Sunlight “D”ilemma: risk of skin cancer or bone disease and muscle weakness

COMMENTARY

This might be the case if recent increases in recorded cases1 are due mainly to increasing numbers of infection during the 1980s rather than increasing incubation hazard. Unfortunately, studies have assumed a particular mathematical form for the entire incubation2–5 that makes extrapolation assumptions only implicitly and may ignore or assume away the possibility of scaling up infections. Only a very strong biological rationale for a particular form would justify ignoring these two key aspects. Because no studies of animals with natural or experimental prion disease or of similar human diseases are large enough to address the very small incubation probabilities potentially involved in vCJD to date, strong reliance on mathematical assumptions is probably not justifiable. A more explicit approach would first consider the initial part of the incubation that is constrained to produce expected cases than match observed data and then separately examine the most pessimistic and optimistic plausible extrapolations and rescalings. Without directly relevant data, only judgment can guide the assumptions, so modellers must clearly show what has been assumed. Thorough examination of a vast number of scenarios is impossible, but such scrutiny is feasible for the few that project the largest epidemics. In addition, methods similar to back-calculation can be used to find early incubation estimates that are most consistent with observed death data and an assumed infection pattern,8,9 so that thorough exploration can be accomplished by examination of many fewer scenarios. This commentary has argued that key assumptions require explicit scrutiny because data limitations make those assumptions so influential. This situation could improve. For example, screening for abnormal prion protein has produced encouraging results,10 but interpretation is currently hampered by uncertainty about what a negative test implies for the probability of future disease. Greater biological understanding might help by guiding incubation assumptions. Also helpful would be continued absence of vCJD among genotypes other than methionine homozygotes and among people born after measures taken in the late 1980s to keep the BSE agent out of the human food chain.11 Without a scientific breakthrough, greater certainty may come only with additional years of surveillance. A downturn in deaths would, of course, be most encouraging, provided it is not due to random fluctuation (apparently the cause of a small drop in 1999), ascertainment delay, or seasonality. But even a slow-down could argue against the explosive subsequent increases needed to produce an extremely large epidemic. Quantitative analyses using additional data may help elucidate the likely future course of the epidemic, but only by making crucial assumptions that must be open to scrutiny. Peter Bacchetti Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94143-0560, USA (e-mail:[email protected]) 1

CJD Surveillance Unit. CJD statistics. Available at http://www.cjd.ed.ac.uk/figures.htm, accessed Nov 19, 2000.

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Cousens SN, Vynnycky E, Zelder M, Will RG, Smith PG. Predicting the CJD epidemic in humans. Nature 1997; 385: 197–98. Cooper JD, Bird SM, De Angelis D. Prevalence of detectable abnormal prion-protein in persons incubating vCJD: plausible incubation periods and cautious inference. J Epidemiol Biostat 2000; 4: 209–19. Donnelly CA, Ferguson NM. Statistical aspects of BSE and vCJD: models for epidemics. London: Chapman & Hall/CRC, 2000. Ghani AC, Ferguson NM, Donnelly CA, Anderson RM. Predicted vCJD mortality in Great Britain. Nature 2000; 406: 583–84. Brookmeyer R, Gail MH. Minimum size of the acquired immuno-

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deficiency syndrome (AIDS) epidemic in the United States. Lancet 1986; 2: 1320–22. 7 Bacchetti P, Segal MR, Jewell NP. Backcalculation of HIV infection rates. Stat Sci 1993; 8: 82–119. 8 Bacchetti P, Moss AR. Incubation period of AIDS in San Francisco. Nature 1989; 338: 251–53. 9 Bacchetti P. Estimating the incubation period of AIDS by comparing population infection and diagnosis patterns. J Am Stat Assoc 1990; 85: 1002–08. 10 Ironside JW, Hilton DA, Ghani AC, et al. Retrospective study of prionprotein accumulation in tonsil and appendix tissues. Lancet 2000; 355: 1693–94. 11 Verity CM, Nicoll A, Will RG, Devereux G, Stellitano L. Variant Creutzfeldt-Jakob disease in UK children: a national surveillance study. Lancet 2000; 356: 1224–27.

Sunlight “D”ilemma: risk of skin cancer or bone disease and muscle weakness Vitamin D is a fat-soluble vitamin found naturally in cod liver oil and oily fish, added to some foods, and produced in the skin with help from the sun.1 Land-based organisms have been producing sunlight-mediated vitamin D for over 300 million years. Early in evolution, as vertebrates left their calcium-enriched ocean environment for terra firma, they depended on the cutaneous synthesis of vitamin D for increasing the efficiency of intestinal absorption of scarce sources of dietary calcium. Vitamin D is rare in the diet consumed by human beings. In countries where some foods are fortified with vitamin D, the assumption is that dietary fortification is more than adequate to satisfy everyone’s requirement for the vitamin. Little recognition is given to sunlight as the major source of vitamin D for most people. Publicity about risk of skin cancer with exposure to sunlight has led to the widespread avoidance of exposure to the sun. Consequently, vitamin D insufficiency has become epidemic in adults over the age of 50 years.2–5 Sniadecki1 recognised the relation between rickets and lack of exposure to sunlight in 1822. 100 years later, Hess and Unger1 reported that exposure of children to sunlight treated and cured rickets. Vitamin D’s main function is to preserve calcium and phosphorus homoeostasis by increasing the efficiency of intestinal calcium and phosphorus absorption in order to maintain signal transduction, metabolic activities, and neuromuscular function, and to promote skeletal mineralisation. Several compelling studies have shown that sunlight is the most important source of vitamin D. Circulating concentrations of 25hydroxyvitamin D (a barometer for vitamin-D status) are maximum in late summer and minimum at the end of winter.1,2,5,6 Arab women who protect all of their skin with clothing are commonly vitamin-D deficient, as are blacks because their increased skin pigmentation greatly reduces the production of vitamin D3 in the skin.6,7 When nursinghome residents in New Zealand were exposed to 15 or 30 minutes of sunlight two to three times a week, their circulating concentrations of 25(OH)D increased sharply.8 In 1997, the Institute of Medicine of the US National Academy of Sciences recommended new adequate intakes for vitamin D.7 On the assumption that young and middleaged adults were more likely than older people to be exposed to sunlight, the recommendations were 200 IU (5 ␮g)/day for adults up to the age of 50, 400 IU/day for people aged 50–70, and 600 IU/day for those aged 70 and above. Is this enough? H Glerup and colleagues9 provide convincing evidence that more attention should be paid to exposure to sunlight as the major source of vitamin D. They conducted a cross-sectional study in middle-aged veiled and non-veiled Arab women and age-matched

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For personal use only. Not to be reproduced without permission of The Lancet.

COMMENTARY

Danish women who lived in Denmark. They found that both veiled and non-veiled Arab women who had a dietary intake of 1·04 ␮g (about 40 IU/day) of vitamin D were vitamin-D deficient (25[OH]D, 7·1 [SEM 1·1] nmol/L and 12·6 [2·6], respectively; normal range >20 nmol/L), as were ethnic Danish Moslems (17·5 [2·3] nmol/L), whose estimated vitamin-D intake, including food supplementation, was about 600 IU/day. The Danish controls, with an estimated daily oral intake of 300 IU, were not vitamin-D deficient (47·1 [4·]6 nmol/L). Serum parathyroid hormone measurements revealed that 57%, 55%, and 20% of the veiled Arab women, non-veiled Arab women, and ethnic Danish Moslems, respectively had hyperparathyroidism secondary to vitamin-D deficiency, compared with only 2% of the Danish controls. Secondary hyperparathyroidism can increase mobilisation of calcium from the skeleton sufficiently to precipitate or exacerbate osteoporosis. The phosphaturia it induces decreases serum phosphorus, which, in turn, causes a mineralisation defect leading, in many cases, to osteomalacia. Muscle weakness is a more subtle and insidious consequence of vitamin D deficiency.10 Glerup and colleagues9 reported muscle pain in 88% of Arab women, compared with 32% among Danish controls. Muscle weakness as measured by rising from a chair or ascending a staircase was experienced by 32% of Arab women but only by 14% of the Danish controls, and muscle cramps by 72% of Arab women, compared with none of the Danish controls. Glerup and colleagues10 suggest that, in the absence of sunlight, 1000 IU of vitamin D is necessary to maintain adequate 25(OH)D concentrations. This point is consistent with the observation that healthy men confined to a submarine for 3 months were barely able to maintain adequate circulating concentrations of 25(OH)D while receiving 600 IU of vitamin D daily.1 Once exposed to sunlight, their 25(OH)D increased by 40% in a month.1 Are there any other consequences of vitamin-D deficiency? There is a latitudinal association with increased risk of dying of breast, colon, prostate, and ovarian cancer.11 Black men, who are prone to vitamin-D deficiency, have a higher risk of prostate cancer and a more aggressive form of the disease. A suggestion is that it is the lack of exposure to sunlight and associated chronic vitamin-D insufficiency that is associated with the increased risk of dying of these cancers.11–13 The possibility that vitamin D is important for cellular health is now appreciated. The prostate, colon, breast, and probably many other tissues have the enzymatic machinery to convert 25(OH)D to its active form, 1,25(OH)2D,14 which is a potent hormone for regulating cell proliferation and perhaps limiting the metastatic activity of some cancers (figure). There are two take-home messages from the work of Glerup and colleagues.10 First, although there is no question that chronic excessive exposure to sunlight can increase risk of skin cancer and cause skin damage,15 recommendations on sun protection should be moderated. Second, fortification of foods with vitamin D should be widened, especially in Europe. The fear of vitamin-D intoxication that swept Europe in the 1950s16 and resulted in laws forbidding fortification of milk and other products is antiquated. Vitamin-D deficiency causes rickets in children and osteopenia and osteomalacia in adults, exacerbates osteoporosis, and increases muscle weakness and pain. It may also predispose to the growth and metastatic activity of some of the more common cancers. Because latitude, season, skin pigmentation, sunscreen

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Metabolism and function of vitamin D

25(OH)D3

Vitamin D3 Skin

Liver

Kidney

Prostate gland, breast and colon

Milk Salmon Diet

1, 25(OH)2D3

1, 25(OH)2D3

Calcium homoeostasis Muscle health Bone health

Regulation of cell growth (cancer prevention)

use, and ozone air pollution can greatly influence the cutaneous production of vitamin D,1 there can be no simple recommendation for the amount of exposure to the sun to satisfy the body’s requirement for vitamin D. Exposure of the body in a bathing suit to 1 minimal erythemal dose (MED) of sunlight is equivalent to ingesting about 10 000 IU of vitamin D. Thus, exposure of 6–10% of the body surface to 1 MED is equivalent to ingesting about 600–1000 IU of vitamin D. Exposure of hands, arms, and face two to three times a week to a third to a half of an MED (about 5 min for skin-type-2 adult in Boston at noon in July) in the spring, summer, and autumn is more than adequate. Excessive exposure to sunlight cannot produce vitamin-D intoxication;1 anybody wishing to stay outside longer than recommended above should apply a sunscreen with a sun-protection factor of 15 to prevent sunburn and the damaging effects of excessive sun exposure. Another means of guaranteeing vitamin-D sufficiency, especially in nursing-home residents, is to give 50 000 IU of vitamin D once a month. A simple remedy for vitamin D deficiency is 50 000 IU of the vitamin once a week for 8 weeks.3 With adequate exposure to sunlight, dietary vitamin D becomes unnecessary. It is remarkable how exposure to sunlight a few times a week can reduce the risk of osteoporosis, osteomalacia, muscle weakness, fractures, and maybe some of the common cancers but also induce a feeling of wellbeing. Michael F Holick Vitamin D, Skin, and Bone Research Laboratory, Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA. (e-mail:[email protected]) 1 2

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Holick MF. McCollum Award Lecture, 1994: Vitamin D: new horizons for the 21st century. Am J Clin Nutr 1994; 60: 619–30. Dawson-Hughes B, Harris SS, Dallal GE. Plasma calcidiol, season, and serum parathyroid hormone concentrations in healthy elderly men and women. Am J Clin Nutr 1997; 65: 67–71. Malabanan A, Veronikis IE, Holick MF. Redefining vitamin D insufficiency. Lancet 1998; 351: 805–06. Gloth FM, Gundberg CM, Hollis BW, Haddad HG, Tobin JD. Vitamin D deficiency in homebound elderly persons. JAMA 1995; 274: 1683–86. McKenna MJ. Differences in vitamin D status between countries in young adults and the elderly. Am J Med 1992; 93: 69–77. Bell NH, Greene A, Epstein S, Oexmann MJ, Shaw S, Shary J. Evidence for alteration of the vitamin D-endocrine system in blacks. J Clin Invest 1985; 76: 470–73. Sedrani SH. Low 25-hydroxyvitamin D and normal serum calcium concentrations in Saudi Arabia: Riyadh region. Ann Nutr Metab 1984; 28: 181–85. Reid IR, Gallagher DJA, Bosworth J. Prophylaxis against vitamin D

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Renal failure after bone-marrow transplantation In an early review of bone-marrow transplantation (BMT), neither acute nor chronic renal failure was mentioned as a potential complication.1 The ever-growing number of BMTs (figure) and the increasing short-term and longterm survival of patients undergoing BMT have changed that assessment. Even though the number of autologous BMTs has declined in the past year because of declining use of BMT for breast cancer, the overall increase in both allogeneic and autologous BMTs since 1980 is unmistakeable. In the USA alone, about as many allogeneic BMTs (10 0000) are done per year, as are kidney transplants.2 Currently, 5–15% of all patients undergoing BMT may develop acute renal failure and, of the long-term BMT survivors, 5–20% will develop chronic renal failure.3,4 The process and course of BMT make it evident why complications develop. The pre-transplantion high-dose chemotherapy and “conditioning” with total body irradiation (TBI), as well as the 2–3 week delay before the graft yields measurable circulating leucocytes, produce a period of neutropenia, which may lead to sepsis and acute renal failure. The gastrointestinal exfoliation caused by the combined chemoirradiation adds to this risk. Months and years later, infertility, hypothyroidism, cataracts, secondary cancer, and even insulin-resistance may develop.5,6 Since 1980, many reports of renal failure after BMT have included discussions of haemolytic-uraemic syndromes, acute tubular necrosis, and radiation nephropathy.3,4,7,8 To these can be added the much rarer tumour-lysis syndrome and drug-induced or virus-induced haemorrhagic cystitis. Haemolytic-uraemic syndromes (HUS) were first reported in 1981, and were associated then with doses of ciclosporin (10–12·5 mg/kg per day) that are several-fold higher than those used today for BMT. However, HUS after BMT still occurs, perhaps of endothelial injury caused by chemo-irradiation given for pre-BMT conditioning. This type of HUS does not respond to plasmapheresis.9 The typical acute renal failure that is seen in the first 30 days after BMT is commoner after allogeneic than after autologous BMT, and has been associated with sepsis, hypotension, use of nephrotoxic antibiotics, and concurrent liver disease.3 In many cases the urine sediment will have the muddy brown casts that are typical of acute tubular necrosis. However, prospective studies of the 6

Bone-marrow transplants worldwide 40 000 Number of transplants

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deficiency in the elderly by regular sunlight exposure. Age Ageing 1985; 15: 35–40. Glerup H, Mikkelsen K, Poulsen L, et al. Commonly recommended daily intake of vitamin D is not sufficient if sunlight exposure is limited. J Intern Med 2000; 247: 260–68. Glerup H, Mikkelsen K, Poulsen L, et al. Hypovitaminosis D myopathy without osteomalacic bone involvement. Calcif Tissue Int 2000; 66: 419–24. Garland CF, Garland FC, Gorham ED. Can colon cancer incidence and death rates be reduced with calcium and vitamin D? Am J Clin Nutr 1991; 54: 193S–201S. Hanchette CL, Schwartz GG. Geographic patterns of prostate cancer mortality. Cancer 1992; 70: 2861–69. Ahonen MH, Tenkanen L, Teppo L, Hakama M, Tuohimaa P. Prostate cancer risk and prediagnostic serum 25-hydroxyvitamin D levels (Finland). Cancer Causes Control 2000; 11: 847–52. Schwartz GG, Whitlatch LW, Chen TC, Lokeshwar BL, Holick MF. Human prostate cells synthesize 1,25-dihydroxyvitamin D3 from 25hydroxyvitamin D3. Cancer Epidemiol Biomarkers Prev 1998; 7: 391–95. Gilchrest BA. Sunscreens: a public health opportunity. N Engl J Med 1993; 329: 1193–94. British Pediatric Association. Hypercalcemia in infants and vitamin D. BMJ 1956; 2: 149.

32 000 Autologous

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1980

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Data from the International Bone Marrow Transplant Registry.

histology of acute renal failure after BMT are lacking. The role of renal epithelial apoptosis, as opposed to necrosis, has also not been studied. Acute as well as chronic renal failure may also be due to the nephrotoxicity of the calcineurin inhibitors ciclosporine or tacrolimus, which are used in the first few months after allogeneic BMT to prevent graft-versus-host disease. Chronic renal failure after BMT was recognised over 10 years ago as being related to the TBI used for conditioning.10 This complication has been confirmed by studies that show a direct dose-response relation between the dose of TBI and the frequency of chronic renal failure after BMT.11 Clinically, when ciclosporin or tacrolimus nephrotoxicity has been ruled out as the cause of chronic renal failure after BMT, the disorder may be labelled BMT nephropathy, a form of radiation nephropathy.4 The more severe cases of BMT nephropathy may present much like HUS. Even with less impressive initial presentations, progressive loss of renal function, with need for chronic dialysis or kidney transplantation, may result. The usual time of occurrence of BMT nephropathy is 8–12 months after BMT, when it presents with hypertension and disproportionately severe anaemia. This interval corresponds to that for the development of acute radiation nephritis, described by Luxton 50 years ago as a complication of abdominal irradiation for the treatment of seminomas.12 Luxton also described chronic radiation nephritis, which occurred several years after such irradiations. Thus late cases of BMT nephropathy may be encountered in the long-term follow-up of patients who have undergone TBI-based BMT. Since renal injury affects only a minority of patients receiving abdominal or total-body irradiation, additional factors may influence the expression of radiation nephropathy. One such factor could be polymorphism of the gene for angiotensin-converting enzyme. Among patients who have undergone allogeneic BMT, those homozygous for the D allele are less likely than those with the I allele to undergo long-term decline in renal function.13 Radiation nephropathy is but a special case of normal tissue-radiation injury, of which the genetic determinants are only dimly perceived. There is a wide range of variability in normal tissue response to therapeutic irradiation.14 A better understanding of this response, and the ability to identify people most at risk of normal tissue-

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