JCL roundtable: Lessons from genetic variants altering lipoprotein metabolism

Because the Human Genome Project reached its first major milestone in completing the full sequence of human DNA, many new discoveries have been made relating genetic variants to disease. The new methodology that allows much more rapid and focused analyses of selected genes and the ability to screen the entire exome of any individual has provided tools to examine literally thousands of individuals for a given study. Genetic analysis has become a large-scale epidemiologic tool for examining variants in gene structure and correlating them with phenotypic markers of human disorders. These genome-wide association studies have been quite revealing about the mechanism of disorders of many types. These tools have been applied to the appearance of clinical atherosclerosis and to the chronic metabolic risk factors for this disease process. We are joined by 2 individuals who have made very significant contributions to this area of research: Dr Brian Ference of Wayne State University School of Medicine and Dr Sekar Kathiresan from Massachusetts General Hospital and Harvard Medical School. In our discussion, we are going to focus on genetic variants, which lead to changes in lipoprotein concentrations and those that have an association with earlier onset of clinical vascular disease. This roundtable was recorded during the November 2016 American Heart Association Scientific Sessions in Orlando, Florida.     

JCL roundtable: Managing lipid disorders in young women

The roundtable discussion in this issue will focus on the problems faced by young women with lipid disorders. This is often the source of confusion for the patient and physician because the myth continues that young women do not have complications of atherosclerosis as a result of elevated blood cholesterol. The essential role of women in bearing children during the early years of adulthood also produces difficult decisions because the mother and fetus are usually experiencing similar exposure to therapeutic regimens. We are joined in this discussion by Drs. Pamela Morris of the Medical University of South Carolina and Robert Wild of the University of Oklahoma Health Sciences Center. Dr Morris is an Internist, and Dr Wild is an Obstetrician and Gynecologist. Both are board certified in clinical lipidology and are actively publishing in this field. We have recorded this roundtable discussion during the National Lipid Association Scientific Sessions held in New Orleans during May 2016.     

JCL Roundtable: Should we treat elevations in Lp(a)?

The focus of this Roundtable discussion is the mysterious lipoprotein Lp(a). There is growing evidence that it confers significant risk of vascular disease at high plasma concentrations. The concentration in plasma is highly variable from person to person but relatively stable in any given individual. The issue of defining this as a target of treatment has many facets, which have stymied clinicians in their management of this risk factor. The pertinent questions are many such as: “How does one obtain the most meaningful measure as there are so many components?” “What agents are truly effective in lowering this lipoprotein particle?” “Does direct treatment with reduction affect risk?” “How does low-density lipoprotein–cholesterol relate to the risk?” “If low-density lipoprotein-cholesterol is reduced, is there residual risk related directly to Lp(a)?” and “Are there effective therapies under development?” For this Roundtable, I am fortunate to have three experts that have studied these questions in various settings and have agreed to answer my questions relevant to these clinical issues. These include Dr Moriarty from the University of Kansas, Dr Remaley from the National Institutes of Health, and Dr Tsimikas from the University of California San Diego.     

The E. Donnall Thomas Lecture: Normal and Neoplastic Stem Cells

Dr. Irving Weissman was the honored E. Donnall Thomas lecturer at the Tandem BMT Meetings, held on February 10, 2007, at Keystone, Colorado. Dr. Weissman has been a major player, and has provided us with enormous insight into many areas of biology, dating back to his high school days in Montana. He led an enormously productive career at Stanford University where he has taught us many lessons involving our understanding of lymphocyte homing, stem cell biology, both of the hematopoietic system and other types of stem cells, and also now, about cancer stem cells. Dr. Weissman has made enormous contributions to this burgeoning field that has provided us new insights and new opportunities for treatment strategies. In addition to a very productive laboratory career, he is also currently the director of both the Stem Cell Institute, as well as the Cancer Center at Stanford University. The following text is a modified transcribed version of the presentation made by Dr. Weissman.     

JCL Roundtable: Enzyme replacement therapy for lipid storage disorders

There are several inherited disorders that involve abnormal storage of lipids in tissues leading to severe compromise of organs. Sadly, these are often accompanied by lifelong morbidity and early mortality. Disorders such as Gaucher, Fabry, and lysosomal acid lipase deficiencies (Wolman and cholesteryl ester storage diseases) have been known for many years, and provide a difficult and frustrating set of problems for patients, their families, and their physicians. With recombinant methods of protein synthesis, it is now possible to literally replace the defective enzymes that underlie the basic pathophysiology of many such disorders. The delivery of these enzymes into the affected cells is possible because of their location in the lysosomes where the natural degradation of their lipid substrates occurs. I have asked 2 well-known investigators to join us for this Roundtable. These are professors who have been involved with the research that has made this type of therapy possible and who have participated in the clinical trials that demonstrated the value of enzyme replacement therapy. They are Dr. Robert Desnick, dean of Genetic and Genomic Medicine and professor and chairman emeritus of the Department of Genetics and Genomic Sciences at the Icahn School of Medicine at Mount Sinai in New York City, and Dr. Gregory Grabowski, professor of Microbiology, Biochemistry, and Pediatrics, at the University of Cincinnati College of Medicine. Dr. Grabowski recently retired from that school to become the chief science officer of Synageva, a company involved in producing enzymes for this type of therapy.     

JCL roundtable: Lipid treatment targets

This Roundtable discussion concerns atherogenic risk markers and treatment targets used by clinical lipidologists in daily practice. Our purpose is to understand the risk marker framework that supports and enables the new ACC/AHA/Multisociety Cholesterol Guidelines. Some biomarkers are highly associated with atherogenic risk but fail to qualify as treatment targets. Prominent examples are high-density lipoprotein cholesterol, for which targeted treatment has failed to reduce cardiovascular risk, and lipoprotein(a), which currently lacks a highly effective mode of treatment. As a consequence, guidelines have focused consistently on low-density lipoprotein cholesterol (LDL-C) and more recently on non–high-density lipoprotein cholesterol. We discuss a new calculation for LDL-C that shows greater accuracy than the commonly performed Friedewald calculation. LDL-C treatment goals have renewed prominence in the 2018 Guidelines. Thresholds for treatment initiation or intensification inherently establish goals of reducing atherogenic cholesterol levels below the thresholds. Treatment goals may be absolute, such as less than 70 mg/dL for LDL-C in very high-risk secondary prevention or relative, such as 50% or greater reduction of LDL-C. The timeframe of treatment is another consideration because milder treatment started earlier may sometimes be preferred over stronger treatment given late in the course of atherosclerotic progression. Advanced lipid testing and vascular imaging, particularly coronary artery calcium, also have their place in risk assessment to guide clinical lipid practice.     

JCL Roundtable: Health information technology in the management of lipoprotein disorders

One of the most serious challenges to all physicians is the maintenance of therapy for those chronic disorders that at present cannot be cured. Elevations of low-density lipoprotein and very low-density lipoprotein are among the most common of those disorders. We are now in an era in which 2 fundamental developments of modern technology have come together. These are the supply of effective and safe lipid-lowering drugs as well as the ability to closely monitor pertinent measures in our patients. The rapid conversion of our health care systems into large teams of professionals with direct support from third-party payers has made it possible to coordinate chronic care through electronic medical records and electronic communication. As a result, with effective planning and organization, we can guide our patients toward better adherence to successful medical regimens. These issues are evolving rapidly and have been presented in some detail in the December 2013 issue of the Journal. I was joined in this Roundtable discussion by 3 health professionals who have had extensive experience with the application of health information technology. They are Dr. Karen Aspry and Dr. Alan Brown, both clinical cardiologists, and Dr. Matthew Ito, a Doctor of Pharmacy.     

Organ transplantation and laboratory tests

The media has recently been featuring organ transplantation from various viewpoints. Furthermore, Novel Prizes 1990 for Medical & Physiological fields were awarded to Drs. JE Murray and ED Thomas, both pioneers of clinical transplantation. Our topic has been timely indeed. This symposium mainly dealt with laboratory tests vs. various types of organ transplantation. In reality though, only kidney and bone marrow transplantations have been practiced in Japan; thus, Dr. I Yokoyama, University of Pittsburgh, discussed liver transplantation. First, Dr. K Uchida lectured on the recent advancement of immunosuppressive drugs and improvement in the clinical outcome of kidney transplantation. Serum creatinine determination is the only parameter for rejection besides renal biopsy. Drs. K Miyamura & Y Morishima discussed about PCR method to detect MRD (minimal residual diseases). There are positive relationships between the remaining leukemic cells and the relapse of leukemia even though the patients are in clinical remission. Dr. H Funada dealt with the importance of "sterile room treatment" for bone marrow transplantation. It protects patients from infection, minimizes GVHD and prolongs survival time after transplantation. Dr. Yokoyama stressed the importance of back-up system, i.e. drug-monitoring, coagulation tests, pathological examination, biochemical tests, blood transfusion services for successful liver transplantations. Dr. T Fukunishi discussed the importance of developing the organ donor and coordinator system to promote kidney transplantation from cadaver. He also dealt with virus antibody tests for selecting donors. All discusssions stressed on the importance of the 24-hour laboratory back-up system performing emergency tests but no specific laboratory test for organ transplantation was necessary.     

Roundtable discussion: Familial chylomicronemia syndrome: Diagnosis and management

Plasma triglyceride concentrations are normally below 150 mg/dL in the fasting state. However, these lipids can reach values of several thousand mg/dL. Elevations in this range are due to a massive retention of chylomicrons and usually result from multiple genetic variants with superimposed influences such as diabetes and immune disorders. Less commonly, major gene defects in lipoprotein metabolism can be the cause. These may present soon after birth with strong evidence of familial penetrance. The causes of this syndrome have been discussed in a Roundtable published in the most recent issue of this Journal. The polygenic etiology may also have a familial presentation with similar clinical import. The diagnosis and management of these disorders is of importance since they can lead to critical clinical syndromes including death from acute hemorrhagic pancreatitis. The chronic management requires a dedicated medical team and a patient committed to an effective regimen. We are joined in this discussion by Dr P. Barton Duell, University of Oregon Health Sciences Center, and Dr Daniel Gaudet of the Université de Montreal, Montreal, Quebec. All have had extensive personal experience in the diagnosis and management of patients with familial chylomicronemia. This Roundtable was recorded on November 11, 2017, during a meeting of the National Lipid Association in New Orleans, Louisiana.     

JCL roundtable: PCSK9 inhibitors in clinical practice

The roundtable this month will involve a discussion of two new drugs that have been approved by the Food and Drug Administration for the reduction of low-density lipoprotein cholesterol (LDL-C). The Food and Drug Administration approved the first of these, alirocumab as an “adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease, who require additional lowering of LDL [low-density lipoprotein]-cholesterol.” Evolucumab has similar indications plus an indication specifically for treatment of homozygous familial hypercholesterolemia. This sets the stage for their clinical use and in this roundtable, we will discuss with two experts, the implications of these indications for the practicing physician. Dr McKenney and Dr Moriarty have had extensive experience in the conduct of clinical trials that provided the evidence of safety and efficacy of these so called PCSK9 inhibitors.     

A groundless hypothesis, megaloblastic madness, and the founding of Duke University.

In a recent issue of Medical Hypotheses, Dr H L Newbold repeats the assertion that the cause of James B Duke's death in 1925 was pernicious anemia. Dr Newbold postulates that Mr Duke was neurologically impaired as a result of vitamin B-12 deficiency and that he suffered from depression. In an attempt to relieve this depression, Dr Newbold argues that James B Duke donated the money necessary to found Duke University. Had he been properly treated for pernicious anemia, James Duke might have not been depressed nor made his donation. The historical record does not substantiate this hypothesis. Dr George Minot, Novel Laureate for his work on pernicious anemia, was a consultant to Mr Duke's physicians, and felt that the patient did not have pernicious anemia. There is no independently verifiable evidence to demonstrate that Mr Duke ever suffered from depression. Duke made his first donations to Trinity College, later named Duke University, in 1900--25 years before his death. The available data discounts the hypothesis that depression related to pernicious anemia played any role in the founding of Duke University.     

Redox pioneer:Professor Christine Helen Foyer

Dr. Christine Foyer (B.Sc. 1974; Ph.D. 1977) is recognized here as a Redox Pioneer because she has published an article on redox biology that has been cited more than 1000 times, 4 other articles that have been cited more than 500 times, and a further 32 articles that have been each cited more than 100 times. During her Ph.D. at the Kings College, University of London, United Kingdom, Dr. Foyer discovered that ascorbate and glutathione and enzymes linking NADPH, glutathione, and ascorbate are localized in isolated chloroplast preparations. These observations pioneered the discovery of the ascorbate-glutathione cycle, now known as Foyer-Halliwell-Asada pathway after the names of the three major contributors, a crucial mechanism for H(2)O(2) metabolism in both animals and plants. Dr. Foyer has made a very significant contribution to our current understanding of the crucial roles of ascorbate and glutathione in redox biology, particularly in relation to photosynthesis, respiration, and chloroplast and mitochondrial redox signaling networks. "My view is that science…is compulsive and you have to keep with it all the time and not get despondent when things do not work well. Being passionate about science is what carries you through the hard times so that it isn't so much work, as a hobby that you do for a living. It is the thrill of achieving a better understanding and finding real pleasure in putting new ideas together, explaining data and passing on knowledge that keeps you going no matter what!" --Prof. Christine Helen Foyer.     

Point-Counterpoint: Consolidated Clinical Microbiology Laboratories

The manner in which medical care is reimbursed in the United States has resulted in significant consolidation in the U.S. health care system. One of the consequences of this has been the development of centralized clinical microbiology laboratories that provide services to patients receiving care in multiple off-site, often remote, locations. Microbiology specimens are unique among clinical specimens in that optimal analysis may require the maintenance of viable organisms. Centralized laboratories may be located hours from patient care settings, and transport conditions need to be such that organism viability can be maintained under a variety of transport conditions. Further, since the provision of rapid results has been shown to enhance patient care, effective and timely means for generating and then reporting the results of clinical microbiology analyses must be in place. In addition, today, increasing numbers of patients are found to have infection caused by pathogens that were either very uncommon in the past or even completely unrecognized. As a result, infectious disease specialists, in particular, are more dependent than ever on access to high-quality diagnostic information from clinical microbiology laboratories. In this point-counterpoint discussion, Robert Sautter, who directs a Charlotte, NC, clinical microbiology laboratory that provides services for a 40-hospital system spread over 3 states in the southeastern United States explains how an integrated clinical microbiology laboratory service has been established in a multihospital system. Richard (Tom) Thomson of the NorthShore University HealthSystem in Evanston, IL, discusses some of the problems and pitfalls associated with large-scale laboratory consolidation.     

Clinicopathological study of chronic kidney diseases (CKD)

I started my life as a medical doctor at Amagasaki Prefectural Hospital after graduation from the Faculty of Medicine, Kyoto University in September 1971. I joined the newly established section of nephrology in the second year. The chief was Dr. Kazuro Kanatsu who had just moved from Kyoto University at the time of the campus disturbances. Dr. Kanatsu not only oriented me in clinical nephrology, but also guided me in medical research. I used to go to the laboratory of Dr. Tadao Tamura, Kyoto University once a week to learn renal biopsy study. In 1977, I entered the Department of Pathology, Postgraduate School of my university to learn immunopathology from Prof. Yoshihiro Hamashima. In the second year, I was willingly involved in the research group on murine SLE organized by the newly invited associate professor, Dr. Toshikazu Shirai, who taught young researchers such as myself how to consider, practice and enjoy experiments. In 1982, I went abroad to Prof. Peter Miescher, University of Geneva, who was a friend of Prof. Hamashima and organized immunopathology research groups. In the laboratory of Prof. Shozo Izui, I performed an isoelectric focused study on anti-DNA antibodies in lupus-prone mice and identified the pathogenetic role of the clonal expansion of autoantibodies. After 3 years, I came back to the 3rd Division of Internal Medicine of my university. Meanwhile, Prof. Chuichi Kawai guided me to go back to Prof. Hamashima's Pathology Department, where I helped young doctors publish a series of papers, including studies on SLE and a murine model of IgA glomerulonephritis. Later, I was obliged to leave the Pathology Department, and moved to Himeji National Hospital in 1992 as a clinical nephrologist by the invitation of the Director, Dr. Tamura. At that time I was very much encouraged by Prof. Shirai at Juntendo University, who gave me a letter with an old saying "Jinkan itarutokoro seizan ari". After 3 years, I moved to Kitano Hospital, Osaka, where I learned up-to-date information and techniques in clinical nephrology. From this hospital, I published a paper in Kidney International entitled, "Mesangiolytic glomerulopathy in severe congestive heart failure", based on the autopsy cases collected at the Pathology Department. This paper became a milestone in starting to study the role of chronic hypoxia in CKD. In 1999, I was elected as a professor of the Department of Clinical Laboratories, Faculty of Medicine, University of Fukui. In Fukui, I could extend my hypoxia study to cellular levels and diabetic mouse experiments in collaboration with Dr. Kimura, Dr. Li, Dr. Takahashi and many other doctors and technicians. When overviewing my research history, I realize that I was fortunate to be involved at the starting point of every laboratory with energetic mood and that I was supported and helped by many people.     

JCL roundtable: Pediatric lipidology

This JCL Roundtable discussion probes the knowledge of 3 experts in pediatric lipidology, an emerging discipline both in the United States and internationally. In the 1990s, only 3 US institutions could be said to have dedicated pediatric lipid clinics; that number has grown to 25 today. The Pediatric Atherosclerosis Prevention and Lipidology Group of the National Lipid Association has regular teleconferences to support advocacy and convey best practices. Guidelines for pediatric lipidology initially focused on low-density lipoprotein cholesterol in 1992 as part of the National Cholesterol Education Program. Today the most comprehensive coverage comes from the 2011 National Heart Lung and Blood Institute Pediatric Guidelines. Universal screening was recommended for children between ages 9 and 11 years and teenagers/young adults between 17 to 21 years, a position echoed as “may be recommended” by the 2018 AHA/ACC/Multisociety Cholesterol Guidelines. While pediatric lipidologists continue to treat uncommon genetic disorders, they increasingly confront an issue of epidemic proportions—dyslipidemia as the initial presentation of metabolic dysregulation associated with obesity. Consequences of such altered metabolism extend to atherosclerosis, diabetes, liver disease, and other serious problems in adult life. Pediatric lipid science and practice differ from adult experience in several ways, including importance of family and birth history as well as genetics/epigenetics, lack of general pediatricians’ familiarity with lipid drugs, value of family counseling, need for biomarkers of early metabolic dysregulation, and anticipation of endpoints in adult life not fully defined by randomized clinical trials in children.     

Clinical application of clinical laboratory tests

Recent advances in clinical laboratory tests have made it possible to study and clarify the pathogenesis of various diseases from various aspects. Such major advances can be very useful for the treatment and prophylaxis of diseases. Better tests can clarify the mutual relationships among diseases. Unfortunately, however, many clinical tests are not used effectively because they are not adequately understood. On this occasion, we are being given the opportunity to learn about the most recent clinical tests related to blood coagulation and fibrinolysis. These tests offer us the means of elucidating the pathogenesis of diseases. By applying the knowledge gained at this workshop in our clinical practice, we will be able to repay, in a small way, Dr. Matsuo, the chairman, for his efforts in the planning of this workshop.     

Diabetes mellitus among first- and second-deǵree relatives of early onset diabetics

This study is based on a material consisting of all first-degree relatives and a group of second- degree relatives (all nieces and nephews) of 187 propositi affected by early onset (i.e. at or prior to 20 years of age) diabetes mellitus, diagnosed before 1946. The incidence of diabetes among the different groups of relatives is expressed as the risk of developing the disease at specified ages. It is concluded that the risk of siblings or children of early-onset diabetics developing the same disease is about ten times that of a normal population chosen for comparison, whereas the risk of siblings developing diabetes later in life does not differ from this normal population. On the basis of the data presented here, combined with reanalyses of previously published data from other authors, it is concluded that early onset and late onset diabetes cannot have an identical genetic background. The initial study was proposed by Professor Mogens Hauge, M.D., to whom we are greatly indebted for his valuable help through all phases of the study. We would like to thank Dr Jacob E. Podsen, M.D., for giving access to the files of the Steno Memorial Hospital and for valuable advice concerning clinical problems. We would also like to thank the Danish National Registries and especially Miss Julie Konow, Registry of the Municipality of Copenhagen. During the initial study B. D. received a scholarship from the University of Copenhagen, and the follow-up study has been made possible by support from the Danish Diabetic Association (Landsforeningen for Sukkersyge) and Dr. med. Erik Garde og Elisabeth Gardes Legat.     

Positive effects of a clinical performance assessment program

Since 1986, there has been a clinical performance assessment program for fourth-year students at the University of Massachusetts Medical School. Students interact with several standardized patients (SPs) and complete other tasks such as interpretation of electrocardiograms and interpretation of X-rays. Scores are generated both by checklists and rating forms completed by the SPs and by paperwork completed by the students at the end of each encounter. Since 1986, students have been asked how frequently they have been observed by faculty and residents as they interacted with actual patients; the students report that such observations have markedly increased. Since 1989, there has been increased feedback to students by the attending faculty during and following clinical rotations. Although it is difficult to claim cause and effect, it is clear that since the inception of this exercise, the faculty have made a conscious effort to improve students' clinical skills by providing increased observation and feedback.     

Genetics of congenital hyperinsulinism

Congenital hyperinsulinism (CHI) is a clinically and genetically heterogeneous entity and causes severe hypoglycemia in neonates and infants. The clinical heterogeneity is manifested by severity ranging from extremely severe, life-threatening disease to very mild clinical symptoms, which may even be difficult to identify. Furthermore, clinical responsiveness to medical and surgical management is extremely variable. Recent discoveries have begun to clarify the molecular etiology of this disease in about 50% of cases. Mutations in five different genes have been identified in patients with this clinical syndrome. Most cases are caused by mutations in the genes ABCC8 and KCNJ11 coding for either of the two subunits of the beta-cell KATP channel (SUR1 and Kir6.2). Recessive mutations of the beta-cell K(ATP) channel genes cause diffuse HI, whereas loss of heterozygosity together with inheritance of a paternal mutation causes focal adenomatous HI. In other cases, CHI is caused by mutations in genes coding for the beta-cell enzymes glucokinase (GK), glutamate dehydrogenase (GDH), and SCHAD. However, for as many as 50% of the cases, no genetic etiology has yet been determined. The study of the genetics of this disease has provided important new information regarding beta-cell physiology.