chemistry – Page 6 – Lablogatory

Newborn Screening – a History

Inborn Errors of Metabolism (IEM) are genetic disorders that often occur as enzyme deficiencies which interfere with the normal biochemical processes of the human body. Very often these disorders are not apparent at birth because the mother’s biochemical processes work for the baby in the womb. Shortly after birth, the infant begins to get into significant trouble when his own enzymes are deficient or insufficient to carry the biochemical load. Many of these disorders are eminently treatable, allowing the treated individual to lead a normal life or a life whose quality is vastly improved over untreated individuals. Thus detecting IEM and treating them before the baby becomes ill is the primary purpose of newborn screening (NBS) programs worldwide. The seeds of newborn screening (NBS) in the US began back in the early 1960s when Dr. Robert Guthrie developed a bacterial inhibition assay for phenylalanine and demonstrated that it could be used to screen entire populations for the presence of a devastating yet treatable disease called phenylketonuria (PKU). In 1960 Maine became the first State to offer newborn screening for PKU to all infants born in Maine.

In the years that followed this advent, the prevalence of NBS grew slowly and sporadically. Along the way there was debate over which disorders to include; at one time a disorder had to meet a long list of criteria to be included. In addition, the NBS performed in any given state is dependent on that state’s ability and willingness to fund the program. Even today, NBS is not nationally mandated but is in the purview of the individual states. Each state decides which disorders to screen for.

As late as 1997, only 2 disorders (PKU and congenital hypothyroidism) were screened for by all 50 states. However in the mid- to late 1990’s a technological development revolutionized NBS. The ability to screen for up to 50 different IEM from a single dried blood spot punch using tandem mass spectrometry changed the face of NBS. The American College of Medical Genetics (ACMG) fielded a task force called the Newborn Screening Expert Group which published a recommendation in 2006 entitled “Newborn Screening: Toward a Uniform Screening Panel and System”(1). This Group recommended a set of 29 “core conditions” that every state should screen for, as well as a set of “secondary conditions” that will be picked up during the differential diagnosis of the core conditions. They also revised the inclusion criteria into a set of three basic criteria for disease inclusion in NBS programs: the disorder must be detectable within 24-48 hours of birth, before it’s clinically detectable, a screening test with appropriate sensitivity and specificity must be available, and the disorder must be treatable with benefits to treatment. Currently all 50 states screen their newborns for the 29 Core Conditions recommended by the ACMG and the US Department of Health and Human Services. Thanks to a laboratory technology, NBS is now much closer to being standardized than ever before and covers the majority of the most common IEM.

1) https://www.acmg.net/ACMG/Publications/Practice_Guidelines_docs/NBS_report.aspx

-Patti Jones PhD, DABCC, FACB, is the Clinical Director of the Chemistry and Metabolic Disease Laboratories at Children’s Medical Center in Dallas, TX and a Professor of Pathology at University of Texas Southwestern Medical Center in Dallas.

The Poisoner’s Handbook by Deborah Blum–Book Review

I recently read The Poisoner’s Handbook by Deborah Blum, a book about poison and forensic investigation in Jazz-age New York City. Dr. Norris and Dr. Gettler transformed death investigation from a good-old-boy coroner system to one based on science and data analysis. Blum weaves several cases into a narrative that covers several poisons used during the 1920s and ‘30s. Over time, poisoning deaths decreased due to public awareness as well as the realization that murderers were increasingly likely to get caught. Blum discusses Prohibition at length and its contribution to poisoning deaths in New York City. I found this particularly fascinating; not only were people willing to risk their lives to drink alcohol, the government tried to dissuade people from drinking by actively poisoning the supply.

Several of the reviews of this book note Blum’s lack of chemistry knowledge, and I can’t disagree. While my own knowledge base isn’t wide, even I notice a few inaccuracies (HCN isn’t a “potent” acid, for example). One must remember that Blum is a journalist, not a chemist; I tend place blame on the publisher’s fact-checker as well as the author. Because this book is about the evolution of the public perception of forensic toxicology and not just the science behind it, I could overlook the scientific stumbles.

As a laboratory professional, I loved reading about the early days of forensic science and forensic toxicology. While these professions existed in Europe well before 1920, Norris and Gettler forever changed how we treat death, murder, and justice in this country.

–Kelly Swails, MT(ASCP), is a laboratory professional, recovering microbiologist, and web editor for Lab Medicine.

Inborn Errors of Metabolism in Adults

In general when people think of a genetic defect or an inborn error of metabolism (IEM), they think in terms of disorders that are diagnosed and treated in infancy or early childhood. Interestingly, the more we learn about IEM, the more we see that IEM can be diagnosed at nearly any age. Milder forms of the disorders may present in later years, anywhere from adolescence through adulthood.

Classical presentations of IEM are generally due to total or near total enzyme deficiencies that result in life-threatening medical crises, or major developmental delay and mental retardation. Adults or near adults who present with a range of milder symptoms may be misdiagnosed or nor diagnosed at all.

A few examples of IEM that may have later and milder presentations include:

1) Ornithine transcarbamylase (OTC ) deficiency, the most common urea cycle defect which is often fatal in newborn male infants, can and does present in the teenage years as altered mental status, when a protein load cannot be handled and ammonia levels rise and impact brain function.

2) Carnitine palmitoyltransferase 2 (CPT2) deficiency, a disorder of fatty acid metabolism, presents with cardiomyopathy and liver failure in the newborn period. It can also present with muscle weakness, myopathy and rhabdomyolysis in the teenage or young adult years when the teenager tries out for a sports team and the muscle cannot metabolize adequate fats.

3) 3-methylcrotonyl-CoA carboxylase (3MCC) deficiency, a disorder of leucine metabolism, may present in infants or toddlers as feeding difficulties, neurological symptoms including seizures, and can cause death. 3MCC can also present in a completely asymptomatic mother whose infant is picked up on newborn screening because of the Mom’s abnormal metabolites in the infant’s blood.

In most of these cases the deficiency is mild enough that the individual is self-regulating, avoiding foods or activities that make them feel bad. In addition, the IEM may not manifest unless some other confounding factor precipitates it, such as stress, illness, or fasting. The important thing to remember though, is that altered mental status in a teenager does not always represent alcohol, drug or other mood altering substances. IEM can be diagnosed at any age and should always be considered as part of the differential diagnosis.

Pain Management Drug Testing

Traditionally, urine drug testing has looked for the presence of drugs that should not be there. You are hoping for a completely negative drug test. Because tests for measuring drugs in urine haven’t always been incredibly accurate at the low end of the measurement range, and interferences from other compounds can cause false positives and negatives, back in the early 1990s the Department of Health and Human Services provided cut-off concentrations for abused drugs that gave the best discrimination between samples that actually contain those compounds and those that don’t. What that means today is that if the concentration of the drug in the sample is higher than the cut-off, that sample is positive for the tested drug. If the concentration is less than the cut-off, the test is negative, whether there is actually any drug present or not.

How is pain management drug testing different? When testing urine samples for drugs for pain management, you are looking for the presence of drugs that SHOULD be there. In essence, you’re hoping for a positive drug test. Controlling pain with medication is a massive industry, but to keep prescribing those drugs, the physician needs proof that the patient is actually taking the medication and not diverting it for sale or use by someone else. Thus pain management drug testing looks for the presence of the specific drug and may actually require a quantitative result rather than a simple positive/negative.

In addition, although the assays used for both types of drug testing may be the same (mass spectrometry or immunoassay), traditional urine drug testing often only includes drugs in the major classes of drugs of abuse. Pain management drug testing must also include specific drugs prescribed therapeutically for pain, like methadone and oxycodone. Thus point-of-care (POC) devices for drugs of abuse drug testing may not be adequate for pain management drug testing.

Here is a list of drugs usually included in POC testing panels:

Drugs of Abuse
Amphetamines
Opiates
Cocaine
Benzodiazepines
Tetrahydrocannabinoids
Barbiturates
Phencyclidine

Pain Management Testing

Amphetamines
Opiates
Cocaine
Benzodiazepines
Tetrahydrocannabinoids
Barbiturates
Phencyclidine
Oxycodone
Methadone
Propoxyphene

-Patti Jones

Cystic Fibrosis Related Diabetes

Cystic fibrosis-related diabetes (CFRD) is a type of diabetes that affects individuals who have Cystic Fibrosis. CFRD is an entity unto itself, having several aspects that make it different from other forms of diabetes.

Cystic Fibrosis (CF) is one of the most common genetic defects among the Caucasian population, and it is a devastating, systemic disease. When CF was first being diagnosed, children with this disorder rarely lived to reach their teens]; now the average life expectancy of an individual with CF is around 36 years. Still horrifically short, but better. The fact that people with CF are living longer means they acquire other disorders, including a type of diabetes. It has been shown that with increasing age in the CF population there is increasing incidence of diabetes mellitus. Roughly 20% of adolescents with CF have diabetes and about 50% of adults with CF have CFRD (1).

CFRD is not as straight-forward to diagnose as type 1 and type 2 diabetes, so it’s important for laboratory professionals to be aware of this disease. People with CF who have diabetes may not always have hyperglycemia. Also hemoglobin A1c (Hgb A1c) values, which is a test recommended by the ADA for diagnosing diabetes, may not be elevated in these patients. The oral glucose tolerance test (OGTT) is recommended for diagnosis of CFRD, and yet even these results may be equivocal in CFRD patients (2). Nonetheless, the ADA/CFF guidelines suggest that all CF patients over 10 years of age should be screened yearly for CFRD using the OGTT. In addition, at least one study in the literature has found that when performing an OGTT on CFRD patients, a glucose level at the 1 hr time point correlates best with the patient’s lung function (3). Thus, if your lab performs OGTT on individuals with suspected CFRD, the physician requesting the test may want the glucose value on a one hour time point as well as the standard 2 hour OGTT.

Individuals with CF who get CFRD tend to have weight loss, protein catabolism, worsened lung function and significantly increased mortality compared to CF individuals without diabetes. The increased mortality is directly related to decreased pulmonary function, rather than to the atherosclerotic vascular disease seen in other types of diabetes. Insulin therapy is the recommended therapy for CFRD.

-Patti Jones

References:

Moran A, Brunzell C, Cohen RC, Katz M, Marshall BC, Onady G, Robinson KA, Sabadosa KA, Stecenko A, Slovis B. Clinical care guidelines for cystic fibrosis-related diabetes. Diabetes care 33(12):2697-2708. 2010.
Rana M, Munns CF, Selvadurai H, Donaghue KC, Craig ME. Cystic fibrosis-related diabetes in children – gaps in the evidence? Nature Reviews: Endocrinology, 6:371-378. July 2010.
Brodsky J, Dougherty S, Makani R, Rubenstein RC, Kelly A. Elevation of 1-hour plasma glucose during oral glucose tolerance testing is associated with worse pulmonary function in cystic fibrosis. Diabetes Care, 34:292-205. 2011.

Estimated Glomerular Filtration Rate (eGFR)

A colleague, upon checking her lab test results after an annual physical, was horrified to discover a flagged eGFR result of 57 ml/min/1.73 m²; even more so after her research indicated this result could mean she had stage 3 chronic kidney disease. She immediately called her primary care physician, who informed her that since her creatinine value hadn’t changed in more than 25 years (it had been 0.9 at 29 years of age and again at 59 years of age), he ignored the eGFR as useless. So what’s the purpose of an eGFR? If physicians are ignoring it, is it necessary and important to report it with every creatinine value?

Chronic kidney disease is an increasingly huge problem facing the American population. According to the the National Kidney Foundation (NKF) Kidney Disease Outcome Quality Initiative (KDOQI) Guidelines more than 4% of the American population suffers from stage 3 chronic kidney disease, with another 3% in stage 2 and 3% in stage 1. It’s well known that renal function decreases with age, and recent estimates suggest that roughly half the US population is over the age of 50. Although creatinine is the most commonly used marker of renal function, it is a remarkably insensitive marker of renal function loss, and new markers are just being discovered and validated. Glomerular Filtration Rate (GFR) is considered the best estimate of kidney function; however it’s not simple to measure. eGFR is an estimated GFR, calculated from the creatinine the age, gender and race of the patient. It is a way of assisting in the early diagnosis of kidney disease. To help make this diagnosis, urine albumin is an important test to use along with eGFR. In addition, both should be abnormal for >3 months in order to make the diagnosis. Early diagnosis can help prevent progression to renal failure.

The equations for calculating eGFR have evolved and improved, from the early 6-parameter formula which came out of the Modification of Diet in Renal Disease (MDRD) study, to the most recent 4-parameter CKD-EPI formula. For adults, the CKD-EPI formula is increasingly being considered the most useful of these formulas. Formulas are also available for children, and online calculators are easy to find.

–Patti Jones