
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Nutrient Testing
Copper and zinc are essential trace minerals, found in all bodily cells and they are necessary for survival. Although, their roles within the body differ. Copper is essential to produce red blood cells and zinc is essential for the proper function of the immune system (1) (2). Whilst both of these nutrients exist naturally in the environment including water and food, both nutrients can exist in the body in higher or lower than normal concentrations which can cause major health complications (3).
Copper
A niche assay from Randox meaning that Randox are one of the only manufacturers of the clinical chemistry Copper assay
Exceptional correlation with standard methods as the Randox Copper assay showed a correlation coefficient of r=0.99 when compared against standard methods
A wide measuring range of 6.6 – 86 µmol/l for the comfortable and accurate detection of abnormal levels
Lyophilised reagents for enhanced stability
Excellent stability of 2 weeks when stored at +2 to +8°C
Applications are available detailing instrument-specific settings for the convenient use of the Randox Copper assay on a wide range of clinical chemistry analysers
Copper is mainly found in the brain, liver, kidneys, heart and skeletal muscle with the highest quantities found in the liver and muscles. It aids in some of the key bodily functions including: the production of red blood cells, the maintenance of nerve cells and the immune system, the formation of collagen to absorb iron for energy production, and the formation of melanin, bone and connective tissue. Ceruloplasmin is the protein responsible for the transportation of Copper around the body (4).
There are various health problems that can cause abnormal copper levels, however deficiency is less likely than toxicity because a normal diet contains plenty of copper including: organ meats, beans and wholegrains. Deficiency is more likely to occur in those who are malnourished, more likely children.
Deficiency more commonly occurs in premature babies, resulting in bone abnormalities and fractures. Menkes Disease is a rare inherited genetic disorder of copper metabolism and is characterised by sparse and kinky hair as children with this disorder are unable to absorb enough copper (5).
Toxicity can be caused by consuming too many dietary supplements high in copper, from drinking contaminated water, or from fungicides containing copper sulphates. Wilson disease is a rare inherited disorder that prohibits the liver from safely storing and excreting copper resulting in it seeping out of the liver and building up in the eyes, liver, kidneys and brain causing nerve damage, and if untreated, it can be fatal (6).
Zinc
A niche assay from Randox meaning that Randox are one of the only manufacturers of the clinical chemistry zinc assay
Strong correlation with standard methods as the Randox Zinc assay showed a correlation coefficient of r=0.9946 when compared against standard methods
A measuring range of 11.3 – 159 µmol/l for the comfortable and accurate detection of abnormal levels
Liquid ready-to-use reagents for convenience and ease-of-use
Stable to expiry date when stored at +15 to +25°C
Applications are available detailing instrument-specific settings for the convenient use of the Randox Zinc assay on a wide range of clinical chemistry analysers
Zinc is required for various biological processes including: cell and enzyme production; the functionality of enzymes, metabolism of carbohydrates, fat and protein from dietary intake; wound healing; and the stabilisation of DNA (7) (8).
Zinc deficiency is identified as a malnutrition problem worldwide, especially in areas of high cereal intake and low animal food intake. However, other factors may contribute to low zinc levels including: the bioavailability of zinc, chronic illnesses such as diabetes, malignancy, hepatic disease and sickle cell disease. Higher zinc requirements have been identified in infants, children, adolescents, and pregnant and lactating women compared to adults. During periods of growth, zinc deficiency can result in growth failure. The most common organs affected by zinc deficiency clinically include: central nervous, gastrointestinal, epidermal, skeletal, immune, and reproductive systems (9) (10).
References
[1] Ware, Megan. Health benefits and risks of copper. Medical News Today. [Online] October 23, 2017. [Cited: November 28, 2018.] https://www.medicalnewstoday.com/articles/288165.php.
[2] Medline Plus. Zinc in diet. Medline Plus. [Online] November 13, 2018. [Cited: November 28, 2018.] https://medlineplus.gov/ency/article/002416.htm.
[3] Jockers, Dr. David. Do You Have A Copper and Zinc Imbalance? DrJockers.com. [Online] 2017. [Cited: November 28, 2018.] https://drjockers.com/copper-zinc-imbalance/.
[4] Macfarlane, Susan. Understanding Nutrient Ratios: Zinc/Copper. Susan Macfarlane. [Online] October 29, 2017. [Cited: November 28, 2018.] https://susanmacfarlanenutrition.com/understanding-nutrient-ratios-zinccopper/.
[5] National Center for Advancing Translational Sciences. Menkes disease. National Center for Advancing Translational Sciences. [Online] Genetic and Rare Disease Information Center, April 7, 2017. [Cited: November 30, 2018.] https://rarediseases.info.nih.gov/diseases/1521/menkes-disease.
[6] Mayo Clinic. Wilson’s disease. Mayo Clinic. [Online] March 7, 2018. [Cited: November 30, 2018.] https://www.mayoclinic.org/diseases-conditions/wilsons-disease/symptoms-causes/syc-20353251.
[7] Frassinetti, S, et al. The roel of zinc in life: a review. National Center for Biotechnology Information. [Online] J Environ Pathol Toxicol Oncol, 2006. [Cited: November 28, 2018.] https://www.ncbi.nlm.nih.gov/pubmed/17073562..
[8] Jockers, Dr. David. How To Test Zinc Levels At Home. DrJockers.com. [Online] 2019. [Cited: November 28, 2018.] https://drjockers.com/test-zinc-levels-home/..
[9] Roohani, Nazanin, et al. Zinc and its importance for human health: An integrative review. National Center for Biotechnology Information. [Online] J Res Med Sci, February 18, 2013. [Cited: November 28, 2018.] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3724376/..
[10] Nordqvist, Joseph. What are the health benefits of zinc? Medical News Today. [Online] December 5, 2017. [Cited: November 28, 2018.] https://www.medicalnewstoday.com/articles/263176.php.
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