Hemochromatosis a Neolithic adaptation?

Hemochromatosis is a genetic disorder caused by one of several mutations related to double-than-normal iron absorption, which increases susceptibility to iron overload (1). Although the disorder affects about one in 200 in the U.S., it’s still largely unrecognized and can lead to deposits in organs—such as the liver—leading to organ damage and failure if not treated early enough (2-4).

Because the disorder is most prevalent in males of Northern European ancestry, particularly Celtic (5), it was hypothesized as recently as 2007 to be a possible Neolithic adaptation (6). The Neolithic period marked an early European dietary transition from high intake of meat to cereal grains (6).

Whether or not this hypothesis is correct, the state of the disorder suggests potential dietary management through eating primarily vegetarian foods such as the one eaten during the time of these early ancestors—cereal grains, little red meat, and limited vitamin C intake. This low-iron diet to prevent to iron overload, according to the Hemochromatosis Management Working Group, can help to “decrease the frequency and severity of iron overload,” thereby preventing many of the detrimental effects of the disorder (4).

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Borgaonkar MR. Hemochromatosis. More common than you think. Can Fam Physician 2003;49:36-43.
3. Dolbey CH. Hemochromatosis: a review. Clin J Oncol Nurs 2001;5:257-60.
4. Barton JC, McDonnell SM, Adams PC et al. Management of hemochromatosis. Hemochromatosis Management Working Group. Ann Intern Med 1998;129:932-9.
5. Pozzato G, Zorat F, Nascimben F et al. Haemochromatosis gene mutations in a clustered Italian population: evidence of high prevalence in people of Celtic ancestry. Eur J Hum Genet 2001;9:445-51.
6. Naugler C. Hemochromatosis: a Neolithic adaptation to cereal grain diets. Med Hypotheses 2008;70:691-2.

Korsakoff syndrome

Korsakoff’s syndrome, or Wernicke encephalopathy, is a serious neurological disorder occurring under conditions of thiamine deficiency. It’s usually caused by long-term abuse of alcohol, which breaks down thiamine in the body. It is characterized at autopsy by lesions in the brain stem.

Thiamine is necessary for proper glucose metabolism in the brain (1). As a B vitamin it acts as a cofactor for enzymes in the Krebs cycle including pyruvate dehydrogenase. Brain insults result when metabolism is inhibited, particularly where there is high demand for energy.

A cascade of injury to the brain occurs when neuronal death reduces production of succinate and GABA as well as neuron stimulation. Without functioning pyruvate dehydrogenase, lactic acid production increases. Nucleotide synthesis and NADPH production is reduced, which in turn reduces glutathione in blood cells.

Individuals carrying apolipoprotein E (ApoE) epsilon 4 (E4) allele are at higher risk of Korsakoff’s syndrome (2). Thus, the ApoE4 genotype is associated with higher risk of Alzheimer’s disease may also be at higher risk of “alcoholic dementia”. These apolipoproteins are protein moietys of a lipoprotein, which transport lipids in the blood.

Reference List

1. Salan, PN. Emedicine from WebMD. Wernicke Encephalopathy. 2009. Available at: http://emedicine.medscape.com/article/794583-overview.
2. Muramatsu T, Kato M, Matsui T et al. Apolipoprotein E epsilon 4 allele distribution in Wernicke-Korsakoff syndrome with or without global intellectual deficits. J Neural Transm 1997;104:913-20.3.

Diabetes: Women and Men

Type 2 diabetes mellitus is considered a major risk factor in cardiovascular disease (CVD) in both men and women, but CVD pathogenesis biochemistry can differ between the sexes.

Both sexes are affected by insulin resistance, which generally precedes the diabetes, and accompanying metabolic syndrome factors dyslipidemia and hypertension (1). The insulin resistance leads to elevated insulin levels, which stimulates sodium reabsorption. The sodium levels can induce prolonged hypertension. The hypertension leads to hardening of the arteries and eventual atherosclerosis. The chronic hyperglycemia leads to glycation of myocardial proteins and microvascular disease (1;2). Gradual nerve damage from abnormal signaling leads to autonomic neuropathy (2).

Although women have overall lower risk of heart disease than men before age 60 due in part because of estrogen, diabetes abolishes difference in CVD risk. In fact, diabetes in women is reported to increase risk of CVD three- to seven-fold whereas in men it increases risk two- to three-fold (3).

Diabetes is thought to affect women uniquely because of hormonal status. Diabetes appears to cancel benefits of estrogen, which “may be lost or hidden by diabetes” (3). With reduced estrogen, other CVD risk factors come into play in a pre-menopausal women just as it would for post-menopausal women (3).

Reference List
1. Grundy SM. Cardiovascular and metabolic risk factors: how can we improve outcomes in the high-risk patient? Am J Med 2007;120:S3-S8.
2. Grundy SM, Benjamin IJ, Burke GL et al. Diabetes and cardiovascular disease: a statement for healthcare professionals from the American Heart Association. Circulation 1999;100:1134-46.
3. Bolego C, Cignarella A, Zancan V, Pinna C, Zanardo R, Puglisi L. Diabetes abolishes the vascular protective effects of estrogen in female rats. Life Sci 1999;64:741-9.

Post-menopausal estrogen therapy

Menopause is the eventual reduced production of sex hormones in women. Follicular cells in the ovaries appear to become exhausted by continual cycles of ovulation and atresia (1). The ovaries become less responsive to stimulation from gonadotropin—follicle-stimulating hormone (FSH) and luteinizing hormone (LH)—causing estrogens and progesterone levels to lower. The ovaries degenerate causing further diminished estrogen production until the hormone is only produced in limited amounts by other tissues (1).

The loss of estrogens production also reduces cardioprotective effects of this particular hormone. Estrogens, estradiol in particular, protects cardiovascular health because of its binding to estrogen receptors (ERs). ERs in absence of estrogen are associated with heat shock protein (HSP); estrogen binding promotes dissociation (2). Estrogen binding also changes gene transcription, altering levels and kinds of cellular proteins (2). The alterations directly affect myocardial, vascular smooth muscle and endothelial cells.

In vascular smooth muscle cells, estradiol has vasodilatory effects and functions in contractibility and growth. Its mechanisms may be related to effects on calcium channel currents, increases of Ca2+ and/or activation of K channels (2). In effect, estradiol leads to increased secretion of NO and cGMP production (2). These are thought to be estradiol’s primary antiatherogenic actions, although other mechanisms may exist such as promotion of endothelial cell regeneration and angiogenesis.

Because estrogen has been found to reduce risk of cardiovascular disease in postmenopausal women, future research on estrogen therapy is merited. Side risks involved, however, may be too serious for estrogen to be prescribed at this time.

Authors who analyzed Women’s Health Initiative (WHI) randomized trials from 1993-2004 on use of conjugated equine estrogens found that death from other hazards such as breast cancer did not favor use of estrogen therapy (3;4). Critics suggest that prescribers of estrogen therapy should have waited WHI results to have avoided cases of breast cancer (3). WHI trials, in fact, also found that hormone therapy, unfortunately, did little to reduce risk of coronary heart disease suggesting that more research is needed (5). The WHI data are related to both pre-menopause and post-menopause therapies with estrogen (4).

Reference List

1. Cohn RM, Roth KS. Biochemistry of Disease: Bridging Basic Science and Clinical Practice. Baltimore: Williams & Wilkins, 1996.
2. Skafar DF, Xu R, Morales J, Ram J, Sowers JR. Clinical review 91: Female sex hormones and cardiovascular disease in women. J Clin Endocrinol Metab 1997;82:3913-8. Available at: http://jcem.endojournals.org/cgi/content/full/82/12/3913
3. Postmenopausal hormone therapy and breast cancer. Prescrire Int 2009;18:66-7.
4. Prentice RL, Manson JE, Langer RD et al. Benefits and risks of postmenopausal hormone therapy when it is initiated soon after menopause. Am J Epidemiol 2009;170:12-23.
5. Banks E, Canfell K. Invited Commentary: Hormone therapy risks and benefits--The Women's Health Initiative findings and the postmenopausal estrogen timing hypothesis. Am J Epidemiol 2009;170:24-8.

Potassium Guards Against Sodium-induced Bone Loss

Reference: Sellmeyer DE, Schloetter M, Sebastian A. Potassium citrate prevents increased urine calcium excretion and bone resorption induced by a high sodium chloride diet. J Clin Endocrinol Metab 2002;87:2008-12. Available at: http://jcem.endojournals.org/cgi/content/full/87/5/2008?ijkey=b46c2855f83d19e380eb6674c66c94e884ed56a0

Purpose of study: To study effects of dietary potassium citrate added to diets high in sodium, as commonly found in industrialized nations, in postmenopausal women. Postmenopausal women are at higher risk of osteoporosis, especially if consuming a high-sodium diet.

Type of study: Randomized, double-blinded placebo-controlled trial

Method used to conduct study: After three weeks in which 60 post-menopausal women adhered to a low-salt diet, they were provided sodium chloride pills, salt packets (for sprinking on food) and one cup of bouillon per day. They were randomized and either take potassium citrate (90 mmol/d) or placebo. Twenty-four-hour urine samples were analyzed to determine compliance after 12 days. When compliance was compromised, subjects were contacted to enforce regimen. After four weeks, urine samples and fasting blood samples were collected. Fifty two of the women completed seven-week study of which 26 had taken placebo and 26 potassium citrate. Exclusions at the beginning of the study included women who were less than 2 years past menopause, on bone metabolism medications or who had past history of bone disease.

Summary: Calcium excretion increased by 42+-12 mg/d (33%) from low-salt to high-salt diet in the women on placebo. Calcium excretion decreased by 8+- 14mg (4%) in women on potassium citrate. The results suggest that potassium citrate prevented bone resorption in response to salt increase in the diet.

The method is thought to be the natriuretic and chloruretic effects of potassium alkaline salts. These potentially reduce extracellular volume expansion associated with higher salt intake. The alkaline salts also reduce endogenous acid, increase blood pH and bicarbonate. Calcium excretion in the urine can change depending on acid production.

Critique: Examining effects of potassium through a placebo-controlled trial goes far to point out the intracellular cations biological effects on calcium excretion. The results are significant. The researchers took appropriate measures in assuring that the postmenopausal women were compliant in their diets. A seven-week study, however, may not be long enough to determine whether or not potassium citrate will make a significant difference in reducing risk of bone loss and hip fracture.

Nutritional implications and implications of future study: Post-menopausal women at risk for osteoporosis, especially who eat a high-sodium diet, should consider increases of dietary sources of potassium, which are mainly fruits and vegetables. For the benefit of post-menopausal women who may dislike fruits and vegetables and eat mainly processed foods, it may be wise to add potassium to these processed foods. Similar trials should be conducted to determine effects of potassium-added, high-sodium processed foods.

Why Gatorade May Not Rehydrate You Any Faster Than Water

Research Summary Critique

Reference: Jeukendrup AE, Currell K, Clarke J, Cole J, Blannin AK. Effect of beverage glucose and sodium content on fluid delivery. Nutr Metab (Lond) 2009;6:9. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=19232115

Purpose of study: The objective of many oral rehydration drinks is rapid fluid delivery to correct fluid balance in sports. This study investigated carbohydrate (CHO) and sodium (Na) effects on fluid delivery with a deuterium oxide (D20) tracer.

Previous research suggests Na concentration may increase delivery, but that CHO content is more important factor.

Type of study: Equivalence trial of eight different solutions.

Method used to conduct study: Two groups of 10 male subjects (ages 20 +- 1 y, weight: 81.2 +-7.5kg) were split into a CHO or NA group. The CHO group ingested four drinks, each with 20 mmol/L sodium, and with a stepped increase of 3% glucose from 0-9%. The Na group ingested four drinks, each with 6% glucose, with a stepped increase of 20 mmol/L from 0 mmol/L to 60 mmol/L. All drinks contained 3g of D20.

Each trial was performed in laboratory after overnight fast (7-9a.m.) and emptying of bladder. After ingesting drink, blood was taken every five minutes in the first hour and every 10 minutes in the second hour. Plasma D20 was analysed using isotope ratio mass spectrometry.

Summary: CHO concentration at 3% increased fluid delivery in comparison to 0%. Concentration above 6% led to fluid delivery that was slower than 0% and 3%. Sodium concentration in any amount did not show any increase in intestinal water absorption.

Critique: The researchers acknowledge that the investigation, which used the “triple lumen technique”, takes into account a section of the small intestine, but not gastric emptying. It may not represent total fluid availability in the body. However, D20 is useful to provide an integrative measure of gastric emptying and intestinal fluid absorption.

Nutritional implications and implications of future study: Because the study’s findings are that added sodium to oral rehydration drinks (sport drinks) has no effect on fluid delivery, it may change the way consumers choose these beverages. Sodium addition may not be preferred or it may still be for other reasons unrelated to fluid delivery such as for possible electrolyte replacement.

Boost brain health by living like an Indian

Getting plenty of sun and eating curry are integral parts of Indian culture. Now scientists have found that this combination also helps guard against Alzheimer's disease.

The biochemical mechanism by which the combination works is through immune system macrophages (1). Vitamin D was found to stimulate type I and II macrophages to break down and clear beta-amyloid plaques through genomic pathways. Curcuminoids, specifically bisdemethoxycurcumin, assisted with stimulating type 1 macrophages through non-geneomic pathways.

Immune therapies to clear beta-amyloid plaque are a new approach that health scientists hope will assist in prevention and treatment of AD.

Because vitamin D and curcumin work in different ways biochemically, both may be used in therapy for most promising effects.

Apart from hereditary implications, obesity, diabetes and hypertension are all risk factors in AD. Other promising dietary interventions are caloric reduction, antioxidant intake from fruits and vegetables, and increased intake of fish-derived omega-3 fatty acids.

Reference List

1. Masoumi A, Goldenson B, Ghirmai S et al. 1alpha,25-dihydroxyvitamin D_3 Interacts with Curcuminoids to Stimulate Amyloid-beta Clearance by Macrophages of Alzheimer's Disease Patients. J Alzheimers Dis 2009.

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