Medical Biochemistry

Since 1998, all wheat white flours for food use sold in Canada and United States are enriched with folic acid as a mandatory legal requirement. The main reason for this supplementation is to prevent neural tube defects in newborns. Folates are found in processed food that contains white flour and in green leafy vegetables, legumes, some fruits and beans.  Folate deficiency is therefore now encountered very rarely in Canada.

For most patients at risk for folate deficiency, like those with malabsorption, it is more practical and economical to treat with multivitamin supplements including folic acid, than to test for deficiency.

The Society of Obstetricians and Gynecologists of Canada recommends universal supplementation for women in the reproductive age group. Investigations are not required prior to initiating folic acid in women considering pregnancy.

ESR is a non-specific inflammation marker influenced by various factors including anemia, pregnancy, and smoking. C-reactive protein (CRP) is a less expensive and more sensitive and specific reflection of the acute phase of inflammation, hence should be used for this purpose. In the first 24 hours of a disease process, the CRP will be elevated, while the ESR may be normal. If the source of inflammation is removed, CRP will normalize within a day or so, while ESR will remain elevated for days.  Only CRP should be used as a measure of systemic inflammation.

In pancreatitis, levels of amylase and lipase have been found to correlate very well. However, multiple studies have shown that lipase is a more sensitive and specific marker of acute pancreatitis than amylase. Moreover, lipase stays elevated longer than amylase, which is useful in cases of delayed presentation. However, false negative results may still be observed after many days, but amylase is not helpful in those cases. For children, pediatric specific reference ranges should be adapted.

Serum protein electrophoresis (SPE) is mainly indicated to detect monoclonal gammopathy in patients who have clinical symptoms and signs related to multiple myeloma, amyloidosis, or Waldenstrom macroglobulinemia. It may also be performed in certain uncommon diseases associated with a monoclonal protein like POEMS syndrome and some forms of polyneuropathy.

About 3% of the population above the age of 50, have a monoclonal gammopathy of undetermined significance (MGUS). Current practice guidelines do not recommend routine screening for MGUS in the general population because of the lack of proven benefit, absence of actionable preventive therapy and creation of unnecessary anxiety for some patients.

SPE is not a sensitive test to detect inflammation, C-reactive protein is a better and less costly alternative that is more responsive to changes in the patient status.

Although evidence of a causative link between hyperuricemia and cardiometabolic risk is mounting, it still does not support the use of pharmacotherapy and its concentration is not used in equations for estimating vascular risk. Asymptomatic hyperuricemia is a frequent, coincidental, biochemical finding that does not require any treatment.

Uric acid should not be measured routinely, but its measurement may be considered mainly in the following situations:

• Investigation of acute joint pain
• Follow-up of hypouricemic treatment
• Follow-up of patients with kidney disease and kidney stone disease
• Preeclampsia
• Tumor lysis syndrome

Serum total bile acids tests (TBA) are used primarily for the evaluation and monitoring of intrahepatic cholestasis of pregnancy (ICP), a condition affecting 1-2% of pregnant women in North America.

ICP is associated with an increased risk of perinatal complications including premature birth, intrauterine asphyxia, fetal bradycardia and even stillbirth. Severe ICP is defined when serum TBA is above 40 umol/L, and the likelihood of stillbirth is significantly increased when the serum TBA concentration is >100mmol/L, which makes it a good prognostic marker.

However, in non-pregnant individuals with suspected cholestasis, TBA is not an effective test to assess liver dysfunction compared to traditional liver panel tests (e.g., bilirubin, albumin, ALT, GGT and ALP).

In the context of familial intrahepatic cholestasis, the serum TBA is considered as a tier 2 investigation which is ordered by pediatric gastroenterologists only. The urine bile acids profile is the appropriate test for the investigation of disorders of bile acid synthesis,  not serum TBA.

Global developmental delay and intellectual disability (GDD/ID) affect 3% of the paediatric population. Since its differential diagnosis is broad, community –based clinicians tend to order copper and ceruloplasmin tests to screen for Wilson’s and Menkes disease (mutations in ATP7A or ATP7B).

However, a recent study determined that neither Wilson’s nor Menkes disease have been identified using these tests in children with global developmental delay/intellectual disability.

In addition, false abnormal copper and ceruloplasmin results lead to an increase in the number of total referrals and unnecessary follow ups (4% in the above study). Children with Wilson’s disease are more likely to present with hepatic manifestations than neurologic symptoms, while those with Menkes disease show multiple abnormalities including developmental delay and epilepsy typically within the first 3 months of life.

Point-of-care-testing (POCT) should be strategically utilized only in scenarios where it significantly influences immediate treatment decisions and offers a distinct advantage over traditional laboratory testing. Unlike laboratory-based tests, POCT may lead to more frequent false results potentially causing misdiagnoses, incorrect treatment decisions, and unnecessary additional testing or procedures contributing to further increased costs and medical waste. POCT’s reliance on single use, fossil-derived plastics, not only generates considerable waste but also poses environmental and health risks through potential toxic emissions from incineration.

Metanephrines are consistently secreted in pheochromocytomas and paragangliomas (PPGL), whereas catecholamine production is intermittent. The risk of false-negative results is therefore high when plasma catecholamines are used as a first-line screening test (sensitivity 85% and specificity 81%). Current guidelines recommend metanephrines (plasma or urinary) as the preferred initial screening test for PPGL.

Plasma metanephrine testing however has limitations including posture related variability, as patients should ideally be supine for at least 20 mins before sampling via a pre-installed intravenous catheter. Additionally, the samples must be transported on ice because metanephrines are unstable in whole blood if they cannot be processed promptly by the laboratory. This instability is not an issue in urine as collection occurs in acidified containers. These preanalytical challenges make urinary metanephrines a more practical alternative for outpatients as failure to meet these conditions increases the risk of false positives for plasma metanephrines. Both plasma and urinary metanephrines have high sensitivity for screening (99% and 97% respectively) and combining these tests do not improve diagnostic performance.

Joint recommendation with the Canadian Society of Endocrinology and Metabolism

Short stature is defined as height more than 2 SD below the mean (or <2.3rd percentile) for age and sex, assessed using WHO growth charts for Canada. Common nonpathological causes include familial short stature and constitutional delay of growth and puberty. Pathologic causes (e.g. systemic illness, malnutrition, endocrine and genetic causes) should be investigated when growth velocity is reduced on serial measurements over at least 6 to 12 months. Growth hormone (GH) deficiency is rare and should only be suspected when the child’s height is greater than 2 SD below the expected mid-parental range with normal weight, and reduced growth velocity.

Random GH levels should not be ordered: secretion is pulsatile with significant diurnal fluctuations, sleep dependent and influenced by exercise, fasting, intercurrent illness and stress making single measurements unreliable. Diagnosis of GH deficiency requires formal stimulation testing, only indicated in selected circumstances and under endocrinology guidance. IGF-1 level is more stable and may be used as a surrogate marker. However, low IGF-1 is non-specific and can result from malnutrition, systemic illness, liver dysfunction, inflammation, pubertal delay, diabetes or hypothyroidism. GH deficiency is unlikely when IGF-1 is above the mean for age and sex, in a child with normal growth velocity and bone age.

Joint recommendation with the Canadian Society of Endocrinology and Metabolism