Hypoglycemia in Hereditary Fructose Intolerance

What are the specific reasons for hypoglycemia seen in hereditary fructose intolerance?

Hereditary fructose intolerance (HFI) an autosomal recessive disorder in which there is subnormal activity of the enzyme fructose 1-phosphate aldolase B (1;2). Largely found in the liver, the enzyme is needed for normal fructose metabolism for splitting fructose 1-phosphate to form dihydroacetone and glyceraldehyde (1).

Hypoglycemia after consumption of fructose (also sucrose or sorbitol) results because of the lack of maintenance of proper blood glucose levels by the liver (2). The fructose ingestion and the lack of aldolase B results in the accummulation of fructose 1-phosphate in cells, particularly in the liver (1). The accumulation leads to depletion of Pi, which in turn keeps mitochondria in hepatocytes from producing ATP causing cell damage, and inhibition of glycogenolysis and, thus, guconeogenesis (1;2).

HFI often goes unrecognized and is life-threatening due to hypoglycemia along with possible liver and renal failure (3;4). Many of patients afflicted with the disorder have a noted distaste for sweet foods due to having suffered symptoms early in life such as vomiting and abdominal pain (2-4). The cure for HFI is exclusion of sources of fructose from the diet (1-4).

Reference List

1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002, pp 597 & 643.
2. Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ. Modern Nutrition in Health and Disease. Baltimore, MD: Lippincott Williams & Wilkins, 2009.
3. Yasawy MI, Folsch UR, Schmidt WE, Schwend M. Adult hereditary fructose intolerance. World J Gastroenterol 2009;15:2412-3.
4. Cox TM. Hereditary fructose intolerance. Baillieres Clin Gastroenterol 1990;4:61-78.

Niacin and Hyperlipidemia

NIACIN FOR HIGH CHOLESTEROL
The recommended daily intake for niacin, or vitamin B3, is only 14 mg for women and 16 mg for men with a tolerable upper intake level of 35mg (1). Nutrition professionals should also be aware that niacin, as nicotinic acid (not nicotinamide), has also been used in much larger doses—up to 6 g per day—for decades as a treatment for hyperlipidemia (1). Note that nicotinic acid is available as a dietary supplement.

Use as a Drug
High-dose niacin, in fact, was the first-ever lipid-modifying drug treatment. It helps increase HDL cholesterol while lowering total serum cholesterol, triglycerides and LDL cholesterol (2). After initial discovery in the 1950s and research in the ‘70s, it was found that niacin helped prevent myocardial infarction and reduced risk of death from myocardial infarction when used in doses of 3 g daily (2;3).

The mechanism of high-dose nicotinic acid is broad and unique. It inhibits lipolysis in adipose tissue decreasing free fatty plasma levels within minutes (1;2). Within a few hours it inhibits the liver’s synthesis of triglycerides reducing overall triglycerides in plasma (1;2). And, although it’s unclear just how, after only a few days it lowers LDL and increases HDL cholesterol (1;2).

Unpleasant Side Effects
Although an effective treatment and cost effective, the unpleasant side effects of high-dose niacin have kept many patients from adopting niacin as a regular drug treatment (2). By the 1980s, statins were on the market and greater in popularity (2). Still, niacin continues to present potential.

The main side effect is vasodilation, which includes flushing and redness like a temporary sunburn-like sensation (1;2). This is harmless, but bothersome (2). It is mediated partly by release of histamine; thus, an aspirin or COX inhibitors can reduce the response (1;2).

Precautions
Other side effects can include gastrointestinal problems like heartburn, elevated plasma glucose concentration, and hyperuricemia that can lead to gout since niacin competes with uric acid for excretion (1). Most worrisome is possible hepatotoxicity, which can go as far as obstructing bile flow, hepatitis or liver failure (1).

Newer forms of extended-release niacin, such as Niaspan from Abbot, are reported to have fewer side effects and no hepatotoxicity (2). This is significant for re-establishing niacin as the preferred, cost-effective treatment in comparison to other drugs. Newer studies are now researching niacin’s effectiveness in comparison to or in combination with other lipid- and cholesterol-lowering drugs (3). See "Research Summary and Critique" below.

Niacin is available in immediate-release (IR), sustained-release (SR), and extended-release (ER) (Niaspan) (4). They all differ in effectiveness, side effects and safety. Flushing is seen most with IR, hepatotoxicity is mostly noted with SR (4). The hepatotoxicity has to do with absorption rate (4). ER apparently allows absorption to be "intermediate" in comparison to IR and SR (4). In conclusion, avoid SR niacin!

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.

2. E T Bodor and S Offermanns. Nicotinic acid: an old drug with a promising future. Br J Pharmacol. 2008 March; 153(S1): S68–S75. Published online 2007 November 26. doi: 10.1038/sj.bjp.0707528. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pubmed&pubmedid=18037924.

3. Guyton JR, Blazing MA, Hagar J, Kashyap ML, Knopp RH, McKenney JM, Nash DT, Nash SD. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Arch Intern Med. 2000 Apr 24;160(8):1177-84. Available at: http://archinte.ama-assn.org/cgi/content/full/160/8/1177#TABLEIOI90276T3

4. Pieper JA. Understanding niacin formulations. Am J Manag Care 2002;8:S308-S314.


RESEARCH SUMMARY AND CRITIQUE
One randomized, double-blind human clinical study in 2000 made a direct comparison using Niaspan and gemfibrozil.

Full reference: Guyton JR, Blazing MA, Hagar J, Kashyap ML, Knopp RH, McKenney JM, Nash DT, Nash SD. Extended-release niacin vs gemfibrozil for the treatment of low levels of high-density lipoprotein cholesterol. Arch Intern Med. 2000 Apr 24;160(8):1177-84. Available at: http://archinte.ama-assn.org/cgi/content/full/160/8/1177#TABLEIOI90276T3

Purpose of Study: To compare effects of Niaspan with gemfibrozil, a lipid-lowering drug from a class called fibrates. Commercially, gemfibrozil goes by names of Lopid, Jezil and Gen-Fibro.

Type of study: Randomized, double-blind human clinical study.

Methods: Patients exhibiting factors for hypercholesterolemia and atherosclerosis were given Niaspan at doses increased sequentially from 1g to 2 g before bedtime and 80 or gemfibrozil at 600 mg given twice daily. Of 173 patients, 72 of 88 given Niaspan and 68 of 85 given gemfibrozil completed the study.

Percentage change from baseline was provided through analysis of blood samples collected after 12-hour fasts. They provided measurements for total cholesterol, HDL cholesterol, LDL cholesterol, lipoprotein levels, total triglycerides and fibrinogen levels.

Exclusions included most diabetics (not with normal-range fasting glucose), patients on blood thinners, patients with active gout as well as those with other serious illnesses and/or abnormalities.

The patients were men and women between ages 21 and 75 years. All were counseled by a National Cholesterol Education Program.

Results Summary: Niaspan increased HDL cholesterol twice as much as gemfibrozil and had better results in improving LDL cholesterol while lowering levels of fibrinogen (protein involved in clotting). The gemfibrozil had greater effects at lowering triglycerides, but increased LDL cholesterol.

Much more Niaspan flushing responses (78% compared to 10%) were observed in comparison to gemfibrozil; however, dyspepsia was observed more often in patients taking gemfibrozil.

Critique of Research Design: The study was well-designed and included appropriate measurements to determine biological response to treatment. The exclusions were appropriate in nature. The support of a pharmaceutical company for the study hinted at a natural bias that could be noted since there was no discussion given by the authors of this study regarding possible confounding variables. The flushing responses clearly indicate that the patients would have known what they were taking, which may have affected results. Also, dietary factors were not noted in the study. There was conversation seeming out of place about the possible use of both drugs for complementary treatment, which would need further research.

Nutritional Implications and Implications for Future Study: Nutrition professionals should have a thorough understanding of its uses and possible side effects when used as a drug for hypercholesterolemia. Because niacin is a vitamin found in many foods, further research should also review the potential role of diet along with niacin treatment.

Bs for Stress and Energy

B-complex supplement products are popular commodities, often marketed for "stress" or "energy." Is there scientific justification for these claims? Why should anyone choose a B-complex supplement as opposed to either broader multivitamin-mineral supplements or narrower single B-vitamin supplements?

You might remember in the early ‘90s when a neuropathy epidemic broke out in Cuba among unsuspecting tobacco growers. They complained of burning sensations in their feet, pain in their arms and legs, frequent urination, blurred vision, weight loss, sensitivity to sunlight, and, well, lots of stress and fatigue (1). After assessing their diets it was discovered they were deficient in B complex vitamins and the amount of alcohol they drank daily contributed to loss of the little Bs they had (1).

The tobacco growers may have not known that B vitamins play essential roles in the health of their bodies relating to energy metabolism and stress, but let’s be sure we do.

Energy

For generating ATP energy in the body, B vitamins act mainly in synergy. Specifically, the vitamins thiamin, riboflavin, niacin and pantothenic acid are all needed to act as co enzymes in the formation of a multi-enzyme complex known as pyruvate dehydrogenase complex (2). Pyruvate dehydrogenase complex is essential for the oxidative decarboxylation of pyruvate to form acetyl CoA, which feeds into the citric acid cycle (2). Take any of the B vitamins away and cellular respiration is no more.

Further, niacin either as nicotinic acid and nicotinamide is necessary for use in the forms of NAD, nicotinamide adenine dinucleotide, and, with a phosphate at the end, NADP. NAD and NADP act as coenzymes for about 200 enzymes (oxidation-reduction reactions). But a major role of NAD in its reduced form as NADH is to shuttle electrons through the electron transport chain creating ATP energy (2). Apart from joining the other Bs in oxidative decarboxylation of pyruvate, NAD and NADH also act as coenzymes in glycolysis, oxidation of acetyl CoA, beta-oxidation of fatty acids and oxidation of ethanol for energy (2).

Riboflavin is needed for its coenzyme derivatives flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD). Like NAD and NADP, FMN and FAD act as coenzymes in oxidative-reduciton reactions for many reactions (2). Apart from use in pyruvate dehydrogenase complex in which FAD acts as an electron carrier, FAD also is needed for the flavoprotein succinate dehydrogenase to remove electrons from succinate to form fumarate (2). Then electrons are passed into electron transport chain by coenzyme Q (2).

Biotin’s role in energy has to do with its coenzyme role in enzymes. Two regulatory enzymes are dependent on biotin: pyruvate carboxylase, regulator of carboxylation of pyruvate, acetyl CoA carboxylase, regulator of fatty acid synthesis (2). Two enzymes need biotin for catabolism of amino acids need biotin, propionyl CoA carboxylase and beta-methylcrotnonyl CoA carboxylase (2). Lack of biotin will produce lethargy, depression, hallucinations and muscle pain (2).

Cobalamin once converted to adenosylcobalamin can act along with biotin in a energy metabolism in which it acts to help convert methylmalonyl CoA mutase convert L-methylmalonyl CoA to succinyl CoA (2). L-methylmalonyl CoA is produced from D-methylmalonyl CoA, which was produced from propionyl CoA that arose from from oxidation of amino acids and odd-chain fatty acids from the biotin-dependent reaction (2).

Pantothenic acid, aside its role in pyruvate dehydrogenase complex as a component of CoA, also acts as a component of CoA in lipid metabolism such as synthesis of ketone bodies and fatty acids (2). Although deficiency is unlikely—it’s ubiquitous in food—among the symptoms would be fatigue and weakness (2). Its deficiency is characterized by numbness in the toes called “burning feet syndrome” of which was no doubt suffered by the Cuban tobacco farmers who lacked it (1;2).

Stress

Some examples of stress were given above, but stress help from B vitamins is largely the work of thiamin. Thiamin, in this case not as a coenzyme, may activate ion transport in nerve membranes as well as regulating sodium channels and acetylcholine receptors in nerve impulse transmissions (2). A thiamin deficiency produces beriberi (beri meaning “weakness”) and one of its first signs is anorexia and weight loss, then neurological symptoms of confusion and apathy in what can only end up as irritability (2).

Riboflavin has its role in stress too—and I’m using the word “stress” as a very wide-reaching general term. FAD-dependent monomaine oxidase is required by neurotransmitters such as dopamine (2). Regeneration of the antioxidant glutathione—which supports against oxidative stress—is dependent also on FAD-dependent glutathione reductase (2).

Without niacin life could be especially stressful due to pellagra, which comes with its four Ds: dermatitis, dementia, diarrhea and death (2). But the B vitamin’s more direct role is in reducing oxidative stress via regeneration of glutathione, vitamin C and thioredoxin (2).

Finally, the pernicious anemia from a deficiency or poor absorption of cobalamin would lead to neuropathy of which is characterized by demyelination of the nerves—painfully stressful indeed (2).

Supplementation

OK, so we know the roles of B vitamins as related to energy and stress. We definitely need them. The question remains, however, whether or not a normally healthy person should supplement? Plus, will taking more of B-complex act as an ergogenic aid such as for athletes?

The studies aren’t showing much promise. There is indication that exercise causes greater need for B-complex supplements (5). Athletes should continue to take them. But, despite widespread use of B-complex supplements among athletes even in massive doses, they should not be expected to increase actual performance unless a deficiency was in existence beforehand (3;4).

Those of us who aren’t athletes would benefit from B-complex vitamins simply to help us avoid deficiency and because of their lack of toxicity. But don’t expect huge increases in “energy” or reductions of “stress” unless you are deficient. Deficiency can happen if you're malnourished, abuse alcohol, are a strict vegetarian (B12 or riboflavin) or if you have a disorder such as pernicious anemia (B12 deficiency) (2).

Reference List

1. Arnaud J, Fleites-Mestre P, Chassagne M et al. Vitamin B intake and status in healthy Havanan men, 2 years after the Cuban neuropathy epidemic. Br J Nutr 2001;85:741-8.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
3. Williams MH. Vitamin supplementation and athletic performance. Int J Vitam Nutr Res Suppl 1989;30:163-91.
4. Williams MH. Vitamin and mineral supplements to athletes: do they help? Clin Sports Med 1984;3:623-37.
5. Woolf K, Manore MM. B-vitamins and exercise: does exercise alter requirements? Int J Sport Nutr Exerc Metab 2006;16:453-84.

Vitamin E

Vitamin E refers to eight compounds (vitamers: tocopherols and tocotrienols) and is found in both plants and animal foods (1). The most studied natural source of vitamin E is alpha-tocopherol because of its prevention of lipoprotein oxidation and inhibition of platelet aggregation, which suggests prevention of cardiovascular disease (1).

Alpha-tocopherol is the only one with biological activity and offers the most protection against oxidative stress through its oxygen-quenching capacity (2). The natural and most active form is designated by its steroisomer RRR alpha-tocopherol and continues to be found on supplement labels as d-alpha tocopherol (2).

Beta-tocopherol also exhibits oxygen-quenching capacity albeit not as much as alpha-tocopherol and its abilities are followed by gamma- and delta-tocopherol (2). The tocotrienols may not exhibit significant antioxidant role, but have another role in which they reduce plasma cholesterol concentration (2).

A recently discovered natural form of vitamin E is alpha-tocopheryl phosphate found to be ubiquitous in tissues of animals and plants (3). Its role is not yet clear.
Supplementation with vitamin E is widely popular for taking guesswork out of how to get enough of this seemingly non-toxic vitamin for cardiovascular health (1;4). Newer research on vitamin E, however, is showing that it may be possible that people are taking too much (1;5).

Clinical trials on alpha-tocopherol have mostly found negative results including possible increased adverse effects on those with high blood pressure and increased risk of death in those with cardiovascular disease (1).

Until further is known about the most appropriate amount to take for reduced risk of disease, the Recommended Dietary Allowance for vitamin E continues to be 15 mg daily, based on the natural form of alpha-tocopherol, and is still considered one of the least toxic vitamins (2).

Reference List

1. Clarke MW, Burnett JR, Croft KD. Vitamin E in human health and disease. Crit Rev Clin Lab Sci 2008;45:417-50.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
3. Gianello R, Libinaki R, Azzi A et al. Alpha-tocopheryl phosphate: a novel, natural form of vitamin E. Free Radic Biol Med 2005;39:970-6.
4. Gutierrez AD, de Serna DG, Robinson I, Schade DS. The response of gamma vitamin E to varying dosages of alpha vitamin E plus vitamin C. Metabolism 2009;58:469-78.
5. Bell SJ, Grochoski GT. How safe is vitamin E supplementation? Crit Rev Food Sci Nutr 2008;48:760-74.

Bugs Bunny diet

Could it be that when Bugs Bunny chose his special diet of carrots because he knew that the discovery of vitamin A in 1915 found it was an essential growth factor in animals (1)? Maybe he knew that vitamin A kept his skin healthy under all that fur (1). Or, more likely, that vitamin A kept his eyes healthy for seeing underground (1).

Bugs can also celebrate that his enjoyment of carrots might keep him from later having to say, “What’s up doc?” This is because clinical evidence has led the U.S. Food and Drug Administration to approve a cancer health claim for a low-fat diet rich in fruits and vegetables when it includes vitamin A (1).

Vitamin A’s benefits are all appealing to humans too. But while vitamin A deficiency is not common in developed countries, a few are deficient not being regular eaters of foods high in vitamin A like carrots, sardines or liver (1).

How much should you get? What kind of vitamin A should you be getting? And, how do you know when you should supplement? Clinicians should be familiar with the differences of the various kinds of vitamin A because it would affect recommendations.

Vitamin A references any compound that can produce biological activity of all-trans retinol (1). These include preformed vitamin A retinoids (retinol, retinal, retinoic acid, retinyl esters and others) and provitamin A carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin) (1).

Absorption of vitamin A first requires digestion in which enzymes help free up vitamin A from proteins and fats (1). The vitamin A compounds then become solubilized into bile micelles to be transported and absorbed across the brush border membrane of the duodenum and jejunum (1).

The preformed vitamin A retinoids are absorbed easily (about 70-90 percent) as long as a meal includes sufficient fat (1). Provitamin A carotenoids are less absorbed ranging from less than 5 percent in raw foods and juices and up to 60 percent when cooked or taken purely in oil (1).

Retinoids, being lipid-soluble, are not as stable as carotenoids and can oxidize when exposed to light, oxygen, heat or some metals (2). But, again being lipid soluble, about 70-90 percent of the preformed vitamin A retinoids are absorbed (1).

In developing countries, vitamin A deficiency is not common (1). It generally occurs among children leading to increased mortality and infectious morbidity (1). The symptoms of vitamin A deficiency can include xerophthalmia (night blindness, Bitot’s spots, conjunctival abnormalities, corneal scarring and ulcerations), anorexia, retarded growth, karatinization of mucous cells (1).

The best measure of vitamin A from which to make recommendations is retinol activity equivalents (RAE) (1). For example, retinol 1 mcg is equal to RAE 1 mcg, beta-carotene 12 mcg is equal to RAE 1 mcg, and alpha-carotene or beta-cryptoxanthin 24mcg is equal to RAE 1 mcg (1). The requirements of vitamin A intake published by the Institute of Medicine’s Food and Nutrition Board published in 2001 that adult men should consume 625mcg RAE and women 500mcg RAE (1).The Recommended Dietary Allowance (RDA) is 900 and 700 mcg RAE for men and women (1).

Pregnant women have a higher RDA ranging from 770 and 1,300 mcg RAE (1)Smokers, however, should watch any increase because newer research shows vitamin A may increase risk for lung cancer rather than decrease it (1). The biochemical reasons for increasing lung cancer risk are not clear yet, but may have to do with break down products and mitochondriotoxicity (3).

Because main food labels still list vitamin A in the older International Units (IU), it’s important to point out that 1 IU vitamin A is equal to 0.3 mcg regtinal, 3.6 mcg beta-carotene and 7.2 mcg of alpha-carotene and beta-cryptoxanthin (1).

It is possible to get too much vitamin A. Hypervitaminosis A is a disorder that can lead to nausea, vomiting, double vision, headache, dizziness and skin problems (1).

The tolerable upper intake level for preformed vitamin A in adults is 3,000 mcg (1). Beta-carotene and the other provitamin A carotenoids do not have any known tolerable upper intake level (1). A tolerable upper intake level of beta-carotene levels in smokers has yet to be established (1).

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Carlotti ME, Rossatto V, Gallarate M, Trotta M, Debernardi F. Vitamin A palmitate photostability and stability over time. J Cosmet Sci 2004;55:233-52.
3. Siems W, Salerno C, Crifo C, Sommerburg O, Wiswedel I. Beta-carotene degradation products - formation, toxicity and prevention of toxicity. Forum Nutr 2009;61:75-86.

Antioxidants - Comparing Apples to Oranges

Which will keep the doctor way? The orange contains about 10 times more vitamin C, which is an essential antioxidant for many complex roles in the human body (1). On the other hand, the apple contains quercetin, which has been shown to have a higher antioxidant capacity than vitamin C, thus, potentially offering better protect against free radicals (2;3). Clearly these antioxidants are not equal.

Free radicals are atoms or molecules that have one or more unpaired electrons. These are mainly result of the mitochondria leaking electrons that bind to oxygen; however, there are a variety of other free radicals from exposure to smog, ozone, drugs, and drugs (1).

Because “oxidative stress” is thought to be associated with many diseases including cancer, antioxidant nutrients are frequently evaluated for ability to neutralize free radicals, particularly the oxygen-centered radicals: superoxide, hydroxyl and peroxyl radicals (1).

While antioxidants help decrease neutralize free radicals, they themselves become free radicals although—in some cases such as vitamin E, C, ubiquinol and glutathione—regeneration pathways in the body often help them function over again (1). The regeneration process is key for optimal defense against oxidative stress and so is receiving enough of different kind of antioxidants (1).

As science continues to discover more and more, high-antioxidant foods continue to grown in the marketplace. Walk down the isle of any health food store and you’re sure to spot the latest and greatest—pomegranate, blueberry, acai berry, green tea. What makes one food greater than another?

These compete by antioxidant capacity including measures of oxygen radical absorption Capacity (ORAC) (4;5). Each ORAC unit indicates greater antioxidant protection—the higher the score, the more “super” the food (5). Another test more relevant biologically is cellular antioxidant activity (CAA), performed on cell cultures, which has found quercetin, pomegranate and berries clear favorites for decreasing oxidative stress (6). Antioxidant capacity can also be helpful to determine one fruit with another of the same fruit. For example, organically grown fruit and vegetables often have a higher ORAC score indicating greater content of fruit (7).

Should consumers rely strictly on ORAC or CAA tests for making food choices? The answer is, no. While single antioxidants may have unique functions that may link them to reduced risk of disease, such as vitamin C and heart disease (1), quercetin and liver cancer (8), no single antioxidant or antioxidant complex has appeared yet to decreases oxidative stress enough overall to reduce risk of all diseases (1).

As discussed above, however, antioxidants often work with each other synergistically in the body. Thus, for superior nutrition, adopt the “color code”: five to nine servings daily of fruits and vegetables of different colors provides the reds, red-purples, oranges, yellows, and greens for your body daily and is in line the National Cancer Institute and American Institute (9). Until more is known about antioxidants, the color code offers the the best guideline for health and prevention of disease (1).

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Wolfe KL, Liu RH. Cellular antioxidant activity (CAA) assay for assessing antioxidants, foods, and dietary supplements. J Agric Food Chem 2007;55:8896-907.
3. Kim DO, Lee KW, Lee HJ, Lee CY. Vitamin C equivalent antioxidant capacity (VCEAC) of phenolic phytochemicals. J Agric Food Chem 2002;50:3713-7.
4. Kohri S, Fujii H, Oowada S et al. An oxygen radical absorbance capacity-like assay that directly quantifies the antioxidant's scavenging capacity against AAPH-derived free radicals. Anal Biochem 2009;386:167-71.
5. Cao G, Alessio HM, Cutler RG. Oxygen-radical absorbance capacity assay for antioxidants. Free Radic Biol Med 1993;14:303-11.
6. Wolfe KL, Kang X, He X, Dong M, Zhang Q, Liu RH. Cellular antioxidant activity of common fruits. J Agric Food Chem 2008;56:8418-26.
7. Di RL, Di PD, Bigioni M et al. Is antioxidant plasma status in humans a consequence of the antioxidant food content influence? Eur Rev Med Pharmacol Sci 2007;11:185-92.
8. Seufi AM, Ibrahim SS, Elmaghraby TK, Hafez EE. Preventive effect of the flavonoid, quercetin, on hepatic cancer in rats via oxidant/antioxidant activity: molecular and histological evidences. J Exp Clin Cancer Res 2009;28:80.
9. Heber D, Bowerman S. Applying science to changing dietary patterns. J Nutr 2001;131:3078S-81S.

What is the biochemical reason why bile secretion is important for health?

Micelles are made up of amphipathic compounds such as bile acids, fatty acids and monoacylglycerols that interact leaving a relatively stable hydrophilic surface and hydrophobic interior (1). They form at certain temperature ranges when a mixture of lipids is present in concentrated amounts (1). Fatty acid and phospholipid micelles are spherical, but pure bile acid micelles are sandwich-shaped rectangles (1p1062).

During lipid digestion after hydrolysis of triacylglycerols by lipases, it’s up to the bile acid sandwiches to solubilize the spheres, thereby forming “mixed” micelles that appear not unlike rods (1p1062). These rods become longer as more lipids (including limited cholesterol) are solubilized (1p1062). The bile acid micelles form at concentrations of 2-5 mM and at pH values above pK, meaning in equilibrium with other micelles in solution (1p1061-2).

From the lumen, the micelles then transfer the lipids to the mucosal surface for absorption by diffusion (1p1063). Lipid-soluble vitamins A, D, E, and K are also transported within the micelles (1p1065). The delivery is dependent on bile acid micelles increasing effective concentration to create solute flux across the unstirred fluid layer (1p1063). Without bile acids, the absorption of triacylglycerols and the lipid-soluble vitamins would be reduced drastically (1p1063).

Reference List

1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.

Why so many proteolytic enzymes?

When studying the evolution timeline that led to modern biochemistry, one can always turn to studying protein architecture. Proteins have been called “molecular fossils” that serve to mark milestones in the “history of life” (1). There is a wide diversity of proteolytic enzymes in humans and the network of enzymes have a grand complexity that calls for investigation of how they were shaped over time (2).

In digestion there is a variety of proteolytic enzymes—pepsins, enteropeptidases, carboxypeptidases, and aminopeptidases (3). Each work to hydrolyse proteins by cleaving off amino acids from differing peptide bonds, in different stages and conditions (gastric, pancreatic and intestinal phases) and at varied pH ranges (3). The system is indeed complex, not exactly perfect (a better system may have used only a one or two enzymes), but it works and that's evolution.

Each highly structured enzyme would have evolved accordingly at some time, and some, which may have had major roles in the past, have only minor ones now. An example of biochemical “fossils” studied currently in Germany are particular aspartic proteases (4). They are structurally similar to other proteases suggesting a common "major role" ancestor", but have evolved now only to act in “chaperone-like” fashion for substrate binding in digestion (4).

More than 2 percent of human genes are proteases or protease inhibitors (5). New genomic data is expected reveal more about how proteases, their substrates, proteolytic complexes, inhibitors, and interactions all co-evolved (5;6). The complete human degradome—set of protease genes—is also being compared with degradomes of other mammals such as chimpanzees and mice and serving to provide further understanding of ancestral relationship of species (5;7).

Reference List

1. Caetano-Anolles G, Wang M, Caetano-Anolles D, Mittenthal JE. The origin, evolution and structure of the protein world. Biochem J 2009;417:621-37.
2. Page MJ, Di CE. Evolution of peptidase diversity. J Biol Chem 2008;283:30010-4.
3. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
4. Hulko M, Lupas AN, Martin J. Inherent chaperone-like activity of aspartic proteases reveals a distant evolutionary relation to double-psi barrel domains of AAA-ATPases. Protein Sci 2007;16:644-53.
5. Puente XS, Sanchez LM, Gutierrez-Fernandez A, Velasco G, Lopez-Otin C. A genomic view of the complexity of mammalian proteolytic systems. Biochem Soc Trans 2005;33:331-4.
6. Southan C. Exploiting new genome data and Internet resources for the phylogenetic analysis of proteases, substrates and inhibitors. Biochem Soc Trans 2007;35:599-603.
7. Ordonez GR, Puente XS, Quesada V, Lopez-Otin C. Proteolytic systems: constructing degradomes. Methods Mol Biol 2009;539:33-47.

Whether or Not to Take Vitamin C

Unlike most other mammals, humans and other primates don't synthesize vitamin C because we lack the enzyme glunolactone oxidase (1). The enzyme was lost long ago without affecting our survival due to frequent intake of high-vitamin C fruits and vegetables.

Thus, we must continue to get vitamin C from our diet by the same manner (fruits or veggies) or otherwise, lest we succumb to scurvy as British sailors did in the early 1800s before they adopted rationing limes on naval vessels (1).

Vitamin C deficiency leading to scurvy is now rare (1) and in the developed world, but studies on North American and European populations have found that many people who do not eat enough fruits and high-vitamin C vegetables continue to have inadequate levels of vitamin C (2;3).

Supplementation or dietary change would serve the majority of these patients because—when taken along with other vitamins—vitamin C may lead to reduced risk of chronic diseases such as cancer, cardiovascular disease and cataracts (1). The antioxidant vitamin is thought to possibly have a role in counteracting and detoxifying carcinogens, preventing myocardial lipid peroxidation and LDL oxidation, and prevent oxidative damage to lens in the eye (1).

Note that the vitamin has not been found to have any effect on reducing risk of colds (1). This is in contrast to what's marketed on many dietary supplements.

Large intakes of vitamin C (above 2g daily) can cause diarrhea (1). The vitamin C competes with uric acid inhibiting renal absorption of uric acid that can lead to increases of uric acid excretion, urine acidification and precipitation of uric acid crystals (1). This may increase risk of urate kidney stones if high doses are taken chronically (1). Chronic high doses may not be appropriate also for those with iron metabolism disorders since vitamin C increases iron absorption (1).

Recommended dietary intake levels are 75mg for women and 90 mg for men (1). If pregnant, elderly, smoking or afflicted with chronic disease, a little more may be needed (4-6). Supplementation with a multivitamin may be sufficient for oxidative stress protection, however, findings on reducing risk of chronic disease are mostly related to antioxidant vitamin intake from fruit and vegetables (6-10).

Based on the above rationale, I would recommend patients first attempt to increase fruit and vegetable consumption to meet desired plasma levels and with optimal synergistic effects of other vitamins. If there’s any doubt of the patient’s ability or motivation to eat fruits and vegetables, then vitamin C in form of a multivitamin would be the next step.

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Hampl JS, Taylor CA, Johnston CS. Vitamin C deficiency and depletion in the United States: the Third National Health and Nutrition Examination Survey, 1988 to 1994. Am J Public Health 2004;94:870-5.
3. Taylor CA, Hampl JS, Johnston CS. Low intakes of vegetables and fruits, especially citrus fruits, lead to inadequate vitamin C intakes among adults. Eur J Clin Nutr 2000;54:573-8.
4. Valdes F. [Vitamin C]. Actas Dermosifiliogr 2006;97:557-68.
5. Brubacher D, Moser U, Jordan P. Vitamin C concentrations in plasma as a function of intake: a meta-analysis. Int J Vitam Nutr Res 2000;70:226-37.
6. Goodwin JS, Brodwick M. Diet, aging, and cancer. Clin Geriatr Med 1995;11:577-89.
7. Genkinger JM, Platz EA, Hoffman SC, Comstock GW, Helzlsouer KJ. Fruit, vegetable, and antioxidant intake and all-cause, cancer, and cardiovascular disease mortality in a community-dwelling population in Washington County, Maryland. Am J Epidemiol 2004;160:1223-33.
8. Nagyova A, Krajcovicova-Kudlackova M, Horska A et al. Lipid peroxidation in men after dietary supplementation with a mixture of antioxidant nutrients. Bratisl Lek Listy 2004;105:277-80.
9. Broekmans WM, Klopping-Ketelaars IA, Schuurman CR et al. Fruits and vegetables increase plasma carotenoids and vitamins and decrease homocysteine in humans. J Nutr 2000;130:1578-83.
10. Zino S, Skeaff M, Williams S, Mann J. Randomised controlled trial of effect of fruit and vegetable consumption on plasma concentrations of lipids and antioxidants. BMJ 1997;314:1787-91.

Carrageenans - Good or Bad for You?

Carrageenans are food additives derived from red seaweed such as Chondrus crispus (Irish moss) and other species and are used as a thickening, stabilizing, and texturizing agents in foods and also for reduced-fat meat products (1;2).

They nicely replace animal-based gelatin found in many foods such as soymilk, chocolate milk, yogurts, beers and wines. Lamda-carrageenan, for example, is used to provide a creamy texture to dairy products.

The polymers are high-molecular-weight polysaccharides made up of repeating disaccharide units have a charged nature and their structure gives them their highly reactive properties (2). Concentration and greater molecular weight increases viscosity further (2).

Safety of use of carrageenans in foods has been a matter of controversy and confusion. Leading manufacturers of carrageenan such as FMC corporation have maintained that the use of carrageenan has a centuries-old history of safety in humans that has been confirmed by studies on animals such as dogs and rodents (3). Food-grade carrageenans are not thought to be degraded or absorbed from the gastrointestinal tract of humans (1).
It is known that, when administered systemically, carrageenans are linked to acute liver toxicity (4), are carcinogenic (5) and affect the immune system (6). Also, a substance formed of degraded carrageenan, now known as poligeenan, has long been banned from use in food because of links to fetal toxicity, birth defects, liver toxicity, ulcerative disease, pulmonary lesions and colon cancer in animals (5).

Toxicity concerns of undegraded carrageenans arose when studies in a few experimental animals found that carrageenans were degraded leading to absorption and toxicity (5;6). Another study on rats found that given small quantities of for 90 days, undegraded carrageenans had “penetrated the intestinal barrier degree” in adult rats (7). Low concentrations were also tested on tissue cultures where it was found that lamda-carrageenans entered cells by what appeared to be endocytosis (8).

Despite these data, however, the World Health Organization Expert committee on Food Additives and Joint Food and Agriculture Organization have kept recommendations of allowable daily intake as “not specified” (6).

The groups cited that there was “no credible evidence” to support that food-grade carrageenans were degraded or absorbed in “rodents, dogs, and non-human primates” or that they presented any toxic or carcinogenic effect in these species or in humans long term (6). High doses of carrageenans had been found to lead to cecal enlargement, but the studied amounts were in excess of which humans would consume normally (6).

Reference List

1. Trius A, Sebranek JG. Carrageenans and their use in meat products. Crit Rev Food Sci Nutr 1996;36:69-85.
2. Food and Agriculture Organization. FAO Corporate Document Repository. Training Manual on Gracilaria Culture and Seaweed Processing in China. Available: http://www.fao.org/docrep/field/003/AB730E/AB730E03.htm.
3. Weiner ML. Toxicological properties of carrageenan. Agents Actions 1991;32:46-51.
4. Abe T, Kawamura H, Kawabe S, Watanabe H, Gejyo F, Abo T. Liver injury due to sequential activation of natural killer cells and natural killer T cells by carrageenan. J Hepatol 2002;36:614-23.
5. Watt J, Marcus R. Harmful effects of carrageenan fed to animals. Cancer Detect Prev 1981;4:129-34.
6. Cohen SM, Ito N. A critical review of the toxicological effects of carrageenan and processed eucheuma seaweed on the gastrointestinal tract. Crit Rev Toxicol 2002;32:413-44.
7. Nicklin S, Miller K. Effect of orally administered food-grade carrageenans on antibody-mediated and cell-mediated immunity in the inbred rat. Food Chem Toxicol 1984;22:615-21.
8. Tobacman JK, Walters KS. Carrageenan-induced inclusions in mammary myoepithelial cells. Cancer Detect Prev 2001;25:520-6.

Tidbit: GLUT6 - the "pseudogene"

GLUT6 is expressed in various tissues in the body, but doesn't encode any functional glucose transport protein (1). Why does it occur at all? It's thought that GLUT6’s nucleotide sequence may have simply occurred from an insertion of GLUT3 reverse transcribed in a region of an untranslated gene (1).

Reference List

1. Kayano T, Burant CF, Fukumoto H et al. Human facilitative glucose transporters. Isolation, functional characterization, and gene localization of cDNAs encoding an isoform (GLUT5) expressed in small intestine, kidney, muscle, and adipose tissue and an unusual glucose transporter pseudogene-like sequence (GLUT6). J Biol Chem 1990;265:13276-82.

Review of study on using antioxidant response as predictor for radiation pneumonitis

A currently unpredictable outcome of radiotherapy on lung cancer patients is radiation pneumonitis (lung inflammation). This study was the first performed on humans to determine how antioxidant response may be used to predict this “potentially lethal treatment-related complication”. The oxidative stress link had been established through studies on irradiated mice.

Type of study: Observational study on humans; physicians grading for pneumonitis were blinded to antioxidant data

Method used to conduct study: Fifteen total lung cancer patients were found eligible for the study after signing informed consents, having stage III disease, receiving concurrent definitive radiotherapy and paclitaxel-based chemotherapy, and having good performance status. Excluded were patients who had received radiotherapy or chemotherapy previously and those with unfavorable Eastern Cooperative Oncology Group performance status or chronic obstructive pulmonary disease.

Blood samples were collected at baseline and weekly during the 6-week treatment. Radiation pneumonitis was diagnosed three months after the treatment according to different grades ranging from mild, moderate, and severe. Cross-validation was used to analyze test sensitivity to variables. Detection of proteins was performed through gel electrophoresis, secondary antibody and enhanced chemiluminescence in the blot analysis.

Summary: Researchers found that the patients who developed pneumonitis had higher levels of superoxide dismutase (SOD) and lower levels of glutathione peroxidase (GPX) overall. The data suggest that higher SOD activity increased the conversion of superoxide anion to hydrogen peroxide. In conjunction with low GPX, an increase of hydrogen peroxide and hydroxyl radicals would occur creating oxidative stress that would predispose patients to radiation pneumonitis.

Critique of research design quality and relevance: Blinding methods and appropriate exclusions make this a well-designed study with few confounding variables. Although strong data from animals confirm its findings, the study’s great weakness is that of being a small one. Its relevance, however, may be large since using GPX/SOD as predictive markers may save lives in the future.

Nutritional implications and implications of future study: High SOD/low GPX activity may serve as a marker for prediction of radiation pneumonits and that increasing the ratio of GPX/SOD would reduce risk of radiation pneumonitis. Clinical trials on use of antioxidant supplements is warranted; however, the researchers warn, antioxidant therapies must take into account other treatments (e.g. chemotherapy) and how it would affect the patient as "a whole".

Reference

Park EM, Ramnath N, Yang GY et al. High superoxide dismutase and low glutathione peroxidase activities in red blood cells predict susceptibility of lung cancer patients to radiation pneumonitis. Free Radic Biol Med 2007;42:280-7. Available at: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1892164

Milk thistle meta-analysis

I have often seen milk thistle (silymarin) touted as a shining star among natural remedies for hepatoprotective benefits. And although still controversial, it is intriguing to learn of its antiperoxidative effects in achieving small increases in glutathione levels (1).

No doubt that a 2008 meta-analysis from Switzerland on silymarin will pique your interest further. After reviewing the only 19 available "double-blind" and "single-blind" studies, no evidence was found to help with viral hepatitis, but in liver cirrhosis sylimarin was able to reduce aspartate aminotransferase, although not alkaline phosphatase (2)--this means it may help protect hepatocytes (liver cells).

The meta-analysis concluded that not enough clinical evidence existed for proper recommendation (2). But risk/benefit analysis would suggest it's reasonable to use sylimarin as a therapy for poisoning and may have minor benefit in liver cirrhosis (2).

References

1. Lucena MI, Andrade RJ, de la Cruz JP, Rodriguez-Mendizabal M, Blanco E, Sánchez de la Cuesta F. Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study. Int J Clin Pharmacol Ther. 2002 Jan;40(1):2-8.
2. Saller R, Brignoli R, Melzer J, Meier R..An updated systematic review with meta-analysis for the clinical evidence of silymarin. Forsch Komplementmed. 2008 Feb;15(1):9-20.

Sliding filament model

What is troponin and what is its diagnostic value?

Troponin is a three-subunit protein complex that regulates striated (skeletal and cardiac) muscle contraction (1-3). Similar to caldesmon in smooth muscle, troponin affects release from actin (3). The process of muscle contraction is best represented by the sliding filament model (3). The model illustrates heavy dependence on calcium regulation for velocity involving “loose coupling” of calcium binding to troponin to determine the rate of “cycling cross-bridges” (4-6).

Cross-bridge cycling is a two-feedback mechanism—positive and negative—depending on its activation and regulation (6). Troponin subunit Tn-T is attached to tropomyocin is attached to actin (3). When a signal transmitted to the sarcoplasmic reticulum induces release of Ca(2+) into the sarcomere, then the Ca(2+) binds to subunit Tn-C, which changes orientation of subunit Tn-I (3). The Tn-I change causes a rotation in which the structure of tropomyosin rotates actin and exposes it to myosin binding sites creating contractibility (3). This action is critical in the heart (1). It’s worth noting that any mutations of cardiac troponin would affect this process, which develops cardiomyopathies (1;7). Contraction is stopped by ATPase pumping Ca(2+) out of the sarcomere furiously (3). Once in the sarcoplastmic reticulum, the Ca(2+) is taken away by calsequestrin (3).

As a diagnostic tool for myocardial infarction, troponins are highly valued because they can detect the smallest of infarctions in comparison to other cardiac markers such as electrocardiogram, creatine kinase (CK) and CK-MB (2). Tn-T can be expressed from skeletal muscle, but Tn-I is specific to myocardium (1). Any elevation of cardiac troponins are serious markers that largely indicate a poor prognosis with unstable angina (2).

Reference List

1. Biesiadecki BJ, Kobayashi T, Walker JS, John SR, de Tombe PP. The troponin C G159D mutation blunts myofilament desensitization induced by troponin I Ser23/24 phosphorylation. Circ Res 2007;100:1486-93.
2. Gaw A, Murphy MJ, Cowan RA, O'Reilly DStJ, Stewart MJ, Shepherd J. Clinical Biochemistry: An Illustrated Colour Text. Edinburgh: Churchill Livingstone Elsevier, 2008.
3. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
4. Homsher E, Kim B, Bobkova A, Tobacman LS. Calcium regulation of thin filament movement in an in vitro motility assay. Biophys J 1996;70:1881-92.
5. Sata M, Yamashita H, Sugiura S, Fujita H, Momomura S, Serizawa T. A new in vitro motility assay technique to evaluate calcium sensitivity of the cardiac contractile proteins. Pflugers Arch 1995;429:443-5.
6. Landesberg A, Sideman S. Mechanical regulation of cardiac muscle by coupling calcium kinetics with cross-bridge cycling: a dynamic model. Am J Physiol 1994;267:H779-H795.
7. Lin D, Bobkova A, Homsher E, Tobacman LS. Altered cardiac troponin T in vitro function in the presence of a mutation implicated in familial hypertrophic cardiomyopathy. J Clin Invest 1996;97:2842-8.
8. Unverir P, Soner BC, Dedeoglu E, Karcioglu O, Boztok K, Tuncok Y. Renal and hepatic injury with elevated cardiac enzymes in Amanita phalloides poisoning: a case report. Hum Exp Toxicol 2007;26:757-61.
9. Livingston JC, Mabie BC, Ramanathan J. Crack cocaine, myocardial infarction, and troponin I levels at the time of cesarean delivery. Anesth Analg 2000;91:913-5, table.

Case Report: Mushroom Poison Gives Off Mixed Messages

Forty-two hours after ingesting an unknown mushroom, a 56-year-old man was admitted to a Turkish emergency department (1). Cardiac markers troponin I, creatine kinase (CK), CK-MB isoenzyme, and myoglobin were all elevated (1). The testing detected nothing less than myocardial infarction (2). This diagnosis, however, was not correct.

The clinicians noted in their report that despite the potentially confusing cardiac markers, the patient was diagnosed with hepatic and renal falure (1). This is because in cases of mushroom poisoning, “amatoxins” bind with “actin filaments within myocardiocytes or renal cells and/or its effects as circulating antitropin antibodies” causing the cardiac markers to become elevated (1).

The patient was treated with fluids, activated charcoal, antibiotics and silibinin (an active constituent of milk thistle) and improvement followed (1).

Reference List

1. Unverir P, Soner BC, Dedeoglu E, Karcioglu O, Boztok K, Tuncok Y. Renal and hepatic injury with elevated cardiac enzymes in Amanita phalloides poisoning: a case report. Hum Exp Toxicol 2007;26:757-61.
2. Gaw A, Murphy MJ, Cowan RA, O'Reilly DStJ, Stewart MJ, Shepherd J. Clinical Biochemistry: An Illustrated Colour Text. Edinburgh: Churchill Livingstone Elsevier, 2008.

Fatty acids and Depression

Sailor Man Should Not Be Without His Olive

Omega-3 fatty acids from fish have largely stolen the spotlight for anti-depression, but recent evidence finds that oleic acid from olive oil may also be useful in women.

Last May a 10-year national cohort followed 1,947 men and 2,909 women (African-American and Caucasian) (1). They were separated according to “lowest, middle and highest” for oleic fatty acid intake as well as linoleic (omega-6) fatty acid intake (1). Estimates adjusted for fish consumption and diseases (1).

The researchers found linoleic acid was associated with increased risk of severe depression in men and that oleic acid (omega-9) was associated with a reduced risk of severe depression in women (1).

Popeye take note.

Depression, Gone Fishing

Stroll along the bank of river peacefully, bait your hook, cast, enjoy a beer. The fish themselves may not think so, but going fishing is a relaxing pastime. But don’t catch and release because eating those fish may even more of a mood booster. Well, that may be a stretch.

Truth is that a dietary deficiency of omega-3 fatty acids—found in amounts highest in fatty fish—may be related to great risk of depression, particularly among pregnant or menopausal women, according to recent studies (2-6).

Scientists have known for a while that an association between omega-3 fatty acids and depression exists, but it is still unclear why and its use as a single therapy has not been found to be effective; still researchers hope omega-3 oils can be used as complementary nutritional therapy to other treatments (2;7-10).

In fact, omega-3 was reconfirmed earlier this month by the Emory University School of Medicine to have a place as in researching emerging targets for antidepressant therapies (11;12). This is in light of frustration of failure of current treatments of depression drugs such as monoamine reuptake inhibitors and nutritional interventions to provide results (7;12).

Reference List

1. Wolfe AR, Ogbonna EM, Lim S, Li Y, Zhang J. Dietary linoleic and oleic fatty acids in relation to severe depressed mood: 10 years follow-up of a national cohort. Prog Neuropsychopharmacol Biol Psychiatry 2009.
2. Hazell P. Depression in children and adolescents. Clin Evid (Online ) 2009;2009.
3. Golding J, Steer C, Emmett P, Davis JM, Hibbeln JR. High levels of depressive symptoms in pregnancy with low omega-3 fatty acid intake from fish. Epidemiology 2009;20:598-603.
4. Rees AM, Austin MP, Owen C, Parker G. Omega-3 deficiency associated with perinatal depression: case control study. Psychiatry Res 2009;166:254-9.
5. Hibbeln JR. Depression, suicide and deficiencies of omega-3 essential fatty acids in modern diets. World Rev Nutr Diet 2009;99:17-30.
6. Lucas M, Asselin G, Merette C, Poulin MJ, Dodin S. Ethyl-eicosapentaenoic acid for the treatment of psychological distress and depressive symptoms in middle-aged women: a double-blind, placebo-controlled, randomized clinical trial. Am J Clin Nutr 2009;89:641-51.
7. Sarris J, Schoendorfer N, Kavanagh DJ. Major depressive disorder and nutritional medicine: a review of monotherapies and adjuvant treatments. Nutr Rev 2009;67:125-31.
8. Colangelo LA, He K, Whooley MA, Daviglus ML, Liu K. Higher dietary intake of long-chain omega-3 polyunsaturated fatty acids is inversely associated with depressive symptoms in women. Nutrition 2009.
9. Su KP. Biological mechanism of antidepressant effect of omega-3 fatty acids: how does fish oil act as a 'mind-body interface'? Neurosignals 2009;17:144-52.
10. Ramakrishnan U, Imhoff-Kunsch B, DiGirolamo AM. Role of docosahexaenoic acid in maternal and child mental health. Am J Clin Nutr 2009;89:958S-62S.
11. Rakofsky JJ, Holtzheimer PE, Nemeroff CB. Emerging targets for antidepressant therapies. Curr Opin Chem Biol 2009.
12. Holtzheimer PE, Nemeroff CB. Novel targets for antidepressant therapies. Curr Psychiatry Rep 2008;10:465-73.

Omega Ratio Rationale?

The plethora of scientific studies on lipids and nutrition would have nutritionists thinking within reason that omega-3s are the chosen fatty acid to deliver humankind from sickness. But despite the seemingly omnipotent oil’s overabundance of qualities, not nearly enough is known about how much to consume in relation to other fatty acids such as omega-6.

In June 2008, top cardiologists convened to examine all clinical evidence and discuss optimal omega-3 dosages (1). The conclusions were summarized with a recommendation of at least 250 mg of DHA and EPA fatty acids for the “primary prevention of cardiovascular disease” (1). No ratio recommendation was given, which was purposeful.

In fact, the focus on omega-3 to omega-6 ratios had been heavily criticized earlier. A report in 2007 by the UK Food Standards Agency said that “ratio is not a useful concept and it distracts attention away from absolute intakes” (2). And a year earlier, top American omega-3 fatty acid researcher William S. Harris, Ph.D., of University of South Dakota’s Nutrition and Metabolic Diseases Research Institute wrote that “although initially appealing” for making nutritional recommendations, ratio is “of little value” (3). Lacking clinical data, the UK Food Standards Agency, Dr Harris and others may be correct in calling for concentration solely on omega-3 for established treatment(4;5).

Many clinicians and researchers, however, continue to advise and perform studies from the theoretical viewpoint of a ratio. A microscopic view reveals answers to why. The function of omega-3 and omega-6 in the cell or an organ such as the liver or brain highlights key differences. Dr Harris does concede these facts: that the two fatty acids compete for enzymes and have opposite effects (3). In addition to omega-3’s anti-inflammatory and omega-6’s inflammatory uniqueness (6), the biochemistry also presents information on how each influences metabolism, genetic expression (6-10), cell membrane function and neurotransmission (6;11). While insightful, however, the information does stop short of any clinical parameters.

As a base for perspective, nutritionists find it useful to turn to dietary origins. Nutritional anthropology and epidemiological studies suggest a ratio of 1-2:1 omega-6 to omega-3, which is in large contrast to the typical Western diet of 15-16:1 (6;12-15). And many ratios resembling the ideal hunter-gatherer 1:1 do propose significant reduction of risk of chronic disease, mainly coronary artery disease and arthritis (6;15). These research approaches come with caution as they are not enough for science in absolute, nor do they offer indication of any exact amounts for best efficacy.

Truer data must come from well-designed randomized, double-blind controlled trials. To reflect proper indications, these studies should take into account ratio, amounts or both. An example of a trial was conducted in 2003 when two parallel groups of 15 patients who each had major elective abdominal surgery were given omega-6 to omega-3 ratio of 3:1, which confirmed a significant anti-inflammatory effect (16). More trials such as this one could illuminate further.

Reference List

1. Deckelbaum RJ, Leaf A, Mozaffarian D, Jacobson TA, Harris WS, Akabas SR. Conclusions and recommendations from the symposium, Beyond Cholesterol: Prevention and Treatment of Coronary Heart Disease with n-3 Fatty Acids. Am J Clin Nutr 2008;87:2010S-2S.
2. Stanley JC, Elsom RL, Calder PC et al. UK Food Standards Agency Workshop Report: the effects of the dietary n-6:n-3 fatty acid ratio on cardiovascular health. Br J Nutr 2007;98:1305-10.
3. Harris WS. The omega-6/omega-3 ratio and cardiovascular disease risk: uses and abuses. Curr Atheroscler Rep 2006;8:453-9.
4. Harris WS. Omega-3 fatty acids and cardiovascular disease: a case for omega-3 index as a new risk factor. Pharmacol Res 2007;55:217-23.
5. Harris WS, Assaad B, Poston WC. Tissue omega-6/omega-3 fatty acid ratio and risk for coronary artery disease. Am J Cardiol 2006;98:19i-26i.
6. Simopoulos AP. The omega-6/omega-3 fatty acid ratio, genetic variation, and cardiovascular disease. Asia Pac J Clin Nutr 2008;17 Suppl 1:131-4.
7. Kang JX. The importance of omega-6/omega-3 fatty acid ratio in cell function. The gene transfer of omega-3 fatty acid desaturase. World Rev Nutr Diet 2003;92:23-36.
8. Takeuchi H, Kojima K, Sekine S, Murano Y, Aoyama T. Effect of dietary n-6/n-3 ratio on liver n-6/n-3 ratio and peroxisomal beta-oxidation activity in rats. J Oleo Sci 2008;57:649-57.
9. Lu Y, Nie D, Witt WT et al. Expression of the fat-1 gene diminishes prostate cancer growth in vivo through enhancing apoptosis and inhibiting GSK-3 beta phosphorylation. Mol Cancer Ther 2008;7:3203-11.
10. El-Badry AM, Graf R, Clavien PA. Omega 3 - Omega 6: What is right for the liver? J Hepatol 2007;47:718-25.
11. Haag M. Essential fatty acids and the brain. Can J Psychiatry 2003;48:195-203.
12. Simopoulos AP. Evolutionary aspects of diet, the omega-6/omega-3 ratio and genetic variation: nutritional implications for chronic diseases. Biomed Pharmacother 2006;60:502-7.
13. Cordain L, Eaton SB, Sebastian A et al. Origins and evolution of the Western diet: health implications for the 21st century. Am J Clin Nutr 2005;81:341-54.
14. Simopoulos AP. The importance of the omega-6/omega-3 fatty acid ratio in cardiovascular disease and other chronic diseases. Exp Biol Med (Maywood ) 2008;233:674-88.
15. Simopoulos AP. The importance of the ratio of omega-6/omega-3 essential fatty acids. Biomed Pharmacother 2002;56:365-79.
16. Koller M, Senkal M, Kemen M, Konig W, Zumtobel V, Muhr G. Impact of omega-3 fatty acid enriched TPN on leukotriene synthesis by leukocytes after major surgery. Clin Nutr 2003;22:59-64.

Acute Tubular Necrosis and Glomerulonephritis

Acute tubular necrosis (ATN) is a condition resulting from tubular cell apoptosis contributing to renal failure (1-3). It can result due to insult from extensive injury such as acute blood loss or septic shock, a specific renal disease such as glomerulonephritis, nephrotoxic drugs or bacterial products, or hypoxia (1-3).

ATN is identified via a rising serum urea creatinine and can be classified as pre-renal, renal or post-renal (1). If identified early, corrective action can stop damage and possible hyperkalemia (1).

Managing ATN includes caring for patient by replacing extra cellular fluid when necessary, controlling an underlying infection that may be cause, monitoring body fluid volume closely and via dialysis (1). Recovery involves three phases: initial oliguric phase (impairment), diuretic phase (high-urine output) and recovery phase (return of complete renal function) (1).

Glomerulonephritis is an inflammation of the glomeruli, which causes progressive renal damage that can lead to ATN and renal failure (4-6). The disease is mainly caused by infection such as streptococcal infection (7;8). In post-streptococcal glomerulonephritis, symptoms can include sudden hypertension, proteinuria, edema and hematuria (9). The inflammatory response causing the damage to the kidneys is thought to be related to hypersensitive immune response (9). Maintenance generally can include treatment of underlying disease, balancing electrolytes and fluids, and possible peritoneal dialysis (10).

Reference List

1. Gaw A, Murphy MJ, Cowan RA, O'Reilly DStJ, Stewart MJ, Shepherd J. Clinical Biochemistry: An Illustrated Colour Text. Edinburgh: Churchill Livingstone Elsevier, 2008.
2. Rosen S, Stillman IE. Acute tubular necrosis is a syndrome of physiologic and pathologic dissociation. J Am Soc Nephrol 2008;19:871-5.
3. Ortiz A, Justo P, Sanz A, Lorz C, Egido J. Targeting apoptosis in acute tubular injury. Biochem Pharmacol 2003;66:1589-94.
4. Vinen CS, Oliveira DB. Acute glomerulonephritis. Postgrad Med J 2003;79:206-13.
5. Feith GW, Assmann KJ, Wetzels JF. Acute renal failure in patients with glomerular diseases: a consequence of tubular cell damage caused by haematuria? Neth J Med 2003;61:146-50.
6. Ruiz P, Soares MF. Acute postinfectious glomerulonephritis: an immune response gone bad? Hum Pathol 2003;34:1-2.
7. Prakash J, Sen D, Kumar NS, Kumar H, Tripathi LK, Saxena RK. Acute renal failure due to intrinsic renal diseases: review of 1122 cases. Ren Fail 2003;25:225-33.
8. Faurie RE, Prado AC. [Streptococcal infection, acute kidney failure and interstitial nephritis]. Medicina (B Aires) 2000;60:953-5.
9. Yoshizawa N. Acute glomerulonephritis. Intern Med 2000;39:687-94.
10. Filler G. Acute renal failure in children: aetiology and management. Paediatr Drugs 2001;3:783-92.

How does alcohol affect kidney function?

What effects do you think alcohol consumption could have on renal function tests?

You’ve heard before that alcohol in moderation (in moderation!) may be good for your heart, but what can it do to your kidneys? Acute and chronic alcohol consumption does alter renal function and other physiological processes such as blood flow and fluid and electrolyte balances, which can directly affect results of renal function tests (1;2). Effects include higher level of creatine clearance and glomerular filtration rate (3). The alterations are especially noticeable in cases of liver disease (1;2).

Heavy drinking—which would be four or more alcoholic drinks a day—has a strong correlation with chronic kidney disease, especially in patients who smoke, have diabetes or hypertension or who are obese (4). When under condition of liver cirrhosis, chronic alcohol intake has been shown in rats and humans to possibly play a role in causing kidney enlargement and alterations in tubules (1). This all suggests renal detriment from consumption of alcohol.

However, prospective cohorts on moderate consumption in men and women tell a different story. A 2005 study on 11,023 healthy men over 14 years found that while there was association between alcohol consumption and glomerular filtration rates, moderate alcohol consumption actually caused a lower risk of renal dysfunction over time (5). A 2005 study on 1,658 female nurses for 11 years showed similar data in that while glomerular filtration rate was affected, moederate alcohol consumption had no adverse effect on renal dysfunction over time (2).

Good news for moderate drinkers!

Reference List

1. Epstein M. Alcohol's impact on kidney function. Alcohol Health Res World 1997;21:84-92.
2. Knight EL, Stampfer MJ, Rimm EB, Hankinson SE, Curhan GC. Moderate alcohol intake and renal function decline in women: a prospective study. Nephrol Dial Transplant 2003;18:1549-54.
3. Chung FM, Yang YH, Shieh TY, Shin SJ, Tsai JC, Lee YJ. Effect of alcohol consumption on estimated glomerular filtration rate and creatinine clearance rate. Nephrol Dial Transplant 2005;20:1610-6.
4. Shankar A, Klein R, Klein BE. The association among smoking, heavy drinking, and chronic kidney disease. Am J Epidemiol 2006;164:263-71.
5. Schaeffner ES, Kurth T, de Jong PE, Glynn RJ, Buring JE, Gaziano JM. Alcohol consumption and the risk of renal dysfunction in apparently healthy men. Arch Intern Med 2005;165:1048-53.

Why 24-hr urine test isn't enough

Why isn’t a total urine volume taken over 24 hours enough to assess renal function?

A total 24-hour urine volume can be useful for identifying reduced or increased urine volume, but it is unreliable (not to mention inconvenient) and still not enough to identify renal dysfunction or failure (it can simply indicate dehydration, high fluid intake or use of diuretics) (1-3).

The measurement of urinary excretion of creatinine of the 24-hour urine volume, called creatinine clearance, reveals more because it can better indicate glomerular filtration rate (GFR) (1;2). However, creatine clearance is still limited in its precision due to possible confounding variables (1).

An approach to support proper investigation into renal function should include other measures inclindin estimated GFR (considering age, sex, ethinicity and weight) as well as tests for other markers of clearance such as cystatin C (a protein almost unaffected by meat intake), inulin (most accurate estimate of GFR) and albumin (indicator of proteinuria) (1).

Apart from GFR, in cases of possible renal tubular dysfunction measurement of tubular reabsorption is necessary because it may contribute to acute renal failure (1). Usually tubular damage occurs due to other conditions (1). Examination may include osmolality measurements of plasma and urine, water deprivation tests, urine pH and acid load tests, specific proteinuria, aminoaciduria or glycosuria tests (1).

Reference List

1. Gaw A, Murphy MJ, Cowan RA, O'Reilly DStJ, Stewart MJ, Shepherd J. Clinical Biochemistry: An Illustrated Colour Text. Edinburgh: Churchill Livingstone Elsevier, 2008.
2. Adebisi SA, Adekunle BA, Etu AK. Creatinine clearance: alternative approach to traditional 24-hour urine collection in normal individuals. Afr J Med Med Sci 2001;30:27-30.
3. MedlinePlus. Urine 24-hour volume. Medical Encyclopedia. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/003425.htm. Accessed on 21 June 2009.