Welcome to the AACC Expert Access Live Online program.

Our July topic is Metabolic Changes Associated with Stress The expert for this session, Larry H. Bernstein, M.D., is a well known proponent of including metabolic and nutritional assessment in the care of hospitalized patients, Dr, Bernstein is currently online and awaiting your questions, so please submit them now.

We would like to extend our most sincere thanks to the Bayer Corporation for making this program possible.

Talk more about the self management revolution introduced by the emerging nutraceutical market.
Washington, DC

Larry H. Bernstein, M.D.: Talk more about the self management revolution introduced by the emerging nutraceutical market. The main discussion today is focused on acute care and the failure to fully distinguish between malnutrition and stress hypermetabolism. This becomes especially critical in the patient with end stage renal disease and the patient with decompensated cirrhosis. There is an element of both malnutrition (marasmus and/or kwashiorkor-like condition) and inflammatory state in many of these patients. Which leads us to examine the underlying condition, which brings in the cytokine response. There exists a state in chronic metabolic and inflammatory conditions that extends the concepts developed here from the acute to the chronic state. Evidence the fact that Type 2 diabetes mellitus, a state of insulin resistance, has a distinct inflammatory component that has implications for treatment. The self management revolution is something like a $28 billion dollar industry, and the laboratory has the key to identifying the element of risk. The pharmaceutical industry requires randomized prospective trials conducted in compliance with FDA protocol requirements. In the process, we learn that certain statins are antiinflammatory, independent of the lipid lowering effect. Such trials haven’t been conducted on many of the “neutraceuticals”, which are unregulated and are classified as foods. A number of them (Gingko, Ginseng,..) have an effect on the INR because of interference with vitamin K. My series of slides on omega-3 fatty acids actually takes us a step in that direction. Platelet and neutrophil mambrane fluidity is determined by the ratio of omega-3/omega-6. This is the tie in with coronary vascular disease. Omega-3 is antiinflammatory. I am unaware of any study to determine the effect of omega-3 on high sensitivity CRP. The Lab's Role in Functional Medicine By Larry H. Bernstein, MD (excerpts from Advance) Consider the lab's distinct and significant roles in an expanding "alternative medicine" approach. Much of this has not been tested by the rigorous clinical trial methods expected of "scientifically validated" medical practice. FM's growth is associated with a shift of financial incentives associated with the high cost of pharmaceuticals and the interest in maintaining a state of wellness. The History of FM The 1994 Dietary Supplement Health and Education Act (DSHEA) includes herbal products in the definition of "dietary supplements" and creates a new class of drugs, "nutraceuticals," all of which are unregulated by the FDA. The DSHEA, in fact, created a huge marketplace in billions of dollars worth of spending with no better information about the safety and efficacy of herbs than for turn-of-the-century patent medicine. Natural product "diet supplements" available in teas, powders, tablets, capsules and single or combination herbal ingredients have: * variable activity for the benefits claimed, * adverse effects and drug interactions and * a biochemistry of action for the primary constituents unknown to the user. There are many sources of information about herbal medicines available. HerbMed, for example, is a database maintained by the Alternative Medicine Foundation Inc. and the Herb Research Foundation (HRF) at www.herbs.org. Since herbs are not regulated as drugs, there are no legal standards for their preparation and their contents and potency are not accurately disclosed on the label. The FDA's Center for Food Safety and Applied Nutrition, however, maintains a database of reports of adverse events that have been associated with the use of dietary supplements. The problem is that information necessary to make a decision about whether to use an herbal product, safety and efficacy compared with pharmaceutical products used for the same purpose is largely unavailable. The issues related to product quality and standardization of botanical preparations and issues for health care professionals in recommending their use was recently reviewed by McDermott and Motyka.1 Contrary to what might be believed, there is a substantial role for the laboratory in FM, specifically: 1. to assess the state of health of the individual at times while on the treatment; 2. to assess toxicity, and if possible, levels of active substance; and 3. to document improvement as a result of the care process. Health, Treatment Assessment In the first role, the laboratory and FM interact with a scope not restricted to the FM population; rather, it extends to a much larger group and includes patients suffering from a chronic disease. Disease management (DM) is a treatment support concept predicated on the principle that health care dollars can be saved by reducing the occurrences and intensity of crises of patients with chronic diseases by meeting evidence-based standards of care. The emergence of Type II diabetes mellitus, hypertension and hyperlipidemias in association with long-term sequellae from a well-nourished population extends the need for the DM concept. The laboratory has a role in -- outcomes (metrics and measurement processes), clinical practice guidelines and quality (including measurement of improvement). An organizational model has been proposed that produces desired outcomes by managing structure and optimizes patient care through prevention using evidence-based interventions, patient self-management and continuous and systematic reassessment. The clinical laboratory will have a role in managing risk reduction for: * chronic undernutrition, * obesity, * coronary artery disease, * hypertension, * stroke and * generalized vascular disease. Exercise and nutrition are key low technology methods for achieving long-term goals. The laboratory provides the measurement tools for assessment and reassessment of short- and long-term outcomes. A repeated health measure would at least include the complete blood count, glucose, albumin, serum electrolytes, urea nitrogen, perhaps alanine aminotransferase and the total cholesterol to HDL cholesterol ratio. References 1. McDermott JH, Motyka TM. Assessing the Quality of Botanical Preparations. Medscape Pharmacology. Medscape, 2000. 2. Flora K, et al. Milk thistle (Silybum marianum) for the therapy of liver disease. Amer J Gastroent 1998;93:139-43. 3. Ridker P, et al. Hepatic veno-occlusive disease associated with the consumption of pyrrolizidine containing dietary supplements. Gastroenterology 1985;88:1050-54. brief observation from Dr. Edward Siguel's article in J Clin Ligand Assay (1999)on Esential Fatty Acids The US Surgeon General's report identifies the type of fat that people eat as a factor in health and disease, but EFA deficiencies (EFAD) are reported very rarely in the United States (p. 58). Even though EFAD was proposed as an important factor in the etiology of CAD in the 1960's the expected link was obscured by insensitive measures of EFA's (2). The emphasis was on reducing dietary cholesterol, saturated fat, and total fat as a means to prevent CAD based on the only evidence available. EFA intake may be more important than previously appreciated (3), and EFAD is more prevalent than previously suspected based on biochemical findings of EFAD on more than 25% of the US adult population (4). Unanswered questions include: What is the prevalence of omega-3 and omega-66 deficiencies? Will fatty acid supplementation reverse or prevent specific conditions associated with EFAD? What are the pathophysiologic correlates of omega-3 and omega-6 deficiencies? What is the desirable intake of omega-3 vs. omega-6 fatty acids? What are the roles for each EFA derivative? What are the differences among commercially available food sources of EFAs and EFA derivatives? The huge shift in food consumption towards low fat foods deprived of EFAs practically guarantees that EFAD will soon become the most prevalent nutritional deficiency in the US. The Nutrition Division has a program at AACC in Orlando on Saturday afternoon titled “The Convergence of Metabolic Management, Nutrition, and Disease management” (July 27, 3-5:30 pm). The program includes Metabolic Syndrome, but Tom Baumgartner (neutraceutical and lab face off) and Herb Henney are stars in the program.

I see that the uploading of the presentation distorted the alpha where there was TNF alpha - which came out TNFI. Larry Bernstein
Bridgeport, CT

Larry H. Bernstein, M.D.: TNFI is intended to be TNF alpha

Thank you for providing information on this often-overlooked area of clinical care, Dr. Bernstein. My question is, what should labs be measuring? Cytokines, TNFs, and retinoids are not standard options in our small facility. The vast literature on albumin reveals significant shortcomings, and it doesn't seem that the IVD companies are too interested in making nutritional testing a priority when it comes to adding tests to their analyzers. How can we make the best of this situation?
Ogden, UT

Larry H. Bernstein, M.D.: It doesn't seem that the IVD companies are too interested in making nutritional testing a priority when it comes to adding tests to their analyzers. How can we make the best of this situation? We can only remedy the situation if the users make their needs known to the industry. Several companies now have prealbumin (transthyretin) on their large analyzers, but for many years it was necessary to purchase an analyzer for immunochemistry to do PAB (TTR) as a special test. Only 8 years ago my friend and colleague, Dr. Michael Meguid, Director of Surgical Metabolism at a prestigeous medical school, went to his laboratory and asked why he couldn't get a TTR and was told that the laboratory had been able to do it for 6 months. Dr. Ingenbleek published his work on TTR and Kwashiokor in the late 60's, and the work went unnoticed for 15 years. The emphasis on subjective global assessment by eminent people in the field didn't help our case. The reliance on albumin for prognosis is too well established by large studies to go away. The change in thinking about TTR comes with an integrated program to identify nutritional problems early and correct deficits. It has gotten better in the last 10 years. Retinol Binding Protein has become more important for measuring Vitamin A level because of the 1:1 molar ratio to prealbumin than for measuring protein energy malnutrition. I think that CRP has to be measured more when it is necessary to identify the stressful condition. CRP is a response to interleukin-6 (IL-6). Tumor necrosis factor (TNF) alpha is as important as CRP for chronic inflammatory-metabolic conditions. I wouldn't be surprised if we shall see a time not far off when there will be a panel that includes IL-1, IL-6, TNF-alpha, and perhaps IL-4. It is technically feasible to have an automated IL assay that would be done as easily as a CRP, but the companies respond to a perception of a market.

Can you recommend the best approach for one or more tests that can be used to diagnose anorexia? If a patient, trying to hide self-starvation, ate normal meals for several days prior to such a test, would that mask the anorexia?
Chicago, Illinois

Larry H. Bernstein, M.D.: Can you recommend the best approach for one or more tests that can be used to diagnose anorexia? If a patient, trying to hide self-starvation, ate normal meals for several days prior to such a test, would that mask the anorexia? I don't think that an anorexic would actually fake it or cover it up. I haven't check the anorexia literature recently, but I don't think that it has been approached using the laboratory. The patients may be primarily thin and MARASMIC looking from loss of subcutaneous fat. Prolonged, they can lose lean muscle. I think that thyroid function will be affected and reflected in a decreased prealbumin (transthyretin, TTR). What about the RBP? There is a 1:1 molar ratio of TTR to RBP. The retinoid pool in the liver might also become depleted.

Years ago we gave patients a carbohydrate-rich diet to follow for three days prior to a glucose tolerance test. We discontinued that ten or more years ago, but based on your data on insulin, do you recommend (or does the ADA recommend) that patients consume a specific amount of carbohydrates prior to a GTT?
Chicago, Illinois

Larry H. Bernstein, M.D.: The GTT has almost become dated. The practice now is to have a normal diet prior to doing the test, but there is almost no reason to do the GTT without also doing an insulin. The revised ADA glucose levels (110 g/dl for fasted) are based on large longitudinal studies and outcomes data. Type 2 diabetes is associated with insulin resistance, and all of the consequences that follow - lipid abnormality, hyperglycemia, obesity and hypertension.

Is a 24 hour urine urea nitrogen an adequate substitute for a 24 hour urine total nitrogen?
Park Ridge, Illinois

Larry H. Bernstein, M.D.: Is a 24 hour urine urea nitrogen an adequate substitute for a 24 hour urine total nitrogen? I don't think that it is, although the contrary was presented at a meeting a few years ago. The total urinary nitrogen is more accurate, but can't be done routinely. There is a linear relationship between the UUN and TUN, but the greatest error is in the most hypercatabolic patients in the first 3 days. The urinary nitrogen actually can't keep up with the losses in the most severely catabolic surgical patients. Prealbumin (TTR) is better. When would you do the UUN. This would be necessary when a patient has a TTR that isn't increasing when adequate calories and protein are provided.

Are there any special considerations when assessing metabolic stress in infants and children?
Baltimore, MD

Larry H. Bernstein, M.D.: Are there any special considerations when assessing metabolic stress in infants and children? Infants that are < 1500 g at birth are high risk, and < 1200 g are very high risk. Transfusion for these patients requires leukoreduction to achieve units that are CMV negative equivalence. They are immunocompromized and MAY GET neonatal GM- sepsis. They have virtually no retinoid stores. Their progress can be followed with transthyretin. The Nutrition Division is planning a special presentation on this next year given by Greg Post.

I am curious about alterations in the phenotypic expression of circulating leukocytes stimulated by immune cytokines. Injured patients appear to change their pattern of responsiveness to such stimuli, with these alterations correlating with the severity of their injury. Has anyone established or characterized an abnormal phenotype that is consistently displayed by immune-suppressed septic trauma patients?
Chicago, IL

Larry H. Bernstein, M.D.: I am curious about alterations in the phenotypic expression of circulating leukocytes stimulated by immune cytokines. Injured patients appear to change their pattern of responsiveness to such stimuli, with these alterations correlating with the severity of their injury. Has anyone established or characterized an abnormal phenotype that is consistently displayed by immune-suppressed septic trauma patients? I am not aware of such a study. It's a very interesting question. My slide on Systemic Inflammatory Response Syndrome shows a spectrum of patients. These patients have a leukocytosis and shift to the left. They can develop pneumonia and bacteremia. Depletion of glutamine has a role with loss of enterocyte barrier function. Glutamine, arginine and omega-3 fatty acid are added to the enteral nutrient solution. The omega-3 is antiinflammatory and potentially suppresses development of sepsis, but the risk of bacteremia is increased if the SIRS is severe sepsis (SIRS criteria are used to define sepsis). The omega 3 fatty acid effects membrane fluidity of the neutrophil as well as the platelet. In the inflammatory state there is increased production of fibrin strands, and increased platelet aggregates.

Please review some of the causes of muscle proteolysis in metabolic stress, and the laboratory tests that can detect this process before it reaches a point where the damage is irreversible.
Seattle, WA

Larry H. Bernstein, M.D.: Please review some of the causes of muscle proteolysis in metabolic stress, and the laboratory tests that can detect this process before it reaches a point where the damage is irreversible. The muscle proteolysis is entirely due to the cannabolization of lean body mass to provide gluconeogenic precursors, especially from branched chain amino acids and glutamine under the effect of cortisol. The effect is exaggerated by low serum cortisol binding globulin levels so that the free cortisol is high. The effect is obligatory, driven by IL-6 and TNF alpha. The major problem with the burn patient before the era of nutritional support was that the body tore itself down to heal the wound. The challenge now is to ablate the catabolic response and to generate a good anabolic effect. This has been done, with adverse side effects using rhGH. IGF1 is expensive. Oxandrolone is being widely used at 2.5 mg X 4 daily. Dr. Herbert Henney will be presenting on this topic on July 27. Prealbumin (transthyretin) is a very suitable test, but you can see how the UUN has been used in the past. A patient losing over 15 g per day is in trouble. they can't keep up with the losses. The biggest problem is unreliable collection of urine that can't get better under present circumstances.

In your facility, do you target certain patient populations (i.e., trauma, chronic disease, the elderly) for metabolic stress evaluation, ? Is it desirable, or even feasible, to perform this type of testing on every admit in the ED? We are an urban hospital, and my experience is that even relatively healthy looking ED patients can suffer from the effects of PEM or metabolic stress.
Houston, TX

Larry H. Bernstein, M.D.: In your facility, do you target certain patient populations (i.e., trauma, chronic disease, the elderly) for metabolic stress evaluation, ? Is it desirable, or even feasible, to perform this type of testing on every admit in the ED? We are an urban hospital, and my experience is that even relatively healthy looking ED patients can suffer from the effects of PEM or metabolic stress. That's the $64,000 jackpot question. JCAHO requires a screen for high risk geriatric patients. It doesn't get done in most hospitals with a hard pressed nursing staff. I'm working with Linda brugler to develop a risk panel that will minimize the nurse's role. The best predictors of risk are - inability to function, high risk disease associated with malnutrition risk (IBD, esophageal cancer), wound, poor oral intake over at least a week, --- labs = lymphocyte count, albumin, and hemoglobin. This automatically triggers a prealbumin (TTR), CRP. We haven't reached this level of sophistication yet. I have a kamikaze group of dietitians. Any patient admitted to ICU is high risk and gets TTR. Any patient over age 69 automatically triggers a rule for TTR. Any patient with albumin < 2.8 automatically triggers a TTR. This is hospital policy as determine by our Nutrition Committee and Nutrition, P&T, approved by the Executive Committee. Your observation that patients can look health and be missed is accurate. The stressed surgical patient is losing lean body mass even if they are overweight. Older patients who are overweight can have SARCOPENIA. Alcoholics can have sarcopenia. Patients with HIV who are successfully treated have a lipodystrophy.

Next month we will take a Summer break, so there is no Expert Access program scheduled for August. When we return on September 3, Mr. James Griffith, Convener for the Coalition on the Clinical Laboratory Workforce, will broach the subject of " Responding to the Workforce Shortage." Mr. Griffith will be online September 3 between 1:00 and 2:00 p.m. Eastern time to answer your questions. Don't miss the opportunity to ask an expert about timely and important topic.

AACC would like to again thank the Bayer Corporation for making this educational program possible.

See you in September!