The sometimes nonsense of ‘normal’ levels and ‘reference values’

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If you’ve ever had blood drawn for testing, most of your results will come with a ‘reference range’ attached. The reference range allows doctors (usually) to compare your result with what is accepted as ‘normal’. Normal, as far as references ranges are concerned, usually encompass around 95 per cent of people. In other words, in order for a value to be deemed ‘low’ or ‘high’ it needs to be in the bottom or top 2.5 per cent of values respectively.

In short, this means that reference values are set very wide. They are also utterly arbitrary. The practice of setting reference values in this way is down to convention.

I was thinking about this when recently advising someone about her likely thyroid function. Usually, the hormone advised for screening thyroid function is TSH (thyroid stimulating hormone). This hormone, secreted by the pituitary gland, tends to go up when the thyroid gland is failing (low thyroid function – hypothyroidism) and down when the thyroid is overactive (hyperthyroidism).

However, for a variety of reasons, some of which I detail here, TSH levels are not utterly reliable for assessing thyroid function. For one thing, TSH references are markedly different between laboratories. For example, this particular lady I was advising had had two previous tests at different labs, one of which quoted an upper limit of TSH of 5.6 mIU/L, while the other quoted a value of 4.0. In the US, the convention is now to regard anything over 3.04 as ‘raised’. Whether someone ends up with a diagnosis and treatment can depend, therefore, at least to some degree on where their blood was analysed.

The nonsense of this way of determining what is normal and healthy came back to me yesterday when I read the summary of a paper which assessed ‘normal’ TSH values in Japanese men and women [1]. Here are, according to this paper, the ‘normal’ TSH values for different age bands:

20-29: 0.39-4.29 mIU/L
30-39: 0.34-3.90 mIU/L
40-49: 0.56-5.02 mIU/L
50-59: 0.51-5.30 mIU/L
60-69: 0.60-4.85 mIU/L
70+: 0.62-6.15 mIU/L

You’ll notice there’s a general tend here for ‘normal’ values to rise as people age. The authors make a call for age-specific references to be set in order to “prevent significant misclassifications of patients with abnormal TSH levels”. In other words, the older people get, the higher their TSH values should be allowed to rise before they are deemed to be suffering from low thyroid function.

As we age, there is generally increased risk that certain organs in the body, including the thyroid, will decline in function. Higher TSH values generally reflect worsened thyroid function. Does the idea of setting age-specific TSH values not just open up the possibility that elderly individuals with low thyroid function are more likely to be regarded as ‘normal’? I think it does.

Some years ago I was talking to clinical chemist about reference ranges regarding the adrenal hormone DHEA (adequate levels of which seem to be very important for general health and wellbeing). The lab where he works applies reference ranges that are age-specific (low reference ranges for older people). I asked him about the wisdom of this, and he commented (and I paraphrase): “I suppose the question is whether a 70-year-old should ideally have the DHEA levels of a typical 70-year-old, or perhaps a typical 30-year-old.” My suspicion is that shooting for levels seen in younger, healthier, more vibrant individuals is better.

The first time I even thought about this issue of ‘normal’ values was at medical school. In a tutorial with a ‘chemical pathologist’, the normal ranges for haemoglobin were being discussed (low levels of this red blood cell substance signal anaemia). ‘Normal’ values for women are lower than those for men. Why this is was being explored in the tutorial. In all likelihood, lower ‘normal’ haemoglobin values in women reflect menstrual blood loss. The chemical pathologist commented that (again, I paraphrase): “Applying normal values in this ways is probably just allowing many women to wander around in a vaguely anaemic state.”

Right there and then it struck me what a nonsense reference values can be, and how slavish adherence to them can be to people’s detriment.


1. Yoshihara A, et al. Reference limits for serum thyrotropin in a Japanese population. Endocr J. 2011 May 7 [Epub ahead of print]

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