Issue # 30: Calcium intake and osteoporosis in men

Is there a relationship between calcium intake and osteoporosis in men? Some guidance on this question has been provided by recently published data from research carried out at Harvard University.

 

Most of the evidence linking long term calcium intake and osteoporosis has come from epidemiological studies in women. The Harvard group looked at data from the Health Professionals Follow-up Study, which provided more than 300,000 person-years of follow-up over an 8 year period in 43,063 men who had completed a dietary and lifestyle questionnaire in 1986.

 

The relative risk of forearm and hip fractures did *not* significantly differ between those in the highest quintile for calcium intake compared with the lowest, nor for those consuming more compared with less milk.

 

COMMENT: In this study, the dietary intake was surveyed only when the men were at least 40 and up to 75 years old.  Calcium intake may be more important during teenage years when bones are still growing. There are also clinical trials in older women which show that calcium supplementation slows non-vertebral bone loss,  especially in those with low dietary calcium intake to begin with.

 

Even so, the importance of this new study is its very large size, which must raise questions about whether there is any link in men between dietary calcium intake and non-vertebral fracture rates in later life.

 

Ref: J Nutrition 1997; 127: 1782-1787

 

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Issue # 31: Antioxidants in aging

 The role of antioxidants in aging has attracted much theoretical interest, but is there any practical clinical application for geriatric care? A recent study from Basle in Switzerland has added to the possibility that there may be reason to consider antioxidant status in the elderly patient.

 

A total of 442 subjects of mean age 75 years was assessed both for antioxidant vitamin status (alpha-tocopherol, ascorbic acid, and beta-carotene) and tests of memory. The subjects in this study had already had these same vitamins assayed in a previous study some 20 years earlier.

 

The first fascinating finding was a strong correlation between the vitamin levels 22 years ago and now (r=0.47, 0.22 and 0.43 respectively for vitamins E, C and A, p<0.001 in each case).

 

More important was a correlation between tests for free recall, recognition, and vocabulary with both the recent and the previous vitamin levels. These correlations remained significant after adjustment for potential confounders, such as age,  education and gender.

 

COMMENT

A correlation does not mean that there is a direct cause and effect relationship between antioxidant levels and cognition. Moreover, it would be a further step to show that correction of borderline antioxidant status produced any change in cognitive function.

 

However, this study adds to the weight of evidence that antioxidant status will prove to be an important clinical parameter  in the elderly.

 

 

Ref: J Am Geriatr Soc, 1997;45:718-24

 

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Issue # 32: Hordaland Homocysteine Study

What approach should the physician take to a patient with elevated blood levels of homocysteine? This syndrome is increasingly recognised as a risk factor for cardiovascular disease, but a consensus is still forming on the best way to manage patients with this finding. New evidence to assist the physician has come from a recent case-control and intervention study from Norway.

 

Researchers working with the Norwegian National Health Screening Service screened 18,043 middle aged subjects in 1992-3. They identified 67 cases with total plasma homocysteine (Hcy) levels >= 40 µmol/liter. These cases were compared with 329 controls.

 

The cases had lower plasma folate and cobalamin levels than the controls, lower intake of vitamin supplements, consumed more coffee, and were more frequently smokers. Ten percent  were considered to have overt vitamin B12 deficiency and were treated accordingly.  An important finding was that there was a high level of homozygosity for the C677T mutation in the methylenetetrahydrofolate reductase gene (73.1% of cases vs 10.2% of controls.)

 

In the intervention phase of the study, 58 of these subjects who had shown elevated Hcy levels and who had not had any specific treatment were reexamined two years later. More than 70% still had Hcy > 20 µmol/liter. From this group 37 were offered treatment with low dose folic acid supplement (0.2 mg/d).

 

This supplement treatment resulted in a drop in Hcy level in all but 2 subjects after just 7 weeks. Levels were back to normal in almost all subjects after 7 months, although a small proportion required much higher doses (5 mg/day) of folic acid. Remarkably, almost all of these 37 subjects were homozygotes for the C677T mutation.

 

Ref: J. Clin. Invest. 1996. 98: 2174-2183

 

COMMENT 

It is becoming increasingly clear that elevated homocysteine levels are an independant risk factor for cardiovascular disease, and that this issue can be related to any of vitamin B12, vitamin B6 and folate status, all of which are involved in homocysteine metabolism. The issue is particularly relevant to the elderly population, in whom folate intake can be low and sub-clinical B12 deficiency due to poor absorption is now recognised as a common problem.

 

There has previously been some evidence that in most cases folate will be more important than either of the other vitamins in correcting the abnormality (e.g. J Nutr 1994;124:1927-1933).

 

This recent study is not a double-blind placebo-controlled trial, but still adds to our knowledge by:

1. Demonstrating that people who have elevated Hcy on one reading are likely to have it persistently unless treated.

2. Suggesting that in the absence of overt vitamin B12 deficiency it can be treated with folate supplementation alone, but that some people will require higher doses.

3. Highlighting a strong genetic dimension to this condition.

 

 

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Issue # 33: Fat and CHD risk in women

 Here is a most important paper in what is becoming a renewed debate on the optimal dietary recommendations for prevention of heart disease.

 

This analysis comes from the long running Nurses Health study. A team from Harvard University looked prospectively at the  diet-heart disease relationship in 80,082 women who were free of cardiovascular and related diseases when first examined in  1980.

 

During follow-up for 14 years, nearly 1,000 women had documented cases of non-fatal myocardial infarction or had died from coronary heart disease. Multivariate analyses were performed on diet and other risk factors and compared with non-affected women.

 

The outcome of interest was a comparison in the relative risk (RR) for heart disease from an increase of fat intake (expressed as a % of energy) for various different types of fat. The relative risk figures shown below were each calculated relative to an equivalent energy from carbohydrate sources.

 

A quick summary of the main results (per 5% increase in energy, except where stated otherwise)....

 

Relative risk of increasing energy from:

 

1.Trans unsaturated fat: RR= 1.93 (95% CI: 1.43-2.61; P<0.001 for a 2% increase in energy)

 

2. Monounsaturated fat: RR= 0.81 (CI=0.65-1.00; P = 0.05)

 

3. Polyunsaturated fat: RR= 0.62 (CI=0.46-0.85; P = 0.003)

 

4. Total fat intake No significant rise in risk, RR=1.02 (CI=0.97-1.07, p=0.55)

 

According to the authors,  the results of this study suggest that it might be more effective in preventing coronary heart disease in women to replace saturated and trans unsaturated fats with unhydrogenated monounsaturated and polyunsaturated fats than to reduce overall fat intake.

 

Ref: NEJM 1997;337 (21):1491-9

 

COMMENT

This issue is of major importance to many groups within our community. The standard dietary recommendations in most countries place primary and often quantative stress on lowering overall fat intake, and only secondarily focus on the source of that fat.

 

It has been difficult, for example, to know exactly how to advise vegetarians who consume high fat diets, albeit that the fat is from vegetable sources. The current interest in soy products (because of reported health benefits from their phytoestrogen content) also raises the question of how much vegetable fat is acceptable in the diet.

 

In interpreting this study, one needs to bear in mind the methodological limitations of the dietary intake data survey approach on which intake data have been based, and the fact that it involves only middle aged women (34 to 59 years in 1980). We await further studies on this issue with interest.

 

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Issue # 34: GIT x-rays and bariatric surgery

Before undertaking gastric surgery for morbid obesity, surgeons commonly request upper GI x-rays. However, this is an unnecessary expense according to a recent retrospective study from North Carolina.

 

A series of 814 consecutive patients with morbid obesity who underwent gastric bypass had their medical records reviewed. The researchers determined whether an upper GIT series had been obtained and, if so, whether the results of these x-rays influenced the surgery in any way.

 

Upper GIT x-ray series was ordered in over 80% of the patients. 60% of these x-rays were entirely normal.  The main abnormality found in the remainder was hiatus hernia (two thirds of the abnormal results or 25% of the total x-rays performed). The next most common abnormality was esophageal reflux (6% of total).

 

The most important finding of this study was that none of the abnormal findings resulted in any significant change in surgical management, in particular delay or cancellation in surgery.

 

Ref: Obesity Surgery 1997;7:16-18

 

COMMENT

Physicians commonly wonder about whether to order a test or investigation that might potentially provide some relevant clinical management information, even though in practice they know it almost never does. The temptation to follow established protocol and order a test "just in case" something important turns up is strong.

 

This study suggests that upper GIT x-rays before gastric bypass are one of those commonly performed tests that do not in fact make much difference to management. If this is true, there seems little reason to perform it. What the study does not show, of course, is the pressure of medicolegal influence on such decisions. 

 

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Issue # 35: Vegetables and lipid peroxidation

Even a short term increase in fruit and vegetable intake can have demonstrable positive effects on susceptibility of smokers to lipid peroxidation. This is the conclusion of an interesting pilot study just published in the European Journal of Clinical Nutrition.

 

Researchers at Joseph Fourier University in Grenoble studied two groups of apparently healthy volunteers, 11 smokers and 11 non-smokers. None were taking nutrition supplements.

 

Both groups were placed on a diet emphasising fruits and vegetables, so that their total carotenoid intake increased to 30mg/day. Various components of plasma vitamin A levels were measured (including alpha and beta carotene, lutein and lycopene) as well as a range of indicators of LDL oxidation (e.g. lag time to oxidation, superoxide-dismutase and selenium-glutathione-peroxidase activities).

 

Before starting on the experimental diet the smokers compared with the non-smokers had significantly lower plasma carotenoid levels (including lutein, alpha carotene p<0.05 and beta carotene p<0.01). The indicators of oxidative stress were similar.

 

After two weeks of higher fruit and vegetable diet, both groups had significantly higher plasma carotene levels, but the  smokers' levels increased twice as much (23%) as the non-smokers  (11%).  The resistance of LDL to oxidation increased 14% in smokers (P<0.05) and 28% in nonsmokers (P<0.025), as did a number of other parameters of lipid peroxidation.

 

Ref: European Journal of Clinical Nutrition 1997: 51 (9): 601 - 606

 

COMMENT

This is a useful contribution to the current debate about the role of vitamin A intake in the health of smokers. The epidemiological evidence had suggested that higher intake of vitamin A-rich foods was associated with some protectition against the adverse consequences of smoking, including the development of lung cancer.

 

However, recent clinical trials involving carotene supplements have not only failed to confirm the hypothesis, but have even suggested that giving supplemental vitamin A could be dangerous as it increases rather than decreases disease incidence.

 

This new study confirms that diets rich in carotenoids can positively affect lipid oxidation in human subjects after only short periods, and suggests that such diets will be particularly helpful to smokers.

 

This should encourage those nutritionists who prefer recommending healthy food to taking of supplements. By contrast, recent evidence on vitamin E has suggested that you might need to take supplements in order to get the full protective effects of that vitamin against heart disease. This paper reminds us that it is worth pursuing controlled studies involving food rather than supplements, difficult though these may be to control. 

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Issue # 36:  Glutamine and immunity in TPN

Although there are a number of in vitro studies showing beneficial effects of glutamine on immune function,  a recent clinical trial from the UK has confirmed the benefits of supplementary glutamine in the context of parenteral nutrition.

 

The researchers conducted a randomized clinical trial comparing glutamine-supplemented total parenteral nutrition (TPN) with non-supplemented TPN as control in patients undergoing colorectal resection. The active treatment solution featured stable dipeptides of glutamine (Glamin).

 

Patients receiving the extra glutamine significantly increased their T cell mitogenic response without any associated alteration in levels of pro-inflammatory cytokines (interleukin-6, tumor necrosis factor).

 

A subsequent clinical trial confirmed these results in patients with severe acute pancreatitis. On this occasion, there was a significant reduction in IL-8 production in the supplemented group.

 

COMMENT

The importance of glutamine status in maintaining intestinal integrity is well known, particularly  in conditions of stress such as usually seen in patients who require TPN.

 

The last several years has seen a considerable interest in the possible benefits of giving such patients extra glutamine, amidst growing evidence that ordinary TPN solutions tend to induce a clinically significant glutamine deficiency.  Much of this work has involved enteral glutamine supplements, since there have in the past been problems with maintaining stability of this amino acid in TPN solutions.

 

Previous studies have suggested that glutamine supplementation will decrease septic complications in trauma patients (e.g. see Ann Surg, 1996 224:531-40). Whilst this may be related to the access of bacteria across the gut, this current study supports the notion that glutamine deficiency in TPN patients might also have direct immune effects.

 

Ref: Nutrition 1996;12:S82-S84 

 

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Issue # 37:  Zinc and diarrhoea

Zinc supplementation significantly reduces the incidence of acute diarrhea in young children of low socioeconomic status, particularly those with zinc deficiency. This is the conclusion of a recent double-blind, randomised trial.

 

A group of 286 children from 6 months to 3 years of age in urban India were randomly assigned to receive zinc (10 mg of elemental Zn as gluconate) plus multivitamins daily for 6 months. They were compared with a similar number of control children given multivitamins alone.  Both groups were assessed for incidence (number of episodes) and prevalence (the number of days) of acute diarrhoea over the six month period by means of regular home visits and physician examinations. Plasma zinc was measured at the outset in both groups.

 

In children aged more than 11 months old there was significantly less diarrhea in the zinc supplemented group. For example, in the boys there was a 26% drop in incidence (95% CI 13- 38%) and 35% drop in prevalence (CI: 20-50%) of acute diarrhoea .

 

Results were more marked in children with low pre-treatment zinc status. On the other hand, zinc supplementation had no effect in children aged 6-11 months of age.

 

Ref: Am J Clin Nutr 1997;66:413-8

 

COMMENT

Since diarrhoeal disease is one of the major causes of morbidity and death in children from the developing world, this is a significant finding.

 

That zinc deficiency is important in diarrhoea is not a new discovery. It has been known for some time, along with the role of vitamin A deficiency. Indeed, administration of zinc chloride solution is part of the standard physician protocol from the WHO for the hospital treatment of dehydration in diarrhoeal patients (see Web Site of the Week below) .

 

However, turning this knowledge into practical management and prevention strategies has proved harder for zinc than for vitamin A. Clinical trials with zinc supplementation go back almost a decade, but have been sporadic and with equivocal results (e.g. see Ann Trop Paediatr 1990;10:63-9). There is also the question of whether zinc supplementation might have an adverse effect on iron status.

 

This new study offers perhaps the best evidence we have to date that giving older children zinc supplementation protects them from acute diarrhoea over an extended time frame. It is particularly interesting that the benefit was seen in comparison to a control group that was taking daily multivitamin supplements as their `placebo'. This reinforces the special role of zinc in acute diarrhoea.

 

Zinc deficiency should not be thought of as just a problem for developing countries. It is by no means an uncommon condition in Western countries also, particularly in the elderly and in surgical patients. Veterinarians have long recognised its importance.

 

The mechanism by which zinc is involved in diarrhoea is most likely its role in intestinal mucosal integrity (as seen most dramatically in acrodermatitis enteropathica). Zinc deficiency is therefore always worth considering as a cause of GIT-linked co-morbidity in critical care and surgical situations, to give just one example.

 

There has also been a great deal of interest in the relationship between low zinc status and susceptibility to respiratory infection and immune dysfunction. Children with low zinc are prone to a combination of both acute diarrhoea and respiratory episodes (Acta Paediatr 1996;85:148-50). Research into the role of zinc in preventing this particularly nasty and regrettably common combination of pathologies is therefore of wide significance. 

 

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Issue #38: Nutrition in obstetrics

Obesity prior to pregnancy is associated with greater risk of late foetal death and premature delivery. However, the link between body weight and pregnancy outcome is not as clear-cut with lesser degrees of overweight and depends on parity.

 

These are the findings from perhaps the largest population-based cohort study ever done on this subject, published last week in the New England Journal of Medicine.

 

Researchers calculated body mass index (BMI) from measurements in 167,750 women in Sweden between 1992 and 1993 and monitored their pregnancy outcomes.

 

In nulliparous women:

  - Those who were obese (BMI>=30) prior to pregnancy had a higher risk of very preterm delivery

         -> odds ratio for delivery at less than 33 weeks =1.6 (95% CI =1.1-2.3)

 - There was a consistent trend across weight categories for the risk of late foetal death

         -> odds ration for BMI: <20=1, 20-24.9=2.2, 25-29.9=3.2, >=30=4.3)

 

In parous women:

 - There was also had a significant increase in the risk of late foetal death

         -> odds ratio= 2.0 (1.2-3.3).

 -  BUT there was no trend for lesser degrees of overweight.

 - AND the risk of very preterm delivery was higher in *lean* subjects.

 - Greater pre-pregnancy weight *protected* against a small-for-gestational-age infant 

         -> the likelihood *decreased* with increasing BMI.

 

Ref: NEJM 1998;338:147-152 

 

COMMENT

The association between excess pre-pregnancy weight and adverse obstetric outcomes has been known for many years. It is mediated through higher risk of twins, gestational diabetes, hypertension, premature rupture of the membranes and, not surprisingly,  more likelihood of Caesarian delivery, amongst other things (See for example Am J Obstet Gynecol, 1992;167:370-2).

 

What is interesting about this latest study is the sheer size of it, and the fine tuning of obstetric risk that these large numbers allow. It is clear that the risk of excessive pre-pregnancy weight depends on parity, and that nullipara are more at risk.

 

The data show that being lighter is also not necessarily ideal, particularly in parous women. This is an important issue now that we are living in an era where many young women seem to regard a BMI of <20 as being the optimal female shape. We can safely assume that, in these Swedish women, aesthetic rather than health grounds were most likely to explain any leanness.

 

The issue of what is an ideal pre-pregnancy weight and how much weight women should gain during pregnancy has been hotly debated in obstetrics for decades. This study does confirm that obesity is a risk, and even suggests that there might be a Goldilocks-like `just right' value for BMI in obstetric terms.

 

So physicians can go on wisely counselling obese women to lose weight before they attempt to become pregnant. However, further work will be needed before physicians know exactly whether it is also appropriate to advise lean young women who wish to  become lean mothers that they should first gain some weight.

 

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Issue # 39:  Vitamin C and cataracts

Long-term vitamin C supplementation is associated with substantially lower prevalence of age-related lens opacities. This is the conclusion of a recently published analysis of data from the Nurses Health Study.

 

The study was cross-sectional in design, involving 247 women aged 56-71 years old from Boston, USA. There was deliberate oversampling of subjects with both high and low vitamin C intakes.

 

Women who consumed vitamin C supplements for at least 10 years had substantially lower prevalence of lens opacities compared with those who did not use any vitamin C supplements. Reductions in prevalence of 77% in early and 83% in moderate lens opacities were found - odds ratios for having opacities: 0.23 (95% CI 0.09-0.60) and 0.17 (0.03-0.85) respectively.

 

These benefits were NOT seen in women consuming vitamin C supplements for less than 10 years. The associations were adjusted for consumption of other antioxidant nutrients and multi-vitamins.

 

Ref:  Am J Clin Nutr 1997;66:911-6

 

COMMENT

This paper is one of the many to come out of the remarkable Nurses Health Study. It adds to a range of work that has strongly suggested that intake of vitamin C is a crucial factor in the eye's ability to deal with oxidative stress, and hence in the development of age-related cataract formation.

 

Its conclusions regarding the relative impact of long-term supplement use compared with intakes derived from food sources can be considered alongside the results from the CHAOS study. Most readers will recall that study, which found that vitamin E intake was associated with a lower prevalence of major cardiovascular events, but only at the level of intake that is found in supplements.

 

Where does this new research fit in? Case-control and other studies have uncovered ample evidence of a link between prevalence of lens opacities and dietary vitamin C intake (e.g. JAMA, 1994;272: 1413-20). But - as always in such epidemiological data - the question is whether this is due to the specific nutrient, the foods which contain it, or some other  confounding factor altogether. This study adds weight to the idea that it is vitamin C itself.

 

By way of background, it is worth noting that there is a clear relationship between dietary intake of vitamin C and tissue levels in the eye (Curr Eye Res, 1991;10:751-9). We also have good experimental models which might explain a protective effect of vitamin C against cataracts (Am J Clin Nutr 1991;54:1198S-1202S).

 

However, it has been harder to go the next stage and show a clear link between vitamin C tissue levels and cataracts in humans (e.g. Epidemiology, 1993;195-203).

 

The present research is useful in narrowing the possibilities. The study design reduces (although does not eliminate) the influence of dietary confounders by focussing on long-term vitamin C supplement use and adjusting for some of the possible confounding nutrients.

 

The differences found here are not trivial either.  In real life clinical terms, an 80% reduction in cataract prevalence would make a substantial impact on public health costs.

 

It would now be helpful to have some large scale prospective primary preventive trials. Another question that remains to be investigated is whether vitamin C has any secondary or tertiary preventive effects in patients who already have early cataracts. But for the meanwhile, this research takes an important step in clarifying whether taking vitamin C supplements will or will not turn out to be helpful prevention for cataracts.

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