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10 Karussis D, Weiner HL , Abramsky O. Multiple sclerosis vs Lyme disease: a case presentation to a discussant and a review of the literature. Mult Scler 1999; 5: 395402. 11 Chmielewska-Badora J, Cisak E, Dutkiewicz J. Lyme borreliosis and multiple sclerosis: any connection? A seroepidemic study. Ann Agric Environ Med 2000; 7: 14143. 12 Coyle PK. Borrelia burgdorferi antibodies in multiple sclerosis patients. Neurology 1989; 39: 76061. 13 Schmutzhard E, Pohl P, Stanek G. Borrelia burgdorferi antibodies in patients with relapsing/remitting form and chronic progressive form of multiple sclerosis. J Neurol Neurosurg Psychiatry 1988; 51: 121518. 14 Brorson , Brorson S-H, Henriksen T-H, Skogen PR, Schyen R. Association between multiple sclerosis and cystic structures in cerebrospinal fluid. Infection 2001; 29: 31519.

Variation in thyroid function within reference range and adverse outcomes

TSH >20 mU/L* Increased 20-year risk of hypothyroidism6 TSH >20 mU/L* Increased frequency of thyroid autoantibodies810 TSH >40 mU/L* Increased risk of heart disease10 TSH 2040 mU/L* Cholesterol values respond to thyroxine replacement9 TSH 0255* Decreased psychological well-being in patients on thyroid hormone compared with controls12 TSH in normal range* Improved psychological well-being if T3 is added to T4 therapy13 Free T4 <104 pmol/L Impaired psychomotor development of infant if occurs in first trimester11
TSH=thyroid-stimulating hormone, T4=thyroxine, T3=tri-iodothyronine. *Typical reference ranges: TSH 0255 mU/L, free T4 98250 pmol/L.

Whose normal thyroid function is better yours or mine?

Stig Andersen and colleagues recently measured the thyroid function of 16 normal men every month for a year.1 The variation within an individual lay in a range that was much narrower than the laboratory reference range. This means that a test result may be abnormal for an individual but still lie within the laboratory reference range. Elegant as the data are, others have made similar observations from repeated measurements of thyroid function, as Andersen and colleagues acknowledge, and there are examples of the same phenomenon in other systems. Many laboratory tests, such as serum calcium or HbA1c, also show narrow individual variation, sometimes referred to as a low index of individuality. Similar results occur for basal cortisol.2,3 Such observations imply that human beings regulate these variables about slightly different set points. Normal or reference ranges are derived using statistics or epidemiology. The statistical approach is the easiest and most commonly used. The reference range is defined, for example, as two standard deviations above and below the mean in a group of apparently disease-free individuals. However, the epidemiological approach is more meaningful, defining abnormal values as those associated with adverse consequences. Hence cholesterol over 56 mmol/L carries a 17 times increased risk of death from coronary heart disease compared with the lowest quintile of the population, and might be considered to be unacceptable (if not abnormal), even though 50% of American men have such a value.4 A diastolic blood pressure above 85 mm Hg in healthy individuals is associated with increased stroke risk, even though a high percentage of the population over 60 have such a pressure.5 Unfortunately the data are not usually available to apply the epidemiological approach and the statistical approach has to be used. So, for thyroid function, what values are associated with adverse outcome? In particular, is there any evidence that variation of thyroid function within the statistical normal range can lead to adverse outcome? If so, it might be worth knowing that an individuals thyroid function is abnormal for them, even though it lies within the statistical normal range for pooled individuals. The answer is, yes, to a limited extent (panel). A typical (statistical) reference range for thyroid-stimulating hormone (TSH) in many laboratories is around 0255 mU/L. However, the 20-year longitudinal Whickham survey indicated that individuals with TSH values greater than 20 mU/L have an increased risk of developing overt hypothyroidism over the next 20 years.6 Subclinical autoimmune thyroid disease is so common in the population (up to 40% of women have lymphocytic infiltration of the thyroid and 1015% have thyroid autoantibodies7) that laboratory reference ranges derived
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from testing apparently healthy subjects could easily be contaminated by diseased individuals. Indeed, if only individuals negative for antibodies against thyroid peroxidase and with no personal history of thyroid disease are tested, 95% of TSH values lie within 048360,8 and the US National Academy of Clinical Biochemistry (NACB) recommends the use of such a revised normal range. Importantly, several studies have detected an increase in thyroid peroxidase antibody positivity with TSH concentrations outside the narrow range 0219 mU/L,8-10 providing evidence that TSH in the upper reference range is often associated with abnormal pathology in the thyroid. Additional evidence that thyroid function within the laboratory reference ranges can be associated with adverse outcomes include an increased prevalence of heart disease with TSH values over 40 mU/L, after correction for other factors,10 impaired fetal neurodevelopment in mothers with a free thyroxine concentration below the 10th centile (<104 pmol/L) at 12 weeks gestation,11 and apparently impaired psychological well-being in patients on thyroxine replacement who have TSH values in the laboratory normal range.12 There is only one interventional study to indicate that TSH values within the reference range are not optimal. Michalopoulou and colleagues9 showed that thyroxine administration to individuals with TSH values in the range 2040 mU/L lowered cholesterol whereas no effect was detected with initial TSH in the range 04199 mU/L. The study of Bunevicius and colleagues,13 in which partial tri-iodothyronine administration improved psychological well-being while maintaining thyroid function broadly within the reference range, may also be relevant.13 So Andersen and colleagues observation of narrow individual variation in thyroid function compared with the reference range is a reminder that with common conditions such as hypothyroidism it is important to derive statistical reference ranges from truly healthy individuals, not just the population at large. Excluding potentially diseased individuals as per the NACB guidelines tightens the normal range to around 0535 mU/L. Stratification can further tighten the statistical normal ranges for a given age and sex, but not by very much.8 Beyond this, the emerging epidemiological data begin to suggest that TSH concentrations over 20 mU/L may be associated with adverse effects. But this is not the same as saying that thyroxine treatment would be beneficial in these individuals. More large epidemiological and interventional studies are required to define this point. Without this information it remains questionable whether it is important 353

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COMMENTARY

to know that an individuals TSH concentration has risen to abnormal levels for them, even though it remains in the reference range. Or put another way, we do not yet know whether my TSH of say, 15 mU/L, might be healthier than yours at, say, 19 mU/L, even if it is abnormal for me.
CMD and PS are in receipt of grant funding from NHS R&D and Goldshield Pharmaceuticals plc for a study of partial tri-iodothyronine replacement in patients with normal TSH concentrations.

*Colin M Dayan, Ponnusamy Saravanan, Graham Bayly

*University Research Centre for Neuroendocrinology, Bristol Royal Infirmary, Bristol BS2 8HW, UK; and Department of Chemical Pathology, Bristol Royal Infirmary (e-mail: colin.dayan@bris.ac.uk) 1 Andersen S, Pedersen KM, Bruun NH, Laurberg P. Narrow individual variations in serum T4 and T3 in normal subjects: a clue to the understanding of subclinical thyroid disease. J Clin Endocrinol Metab 2002; 87: 106872. Hearing SD, Norman M, Smyth C, Foy C, Dayan CM. Wide variation in lymphocyte steroid sensitivity among healthy human volunteers. J Clin Endocrinol Metab 1999; 84: 414954. Huizenga NATM, Kooper JW, de Lange P, et al. Interperson variability but intraperson stability of baseline cortisol concentrations, and its relation to feedback sensitivity of the hypothalamic-pituitary-adrenal axis to low-dose dexamethasone in elderly individuals. J Clin Endocrinol Metab 1998; 83: 4754. Martin MJ, Hulley SB, Browner WS, Kuller LH, Wentworth D. Serum cholesterol, blood pressure and mortality: implications from a cohort of 361 662 men. Lancet 1986; 2: 93336. Hansson L, Zamchetti A, Carruthers SG, for the HOT Study Group. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. Lancet 1998; 351: 175562. Vanderpump MPJ, Tunbridge WMG, French JM, et al. The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey. Clin Endocrinol (Oxf) 1995; 43: 5568. Dayan CM. Natural history of autoimmune thyroiditis: how normal is autoimmunity? Proc R Coll Phys Edin 1996; 26: 41933. Bjoro T, Holmen J, Kruger O, et al. Prevalence of thyroid disease, thyroid dysfunction and thyroid peroxidase antibodies in a large unselected population: the Health Study of Nord-Trondelag (HUNT). Eur J Endocrinol 2000; 143: 63937. Michalopoulou G, Alevizaki M, Piperingos G, et al. High serum cholesterol levels in persons with high-normal TSH levels: should one extend the definition of subclinical hypothyroidism? Eur J Endocrinol 1998; 138: 14145. Hak AE, Pols HAP, Visser TJ, Drexhage HA, Hofman A, Witteman JCM. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam study. Ann Intern Med 2000; 132: 27078. Pop VJ, Kuijpens JL, van Baar AL, et al. Low maternal free thyroxine concentrations during early pregnancy are associated with impaired psychomotor development in infancy. Clin Endocrinol (Oxf) 1999; 50: 14955. Saravanan P, Chau W-F, Roberts N, Vedhara K, Dayan CM. Psychological well-being in patients on adequate doses of L-thyroxine: results of a large controlled community based questionnaire study. Clin Endocrinol (Oxf) (in press). Bunevicius R, Kazanavicius G, Zalinkevicius R, Prange AJ. Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N Engl J Med 1999; 340: 42429.

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deaths a year in the USA is widely quoted these days, and the combined toll for 198895 was 1318, for an average of 82.1 In Australia, the annual toll was two in the decade 199099.2 There seems to be some under-reporting of injuries; on the other hand, case-fatality rates in published series of lightning injury are likely to be atypical because of an emphasis on the more tragic episodes, such as the four girls killed when lightning struck a metal tent-pole in South Africa in 1994. 22 girls survived, only three of them without injury.3 Muehlberger and colleagues4 followed up ten lightning victims who had been admitted over a 12-year period to a burns intensive-care unit, and agreed with a 1936 view that survivors escape long-term harm. Publication of the South African accident is accompanied by a reissue of US guidelines,5 and recommendations focusing on outdoor sports have just come out in Australia.2 True primary prevention is impossible; avoidance of lightning strikes is the issue. The best advice is still fairly basic. For example, look at the weather forecast before planning or proceeding with any open-air activity and be prepared to run for appropriate shelter if the interval between the lightning and the thunder is less than 30 s and do not venture out again until 30 min of silence has passed (the 30/30 rule). For major open-air functions, the suggestion is the appointment of a lightning spotter,2,5 with powers to cancel or postpone the event. This advice is all very sensible but risk-benefit arguments have their place. The average number of cloud-to-ground lightning strikes in the USA is at least 22 million and one estimate of the casualty rate is one per 86 000 strikes.6 If there was a lightning spotter for the British Open golf championship near Edinburgh on July 18-21and the weather on one of the days was horrid, if lightning-freehe or she would have carried an awesome responsibility. Being struck by lightning may not mean a direct hit, and puzzling fatalities with no obvious sign of contact have prompted a search for other explanations. Contact with a struck object or side flashes from the object, high-voltage gradients in the ground near a strike, and injury from the force of rapidly expanding and contracting air are widely recognised. A complete lightning strike from cloud to ground arises when the down-headed leader of a lightning strike meets an upward streamer. That the upward part itself may be harmful if it does not fully connect has been proposed, but not yet confirmed, as a fifth mechanism.7 Then there is the theoretical possibility of lightning creating magnetic fields that induce current in bystanders.8 Keraunopathology (keraunos=thunder) is a complex specialty. The three recent papers2,3,5 provide an excellent introduction to and further reading on the public-health aspects of this spectacular natural force. David Sharp
c/o The Lancet, London NW1 7BY, UK 1 2 3 4 5 6 7 8 Anon. Lightning-associated deathsUnited States, 19881995. MMWR Morb Mortal Wkly Rep 1998; 47: 39194. Makdissi M, Brukner P. Recommendations for lightning protection in sport. Med J Aust 2002; 177: 3537. Carte AE, Anderson RB, Cooper MA. A large group of children struck by lightning. Ann Emerg Med 2002; 39: 66570. Muehlberger T, Vogt PM, Munster AM. The long-term consequences of lightning injuries. Burns 2001; 27: 82933. Zimmermann C, Cooper MA, Holle RL. Lightning safety guidelines. Ann Emerg Med 2002; 39: 66064. Curran EB, Holle RL. Lightning fatalities, injuries, and damage reports in the United States from 19591994. www.nssl.noaa.gov/papers/tech memos/NWS-SR-193/techmemo-sr193.html (accessed July 15, 2002). Cooper MA. A fifth mechanism of lightning injury. Acad Emerg Med 2002; 9: 17274. Cherington M, Wachtel H, Yarnell PR. Could lightning injuries be magnetically induced? Lancet 1998; 351: 1788.

Lightning strikes
Shortly before the open-air performance in the Roman arena of Il Trovatore on the night of July 6, 2002, Verona was assaulted by a severe thunderstorm. Even if bad weather had not been forecast, the day had been ominously muggy, yet few locals seemed prepared. The performance went ahead, and when, towards midnight, the Verdi was suspended it was simply because the air was deemed a little damp for strings. I do not know what Veronas lightning precautions are but in Italy a soggy Stradivarius is clearly a serious threat to civilised living. The shift from a rural to an urban society in many countries explains in part the historical decline in deaths and injuries from lightning strikes. A figure of 73 such 354

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