Dermato-Endocrinology remembers Dr. Frank C. Garland

We were very sad when we heard the news that Dr. Frank C. Garland, a great scientist who substantially improved our understanding about the importance of vitamin D for human health, had peacefully passed away on Tuesday, August 17 at University of California San Diego (UCSD) Medical Center's Thornton Hospital after an almost year-long fight against cancer. With his death, the world has lost one of the pioneers of the so-called “vitamin D and cancer hypothesis.” In the eighties of the last century, Dr. Frank Garland and his brother Dr. Cedric Garland were the first to report an association between vitamin D deficiency and cancer, an observation with enormous impact on the scientific community worldwide. At present, there is evidence that vitamin D deficiency/insufficiency represents a risk factor for more than 20 different types of cancer, and more may be identified in the future. For his pioneer work in the area of vitamin D and cancer prevention, that impressively underlines the importance of the cutaneous vitamin D endocrine system for human health, Dr. Garland received numerous awards, including the Arnold-Rikli Prize for Advancement in the Field of Photobiology. It was a great honor, that in 2006, the International Journal of Epidemiology re-published the 1980 article by the Garland brothers entitled “Do sunlight and vitamin D reduce the likelihood of colon cancer?” followed by a set of commentaries on the importance of this pioneer work concerning vitamin D and cancer prevention that had such a great impact on the scientific community worldwide. The pioneer work of Dr. Frank Garland is honored in this issue of Dermato-Endocrinology by a Perspective written by William B. Grant and Edward Gorham entitled “Dr. Frank Caldwell Garland, June 20, 1950–August 17, 2010,”¹ and several other articles (refs. ^{2, 3, 6–8}), that highlight the importance of the (cutaneous) vitamin D endocrine system for human health.

In the second paper, Moan et al.² report their findings on seasonal variations of cancer incidence and prognosis. The authors describe that the overall death rates are highest in the winter season in many countries at high latitudes. In some but not all countries, this is also true for more specific diseases such as cancer, cardiovascular diseases and influenza. For internal cancers no consistent, significant seasonal variation was found, neither of incidence nor of death rates. On the other hand, the authors report a significant seasonal variation of cancer prognosis with season of diagnosis in Norway. The best prognosis is found for summer and autumn diagnosis; i.e. for the seasons of the best status of vitamin D in the population. There were no corresponding seasonal variations, neither of the rates of diagnosis nor of the rates of death that could explain the variations of prognosis. The authors explain that the most likely reason for this variation is that the vitamin D status in Norway is significantly better in summer and autumn than in winter and spring. Earlier, seasonal variations have been explained by circannual variations of certain hormones, but the data are not consistent.

In the following paper, W.R. Ware³ asks the question whether there is a connection between the so-called JUPITER lipid-lowering trial and vitamin D. He explains that there is growing evidence that vitamin D deficiency significantly increases the risk of adverse cardiovascular events and that a vitamin D status representing sufficiency or optimality is protective. Unfortunately, in clinical trials that address interventions for reducing risk of adverse cardiovascular events, vitamin D status is not generally measured. Failure to do this has now assumed greater importance with the report of a study that found rosuvastatin at doses at the level used in a recent large randomized lipid-lowering trial (JUPITER) had a large and significant impact on vitamin D levels as measured by the metabolite 25-hydroxyvitamin D. The statin alone appears to have increased this marker such that the participants on average went from deficient to sufficient in two months. The difference in cardiovascular risk between those deficient and sufficient in vitamin D in observational studies was similar to the risk reduction found in JUPITER. Thus it appears that this pleiotropic effect of rosuvastatin may be responsible for part of its unusual effectiveness in reducing the risk of various cardiovascular endpoints found in JUPITER and calls into question the interpretation based only on LDL cholesterol and CRP changes. In addition, vitamin D status is a cardiovascular risk factor which up until now has not been considered in adjusting study results or in multivariate analysis, and even statistical analysis using only baseline values may be inadequate.

The following two case reports by Nakamura and Tokura^4,5 underline the connection of dermatology and internal medicine. In the first case report, Nakamura and Tokura⁴ report systemic cholesterol embolization syndrome (CES) in a patient positive for cardiolipin antibodies. The authors explain that ES is caused by a cholesterol crystal embolization from atherosclerotic plaques on the walls of arteries that often occurs after an invasive vascular procedure. CES may exhibit several cutaneous manifestations before systemic symptoms take place, and the authors conclude that the existence of phospholipid antibodies may be a risk factor for CES after an invasive vascular procedure.

In their second case report, Nakamura and Tokura⁵ report a case of methylmalonic aciduria presenting with recurrent multiple mollusca contagiosa. The authors describe methylmalonic aciduria as a rare metabolic disorder with autosomal recessive inheritance. They report that patients with methylmalonic aciduria may develop a variety of skin manifestations: superficial scalded skin lesions, alopecia, psoriasiform eruptions, acrodermatitis enteropathica-like lesions, fulminant ecthyma gangrenosum and ichthyosis. In their second case report,⁵ they describe a Japanese boy diagnosed with methylmalonic aciduria who suffered from recurrent multiple mollusca contagiosa around the eyes.

In the following paper, W.B. Grant⁶ reports an ecological study of cancer incidence and mortality rates in France with respect to latitude, an index for vitamin D production. He explains that France has unexplained large latitudinal variations in cancer incidence and mortality rates. He also summarizes that studies of cancer rate variations in several other countries, as well as in multicountry studies, have explained such variations primarily in terms of gradients in solar ultraviolet-B (UVB) doses and vitamin D production. To investigate this possibility in France, he obtained data on cancer incidence and mortality rates for 21 continental regions and used this information in regression analyses with respect to latitude. In this study, he also used dietary data. Interestingly, significant positive correlations with latitude emerged for breast, colorectal, esophageal (males), lung (males), prostate, both uterine cervix and uterine corpus, all, and all less lung cancer. Although correlations with latitude were similar for males and females, the regression variance for all and all less lung cancer was about twice as high for males than for females. Lung cancer incidence and mortality rates for females had little latitudinal gradient, indicating that smoking may have also contributed to the latitudinal gradients for males. On the basis of the available dietary factor, micro- and macronutrient data, dietary differences did not significantly affect geographical variation in cancer rates. Grant concludes that these results are consistent with solar UVB's reducing the risk of cancer through production of vitamin D, and that in the context of serum 25-hydroxyvitamin D level-cancer incidence relations, cancer rates could be reduced by about 25% in France if everyone obtained an additional 2000–3000 IU/day of vitamin D. He also emphasizes that many other benefits of vitamin D exist as well.

In the following article, W.B. Grant⁷ reports an ecological study of cancer mortality rates in the United States with respect to solar ultraviolet-B doses, smoking, alcohol consumption, and urban/rural residence. He explains that the Cohort Consortium Vitamin D Polling Project of Rarer Cancers (VDPP) study failed to find a beneficial role of prediagnostic serum 25-hydroxyvitamin D (25(OH)D) levels on risk of seven types of rarer cancer: endometrial, esophageal, gastric, kidney, ovarian, and pancreatic cancer and non-Hodgkin's lymphoma (NHL). However, ecological studies and studies of oral vitamin D intake have generally found solar ultraviolet B (UVB) and oral vitamin D inversely correlated with incidence and/or mortality rates of these cancers. To explore the discrepancy, the author conducted an ecological study of cancer mortality rates for white Americans in the United States for 1950–1994 with data for 503 state economic areas in multiple linear regression analyses with respect to UVB for July, lung cancer, alcohol consumption, and urban/rural residence. Grant finds that UVB was significantly inversely correlated with six types of cancer (not pancreatic cancer) in both periods. However, the adjusted R2 values were much lower for cancers with lower mortality rates than those in an earlier ecological study that used state-averaged data. Grant explains that this finding suggests that the VDPP study may have had too few cases. He concludes that thus, the VDPP study should not be considered as providing strong evidence against the solar UVB-vitamin D-cancer hypothesis.

In the following paper, Linde et al.⁸ investigate and discuss the role of vitamin D and SLCO1B1 gene polymorphism in statinassociated myalgias. They explain that myalgias are the most common side effect of statin use and the commonest cause for discontinuing therapy. On the other hand, vitamin D has known physiologic functions in muscle and vitamin D deficiency is known to cause myalgias, with its correction leading to disappearance of muscle symptoms. Interestingly, the 521T>C SLCO1B1*5 gene polymorphism decreasing function in the gene coding for a liver anion transporter that is responsible for statin uptake has been found to explain the majority of statin-associated muscle symptoms and patients with statin-associated myalgias have been reported to improve with vitamin D supplementation. The autors therefore have investigated whether repletion of vitamin D in deficient patients with myalgias could lead to tolerance for subsequent statin therapy, and whether vitamin D status modifies the effect of the SLCO1B1*5 genotype on myalgia risk. Using a retrospective cohort of 64 patients in whom 25-hydroxyvitamin D [25(OH) D] had been measured for any reason while on statin therapy, including 46 patients who consented to be genotyped, they found strong evidence showing that repletion of vitamin D in vitamin D deficient patients improved myalgias. Interestingly, of 21 vitamin D deficient patients with intolerable statin-associated myalgias, 14 of 15 rechallenged with statins were subsequently symptom-free, with one patient experiencing mild and tolerable symptoms, far exceeding expected rates of acquired tolerability with no therapy (p = 0.01). In addition, while the SLCO1B1*5 genotype was associated with a three-fold increased risk of myalgias (p = 0.07), this risk was not found to differ by vitamin D status (p = 0.60).

In summary, the articles in this issue, again, reflect many of the interesting facets of Dermato-Endocrinology and highlight the importance of the cutaneous endocrine system not only for a broad variety of common skin diseases but also for internal medicine and other medical disciplines.