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The role of prealbumin as a marker of malnutrition

Figure 1. Nutritional deficiencies in elderly Swiss hospital patients. Source Lauber et al: Akutgeriatrische Universitätsklinik, Dissertation, Basel, Switzerland (1994).
Figure 2. The negative correlation with CRP versus prealbumin identifies patients with an acute phase response. Source - personal submission, Tony Tetlow BSc, MSc, DipCB, FRCPath, Consultant Clinical Scientist Tameside Hospital, UK, based on patient monitoring as part of their ongoing nutritional study.
Table 2. The level of prealbumin correlated with risk stratification. Source: Bernstein L, Ingenbleek Y: Transthyretin: Its Response to Malnutrition and Stress Injury. Clinical Usefulness and Economic Implications. Clin. Chem. Lab. Med. 2002; 40: 1344–8.
Table 3. Diagnostic tools define the parameters for assessing malnutrition. Source: Prof W. O.Seiler, former head of the Geriatric Department, Basel University Hospital, Switzerland. (Modified from Omran L, Morley JE. Assessment of Protein Energy Malnutrition in Older Persons Part I. Nutrition 2000; 16:50-63 & Part II. Nutrition 2000; 16:131-140 Copyright Elsevier ; and Mitrache C, Passweg JR, Libura J, Petrikkos L, Seiler WO, Gratwohl A, Stähelin HB, Tichelli A. Anemia: an indicator for malnutrition in the elderly. Ann Hematol. 2001; 80: 295-8. With kind permission of Springer Science and Business Media).
Figure 3. Comparing biomarker levels in nutritional improvement and deterioration.

The World Health Organisation estimates that malnutrition affects 792 million people globally including 20% of the population in developing countries. This equates to approximately one in three people worldwide affected by some form of malnourishment. We accept that populations most at risk are those who live in poverty or who have inadequate access to healthcare [1]. However, the hidden danger of malnutrition in affluent societies has gone largely unacknowledged. Nutritional care in European hospitals is frequently inadequate because there is a lack of consistent criteria to identify and treat malnutrition. It is only recently that data has emerged on the impact on patient outcomes and healthcare resources.
by Dr Thomas Brinkmann

Research from the European Nutrition for Health Alliance indicates that four out of 10 older people admitted to hospital have malnutrition on arrival [2]. Other data suggest that 90% of hospitalised geriatric patients and 90% of residents in old people’s care establishments suffer from the condition [3]. Patients over the age of 80, when admitted to hospital, are five times more likely to be poorly nourished than those under 50 [4]. Six out of 10 older people are at risk of becoming malnourished,  or of having the condition exacerbated, by any stay in hospital [5]. Malnutrition has major implications for all people in ‘at risk’ groups, not just the elderly and the very young, including those who are immuno-compromised, suffering from liver disease or undergoing renal dialysis.

Poor patient outcomes
The Council of Europe’s 2003 Resolution on Food and Nutritional Care in Hospitals has drawn attention to ‘the beneficial effects of proper food service and nutritional care in hospitals on the recovery of patients and their quality of life’. It recommended the ‘nutritional risk of all patients to be routinely assessed prior to or at admission’ and that this should be repeated regularly during their hospital stay.

Undernourished hospital patients are more likely to develop medical complications and have poorer outcomes with higher mortality rates. They are more likely to occupy hospital beds for longer periods, conflicting with current best practice to speed up diagnosis and treatment so that patients may be safely discharged as quickly as possible [6]. Estimates suggest that malnourished patients can spend 50% longer in hospital and are at risk of further complications from their illness [7]. This can be two- or threefold that of adequately nourished patients. The cost implications for healthcare resources are uncharted but are likely to be significant. This cost will increase unless steps are taken both to identify patients at risk of malnutrition and to devise a strategy for nutritional support of patients.

Defining malnutrition
Malnutrition essentially means ‘bad nourishment’ and encompasses a range of nutrition states including over- as well as undernutrition. The condition is typically associated with developing countries where availability of food or the available range of foods is limited. However, the increasing prevalence of the condition in wealthier societies occurs where a balance of foods is not, or cannot be consumed. Lack of food variety leads to an inadequate intake of the nutrients that enable the body to function effectively and consequently increases susceptibility to illness and disease. 
This situation may be due to problems such as loss of appetite, undereating or underfeeding, but can also be attributed to metabolic issues such as malabsorption. This can occur in patients with an underlying illness or organ malfunction that prevents nutrients being absorbed or distributed throughout the body. Nutrients are essential for maintenance and renewal and are necessary facilitators of biochemical pathways that control systems such as heart regulation, respiratory control, immune response and cognition. Proteins are especially important for muscle and tissue synthesis and their component amino acids have a wide range of biological roles.

Impaired wound healing
In malnourished individuals, body systems are impaired leading to a variety of effects such as reduced strength and fatigue, weakened immunity, apathy and depression, impaired wound healing and thermoregulation mechanisms [8]. These conditions may manifest themselves in symptoms such as weight loss, oedema, muscle wasting and cramps, diarrhoea, pallor and glossitis [9]. Malabsorption is also commonly seen in patients with pancreatitis and renal failure, and has major implications for those patients who are immuno-compromised or are recovering from illness. Malnourishment combined with weakened or sub-optimal body functioning decreases
resistance to disease and prolongs recovery time.

Patients suffering from malnutrition, due either to malabsorption or undernourishment, need to be identified quickly and effectively to ensure that  they receive appropriate care. In a clinical setting, patients who are malnourished have longer recovery times due to a weakened immune response and impaired wound healing. Conditions such as anaemia and vitamin B12 deficiency further impair recovery and, in addition, patients are prone to fatigue, which reduces their psychological capacity to fight illness and contributes to a slower recovery.

The need to monitor protein-energy status
Malnutrition is traditionally measured via anthropometric methods such as body mass index (BMI) and retrospective body weight [Table 1]. However there are numerous difficulties in taking measurements of elderly and bed-bound patients who cannot be weighed accurately. Increasingly, health services are recognising that body mass index for monitoring of malnutrition is unreliable, and that the use of these measurements in conjunction with specific malnutrition tools provide a better indication of malnourishment. 
This article refers to several valuable measurement tools. The first, the Malnutrition Universal Screening Tool (MUST) established by the British Association for Parenteral and Enteral Nutrition (BAPEN), states that 10-40% of patients admitted to hospital are underweight (BMI <20 kg/m2) but malnutrition established by using the MUST tool is even higher [10]. However, the MUST report points out that there are over 50 published screening tools to assess malnutrition, and in the absence of any established overall criteria, such tools utilise different criteria, weighting factors and scoring systems. Many are time-consuming and unreliable, with some indicators having to rely on subjective opinion.

In addition, there are the numerous difficulties involved in taking measurements from elderly and bed-bound patients who cannot be weighed accurately. Increasingly, health institutions are aware that focusing on the body mass index for malnutrition monitoring is unreliable. Their limitations and lack of standardisation for nutritional assessment have led to interest in laboratory tests for certain biological markers of nutritional status such as prealbumin, plasma albumin, cholesterol, zinc, iron, vitamin B12 and folic acid, levels of which are significantly lower in malnourished patients. These markers have yet to be routinely used in combination to specifically assess the nutritional status of patients. 

Albumin and prealbumin levels are indicators of visceral protein status. For wound healing to occur, any protein deficiency is counterproductive. Low levels of albumin and prealbumin are found in 65% of malnourished patients but these markers play different roles in diagnosis. When evaluating albumin levels, clinicians should keep in mind that the half life is 21 days. Low levels are likely to reflect a longstanding nutritional deficiency of at least several weeks, and probably several months. With this in mind, low or decreased albumin levels should be considered as a contraindication for elective surgery on elderly patients. Wound healing, for example, will be severely impaired. (Prof. W. O. Seiler, former head of the Geriatric Department, Basel University Hospital, Switzerland). However, tests of albumin status are not commonly used to assess nutritional status. In order to increase albumin level, at least two to three weeks of nutritional intervention are necessary before beneficial changes can be confirmed, and the level can be affected by factors other than nutritional status.

Prealbumin is a tryptophan-rich protein, and like albumin, it is synthesised in the hepatocytes of the liver. Prealbumin’s main function is as a binding and transport protein. The term prealbumin is actually a misnomer implying that it is a precursor for albumin, which it is not. The more accurate name for prealbumin is transthyretin. This name was chosen by the Joint Commission on Biochemical Nomenclature to indicate that it is a serum transport protein for thyroxin and retinol-binding protein.

Low prealbumin and CRP denotes risk
Prealbumin is potentially a more useful marker of nutritional status than albumin, demonstrating a quicker response. It has a half-life of two days, and a small serum pool that allows even small changes in nutritional status to be detected quickly. It acts as a negative acute phase marker and has been the subject of numerous independent studies demonstrating its correlation with nutritional status and patient outcome [11, 12, 13]. New laboratory techniques allow prealbumin to be measured cost-effectively. In the past, most labs analysed prealbumin levels nephelometrically on specialised instruments. In recent years, this technique has been replaced by more cost-effective immunoturbidimetric technology, which is more suitable for use on a high-volume, automated platform such as the Beckman Coulter UniCel DxC 800; this instrument is able to run up to 1,400 tests per hour.

Levels can be affected by inflammation or an acute phase response to trauma, so prealbumin should always be tested in conjunction with C-reactive protein [14]. Low levels of both markers together are a safer indication of malnourishment. If prealbumin levels are rising, it is likely that at least 65% of protein and energy needs are being met. A reduced prealbumin level in the absence of an elevated CRP indicates malnourishment.

However, some care needs to be taken with interpretation. It should be noted that since prealbumin is synthesised by the liver, abnormal liver function could feasibly alter prealbumin levels. However production is maintained until late in the course of liver disease. An additional factor to note is that elevated levels are found in alcoholics (leakage from hepatocytes which returns to baseline a week post ‘binge’), and zinc deficiency may also cause low levels of prealbumin whereas vitamin deficiencies do not. Certain drugs can also lower prealbumin levels, including amiodarone, oestrogens and oral contraceptives. Drugs that can cause prealbumin levels to rise are anabolic steroids, androgens (male hormones), and prednisolone.

As long as these factors are considered, measurement of prealbumin as a means of assessing nutritional status is recommended, and this initiated the first International Congress on Transthyretin in Health and Disease in 2002 [15]. However, the key benefit of prealbumin testing is not obtained from a one-off test, but by its use as an indicator of nutritional improvement and as a measure of how well nutritional interventions are working. Prealbumin levels monitored regularly, with measurements taken three to five days apart, enable clinicians to see the trend in prealbumin levels, and assess results together with CRP levels [8] [Figure 2].

This is the policy of Tameside Hospital, UK, which currently measures prealbumin status in patients identified at risk as part of their NHS trust’s strategy for nutritional improvement in patients. Working with Beckman Coulter nutritional experts, measurements are being taken from approximately 300 samples a month, mainly from elderly patients, but also from paediatric and intensive care patients. In the latter case, patients have regular daily measurements to help detect that sufficient feeding is taking place, since a small rise on prealbumin is sufficient to indicate this is happening.

The results are used by the hospital’s dieticians to fully assess patients’ nutritional status thereby enabling doctors to make informed decisions on the viability of their patients for surgical procedures and treatments. Patients are given the best chance of recovering in the speediest time possible without suffering further complications. Those identified as having low prealbumin are automatically followed up for more ‘in–depth’ nutritional assessment by a specialist nutritional support nurse [Table 2].

Nutrogram to define parameters of malnutrition
As part of an improved nutritional assessment of patients, Prof Seiler, former head of geriatrics at the University Hospital Basel routinely and manually assessed the biochemical status of his patients using the nutrogram [Table 3].

Two senior laboratory scientists, Dr med. Axel Regeniter, Head of the protein laboratory at the University Hospital Basel, Switzerland, and PD Dr med. Werner Siede, Head of Laboratory Medicine, Klinikum Lippe, Lemgo, Germany, in close collaboration developed a visual MDI Lablink module to show the complex biochemical changes and relationships involved in malnutrition. The laboratory values are transformed to show graphically a percentual increase/decrease in markers, corresponding to the upper and lower reference limits [16]. This enables clinicians to speedily and accurately assess and follow up any nutritional deficiences and thus early intervention is possible.

For each single reading/test report, the nutrogram provides a multitude of reference ranges so that the clinician can see at a glance the progress or deterioration of the patient’s nutritional status. The two graphs [Figure 3] summarise different results.

The need for European hospitals to develop nutritional assessment and monitoring protocols is gaining ground, having already become accepted practice in most U.S hospitals. It is now more widely recognised that patients run the risk of becoming more seriously malnourished within days of hospitalisation unless active steps are taken to assess and address their nutritional deficiencies. Hospitals need to develop more proactive nutritional assessment policies, and prealbumin has an important role to play in ensuring a successful outcome for patients.

References
1. Water, sanitation and health: Malnutrition; World Health Organization 2000.
2. Malnutrition within an Aging Population: Call to Action European Nutrition Alliance. August 2005.
3. Löser C. Malnutrition in the hospital--prevalence, clinical consequences, economic relevance.
Dtsch Med Wochenschr 2001; 126: 729-34.
4. Malnutrition within an Aging Population: Call to Action European Nutrition Alliance. August 2005.
5. Ibid.
6. Shenkin AS. Serum Prealbumin: Is it a Marker of Nutritional Status or of Risk of Malnutrition?  Chemistry 2006; 52: 2177-9.
7. Mears E. Outcomes of continuous process improvement of a nutritional care program incorporating serum prealbumin measurements. Nutrition 1996; 12: 479-84.
8. BAPEN, Malnutrition Universal Screening Tool. 2006.
9. Hodgson HJF and Epstien O. Malabsorption. Medicine 2007; 35: 220-5.
10. BAPEN, Malnutrition Universal Screening Tool. 2006.
11. Frederick KB and Rosenthal TC. Prealbumin: A Marker for Nutritional Evaluation. Am Fam Physician 2002; 65: 1575-8.
12. Shenkin AS Biochemical Monitoring of Nutrition Support. Ann Clin Biochem 2006; 43: 269-72.
13. Devoto G et al. Prealbumin Serum Concentrations as a Useful Tool in the Assessment of Malnutrition in Hospitalized Patients. Clinical Chemistry 2006;
52: 2281- 5.
14. Shenkin AS. Serum Prealbumin: Is It a Marker of Nutritional Status or of Risk of Malnutrition? Clinical Chemistry 2006; 52: 2177-9.
15. Ingenbleek Y ed. First International Congress on Prealbumin in Health and Disease. Clin Chem Lab Med 2002; 40: 1189-1369.
16. Seiler WO, Regeniter A. Dekubitusprophylaxe und -therapie aus ernährungsmedizinischer Sicht.  Schweizer Zeitschrift für Ernährungsmedizin 2005; 3: 25-35.
17. Omran L, Morley J E. Assessment of Protein Energy Malnutrition in Older Persons Part I. Nutrition 2000; 16: 50-63 & Part II. Nutrition 2000; 16: 131-140.
18. Mitrache C, Passweg JR, Libura J, Petrikkos L, Seiler WO, Gratwohl A, Stähelin HB, Tichelli A.
Anemia: an indicator for malnutrition in the elderly. Ann Hematol. 2001; 80: 295-8.

The author
PD Dr Thomas Brinkmann
European Scientific Group Manager
Diagnostics and Life Science,
Europe, Middle East,
Africa and India
Beckman Coulter Eurocentre



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