Biochem of starvation

Humans didn’t always have restaurants and grocery stores to visit on every corner. As part of human evolution, in fact, most of the time it’s likely our ancestors were starving quite often and got pretty good at it while foraging and hunting.

It took the agricultural revolution to really make a shift to food aplenty. But starvation hasn’t gone away by any stretch. It’s a daily reality for much of the underdeveloped world.
And, a bit closer to my reality, my own great grandmother often shared stories with me about how she’d go for weeks without meals as a little girl.

To be able to survive from meal to meal, we depend on a starve-feed cycle. It refers to the changes in metabolism that allows variable fuel and nitrogen consumption to meet variable metabolic and anabolic demand (1). In plain English, it is what gives humans capacity to eat food well beyond caloric requirements and store it as glycogen and triacylglycerol to utilize when needed (1).

This is what happens to someone biochemically as they enter starvation.

Early Starvation State (about two-five days after last meal)

About two days after a last meal with insulin low and glycagon on the rise, glycogen is depleted and muscle proteolysis is predominating (1). The protein catabolism would release of a mix of amino acids high in alanine and glutamine into the blood (1p246).

The alanine stimulates glycogen and is taken up from the liver where it's deaminated for conversion to urea and where pyruvate can be used for gluconeogenesis (1p246). Gluconeogenesis is also made from recycled lactate, pyruvate and from glycerol from fat tissue lipolysis (1p245). Blood glucose levels are successfully kept normal (1p246).

Prolonged Starvation State (one week or longer after last meal)

As starvation becomes prolonged, the body enters a metabolic shift. The shift is away from the glycogen-depleting and muscle-protein-breakdown fasting state (1). The body now intends to conserve vital body proteins to preserve vital functions such as antibodies fighting infection, enzymes catalyzing reactions and hemoglobin transporting oxygen (1).

For energy, the body begins using fat conveniently stored in adipose tissue during a time when more calories were consumed than expended (1). Thus, the blood’s level of fatty acids increases as those fatty acids become fuel (1). The heart, liver and muscle all oxidize them, but not the brain because fatty acids can’t cross the blood-brain barrier (1). The brain can use glycerol backbones, however, and these largely replace amino acids and glucose as its fuel (1).

TCA cycle intermediates for gluconeogenesis eventually become depleted and low levels of oxaloacetate coupled with rapid production of acetyl CoA from fatty acid catabolism create accumulation favoring ketone bodies (1). The ketone bodies are valuable as an energy source for sparing protein (1).

To survive in a starvation state generally depends on stored fat before starvation, although ketosis can cause significant physiological damage and even death (1). The ketosis is kept in check as long as possible by directing glutamine to kidneys, but acidosis increases as ketone production accelerates (1). Once fat stores are used up the body starts on essential protein leading to liver and muscle function loss that ultimately leads to death (1).

Reintroducing Food

As a starved person begins to eat again, there are metabolic interrelationships between the liver, muscle and fat tissue. Triaylglycerol is metabolized normally, but glucose metabolism must be slowly re-established (1). The reason is because the liver extracts glucose poorly and ends up staying in a gluconeogenec mode for awhile after feeding (1).

But the hepatic gluconeogenesis is not producing blood glucose (1). It's providing glucose 6-phosphate for glycogenesis (1). It's an indirect pathway for glycogen synthesis because glucose is catabolized in other tissues (muscle, fat) and then sent to the liver to be converted to the glycogen (1).

Finally, after a few hours, gluconeogenesis declines and glycolysis predominates (1). The liver glycogen then can be sustained again by direct synthesis from blood glucose (1).

Reference List

1. Devlin TM. Textbook of Biochemistry with Clinical Correlations. Philadelphia: Wiley-Liss, 2002.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.

Other:

Johnstone AM. Fasting - the ultimate diet? Obes Rev 2007;8:211-22.
Cahill GF, Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006;26:1-22.

How does fat get absorbed and stored as fat?

Fat is absorbed in the intestine contained in chylomicrons and then secreted into lymphatics (1). The lymphatics drain the intestine, then lead to the thoracic duct and deliver the chylomicrons into the blood at a site of rapid blood flow (1). The rapidity is necessary to distribute the chylomicrons well preventing them from coalescing (1). Then lipoprotein lipase, which is attached to endothelial cell survaces in the lumen of capillaries, acts on the chylomicrones to liberate fatty acids via hydrolysis (1). The fatty acids are taken up by adipocytes and reesterified with glycerol 3-phosphate to form triacylglycerols and be stored as fat droplets (1).

Reference

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

Levels of consciousness (and no, I'm not Deepak Chopra)

Odd as it is to measure something like consciousness, it is a must to determine a possible medical condition, and the levels must be precise to give an accurate status before and after treatment (1). A state of consciousness can indicate a person’s wakefulness, awareness and alertness (2). Consciousness may “lower” a level or more depending on a range of factors that include alcohol or barbiturate overdose, stroke, epilepsy, bacterial meningitis, diabetes, kidney failure or heart disease (1).

Example of consciousness terminology (1):

• Normal consciousness is characterized by a fully responsive, self-awareness and awareness of surroundings
• Inattention is when a patient finds it difficult to identify and attend revelant stimuli
• Confusion happens when thinking is slower or less clear; or when a patient is distracted
• Clouding (obtundation) is when inattention and confusion are more profound; rousing is more difficult
• Stupor is physical and mental activity at its minimum (kind of like me in the morning); you have to use persistent and vigorous stimulation to arouse them
• Coma is when a patient simply can’t be aroused, but might produce a pattern of behavior if stimulus is intense
  

Many clinical methods of have been used to determine the conscious state. The Glasgow Coma Scale, introduced in 1974 (2), has been functional in many hospitals including Grady Memorial Hospital in Atlanta, Georgia, for 30 years (3). The scale is easy to use using eye, verbal and motor responses (1;3). But it does have many limitations because there is a tendency to skew scores depending on experience of examiners and their paradigms (2). New techniques for determining consciousness may come in the future. They may include new terminology and new scales (2;3).

Reference List

1. Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.
2. Matis G, Birbilis T. The Glasgow Coma Scale--a brief review. Past, present, future. Acta Neurol Belg 2008;108:75-89.
3. Tindall S. 1990. Levels of Consciousness. Clinical Methods: The History, Physical, and Laboratory Examinations. Available at: http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=cm&part=A1731

Don't depend on Glasgow Coma Scale

The Glasgow Coma Scale is easy to use for almost anyone to determine the state of a head injury. It includes eye, verbal and motor responses (see http://en.wikipedia.org/wiki/Glasgow_Coma_Scale).

But it should be clear that it should not be the only test used. This was a hard lesson for the medics that treated Natasha Richardson after her skiing head injury (2). For this reason when my daughter fell off a scooter and hurt her head, her doctor suggested I take her to the hospital for a scan.

Reference
1. Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.
2. Tremblant M. 2009. 911 Calls Show Urgency of Richardson Fall. CBS News. Available at: http://www.cbsnews.com/stories/2009/03/31/entertainment/main4906004.shtml

Neural tube defects may not be related to high sugar intake

High glycemic load was previously thought to increase risk of neural tube defects after California researchers found that there appeared to be an association with maternal diets high in sugar in their state (1). However, the more recent National Birth Defects Prevention Study has found that the association does not exist among national population and other regions in the country (1). It is unclear why this is the case (1).

Reference List

1. Shaw GM, Carmichael SL, Laurent C, Siega-Riz AM. Periconceptional glycaemic load and intake of sugars and their association with neural tube defects in offspring. Paediatr Perinat Epidemiol 2008;22:514-9.

Going senile

My grandfather has, more than once, left my stove on for hours until a pan burns and a cloud sets off the smoke alarm. The other day he forgot to turn off the faucet and flooded my bathroom. I fear I can’t leave him alone. He could hurt himself or he could burn down my house.

Dementia is a symptom used in a broad way to describe any loss of ordered neural function. It affects my grandfather as senility—its cause being his age of 82. It is a relief that my grandmother, just as old, does not show similar signs. And I just hope my parents don’t get it. I hope I don’t get it. Worst case scenario would be Alzheimer’s disease—the slow progression of dementia to the point that mental function is surrendered. If you happen to live with a parent or grandparent who is one of the 6 percent of the population that has Alzheimer’s, then, yes, I feel for you. My situation doesn’t come close.

Depending on the pathological cause, dementia can be reversible. If altered mental function is due to depression, impaired heart function, or anemia, it can be helped. We know now that Pick’s and Alzheimer’s disease are different because they affect the cerebral cortex.

Although symptoms may be indistinguishable to Alzheimer’s, Pick’s causes atrophy of the gyri, which at autopsy is called “walnut brain.” Alzheimer’s doesn’t just affect the cerebral cortex. It also affects the hippocampus, the amygdale and the basal nucleus of Meynert. This is because of widespread depletion of acetylcholine (and other chemicals) resulting from loss of cells in the nucleus of Meynert. Neurons called pyramidal cells die, their associated axons die and the brain loses its white matter. The gyri shrinks and ventricals expand worsening the atrophy.

The severity and progression of Alzheimer’s depends on three findings: 1) neurofibrillary tangles that encircle or displace the nucleus of pyramidal cells; 2) neuritic plaques that contain a cluster of neural processes filled with filaments; 3) amyloid precursor protein, which is normal in cells, but is elevated in the brains of patients with Alzheimer’s. Ten percent of cases are familial due to a gene that produces amyloid protein, which may be related to Down syndrome. Most of those with Down syndrome do develop Alzheimer’s if they live beyond 45. A mutation of another gene called APP may be related to early-onset Alzheimer’s. And research also has identified enzyme (secretases) abnormalities that may result in increased conversion of abnormal APP to amyloid beta protein.

No, there are no practical treatments for Alzheimer’s, unfortunately. Someday maybe we’ll have something to degrade amyloid protein. Elevated aluminum levels found in patients who’ve had Alzheimer’s raises concerns that those with a genetic predisposition shouldn’t use aluminum cookware or other products such as deodorants containing aluminum. To remove aluminum, chelating agents have been used to reverse symptoms. Another experimental treatment is tetrahydroaminoacridine to enhance memory, but may cause liver damage. Aspirin also appears to slow inflammation that is part of Alzheimer’s.Healthy diet and exercise as well as exercise of cognitive skills remain the most important ways to help slow the progression of dementia and Alzheimer’s.

Reference List

Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.

MS patients can look forward to stem cell therapy

Stem cell therapy may be the treatment of the future for severe multiple sclerosis patients. Swedish researchers reported last February that bone marrow stem cell transplantation was successful for treating severe multiple sclerosis (1).

The researchers found improvement in symptoms after testing the therapy for five years on nine patients with severe MS, ages between 9 and 34 (1). The therapy has been studied for a total of 15 years (1).

Reference List

1. Fagius J, Lundgren J, Oberg G. Early highly aggressive MS successfully treated by hematopoietic stem cell transplantation. Mult Scler 2009;15:229-37.

Feel down in the dumps? Could be Alzheimer’s disease

Lack of motivation may serve as a diagnostic criteria for Alzheimer’s disease. According to a discussion during the European Alzheimer’s Disease Consortium earlier this month, the apathy may be caused by functional impairment (1). The researchers noted that reduced “goal-oriented behavior, goal-directed cognitive activity and emotions” must persist over time, thought to be “at least four weeks”.

Reference List

1. Robert P, Onyike CU, Leentjens AF et al. Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders. Eur Psychiatry 2009;24:98-104.

Why insulin is key for intracellular protein synthesis

When you’ve just eaten some protein, insulin, glucagon, growth hormone and glucocorticoids increase because of the presence of elevated amino acid concentration (1p232). The insulin promotes the protein synthesis and the other hormones have an opposite effect (1p232). Growth hormone is anabolic like insulin, although counterregulatory (1p232). Insulin to glucagon ratio favoring insulin stimulates protein synthesis enzymes and vice versa (1p232). The insulin is needed for uptake of amino acids across the cell membrane and antagonizing activation of amino acid oxidation by some enzymes (1p206-207).

Protein synthesis is also sensitive to multiple influences including stability of mRNA, amount of rRNA, activity of ribosomes, and (most important from diet), the presence of essential and nonessential amino acids in appropriate concentration to charge the tRNA and hormone environment (1p232). When amino acids are not present or not present in sufficient quantity, amino acid oxidation increases (1p232).

Reference List

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

After my high-protein shake

I just got done working out, sort of; I did manage to break a sweat. Then I made myself a high-protein shake and was sure to include a banana for carbs. Why do I do this again? Aren’t carbs a bad thing?

Well, it turns out that I need those carbs to stimulate insulin secretion to promote tissue cell uptake and use of the amino acids (1p206)(1). For this reason, it doesn’t make too much sense to take protein with some other kind of sweetener. The insulin affects movement of amino cid transporters to the membrane and their activity while also antagonizing activation of some enzymes that oxidize amino acids—very important if you’re trying to put on muscle (1p206-207)! You don’t want glucagon to dominate, leaving you with protein degradation (1p207). At least I don’t. Insulin stimulates protein synthesis and inhibits its degradation (1p207).

My shake’s protein content happens to be made up of contain whey and casein. That’s a good thing for me because whey is considered a “fast” protein that’s quickly digested, absorbed and oxidized to get that protein synthesis I want (1p207); the casein, a “slow” protein, prolongs amino acid concentration in the plasma at a low degree to keep protein synthesis up and protein degradation by around 30 percent (1p207). It’s unclear if older people are better off with the faster proteins and if younger people are better off with the slower proteins (1p207), but I’m 30 so I take both just in case. Plus, that casein keeps me feeling full longer (personal experience).
What’s also great about my protein shake is its amino acid profile. Leucine is important for promoting protein synthesis in my liver, muscles and skin because it accelerates phases of mRNA translation (1p207); plus, it’s involved in a signaling cascade to stimulate the mRNA translation (1p207). Leucine is great for me. And the whey apparently causes a rapid absorption of that leucine along with other branched-chain amino acids isoleucine and valine (2). The other amino acids will promote protein synthesis too along with cell volume through intracellular signaling, like leucine does (1p207).

Pretty much because I’ve just eaten (and just worked out), protein synthesis is dominating in my body (1p208) and the high-protein is speeding recovery of my muscles, specifically the whey more than the casein (3;4). About 20 percent of the amino acids going into the liver end up used for protein synthesis (most of what stays in the liver) and nitrogen-containing compounds (like creatine, glutathione, carnitine, carnosine, and choline) (1p198). The other amino acids end up in the plasma (1p198). Some of the amount will be used for purine and pyrimidine bases, which mainly make up DNA and RNA.

Because 40 percent of body protein is in muscle, a lot of activity occurs there (1p223). The muscle catabolizes aspartate, asparagines, glutamate and the branched-chain amino acids to a greater extent (1p223). My muscles are especially liking the content of branched-chain amino acids from the whey (2) that are circulating (1p218). Enzymes in my muscles as well as heart, kidneys, diaphragm, adipose and other organs like the liver transaminate them to be further oxidized into energy or for reamination (1p224).

Glutamine, for example, is generated in the muscle through several pathways (1p226). One such pathway includes transamination of branched-chain amino acids combined with alpha-ketoglutarate to form branched-chain alpha-keto acid and glutamate, then an enzyme combines glutamate with ammonia to form glutamine (1p226). Glutamine synthesis is relatively higher in skeletal muscle, lungs, brain and adipose tissues (1p226).

Creatine, which contains nitrogen from amino acids arginine and glycine with methyl groups donated from methionine, is also functioning in the skeletal muscle for energy (1p226). If not used it doesn’t stay there forever, but leaves the muscle as creatinine to the kidney and is excreted in urine (1p226). I can use the excretion, in fact, as a great indicator of my existing muscle and rate of degradation (1p226).

Along with creatinine, the urine will have nitrogen from urea, amino acids, ammonia and uric acid (1p238). Feces may have amino acids and ammonia too (1p238). A calculation that shows my nitrogen balance—how much protein I consume versus how much nitrogen comes out—can help me measure whether or not my protein intake is adequate and if the quality of my protein is good (1p237). After a high-protein meal the balance may be more likely to be on the side of delivering a positive result.

Reference List

1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Farnfield MM, Trenerry C, Carey KA, Cameron-Smith D. Plasma amino acid response after ingestion of different whey protein fractions. Int J Food Sci Nutr 2008;1-11.
3. Buckley JD, Thomson RL, Coates AM, Howe PR, Denichilo MO, Rowney MK. Supplementation with a whey protein hydrolysate enhances recovery of muscle force-generating capacity following eccentric exercise. J Sci Med Sport 2008.
4. Cribb PJ, Williams AD, Carey MF, Hayes A. The effect of whey isolate and resistance training on strength, body composition, and plasma glutamine. Int J Sport Nutr Exerc Metab 2006;16:494-509.

Should I starve or should I receive bodily injury?

Last week while attempting to meet a deadline at work I skipped lunch and soon enough began hearing my stomach growl. The “hunger hormone” ghrelin, I knew, had kicked in; it would react with the receptors of my hypothalamus to release certain neurotransmitters and my brain would tell me I wanted macronutrients (1p299). Carbs, fats, protein, anything would do. But I didn’t have anything to eat so I thought, “What happens if I starve?”

The answer is pretty straightforward. My body’s insulin would drop while glucagon would rise (1p246). Muscle and fat tissue would also become a bit resistant to insulin (1p246). Protein synthesis would drop (1p246). Glycogen from my liver would start becoming used up and muscles would release a mix of amino acids for gluconeogenesis (stimulating the glucagon) (1p246). The liver would keep my blood sugar level stable (1p246). If I didn’t eat for awhile, then my tissues would keep using fatty acids and glucose, but also start using ketones (from the fatty acid oxidation) for gluconeogenesis too (1p246). This is an important step to limit to conserve body protein, but does increase acidosis (1p246). The body has a way to deal with that too: more glutamine directed to the kidneys produces ammonia that combines with hydrogen ions to make urea for excretion (1p246). Acidosis is corrected and the kidney simply uses the carbon skeleton of glutamine to make glucose (1p246).

Summary of Starvation –

• Glucagon up, insulin down
• Reduced mRNA for translate of proteins
• Protein synthesis drops
• Increased starvation leads to decrease in secretion of glucocorticoids including cortisol
• Few days of fasting or starvation, glycogen is depleted and muscles undergo proteolysis for gluconeogenesis
• As fasting continues, tissues use fatty acids and glucose, but also ketones from fatty acids.
• Decrease in protein catabolism.

Now I value my hard-earned muscle because, frankly, I don’t have much left. The thought of losing some amino acids from my muscle was something I wasn’t too OK about. But the alternative would be to not get my work done on time. If that should happen, I’d be in a load of trouble. In fact, my boss might consider causing me bodily harm. Well, probably not. But it could happen. So I thought, “What would happen if I did end up injured?”


Apart from hurting pretty bad, stress from trauma like from a gun shot wound or burn would cause a bunch of problems. Mainly, it would send hormones in my body into a frenzy; glutocorticoids (primarily cortisol), catecholamines, cytokines, insulin and glucagon would all shoot up (1p246). Unlike starvation, the insulin presence would inhibit use of ketones for energy, thus, leaving me defenseless against muscle wasting (1p246). I’d lose more fast-twitch muscle than slow-twitch muscle (1p247). And yet, because tissues would be resistant to insulin, it would be useless in guarding against hyperglycemia caused partly by elevated cortisol (1p247). The cortisol, in fact, would be promoting the proteolysis (1p247). Cytokines would mediate proteolysis as well as hormonal response (1p247). The cytokines and glucocorticoids are thought to start synthesizing proteins including acute phase reactant and acute phase response proteins that cause fever, further hormonal changes and blood cell count changes (1p247). Other protein synthesis would decrease (1p247). To cope with possible loss of blood or to restore circulation depressed by shock, luckily, I’d have release of aldosterone and antidiuretic hormone to promote renal sodium and fluid reabsorption (1p247).

Summary of Stress –

• Glutocorticoids (primarily cortisol), catecholamines, cytokines, insulin and glucagon all up
• Tissues becomes resistant to insulin and hyperglycemia results
• Cytokines change substrate use
• Cortisol remains elevated causing proteolysis and hyperglycemia
• Cytokines and cortisol thought to increase synthesis of some proteins in liver to modulate body’s response; albumin and transferring to diminish stress
• Release of aldosterone causing sodium and fluid reabsorption and increasing blood volume (helps diminish fluid loss)
• Basal metabolic rate elevated
• Protein catabolism and lipolysis
• Lipolysis does not produce ketones for ketogenesis because of insulin presence and cannot defend against muscle catabolism
• Muscle wasting – white first, then red
• Protein turnover worsened by immune and acute phase responses (fever, etc.)
• Protein degradation exceeds starvation
  

All in all, I prefer starvation over stress. And, thus, I skipped lunch. Turned out to be a good plan: My very nice boss (who wouldn’t hurt a fly) gave me part of her lunch later on.

Reference List

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

Raw or pasteurized

Raw milk and undenatured whey has been claimed to be better for you than their pasteurized and ultra-high-heat treated alternatives. Considering, however, that protein simply becomes denatured anyway in your gut (1), it would hardly make sense to care whether or not it was denatured.

But a French study in the latest J Nutr and other studies explain that when milk protein is exposed to ultra-high heat (but not pasteurization), digestibility and nutritional content due can be affected (2-4). The change occurs not specifically due to denaturation, but due to Maillard reactions (reaction between amino acids and sugars) from heat, production of unusual amino acids such as furosine, and reduced availability of essential amino acids (2-4). Pasteurization resulting in partial denaturation of milk and whey has also been shown to create a biological significance on the bioavailability of nutrients such as folic acid (5).

Still, I fear microbes, so suggest avoiding raw milk. Instead, try low-temp processed milk. Undenatured whey is good because it's filtrated, the cleaner the better for flavor.

Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Lacroix M, Bon C, Bos C et al. Ultra high temperature treatment, but not pasteurization, affects the postprandial kinetics of milk proteins in humans. J Nutr 2008;138:2342-7.
3. Corzo N, Lopez-Fandino R, Delgado T, Ramos M, Olano A. Changes in furosine and proteins of UHT-treated milks stored at high ambient temperatures. Z Lebensm Unters Forsch 1994;198:302-6.
4. Mauron J. Influence of processing on protein quality. J Nutr Sci Vitaminol (Tokyo) 1990;36 Suppl 1:S57-S69.
5. Gregory JF, III. Denaturation of the folacin-binding protein in pasteurized milk products. J Nutr 1982;112:1329-38.

Deamination and transamination

Deamination examples

The amino acid threonine has its amino group removed by threonine dehydratase (1p209). This particular amino acid is commonly deaminated along with glutamate, histidine, serine and glycine (1p209). In the case of thronine, the reaction proceeds with loss of water, which is why the enzyme catalyzing the reaction is called a dehydratase instead of a deaminase (1p209). Vitamin B6 is important for this reaction to occur (1p209). The amino group is used by periportal hepatocytes to synthesize urea (1p209).

Transamination examples

The transfer of an amino groupf from one amino acid to an amino acid carbon skeleton or alpha-keto acid occurs to feed protein synthesis (1p209). The enzymes include tyrosine aminotransferase, branched-chain aminotransferases, alanine aminotransferase, and aspartate aminotransferase (1p209). The enzymes can often require vitamin B6 in a coenzyme form (1p209). The reactions are reversible and are often used to create non-essential amino acids from essential ones except lysine, histidiene and threonine (1p209).

Reference List

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

Emergency contraception and ectopic pregnancy

One of the worst risks of emergency contraception is possible failure leading to ectopic pregnancy. Yes, it can occur, according to Indian researchers from All India Institute of Medical Sciences (1). A case report in 2001 occurred as a result of the use of levonorgestrel (1). For the most part, however, levonorgestrel is considered safe and effective (1).

Reference List
1. Ghosh B, Dadhwal V, Deka D, Ramesan CK, Mittal S. Ectopic pregnancy following levonorgestrel emergency contraception: a case report. Contraception 2009;79:155-7.

Dysmenorrhea news

Endometriosis can ultimately result in causing dysmenorrhea (1). According to Chinese researchers, there has been conflicting reports leading to debate about the actual relationship, but statistical models suggest a stage and site of the endometriotic lesions (1). According to the researchers, there is still variation recognized and further research is needed (1).

Reference List
1. Liu X, Guo SW. Dysmenorrhea: risk factors in women with endometriosis. Womens Health (Lond Engl ) 2008;4:399-411.

Increased Intracranial Pressure

Although its name sounds as though it may occur from studying for a pathophysiology exam, increased Intracranial Pressure (ICP) actually is associated with impaired cerebral venous drainage and reabsorption of cerebrospinal fluid (CSF) (1).

The potential complication can come from a variety of pathologies including central nervous system edema, tumor masses, hematoma, hydrocephalus, venous obstruction and increased CSF volume (1p557-8).

Increased ICP can occur in four stages:

• Stage 1 is a phase of potential danger from one of the complications listed previously.
• Stage 2 is a gradual rise in ICP effectively causing cerebral perfusion to drop and a decrease in oxygenation that stimulates vasoconstriction to increase cardiac output, resulting in lowered consciousness of the patient.
• Stage 3 is the established condition of rapid rise of ICP at a point where it is called the stage of decompensation and autoregulation is lost, resulting in increased blood volume in the brain, hypoxia and cytotoxic edema, which only makes things worse anc causing coma to deepen (1p558). A pattern of apnea for 15-60 seconds followed by deep, labored breathing that eventually becomes shallow and apneic again is called Cheyne-Stokes respiration (1p558). Carbon dioxide accumulation induces the cycled breathing (1p558). Hypoxia and vasoconstriction stretches pressure receptors in carotid arteries signaling the medulla to induce bradycardia (1p558).
• Stage 4 results when cerebral perfusion pressure falls below 30 mm Hg, widespread necrosis begins, and compression of brain stem respiratory centers leads to respiratory arrest and death.

Reference List
1. Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.

Post-32-HyperPsychoProteinuria Stages 1 and 2

When a woman reaches 32 weeks into a first pregnancy, it’s possible that a peculiar syndrome may occur—possibly due to loss of a genetic imprinting in placental tissues (1)—that appears to originate from an implantation abnormality (1). The abnormality causes ischemia in placental blood vessels and could potentially cause a placental infarct, but usually triggers vasoconstrictors to activate fluid retention that causes hypertension (1).

The ischemic placenta also disrupts endothelia causing a predisposition to disseminated intravascular coagulation (1). This blocks microcirculation causing tissue hypoxia and reduced blood flow in the kidney causes albuminuria, which leads to systemic edema (1). The symptoms may be accompanied by headache and vision disruption (2). In addition, the woman may have memory and concentration problems, according to a study published in March (3).

Also, a March-published “revised view” in Placenta also reviews placental stress as leading to the syndrome (4). The study suggests a two-stage model claiming, “it is not only an endothelial disease, but a disorder of systemic inflammation” (4).

The syndrome was previously called toxemia, but wasn’t a good name since no toxins are involved (1). The syndrome is now called preeclampsia referring to late occurrence of convulsions and coma (1). But it could use another name more in line with its symptoms for early detection… Post-32-HyperPsychoProteinuria. And it could be separated into Stage 1 and 2.

Reference List
1. Yu L, Chen M, Zhao D et al. The H19 Gene Imprinting in Normal Pregnancy and Pre-eclampsia. Placenta 2009.
2. Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.
3. Baecke M, Spaanderman ME, van der Werf SP. Cognitive function after pre-eclampsia: an explorative study. J Psychosom Obstet Gynaecol 2009;30:58-64.
4. Redman CW, Sargent IL. Placental stress and pre-eclampsia: a revised view. Placenta 2009;30 Suppl A:S38-S42.

When insulin becomes denatured

Protein denaturation is the unfolding of the secondary or tertiary structures (1). For example, heat can denature proteins in eggs by disrupting hydrogen bonds and non-polar hydrophobic interactions and as a result the egg proteins coagulate during cooking (1). Alcohol, like heat, can also disrupt hydrogen bonds, and acids, bases and heavy metal salts denature proteins by disrupting salt bridges (1).

What are biochemical consequences of denaturation of insulin?

In the body, protein denaturation can affect processes biochemically. Native insulin, for example, in the presence of increased, urea may be denatured because of changes in pH or, in the presence of a thiol catalyst, may be denatured due to isomerization (2). The insulin, thus, is unable to properly cause cells to take up glucose as it should (2).

Reference List
1. Ophardt CE. 2003. “Denaturation of Proteins.” Virtual Chembook. Available at: http://www.elmhurst.edu/~chm/vchembook/568denaturation.html
2. Jiang C, Jui-Yoa Chang. 2005. Unfolding and breakdown of insulin in the presence of endogenous thiols. FEBS Letters, 579;18. Available at: http://www.febsletters.org/article/S0014-5793(05)00720-9/abstract.
3. Chemistry and Biochemistry Department of Ohio University [Web page]. “Proteins.” Available at: http://dwb4.unl.edu/Chem/CHEM869K/CHEM869KLinks/main.chem.ohiou.edu/~wathen/chem302/protein.html

What happens in untreated type 1 diabetes?

Type 1 diabetes is characterized by autoimmune destruction of beta cells in the islets of Langerhans, which results in lack of insulin secretion (1). Glucose, then cannot be taken up by cells leading to hyperglycemia and osmotic diuresis (1). The low insulin will also stimulate hepatic glycogenolysis and gluconeogenesis to produce glucose released into blood leading into accentuated hyperglycemia (1).

What’s more is that gluconeogenesis becomes chronic depleting body proteins to break down into amino acids (1). Muscle,in effect, atrophes converting to glucose and lost through the diuresis (1). Weakness, fatigue and weight loss all occur (1).

Insulin inhibits degradation of protein and increases protein synthesis (2). Opposite to this, lack of insulin creates an environment favoring glucagon leaving degradation of protein unchecked and protein synthesis diminished (2). The degradation occurs by action of proteases—lysosomal or proteosomal—or via the calcium-activated proteolytic degradation pathway (2p234). The increased protein degradation increases nitrogen output resulting in a negative nitrogen balance (2p232).

One example of proteosomal degradation relies on activation of ubiquitin, steps of which are inhibited by insulin (2p208). Insulin also antagonizes activation of a few enzymes—such as the phosphorylation of phenylalanine hydroxylase—responsible for amino acid oxidation (2). The catabolism of amino acids involve transamination or damination (2p209). The amino groups are form alpha-ketobutyrate and ammonia, which must be removed in the urea cycle (2p209).

A mixture of amino acids that is high in alanine and glutamine would be released into the blood (2p246). Alanine, in particular, is a preferred substrate for gluconeogenesis and also stimulates secretion of glucagon, which stimulates gluconeogenesis (2p246).

Deamination/transamination of glycine, serine, cysteine, tryptophan and threonine leaves skeletons oxaloacetate and pyruvate ready for glucose production (2p212). Apart from those, phenylalanine and tyrosine could also be used for glucose when degraded to fumarate (2p212). Valine and methionine are gluconeogenic and isoleucine and threonine are partially glucogenic and partially ketogenic (2p212). Leucine and lycine would not contribute to gluconeogenesis since theyare ketogenic and catabolized to acetyl CoA (2p212).

Because muscle protein provides most of amino acids, particularly in stress situations, muscle cachexia occurs (2p242). The degradation of fast-twitch muscle would be more pronounced than that of the red slow-twitch (2p242). The protein degradation would not be unlike that of starvation with each gram of nitrogen equivalent to 30g of hydrated lean tissue (2p246).

Ketoacidosis is also a logical result. Just as in fasting and starvation, lack of insulin in type 1 diabetes disabling uptake of glucose in cells would lead tissues to use fatty acid oxidation for energy (apart from amino acids) (2p247). Fatty acid oxidation provides energy through production of acetyl CoA, a TCA cycle substrate (2p160). The acetyl CoA use can end up in the "overflow" pathway of ketone body formation (2p160). The ketones would be used as a source of fuel, but in excess can disturb acid-base balance causing acidosis (2p160;2p247).

Reference List
1. Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.
2. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.

When do you need arginine?

Arginine is used for synthesis of protein, agmatine, polyamines and creatine [1]. Because kidneys synthesize arginine usually in sufficient amounts in the urea cycle(releasing 2-4g daily), it's normally not necessary to attain it from the diet [1p196;229].

At times, however, arginine can become conditionally essential [1p229]. Such times would include protein malnutrition, excessive ammonia production, excessive lysine intake, burns, infections, peritoneal dialysis, rapid growth, urea synthesis disorders, or in the inflammatory state of sepsis [2]. A deficiency could result in fatty liver, poor wound healing, hair loss, skin rash and constipation [2].

Arginine is changed into nitric oxide causing blood vessel relaxation [2], which can lower blood pressure. Thus, should not be used by a patient with low blood pressure [3]. If suffering of sickle cell disease, arginine can worsen symptoms [3].

One should exercise caution if supplementing with arginine because the amino acid is known to result in anaphylaxis in patients with certain allergies [3]. Those on anticoagulants should note that arginine can increase risk of bleeding [3]. It can increase potassium levels, especially in liver disease patients [3]. And the amino acid can increase blood sugar levels so may be contraindicated for patients who are trying to control blood sugar levels [3].

Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Mayo Clinic. "Arginine (L-arginine): Background." Available at: http://www.mayoclinic.com/health/l-arginine/NS_patient-arginine.
3. Mayo Clinic. "Arginine (L-arginine): Safety." Available at: http://www.mayoclinic.com/health/l-arginine/NS_patient-arginine/DSECTION=safety.

Hypoparathyroidism

Hypoparathyroidism is not as common as hyperparathyroidism and is characterized by secretion of low levels of parathyroid hormone (1). The disorder can be result of removal of parathyroid glands, the glands’ possible autoimmune destruction, or, in some genetic cases, when the kidney is insensitive to parathyroid output (1).

When low parathyroid hormone occurs, hypocalcemia and hyperphosphatemia can become end results. Symptoms include weakness, mental process alterations and faulty muscular function (1).

Patients with hypoparathyroidism are advised to make dietary changes to increase calcium and avoid phosphorus such as found in many soft drinks (2). Treatment for hypoparathyroidism include dietary supplementation with calcium and vitamin D, which helps the body absorb calcium and get rid of phosphorus (2).

Reference List

1. Nowak TJ, Handford AG. Pathophysiology: Concepts and Applications for Health Professionals. New York: McGraw-Hill, 2004.
2. Mayo Clinic. Hypoparathyroidism. Available at: http://www.mayoclinic.com/health/hypoparathyroidism/DS00952/DSECTION=treatments-and-drugs.

How is urea regulated?

Urea cycle regulation is dependent on dietary factors and hormone concentrations (1). A feed-forward regulation exists in that available ammonia causes more urea to be created (1). This can also mean that higher protein can also act as a feed-forward regulation since it increases urea enzyme levels (1-2). Ammonia can come from diet, from deamination, or bacteria in the GI tract inducing formation of carbamoyl phosphate by mitochondrial carbamoyl phosphate synthetase (1).

Other regulation also exists. First, synthesis of n-acetyl glutamate, which is the allosteric activator of the carbamoyl phosphate synthetase (2). The activator is made in the liver and intestine when stimulated by available arginine (1-2). Second, arginase is inhibited by ornithine and lysine making it able to become rate limiting (1).

Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Lieberman M, Marks A, Smith CM, Marks DB. Marks’ basic medical chemistry, ed 3. Lippincott Williams & Wilkins, 2008.

“Goods” and “bads” of extra protein in sports

While Dietary Reference Intakes for protein are 0.8g protein per kg for adults, data suggest athletes may need more depending on their sport, particularly strength-training athletes (1). Research also indicates that even non-athletes who weight train may benefit from the added protein (2). Endurance exercise sports such as cycling and running increase protein turnover, including a lot more oxidation amino acids, so it is suggested that extra protein would also be wise (3;4).

However, many athletes often exceed intake required (5). While the positive balance may not affect competitiveness, excessiveness does not encourage further muscle growth or strength gain (5). It should also be noted that strength-training itself also encourages improved utilization of dietary protein possibly reducing need of added protein (5). When consumed with carbohydrate, net protein balance during and after endurance exercise is improved, but there is little evidence of actual improved performance due to the extra protein (3). There is also little evidence that the extra protein will stimulate muscle growth or strength (6).

Because daily requirements for protein are set by amount of protein lost, any extra protein should be added to make up for the loss and to maintain nitrogen balance (5). Protein intake that is excessive can lead to potential complications such as in the kidneys (if disease is onset) (7-10) and possible bone fracture if acidosis occurs (11).

Reference List

1. Phillips SM. Dietary protein for athletes: from requirements to metabolic advantage. Appl Physiol Nutr Metab 2006;31:647-54.
2. Evans WJ. Protein nutrition, exercise and aging. J Am Coll Nutr 2004;23:601S-9S.
3. Gibala MJ. Protein metabolism and endurance exercise. Sports Med 2007;37:337-40.
4. Tarnopolsky M. Protein requirements for endurance athletes. Nutrition 2004;20:662-8.
5. Phillips SM. Protein requirements and supplementation in strength sports. Nutrition 2004;20:689-95.
6. Dohm GL. Protein nutrition for the athlete. Clin Sports Med 1984;3:595-604.
7. Pecoits-Filho R. Dietary protein intake and kidney disease in Western diet. Contrib Nephrol 2007;155:102-12.
8. Manninen AH. High-protein diets are not hazardous for the healthy kidneys. Nephrol Dial Transplant 2005;20:657-8.
9. Friedman AN. High-protein diets: potential effects on the kidney in renal health and disease. Am J Kidney Dis 2004;44:950-62.
10. Donini LM, Pinto A, Cannella C. [High-protein diets and obesity]. Ann Ital Med Int 2004;19:36-42.
11. Mardon J, Habauzit V, Trzeciakiewicz A et al. Long-term intake of a high-protein diet with or without potassium citrate modulates acid-base metabolism, but not bone status, in male rats. J Nutr 2008;138:718-24.

Spoonful of any kind of sugar makes the protein go down after exercise

It's clear that carbohydrates with protein affects insulin, thereby inducing glycogen synthesis. However, I was left thinking, “But what kind of carbohydrate is best?” And I found a study that suited my curiosity. One published in 2007 in J Int Soc Sports Nutr showed that 40 subjects who weight trained taking 40g of whey protein were also given 120g of sucrose, honey or maltodextrin (1). After 30 minutes, the honey group showed greatest glucose concentration and best degree of blood glucose maintenance; however, there was really no significant difference and either can be used (1).

Reference List
1. Tipton KD, Elliott TA, Cree MG, Aarsland AA, Sanford AP, Wolfe RR. Stimulation of net muscle protein synthesis by whey protein ingestion before and after exercise. Am J Physiol Endocrinol Metab 2007;292:E71-E76.

Can arginine make you look like Arnold?

Arginine is a precursor for nitric oxide, which relaxes vascular smooth muscle leading to improved blood flow and, thus, the flow of nutrients to muscles (1;2). Oral arginine appears to also stimulate growth hormone release, especially when taken with exercise (3). Supplementation with arginine didn’t increase body mass significantly in a study in 2008; although, when taken with creatine, arginine did improve endurance and power of muscle (2).

Reference List
1. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
2. Little JP, Forbes SC, Candow DG, Cornish SM, Chilibeck PD. Creatine, arginine alpha-ketoglutarate, amino acids, and medium-chain triglycerides and endurance and performance. Int J Sport Nutr Exerc Metab 2008;18:493-508.
3. Kanaley JA. Growth hormone, arginine and exercise. Curr Opin Clin Nutr Metab Care 2008;11:50-4.

Will glutamine give you big guns?

You might think so.

In theory, glutamine supplementation appears to make sense. Supplementation increases plasma glutamine in the plasma (1), which is thought to support the immune system (2;3) because the immune system uses glutamine for energy production (4). Plus, because exercise causes muscles to increase use of glutamine, stores are depleted (4). However, according to a 2001 study showed glutamine does not have any “significant effect on muscle performance, body composition or muscle protein degradation” (5).

Reference List
1. Maughan RJ. Nutritional ergogenic aids and exercise performance. Nutr Res Rev 1999;12:255-80.
2. Williams MH. Facts and fallacies of purported ergogenic amino acid supplements. Clin Sports Med 1999;18:633-49.
3. Nieman DC. Exercise and resistance to infection. Can J Physiol Pharmacol 1998;76:573-80.
4. Gropper SS, Smith JL, Groff JL. Advanced Nutrition and Human Metabolism. Belmont, CA: Thomson Wadsworth, 2009.
5. Candow DG, Chilibeck PD, Burke DG, Davison KS, Smith-Palmer T. Effect of glutamine supplementation combined with resistance training in young adults. Eur J Appl Physiol 2001;86:142-9.