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Diagnosis work-up of iron deficiency anemia in patients with inflammatory bowel disease
Iron deficiency and anemia are common side-effects of inflammatory bowel disease. Analysis of a number of components of the iron-metabolism pathway can aid a differential diagnosis.
by Professor Jürgen Stein
Iron deficiency occurs in about 60–80% of patients with inflammatory bowel disease (IBD), and anemia manifests in approximately one-third of patients. Anemia is thus by far the most common extraintestinal complication of IBD. In a recent review by Gisbert and Gomollón, study data showed the prevalence of anemia in patients with IBD to range from 16% to 74%, with a mean value of 16% in outpatients and 68% in hospitalised patients [1]. Goodhand et al. demonstrated in a more recently-published prospective trial that anemia and iron deficiency anemia (IDA) are particularly prevalent in children, the incidence of anemia being 70% in children, 42% in adolescents, and 40% in adults [2]. Iron deficiency was also found to occur more commonly in children (88%) and adolescents (83%) than in adults (55%).
The cause of anemia in patients with IBD is multifactorial [Table 1]. The two most frequent etiological forms by far are IDA (resulting from iron deficiency secondary to blood loss through the ulcerations of the intestinal mucosa, reduced iron absorption and reduced intake) and anemia of chronic disease (ACD), described for the first time by Cartwright in 1946 [3]. ACD is characterised by normal or reduced mean corpuscular volume (MCV), reduced serum iron, reduced total iron binding capacity (TIBC), normal to elevated serum ferritin level, and reticuloendothelial system (RES) stores that are elevated relative to total body iron. While vitamin B12-folate deficiency and drug-induced anemia (sulfasalazine, thiopurines, methotrexate, calcineurin inhibitors) are less widespread, these possibilities should also be considered (for extended reviews
see Stein and Diagnass 2010, 2011, 2012 [4–6]).
Depending on severity, it is differentiated into three stages: (I) depleted iron stores, (II) functional iron deficiency with iron-deficient erythropoiesis, and (III) iron deficiency anemia.
Stage I depletion of iron stores is not associated with functional problems. It is only upon transition to stage II (iron-deficient erythropoiesis) that iron deficiency becomes a disorder because the cells can no longer be adequately supplied with iron. In stage III, the deficient iron supply to the body’s cells is already so pronounced that hemoglobin concentrations fall below the normal range.
In principle, all compartments of the body’s iron metabolism can be conveniently monitored with routine laboratory methods:
• Iron stores: serum ferritin
• Iron transport: transferrin saturation
• Iron utilisation with erythropoiesis: e.g. proportion of hypochromic erythrocytes or reticulocytes
Serum iron concentrations are governed by a circadian rhythm and can be low even in cases of anemia of chronic disease (ACD). Its role in the work-up of iron deficiency is, therefore, obsolete.
Serum ferritin
Serum ferritin is an indicator for the iron stores contained in the reticulohistiocytic system. Determining the serum ferritin concentration serves to identify disorders of the cellular iron stores (total body iron stores). The reference range for women is 15–100 μg/L and 30–200 μg/L for men; a serum ferritin concentration of 100 μg/L represents about 1000 mg of stored iron. Reduced concentrations are a sign of iron deficiency: a serum ferritin concentration <15 μg/L is considered a sign of an absolute iron deficiency. Because both ferritin and transferrin belong to the family of acute-phase proteins (APP), these reference ranges do not apply to patients with active inflammatory bowel disease.
In the context of inflammatory processes and the increased release of ferritin from damaged tissue, there may be an increase in serum ferritin levels. Hence, patients who actually suffer from iron deficiency will appear to have a normal iron status. In such cases, ferritin concentrations of 15 (30)–100 μg/L should be considered suspicious for iron deficiency. The differential diagnosis should, therefore, be based on serial measurements of inflammation parameters that are independent of iron metabolism [erythrocyte sedimentation rate (ESR), CRP].
Transferrin/transferrin saturation
Disorders of iron transport can be identified by determining the transferrin concentration. Iron deficiency is usually associated with a reduced transferrin saturation (TSAT). TSAT, expressed in per cent, is the quotient of the iron concentration (μmol/L) divided by the transferrin concentration (mg/dL) in serum or plasma multiplied by 70.9 (fasting blood sample).
Transferrin saturation is a measure for the iron load of circulating transferrin, the plasma protein responsible for transporting iron from its storage site to the bone marrow. Thus, determination of transferrin saturation does not provide any information regarding the status of the iron stores and provides only an indirect indication of the extent of iron utilisation in the bone marrow. Under physiological conditions, 16–45% of transferrin molecules in plasma are “loaded” with iron (3–4 mol of iron per mol of transferrin). Saturations <16% are considered to represent a suboptimum iron supply for the erythropoietic process. A reduced transferrin saturation (<20%) is associated with a relatively good sensitivity (90%) for recognising iron deficiency states, with, however, only a relatively low specificity (40–50%). Because the measurement of serum iron and serum transferrin are both subject to fairly significant circadian effects, blood samples should always be obtained at the same time of day and repeated frequently. Serum transferrin levels are increased in patients taking oral contraceptive steroids and reduced with inflammation (negative APP), meaning that, in patients with acute or chronic inflammatory disorders, TSAT may be reduced despite normal iron stores.
Soluble transferrin receptor
While all cells in the body are supplied with transferrin receptors, the bulk of these (80%) are found in the bone marrow. The number of transferrin receptors on the cell surface is an indicator for that cell’s iron requirements. In cases of functional iron deficiency, i.e. inadequate availability of iron for normal erythropoiesis, the number of receptors on the cell membrane is up regulated. Because the transferrin receptors are continuously shed from the cell membrane and pass into the plasma as soluble transferrin receptors (sTfR), the serum concentration of sTfR serves as an indicator of iron supply for erythropoiesis. TfR is up regulated in iron deficiency. In contrast to ferritin and transferrin, neither chronic inflammation nor liver damage has any effect on TfR. Elevated concentrations of sTfR are found in iron deficiency as well as every other expansion of erythropoiesis, including haemolytic anemia, the thalassemias and polycytemias. Conversely, sTfR concentrations are reduced in aplastic anemia and other conditions characterised by hypoproliferative erythropoiesis, such as renal anemia.
TfR-F index
The sensitivity and specificity of sTfR as a parameter for assessing iron-deficient erythropoiesis can be enhanced by the parallel determination of sTfR and ferritin, which can then be used to calculate the so-called TfR-F index. The TfR-F index is defined as the quotient of the concentration of sTfR (mg/L) and log serum ferritin (μg/L). This quotient represents a marker that is dependent on the status of the iron stores, the availability of iron for erythropoiesis as well as the erythropoietic activity. In individuals with a deficiency of iron stores, the TfR-F index is increased. Disadvantageous for the routine diagnostic use of the TfR-F index are its lack of uniform reference range (the reference ranges of the
individual components are assay-dependent) and the relatively high costs.
Hypochromic erythrocytes/reticulocyte hemoglobin
Determination of the cellular hemoglobin content of reticulocytes (CHr) and the proportion of hypochromic red cells (%HYPO) is a valuable marker in the temporal differential diagnosis of iron deficiency anemia. Because the maturation time for reticulocytes is 3–5 days in the bone marrow and 1 day in the peripheral blood, the drop in CHr represents a marker for current iron deficiency. By contrast, a decline in %HYPO, because it is dependent of the normal red cell life span of 120 days, reflects longer-standing iron deficiencies. Thus, CHr and %HYPO can be considered analogous to blood glucose and HgA1C determinations in diabetics.
Some blood count units (Adiva-120, Technicon H1, H2 und H3; Bayer, Leverkusen, Germany) have the capability, without significant additional expense, to measure the hemoglobin content of each individual erythrocyte and calculate the proportion of hypochromic red cells while at the same time assessing reticulocytes for their volume and hemoglobin content. In people without iron deficiency and in those in stage I, the proportion of hypochromic red cells (hemoglobin content <28 pg) is less than 2.5%. Values >10% are considered confirmatory for iron deficient erythropoiesis. The increase in %HYPO precedes microcytic changes in the blood count. CHr values <26 pg are also considered confirmatory for iron-deficient erythropoiesis.
Zinc protoporphyrin
A deficiency in available iron for erythropoiesis leads to a compensatory incorporation of zinc into the protoporphyrin complex [Figure 1], and the increased formation of zinc protoporphyrin (ZPP), because of its relatively strong fluorescence in whole blood, is easily measured using HPLC-coupled fluorescence detection. Individuals with iron store deficiency exhibit normal ZPP values as long as the erythropoietic process is adequately supplied with iron. The onset of iron-deficient erythropoiesis triggers continuously increasing ZPP concentrations. Concentrations <40 μmol/mol haeme are considered normal. Values of 40–80 μmol/mol haeme represent latent iron deficiency (hemoglobin normal); >80 μmol/mol haeme are associated with manifest iron deficiency. In severe cases, values up to 1000 μmol/mol haeme have been reported. Thus, ZPP determination not only recognises iron-deficient erythropoiesis but also quantifies it.
Hepcidin
The regulation of iron homeostasis in IDA, ACD and ACD/IDA involves the iron regulatory protein hepcidin, a type II acute phase protein. During inflammation, interleukin (IL) 6 induces hepcidin production which leads to a decrease in dietary iron absorption and macrophage iron release, leading to decreased circulating iron and impaired iron distribution within the body. Based on previous studies carried out in rats and humans showing elevated hepcidin-25 levels in ACD individuals and intermediate levels in ACD/IDA, it was assumed that measuring serum hepcidin levels could help differentiation between ACD and ACD/IDA.
Abbreviations
%HYPO, proportion of hypochromic red cells; APP, acute phase proteins; ACD, anemia of chronic disease; CHr, cellular hemoglobin content of reticulocytes; CRP, C-reactive protein; Hb, hemoglobin; IBD, inflammatory bowel disease; IDA, iron deficiency anemia; MCV, mean corpuscular volume; TSAT, transferrin saturation; (s)TfR, (soluble) transferrin receptor; ZPP;
zinc protoporphyrin.
References
1. Gisbert JP, Gomollon F. Common misconceptions in the diagnosis and management of anemia in inflammatory bowel disease. Am J Gastroenterol 2008; 103(5): 1299–1307.
2. Goodhand JR, Kamperidis N, Rao A, Laskaratos F, McDermott A, Wahed M, Naik S, Croft NM, Lindsay JO, Sanderson IR and others. Prevalence and management of anemia in children, adolescents, and adults with inflammatory bowel disease. Inflamm Bowel Dis 2012; 18(3): 513–519.
3. Cartwright GE, Lauritsen MA, Humphreys S, Jones PJ, Merrill I M, Wintrobe MM. The anemia associated with chronic infection. Science 1946; 103(2664): 72–73.
4. Stein J, Hartmann F, Dignass AU. Diagnosis and management of iron deficiency anemia in patients with IBD. Nat Rev Gastroenterol Hepatol 2010; 7: 599–610.
5. Stein J, Dignass A. Management of Iron Deficiency Anemia in Inflammatory Bowel Disease with Special Emphasis on Intravenous Iron. Practical Gastroenterol 2011; 35: 17–30.
6. Stein J, Dignass A. Management of iron deficiency anemia in inflammatory bowel disease – a practical approach. Ann Gastroenterol 2012, in press.
The author
Jürgen Stein MD, PhD
Crohn Colitis Clinical Research Center Rhein-Main
Frankfurt/Main, Germany
E-mail: J.Stein@em.uni-frankfurt.de
The ‘Virtual Patient’ in healthcare: IT Future of Medicine
To be able to mobilise our healthcare system to treat patients as individuals rather than as members of larger, divergent groups, the IT Future of Medicine (ITFoM) initiative proposes to develop a new, data rich computation-based individualised medicine of the future, based on integrated molecular, physiological and anatomical models of every person (‘Virtual Patient’) in the healthcare system. The establishment of such ‘Virtual Patient’ models is now possible due to the enormous progress in analytical techniques, particularly in the ‘omics’ technology areas and in imaging, as well as sensor technologies. Complemented by continuing developments in ICT, these technological developments could, over the coming years, make the ‘Virtual Patient’ a key component in healthcare and disease therapy and prevention. ITFoM is an European consortium combining unparalleled expertise in medicine, analytics and ICT to develop the ‘Virtual patient’.
by the ITFoM consortium
Today´s medicine
Currently medicine assesses patients as parts of large, often inhomogeneous groups. Rather than as individuals, patients are treated as members of a group for which a specific therapy has been statistically shown to be more effective than other therapies. This is even regardless of the fact that this therapy might very well make the majority of patients more ill than they would be without treatment.
Today’s medicine does not take into account the tremendous diversity between human individuals. Moreover, diseases are not homogenous either in regard to clinical manifestation or underlying causative effects. In cancer this is taken to an extreme with each tumour being different, because each of these tumours is the product of a specific and unique accumulation of mutational events.
Symptoms and signs of disease often appear only late in disease progression when a large portion of the involved organ has already failed. The symptoms might be non-specific, making a diagnosis difficult. Today´s routine clinical workup of sick patients can be extensive, expensive and can have side effects. For these reasons, many advocate preventive measures that mandate predefined checkups to be carried out by primary care physicians. Only a few preventive measures are currently useful including blood pressure control, blood sugar and lipid measurements, colonoscopy in older people, gynaecological tests in women and last but not least weight control. Both in the presence or absence of symptoms and signs of diseases, the knowledge of the full genome, the metabolome, the proteome, the microbiome and the total exposure to toxins from the environment, would have a tremendous impact on both disease workup and preventive measures.
Tomorrow´s medicine
The medicine of the future will use a ‘Virtual Patient’ system that can integrate all molecular, physiological and anatomical data into personalised models of individual people, enabling prediction of the result of lifestyle choices and medical interventions on a tailored case-by-case basis. This innovative approach will revolutionise healthcare systems, with enormous benefits for prevention, diagnosis and therapy of patients. The possibility to personalise the models allows tailor-made therapy and treatment strategies for each individual. With the model-based decision of which drug or which doses of drugs will have the optimal effect in an individual patient, the model approach will help to optimise treatment and reduce side-effects dramatically. A model-based approach will also serve as a research tool to discover and validate new compounds for drug development, potential drug treatments and applications, but also new commercial opportunities in ICT, analytics and healthcare.
ITFoM: IT Future of Medicine
ITFoM – one of the six pilot initiatives within the European Future and Emerging Technologies Flagship scheme competing for a total of 1 billion EUR over a time span of 10 years – will lay the groundwork for a project that will integrate medicine, analytical techniques and IT hardware and software development for the IT driven, data-rich, individualised medicine of the future.
By now, it has become quite conceivable to develop sequencing strategies allowing the determination of the genome, epigenome and transcriptome of a tumour, for instance, in parallel to its surgical removal, allowing the surgeon to scale the extent of the operation based on the real time computational modelling of its detailed genomic, epigenomic and transcriptomic characterisation. Dramatic improvements are also expected in the capabilities of other molecular analysis techniques, such as proteomics and metabolomics.
Why ITFoM makes the difference in ‘personalised medicine’: next generation of molecular analytics
The generation of the first draft of the human genome was a worldwide concerted action that had a strong impact on the development of new technologies for molecular biology. During the last ten years high throughput technologies have been emerging not only for DNA sequencing, but also for protein and metabolite analysis. These high throughput technologies are called ‘omics’ technologies, highly parallelised approaches aiming at the generation of information on complete sets of molecules in organelles, cells, whole pathways or even organs in order to get a comprehensive view of a biological system. A variety of ‘omics’ subdisciplines have emerged, each developing its own instruments, techniques and processes. With the increasing amount of data generated by the ‘omics’ technologies, development of tools for intelligent mathematical analysis and data mining are needed. This demand has developed into a completely new area in biology, namely bioinformatics.
For the first driver of the ‘omics’ technologies, DNA sequencing, currently the so-called ‘third generation’ sequencing technology is already appearing on the market. This innovation will allow the sequencing of a whole genome within one day, the costs for sequencing are in almost free fall, it can be anticipated that very soon the goal of sequencing a whole genome for less than 1.000 $ will be reached. These innovations open the door to allowing the sequencing of the genome of each single patient and using this information for truly personalised medicine. DNA sequencing is also used to study transcriptional expression, microRNA, DNA methylation, hydroxymethylation, transcription factor
occupancy, histone modification at specific sites in the genome and overall organisation of genomes in cells.
The personal genome information will be a very important basis for future medicine, but more ‘omics’ information will be integrated: information about proteins and metabolites will allow a much more precise picture of the physiological status of a person. The aim for protein and metabolite analysis now is to apply a method that allows the detection of all proteins and all metabolites in a given sample or tissue. The same holds true for the information about protein modifications and interactions.
Other lab technologies for molecular analysis including imaging and sensor technology are also starting to increase in speed, precision, application range and information output.
Another level of complexity takes into account life style and environmental factors, and more specifically the microorganisms interacting with the human body.
All these technologies allow the generation of highly detailed information about an individual’s genetic make-up and physiological status to give an unprecedented insight into the functioning of a person’s cells, tissues, organs and even the individual as a whole.
Systems biology is a solution that provides the methodologies and tools for mathematical analysis, integration and interpretation of biological data, employing mathematical models of biological processes. Mathematical models support the understanding of data sets on a large scale and integrate existing knowledge for interpretation. Model approaches in the ITFoM will drive the development further into models that are able to generate computational simulations to predict what cannot be measured directly. The translation of these novel approaches into clinical application will allow identification of the optimal therapy or medical treatment for each person based on the individual data available.
To generate the models and implement the ‘Virtual Patient’ model into clinical practice, substantial advances must be made in underpinning hardware and software infrastructures, computational paradigms, human computer interfaces and visualisation, as well as in the instrumentation and automation of techniques required to gather and process all relevant information. Examples of the major challenges in the information and communication technologies are interoperability, data storage and processing, efficient use of computing power, statistics and medical informatics. Integration of the individual datasets is realised via the ITFoM ‘Virtual Patient’ models enabling the provision of concrete health advice on a personal basis.
The authors
IT Future of Medicine Consortium (ITFoM)
Max Planck Institute for Molecular Genetics
Ihnestrasse 63-73
14195 Berlin
Germany
Helping elite athletes to give a peak performance
According to applied physiologist Dr Brian Moore, and Dr Andrew Hodgson, Consultant Physician (Haematology) – co-founders of the Irish company ORRECO – one of the most difficult elements of competing in sport at a world class level is to balance training hard whilst ensuring adequate recovery. Dr Moore and his integrated team of high performance practitioners advised Olympic medalists and competitors at the last three Olympic games, and will do the same at the London Olympic games this year. CLi spoke to Dr Moore and his team to find out more about ORRECO’s mission and the methods it uses to help athletes reach peak performance without overtraining.
Q. Could you first tell us a little about your company. What inspired you to set up ORRECO and what did you hope to achieve? Briefly how does the company operate?
ORRECO was founded with the aim of joining the disciplines of clinical and sports haematology to deliver a unique proposition for world sport. We facilitate blood and saliva analysis for some of the world’s best athletes from an administrative base on Ireland’s western coast – the Innovation Centre at the Institute of Technology, Sligo.
Analysis occurs through a global network of partner laboratories that are located close to training (altitude, warm weather) and competition (World Cup, Championship, Olympic) venues. Results are reported in real time through our software solution DAVE (Download, Analyse, Validate and Export your results) to allow team physicians, coaches and performance staff to review information immediately and compare the results to an athlete’s performance. We cross-reference the results with training and competition data, (e.g. speed and power, GPS tracking) to understand the individual’s adaptation to training.
Recognising that testing and result reporting are just one part of the solution; we also provide a consultancy service for elite athletes and their teams. Our performance staff assists in interpretation and comparison of results against sports-specific reference ranges, as well as provides practical guidance and interventions where needed. This includes nutritional support, training-plan modification and more. Rather then rely on one specific biomarker, we use multiple assays that are aggregated by our bio-statisticians and map the athlete on a range from ‘well’ to ‘unwell’, and, from ‘peak performance’ to ‘over-reached’ or ‘over trained.’
Q. Tough training programmes are integral to sporting success, but what are the main problems that can occur if athletes over train?
We know that in the elite sport world, very small margins exist between defeat and victory. To succeed, an athlete must train extremely hard, and there are situations when a training programme requires an athlete, player or squad to be selectively overreached or overloaded for a short time period. With a subsequent, controlled reduction in training volume, a super-compensation occurs, allowing for a positive adaptation to the intense training dose and overall improved performance.
However, if athletes train too hard for too long in their pursuit of success, they will eventually fatigue and follow the performance continuum [Figure 1], which leads to injury and increased frequency of illness, such as upper-respiratory tract infections, immunosuppression, disturbed sleep patterns and depressed mood states. Biomarker analysis can help navigate the fine line required to balance adequate load with sufficient recovery.
Q. How did you establish which biomarkers were the most important for monitoring athletes in training and how do you carry out analysis of these biomarkers?
Our starting point is leveraging clinical markers that are routinely used for general health and wellness. In the context of training, we rely on biomarkers found in blood and saliva that are known signs of a normal process (e.g. adaptation), abnormal process (e.g. maladaptation), a particular condition (e.g. under performance syndrome) or disease (e.g. infection).
Biomarkers may be used to see how well the body responds to an intervention/process (e.g. training modification), a treatment (e.g. recovery solution) or a stress inducer (e.g. game, match). Our specialist team includes former speed and power coach to the New Zealand ‘All Blacks’ and Americas Cup sailing team, Dr Christian Cook; the first team physiologist to Real Madrid, Dr Carlos Gonzalez-Haro; the former Director of the Australian Institute of Sport Haematology Lab, Robin Parisotto; and Clinical and Performance Nutritionist to the British Olympic Team, Nathan Lewis (MSc). We have significant collective experience of applying, analysing and interpreting biomarkers across a range of elite sports at the very highest level of world competition. We facilitate analysis of markers that have been applied and validated in the world of elite sport. Our combined experience of working with thousands of elite athletes and monitoring them at key times during the season means we can discern trends that are consistent with either peak, or, at times, underperformance. We are especially interested in athletes’ cell counts, inflammatory markers, trace metal status, immunoglobulins and hormonal profiles.
Q. Are you satisfied with the methods and equipment used?
We are constantly looking for improvement and searching for markers that can give us objective information about an athlete’s response capabilities and/or status. For example, we utilise the routine parameters, including the differential WBC, haemoglobin and reticulocyte counts, available on the Siemens Healthcare Diagnostics ADVIA 2120 Haematology System, to give us rapid insights into an athlete’s health and wellness. We also rely on additional parameters available on this platform, such as the cellular haemoglobin of the reticulocyte (CHr) and the percentage hypochromasia of both the reticulocytes and mature red cells (%hypor and %hypom). These parameters are also routinely utilised in renal medicine to deliver specific information about the quality of erythropoiesis.
Historically, we would have used ferritin to assess the iron stores, but given the acute phase response of the parameter, we interpret the result in concert with the white cell counts and creatine kinase (CK), as we know the parameter is elevated in infection and inflammation. This information is especially important when an athlete is undertaking altitude or endurance training, as we can ensure enough iron is being made available to the developing red cells and they benefit from all their hard work. We can also pick up a functional or pre-latent iron deficiency before it impacts upon performance and track the responses to prescribed iron supplementation. Thus, in addition to looking for new techniques, we also seek to apply established principles in new ways.
Q. How do you see the future for sports medicine in general and ORRECO in particular?
As explained by our colleague, Dr Bruce Hamilton, sports medicine is no longer focused on just treating injury and illness in athletes. Increasingly, early recognition and prevention of injury and illness is the goal. Particularly when working with elite athletes, being able to identify athletes at risk of developing problems is a constant challenge, and vast amounts or research and resources are being directed at this task. Despite this, we are only just beginning to understand the risk factors behind even common injuries (e.g. hamstring muscle strains) and techniques that may be used to prevent them. Similarly, while illness and fatigue have been recognised as significant limitations to elite athletic performance for many years, to date, the understanding of risk factors and the ability to identify athletes at risk has been limited by both our knowledge base and our technical ability. The goal of tools, such as those developed by ORRECO, are to facilitate the identification and prevention of illness in highly tuned athletes, thereby allowing them to compete to the best of their ability. This is consistent with the aspirations of modern sports medicine around the world.
By integrating sports haematology and biochemistry with knowledge and expertise in clinical and performance nutrition, applied physiology, speed and power physiology, biostatistics and cellular nutrition across our team, whole avenues of possibility open up to performance science in general. ORRECO aims to provide a global resource for real-time sports haematology and biochemistry results for athletes training and competing around the world.
For more information go to www.orreco.com. An introductory video can be seen at http://vimeo.com/41485500.
Siemens Healthcare Diagnostics
Book review: Atlas of Genetic Diagnosis and Counseling. 2nd ed.
by Harold Chen. Pub. by Springer 2012, 2472pp., €519. In 3 volumes, not available separately.
ISBN 978-1-4614-1036-2.
With almost 40 years of experience in clinical genetics, Dr Chen has shared his knowledge of almost 250 genetic disorders, malformations and malfunction syndromes. The author provides a detailed outline for each disorder, describing its genetics, basic defects, clinical features, diagnostic tests, and counselling issues, including recurrence risk, prenatal diagnosis, and management. Numerous colour photographs of prenatal ultrasounds, imagings, cytogenetics, and postmortem findings illustrate the clinical features of patients at different ages, patients with varying degrees of severity, and the optimal diagnostic strategies. The disorders cited are supplemented by case histories and diagnostic confirmation by cytogenetics, biochemical, and molecular techniques, when available. The Atlas of Genetic Diagnosis and Counseling will lead to a better understanding and recognition of genetic diseases and malformation syndromes as well as better evaluation, counselling and management of affected patients. In this new edition, 47 additional genetic disorders are added, as well as extensive updates made to the previous disorders. New illustrations, as previous edition, will be supplemented by case and family history, clinical features, and laboratory data, especially molecular confirmation.
SPRINGERwww.springer.com