Lars H. Breimer

Is bilirubin a marker of vascular disease and/or cancer and is it a potential therapeutic target?

Normal aerobic metabolism is associated with reactive oxygen species (ROS) that can damage cellular macromolecules. Analogous free radicals are formed by exposure to ionizing radiation and many dietary products are considered to contain free radical generators. During the past 15 years epidemiological studies and animal experiments have identified bilirubin as a molecule at the crossroads of the protection of the body against ROS. The studies have focused on bilirubin as a biomarker of arterial disease. This review assesses the current state of evidence and sets the data in context. There is no definitive evidence from prospective studies of a causal protective effect from bilirubin in arterial disease or that various genetic polymorphisms, (particularly the 7/7 UGT1A1 repeat polymorphism) impacts coronary artery disease. There is no definitive evidence that high bilirubin levels confer protection against cancer. There is some preliminary evidence that bilirubin may have a protective effect in lung disease and stroke, but the reports have yet to be confirmed. The role of various genotypes of UGT1A1 and HMOX1, if any, in cancer is unclear.

Could carbon monoxide and bilirubin be friends as well as foes of the body

Abstract Endogenous carbon monoxide (CO) production was first described 60 years ago. CO is a by-product of the metabolism of haeme to biliverdin. This, in turn, becomes bilirubin. During the past 15 years epidemiological studies and animal experiments have identified bilirubin as a molecule at the crossroads of the protection of the body against reactive oxygen species (ROS). The studies have focused on bilirubin as a biomarker of arterial disease. Recently the potential of CO as a therapeutic agent has been explored. This review assesses the current state of evidence and sets the data in the context of whether CO is an endogenous signalling molecule, a marker of vascular disease and, whether, together with bilirubin, CO could be a potential therapeutic agent.

Has folate a role in the developing nervous system after birth and not just during embryogenesis and gestation

It is now 30 years since the first publications stating that supplementation with folate could prevent neural tube defects appeared and 20 years since the definitive data, including prevention of other birth defects. Since then epidemiological studies and animal experiments have identified folate as a molecule at the crossroads of neural development. Fortification of food has greatly reduced the incidence of spina bifida. Much interest has focussed on long-term sequelae in children born to mothers severely deprived of folate (and other nutrients) such as during the Dutch Hunger Winter of 1944 and in poor parts of the world. In addition, deficiency in folate and B12 are increasingly discussed as a possible contributing factor in dementia and congenital orofacial and heart malformations. The year 2011 saw the publication of a study that implicated low folate intake in poorer school performance of adolescents as judged by school marks. This has enormous social implications but needs confirmation from other settings. This review assesses the current state of evidence and sets the data in context of whether folate has a role in the development and plasticity of the nervous system even after birth, with particular emphasis on childhood and adolescence.

Swedish biomedical PhD examination: an international forum and a proposed procedure for Europe

In 538 randomly selected Swedish biomedical PhDs from 2008, 50% of the external examiners came from abroad, most commonly USA and UK. The sex distribution between candidates was equal, while 17% of the external examiners were women. Twice as many women candidates as men had women examiners. Swedish PhDs are based on work published in international peer-reviewed journals; the median number of works per thesis was 4. The Swedish thesis examination system offers a model for international cross-fertilisation.

Tissue zinc levels in a child with hypercalprotectinaemia and hyperzincaemia: A case report and a review of the literature.

Abstract Background. A girl suffering from a rare syndrome of unknown aetiology, termed hypercalprotectinaemia, was evaluated for tissue zinc status, because calprotectin is a protein which chelates Zn at multiple binding-sites, which might have affected the distribution of Zn in her body. Methods. Measurement of serum, urine, hair and nail zinc (Zn) concentration, complemented with measurement of total Zn in ultrafiltrates of plasma. Results. Her serum Zn concentration was 105–133 μmol/L. Zn levels in her hair (102 μg/g), nail (90 μg/g) and urine (3–12 μmol/L; 20–80 μg/dL) were all at the lower end of the reference intervals described in the sparse literature. Zn concentrations in ultrafiltrates of plasma were below the detection limit (<100 nmol/L). Thus, the elevated serum Zn did not translate into a similarly increased level of Zn in any of the tissues tested, nor in free Zn concentrations. Instead it appeared to be a result of Zn being chelated to binder proteins, most probably calprotectin. Conclusion. Her grossly elevated serum calprotectin concentration is probably able to raise circulating total Zn concentrations without raising ionized concentrations, but this Zn remains confined to the circulating blood as well as to excreted body fluids, particularly faeces.

Unified European higher medical degrees.

Unequal access to higher medical degrees, which are important for career advancement, is a problem that is likely to plague UK medicine as integration within Europe proceeds. This paper analyses the characteristics of M.D.s at the Royal Free Hospital School of Medicine and proposes a solution of creating a common European doctorate.

Bilirubin and peripheral arterial disease: 15 years later

The past year has seen renewed interest in the link between peripheral arterial disease and plasma bilirubin. Two important studies that evaluate this relationship have been published: Perlstein et al., in a cross-sectional cohort study, and Kronenbergs group, in a retrospective case control study, provide substantial evidence that serum bilirubin may play a protective role in peripheral arterial disease as well as ischaemic heart disease, as suggested almost 15 years ago in a small retrospective analysis. Briefly, that study found that serum bilirubin concentrations in peripheral arterial disease patients were significantly (p < 0.001) lower than those in a healthy reference population. This editorial discusses the new data in a historical context.

Age, sex and standards of current doctoral theses by Swedish medical graduates

Recent Swedish publication-based doctoral dissertations by medical practitioners contained an average of four published papers and one manuscript per theses. The average number of authors per paper was four. The candidate was the first author on 83% of papers indicating that the same paper was not used to support several theses. 82% of the candidates had completed their specialist training: 24% of these were women; surgeons were the biggest single group. The average age in years was: surgeons 40 (34–48); non-surgeons 41 (34–49); and 35 (32–36) for those who had just completed their basic post-qualification registration. These findings are in keeping with the Swedish tradition of scientific and evidence based medicine.

Does bilirubin protect against developing diabetes mellitus

After 25 years of evaluating bilirubin as a possible protective agent in neonatal and cardiovascular disease, interest has moved on to a exploring a possible protective role in diabetes mellitus (DM). This review finds conflicting prospective data for a protective relationship though there are retrospective, case-controlled data, that can only show association, which is not causality. Only prospective studies can show causality. Also, it would appear that the underlying biochemical assumptions do not readily translate from the animal to the human setting. Given that many factors impact on circulating bilirubin levels, it is not surprising that a clear-cut answer is not available; the jury is still out. Any relationship between DM and bilirubin might relate to intermediates in bilirubin metabolism, including relationships involving the genes for the enzymes participating in those steps. Nevertheless, the pursuit of bilirubin in disease causation is opening new avenues for research and if it is established that serum bilirubin can predict risks, much will have been achieved. The answer may have to come from molecular genetic analyses.

Where Are We Now With Bilirubin as a Marker of Vascular Risk

Aerobic life is unavoidably associated with the chance occurrence of free radicals of oxygen (also colloquially known as reactive oxygen species) that combine with other molecules and can damage key macromolecules such as nucleic acids, sugars, proteins and fats (see). The discovery of superoxide dismutase, eventually a group of 3 different enzymes, which catalyzes the deactivation of the superoxide radical, underpinned the notion that free radicals of oxygen could be biologically significant. It has long been known that the hydroxyl radical mediates most if not all the damage caused by ionizing radiation, including turning the coding bases in DNA into highly mutagenic derivatives. The existence of a whole host of DNA repair systems to deal with those lesions illustrates the critical importance of oxidative stress to the integrity of the genome. Self-evidently, there are also natural molecules that quench free radicals before they can do damage, such as vitamin C and E and glutathione. About 30 years ago, Steinberg and his group proposed that oxidation of low-density lipoprotein may be a key component in the atherosclerotic process. A couple of years later, Ames drew attention to the antioxidant properties of bilirubin a compound generally viewed as a waste product. In spite of a series of clinical papers in children as well as adults, during the past 20 years or so, there are few surprising facts that either support or refute a significant protective role of bilirubin in man. Recently, two articles have been published, which seem to lend weight to the bilirubin hypothesis. In the article by Horsfall et al, the most striking impression are the graphs in their Figure 1, which show a U-shaped relationship for cardiovascular disease (CVD), coronary heart disease (CHD), and myocardial infarction (MI), and only for death is there a continuous fall. It would appear that they merely have reconfirmed the U-shaped relationship described in a prospective study of 7865 middle-aged British men followed for 11.5 years within a year of Schwertner et al’s retrospective study and which is the norm: in men the relationship is U shape and among women either U shape or no relationship at all in prospective studies. More surprising is the lack of reference to Fulks et al who 3 years ago reported on serum bilirubin in a healthy population screened for insurance purposes in almost 2 million people—also a prospective study with a median follow-up of 12 years—where bilirubin values below the midpoint showed excess mortality in men, but there was no consistent relationship for women and for the men it was U shaped. Those findings are a big contrast to the findings of this group on albumin, which was convincingly linear for both sexes. Albumin may have antioxidant as well as other properties that may decrease the risk of vascular disease. There are some data from Asian patients that bilirubin might have a protective role for hemorrhagic stroke in men but not women (reviewed in). Seeing that the 3 main causes of death are heart disease, cancer, and stroke, if there is really a relationship with overall death but not with CVD, CHD of MI as Horsfall et al’s data imply, because several of the large studies included in the recent meta-analyses of stroke do not address hemorrhagic stroke specifically (possibly owing to lack of information about this type of stroke in many of the studies), it would appear unwise to write off a role of bilirubin in hemorrhagic stroke. An added complication is that there is surprisingly contradictory evidence from genetic studies regarding a protective role for bilirubin in CVD. Also, there is no good evidence that bilirubin acts as a free radical quencher of clinical significance in neonates and young children. A frequently overlooked confounding issue is that the formation of bilirubin from heme involves the liberation of both iron and carbon monoxide, and carbon monoxide-releasing molecules (CORMs) are being tested for clinical benefit. Given the extensive safety monitoring of big randomized clinical trials and that the databases of those used for registration of the statin drugs are available to the regulatory authorities, one way of exploring the bilirubin story further would be to mine those databases. Patients are not usually enrolled in clinical trials if they have significant baseline laboratory abnormalities. This means that patients with raised liver function tests at baseline would most likely be excluded as would most, if not all, cases of Gilbert syndrome. So far, one randomized study has been analyzed and reported—the Fenofibrate