Newborn screening of inborn errors of metabolism is based on examination of metabolic profiles and as to whether important biomarkers are outside a normal range.
The problem is that this range is optimized for term newborns. Prematurity and the consequential immature biochemistry, plus the way nutrition is applied in the NICU will create profiles outside these normal ranges. However, that does not mean that the preterm infant has an inborn error of metabolism and that the result is false for this conclusion. Yet, the result is not false – rather, it was the interpretation.
In part 2 of metabolism and nutrition, the data from a newborn screen can be used by the neonatologist to provide information that may be helpful in providing data and understanding in the way nutrition is applied and how the neonatologist responds to that data.
Beyond Newborn Screening: Nutrition and Metabolic Profiles
In two large clinical trials that examine nutrition and metabolism for preterm infants in the NICU, the median values of amino acids, L-carnitine and acylcarnitines were established at four different days over the course of a NICU stay. It was clear from these studies that metabolic profiles reflected the nutritional status of the preterm infant, and that many of those false positive results in newborn screening were not false analytically but rather true for the current metabolism of that infant.
In fact, most preterm infants, at birth, do not have an abnormal amino acids or fatty acid profiles (as represented by acylcarnitines). This changes by day seven, when parenteral nutrition is at its maximum, for not just amino acids but also acylcarnitines.
In fact, organic acylcarnitine, like valproic acid, must be formed from the major amino acid in parenteral nutrition, Leucine, and cannot be a “contaminant” of parenteral nutrition. Rather it is a catabolic (breakdown) product of Leucine that is not incorporated into protein.
Isovaleric acid (observed as isovaleryl carnitine) is produced after removal of the amine nitrogen of this amino acid with the nitrogen forming ammonia, which in turn form urea and is measured as blood urea nitrogen (BUN). In fact, isovaleric acid acylcarnitines parallels that for BUN and is a more specific marker of Leucine catabolism.
When nutrition is nearly completely switched from parenteral to enteral by day 28, the metabolic profiles change dramatically with fewer false results due to high amino acids and elevated organic acid acylcarnitines. However, in about half of the cases, an L-carnitine deficiency is observed. This deficiency is caused by elimination of the acylcarnitines form during catabolism of amino acids and beta oxidation or their organic acids. The carnitine portion of acylcarnitines is not recovered and is eliminated in bile and urine.
At discharge, most infants’ metabolism returns close to normal (day 42). L- carnitine increases in part because of increased endogenous synthesis and its presence in human breast milk and bovine formula (it is highly supplemented). A more extensive discussion of metabolism and profiles in preterm infants will be provided in another blog.
Metabolic Markers: Early Warning Indicators to Toxicity
Most false positive results for preterm infants are not due to laboratory error. The analytical results are generally correct. This issue is with interpretation, regulation, and public health mandates.
In other words, the goal of public health newborn screening is to detect (or rule out) inherited disease. Any presumptive results for hypothyroidism require follow-up to ensure a normal result is achieved.
As described previously, as many as four samples may be collected during a preterm infant’s NICU stay. In addition to abnormal values from metabolites like isovaleryl carnitine (an indicator of the rare disorder, isovaleric acidemia), methionine and tyrosine may be elevated and not simply due to the dose of amino acids.
These metabolites specifically indicate liver metabolic problems that may arise because of an inability to metabolize high amino acid or fatty acids during high dose amino acids and lipid intravenous nutrition. Building blocks of cells, amino acids, and lipids that are not used in growth of that cell are recycled through beta oxidation. That system can be “flooded” with oxidative products in a manner akin to a subway escalator that “backs up” during rush hour: other routes to the platforms are used, some which get backed up more easily (an elevator) while others (stairs) are less so.
The bottom line is that there is a way to monitor these metabolic pathways now. It already exists, in part, in the newborn screening data.
Nutrition is a significant influence on metabolism
Cellular growth requires synthesis of macromolecules including protein, lipids, carbohydrates, and nucleotides from small molecules absorbed through our gut. It also requires energy from these same small molecules. These processes are known as metabolism.
Any defect in these processes is a metabolic disorder. Some of these disorders are rare. They can be treated by dietary intervention as that is what fuels metabolism in part. Most metabolic change that we observe is not due to a rare disease, but may be caused by non-genetic influences such as prematurity, other diseases, infections, adverse drug reactions, the environment etc.
The most significant influence on metabolism is nutrition, as these are the critical components that precede growth and can drive it in a positive state known as anabolism.
However, a lack of nutrition will cause cells to stop multiplication, and in many instances, be recycled for their components to supply critical organs such as the heart and brain with nutrients. There is a dynamic of both processes and it can be observed.
The amino acid and acylcarnitine profile used is newborn screening to detect inborn errors of metabolism can also be observed to monitor anabolic and catabolic processes. The profile enables observation of the building blocks of proteins used in anabolism as well as the breakdown products from proteins being used to provide energy or to store excess components as fat.
Most neonatologists are not aware of this tool that is similar to a newborn screen (same test, different interpretation). Metabolic profiles reveal whether an infant is tolerating nutrition well. They are doing it already using a less precise tool in the form of blood urea nitrogen (BUN). The difference is that BUN is a single test for a single marker analyzed only when needed. The goal of metabolic screening is to do a metabolic checkup® regularly and associated with the various phases of growth and nutrition: from birth to maximum intravenous nutrition, the transitional phase from intravenous nutrition to enteral nutrition, and then to normal feeding required for discharge.
It is difficult to capture the concept of metabolism in a two-part blog. Each topic requires its own examination and discussion.
Nevertheless, much of this work comes out of newborn screening for which there are many resources. Note that one of the reasons newborn screening exists is because these rare diseases are treatable, most of which is through a dietary modification that occurs early in development to prevent toxicity, organic damage, and even death.
It is not difficult to understand the “next step” is the step beyond newborn screening and nutrition. You are using it now, but often simply not aware of it.
About the Author
Donald H. Chace, PhD, MSFS, FACB is the Chief Scientific Officer for Medolac, a public benefit corporation. He is one of the primary developers of newborn metabolic screening using tandem Mass Spectrometry. Developed 25 years ago with the first screening publication in Clinical Chemistry that describes the MS-based newborn screening of PKU, the method is now used to screen millions of infants per year, worldwide. Dr. Chace is an expert in metabolism and clinical chemistry using mass spectrometry as well as microsample analysis, e.g. the dried blood spot. Learn more about Dr. Chace by visiting his LinkedIn profile.