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February 12, 2018

Iron Man: Lab Markers for Iron Deficiency

Iron Deficiency

by Aaron Mello, CNTP, MNT and Dr. Miles Nichols, DAOM, MS, LAc

We wrote in a recent post about functional laboratory testing for anemia. Different forms of anemia result from many different causes, and iron deficiency anemia is the most common form. In this post we’re going to expand on iron dysregulation and some other sequelae of iron deficiency. We’ll also get into markers for iron status that weren’t covered in the anemia post, so keep reading to learn more!

Most of the iron in the body is found in hemoglobin, which is utilized by RBCs to make oxygen transport possible. Much of the remaining iron not utilized by hemoglobin is bound by proteins like transferrin and ferritin because free iron must be tightly regulated to prevent damage. Free iron is extremely reactive and can also be utilized by pathogenic bacteria to proliferate (1).

In this post we’ll go into more detail about iron status markers and iron deficiency, whereas in the previous post on anemia we concentrated more on the RBC section of the CBC. We’ll be focusing on the other side of the coin, iron overload, in an upcoming post. To learn more about how to evaluate iron status and identify iron deficiency, keep reading! We’ll talk about several iron markers, including ferritin, transferrin, serum iron, TIBC, UIBC and iron saturation.

Roles of iron in the body

Let’s begin by talking about how the body utilizes iron in more detail. In our previous post about anemia, we wrote about iron deficiency anemia, which is one of the main consequences of iron deficiency. Other sequelae of iron deficiency we’ll discuss here include heart issues; dry, damaged skin and hair; restless leg syndrome; pica and brittle or spoon-shaped fingernails. Many of these symptoms result from inadequate oxygenation, and as we’ll see from a study we’ll get to shortly, iron deficiency symptoms can be present even without a diagnosis of anemia.

Nitric oxide production is iron-dependent

In addition to negatively impacting the body’s ability to transport oxygen, iron deficiency also reduces the body’s ability to synthesize nitric oxide (NO), which dilates blood vessels. Iron is a necessary cofactor for NO synthesis, so iron deficiency impairs blood vessel dilation is impaired. It’s not just that oxygen can’t be transported, it’s that the flow of blood to peripheral tissues is also impaired due to a lack of NO (2).

Iron necessary for liver detoxification

Iron is not just limited to oxygen transport and utilization. Iron is also a critical nutrient for the function of many cytochrome enzymes, including cytochrome P450 enzymes that are responsible for liver detoxification (2). Consequently, iron deficiency can downregulate phase 1 liver detoxification. Iron also relates to thyroid health, which we wrote about several months ago in a post on Hashimoto’s thyroiditis.

Peroxidase enzymes need iron

Thyroid peroxidase enzyme (TPO) synthesizes thyroid hormone and is dependent on iron. Consequently, thyroid hormone production may fall in iron deficiency. TPO uses hydrogen peroxide (H2O2) to ready iodine for thyroid hormone production. Myeloperoxidase (MPO) is another iron-dependent peroxidase enzyme that controls pathogenic bacteria by producing sodium hypochlorite (NaClO), or bleach, from hydrogen peroxide in order to kill pathogens. MPO malfunction can lead to immune function failure, gut infections and dysbiosis.

Catalase is a third iron-dependent enzyme. It converts hydrogen peroxide (H2O2) to water in order to control levels of H2O2 and prevent cellular and metabolic damage. Free iron that is not bound by a protein can be particularly destructive in the presence of H2O2, with which it can interact to produce dangerous hydroxyl radicals (OH), which causes more damage than just H2O2 or free iron alone (3). It’s easy to see from these examples how far-reaching the roles of iron are.

Like many nutrients, there is a sweet spot for iron levels, and this is doubly true given its role in many metabolic processes, as well as its potential to cause damage. Next we’ll discuss the context of iron deficiency anemia in the larger picture of health before moving on to heme vs non heme iron and some other nutrients required to utilize iron properly.

Anemia is priority

Let’s pause for a second, zoom out and reorient ourselves in the larger picture of health. In challenging patients it can be tempting to sometimes deprioritize anemia and focus on what may appear to be more pressing concerns. Although there may be situations where this is necessary, they are generally few and far between, especially in the chronic disease world. Because nearly every biochemical process in the body is energy dependent – that is – requires ATP, anemia affects every cell with mitochondria and every system in the body.

For this reason it’s often advisable to get the anemia patterns straightened out early on, before moving on to other areas of treatment, unless there is a good reason to start somewhere else first. With that bigger picture in mind, let’s zoom back in and review the importance of heme vs non-heme iron.

Heme vs non-heme iron

One big determining factor for iron intake is the form of iron an individual is consuming. Non-heme iron from vegetarian sources is poorly absorbed and utilized compared to heme iron in meat, especially red meat. This can be an issue for long-term vegans and strict vegetarians, especially those who do not eat any shellfish, which are also a good source of heme iron. Non-heme iron is typically present in an oxidized form, whereas iron needs to be in its reduced form in order to be absorbed (4).

Other factors that affect iron absorption include vitamin C, which increases absorption of non-heme iron by reducing it into more absorbable form (5). Vegetarians who want to increase absorption of plant-based non-heme iron can try consuming with Vitamin C with food. On the other hand, plant foods contain phytates and polyphenols that inhibit iron absorption, so properly soaking seeds and grains before eating is also important to maximize iron absorption.

Calcium also blocks absorption of iron, so calcium-rich foods like spinach and dairy may reduce absorption of iron from iron-rich foods (6). To raise iron levels, concentrate on isolating calcium-rich foods to one meal per day and have another meal that is rich in iron foods like red meat, liver and clams. Now that we’ve covered these factors affecting iron absorption, we’ll next discuss the role copper and vitamin B6 play in iron regulation.

Vitamin B6 and copper

Vitamin B6 and copper affect the body’s ability to absorb and utilize iron. B6 in particular is required to absorb iron. One study on anemic pregnant women treated with iron supplements found that the women who did not initially improve were deficient in B6 and after adding B6 to the iron supplement, anemia improved (7). In addition, both B6 and copper are involved in the utilization of iron to synthesize RBCs.

Copper has a complicated relationship with iron. On the one hand, copper can impede iron absorption by binding to mucosal transferrin at the expense of iron, and excess copper inhibits the ability of spleen reticuloendothelial cells to reuse iron (8). On the other hand, copper is also needed to mobilize sequestered iron from storage tissues. Similar to B6, this can lead to a form of anemia that does not respond to iron supplementation unless copper is also added (9).

It can be worth looking at B6 and copper status and intake in cases of anemia, especially if there are other clues present. Other indicators that copper and B6 may be involved are mood and temperament issues. B6, copper and zinc are required for neurotransmitter synthesis and zinc/copper balance can contribute to aggressive behavior, deficiencies or imbalances in these nutrients may manifest as symptoms of mood, anxiety or temperament (10).

High levels of zinc supplementation for prolonged periods of time without copper supplementation can lead to copper deficiency. This is worth noting for people who supplement with zinc.

Next we’ll talk a bit more about iron deficiency before moving on to related laboratory markers.

Iron deficiency

Iron deficiency is the most common nutritional deficiency worldwide (11). The most prominent consequence of iron deficiency is iron deficiency anemia, which is also the most common form of anemia. Iron deficiency reduces the ability’s body to transport oxygen via iron-containing hemoglobin on RBCs and results in classic anemia symptoms like fatigue, shortness of breath, pale skin and brittle nails.

Although iron deficiency anemia is the main consequence of deficiency, it’s not the only one. We mentioned a study in the introduction about non-anemic iron deficiency. It found that in a population of 198 menstruating women with low ferritin but normal hemoglobin, oral iron supplementation improved fatigue symptoms (12).

Other iron deficiency issues can include:

  • Heart abnormalities like irregular heartbeat, heart palpitations, and in extreme cases enlarged heart, heart murmur or failure
    • When cells are starved of oxygen, the heart must work harder to circulate more RBCs because they can’t carry much oxygen
    • Compounding the issue, the heart itself may lack sufficient oxygen for muscle contractions
  • Dry, damaged skin or hair (13)
    • In a mouse model, reversal of iron deficiency led to a restoration of hair growth
    • Iron deficiency may contribute to hair loss by inhibiting the iron-dependent ribonucleotide reductase enzyme, which is a rate-limiting enzyme for DNA synthesis
    • Hair and skin cell lines both turn over rapidly
  • Restless leg syndrome (RLS)
    • RLS can result from many different causes but iron deficiency is a common cause (14)
    • One study of 251 iron deficiency anemia patients found that RLS was nine times more prevalent in their group than the general population (15)
  • Pica
    • Pica is a condition of craving or eating dirt
    • It can result from many causes, some psychological
    • Iron deficiency pica is characterized by a compulsion to consume iron-containing substances like clay, soil and even small rusty pieces of steel
  • Pagophagia (pica for ice) may also indicate iron deficiency (16)

Because iron plays a central role in transporting and utilizing oxygen to produce ATP, it’s important to resolve iron deficiency and anemia early on in care. Countless critical processes in the body are energy dependent, and if cells are starved for energy they are not going to function properly. In this way, iron deficiency can be central to many diverse health conditions. Next, let’s shift gears and talk in more detail about iron status markers.

Iron status markers

In addition to the anemia markers on the CBC we discussed in our previous post, iron status markers are helpful in cases of suspected iron deficiency anemia or iron overload. In this section we’ll go into more detail about each of the markers and how to use them clinically. As we mentioned earlier, iron is tightly regulated by the body because of its massive reactive potential and the ability of pathogens to use iron to their advantage (17).

In addition, the body has no way to eliminate excess iron other than bleeding and menstruation, so iron status is dependent on two factors – dietary iron intake coupled with how iron is utilized and stored in the body. As mentioned previously, the body strives to keep most iron either in use in hemoglobin or bound to proteins like transferrin and ferritin to prevent free iron ions from creating oxidative stress and encouraging the proliferation of pathogenic bacteria.

With anemia we are looking primarily at cells – RBCs and their components like hemoglobin. These markers are found on a standard CBC.In contrast, the markers on a complete iron panel are not part of a CBC and must be ordered separately to confirm or rule out suspected iron deficiency or overload. We’ll get into each of these iron panel markers in more detail now, as well as a few other markers that can be relevant.

Ferritin: our preferred functional range is 50-150 ng/ml* (Iron Disorders Institute prefers 25-75 ng/ml for those with hereditary hemochromatosis and for anyone levels above 100 ng/ml may indicate an increased disease risk*)

Iron is bound to ferritin to create iron stores in tissues including the liver, spleen and bone marrow. Depressed ferritin may indicate iron depletion, but many factors can affect ferritin and it’s best to view it in the context of a full iron panel. Ferritin sequesters iron in long-term storage to prevent free iron from causing oxidative stress and to make it unavailable to pathogens which will use it for their own growth.

Ferritin on its own without other markers for context can be misleading, as several factors such as oxidative stress and inflammation can elevate ferritin levels. Inflammation can mask iron deficiency and result in a false normal ferritin level. Inflammation can be confirmed by running hsCRP, which we’ll talk about shortly.

Other possible influences on ferritin levels include intake of sulfuraphane (18), milk thistle (19) and green tea extract (20), which can all upregulate ferritin. These products can also lead to anemia by causing the body to store more iron and diverting it away from hemoglobin. Ferritin is also elevated in liver damage, hemochromatosis, neurodegenerative diseases and in response to inflammation.

As we can see, ferritin is impacted by many factors. It also has antioxidant properties, and factors that increase synthesis of glutathione and catalase also increase ferritin because it’s part of the antioxidant defense system (21). Because many biochemical causes can impact ferritin and potentially cancel each other out, it is important to view ferritin in the context of other markers on a complete iron panel, which we will discuss now.

* Cardiovascular and blood sugar disease risk increases with ferritin levels above 100 ng/ml. However, these risks can be mitigated with properly functioning antioxidant defense mechanisms. With properly functioning antioxidant defense, levels of 150 ng/ml or above may be safe.

Transferrin: 

The protein transferrin is largely synthesized in the liver and binds iron for transportation through the blood. In addition to binding iron for transport, transferrin is a major component of iron regulation primarily found in the blood and tissue fluids (22).

Serum transferrin is a somewhat expensive test. We sometimes order TIBC instead, which we’ll talk about shortly, as TIBC can be an indicator of transferrin status. Other factors influencing transferrin include liver disease, which can reduce synthesis, and dietary iron. Transferrin can vary considerably based on the iron content of a person’s last meal, so it needs to be performed with the patient fasting.

Serum iron: 

This is simply the amount of iron in the bloodstream bound to transferrin. It is not the most reliable marker of iron deficiency but it’s a better marker for iron overload like hemochromatosis, especially when combined with iron saturation. We’ll talk more about hemochromatosis in an upcoming post.

TIBC: our preferred functional range is 275-430 ug/dL

Total iron binding capacity (TIBC) measures ability of RBCs to bind to transferrin. TIBC is elevated in iron deficiency, pregnancy and blood loss, and it’s normal in anemia of chronic disease and inflammation. TIBC is depressed in elevated iron loads, liver disease, hypoproteinemia, infection and chronic disease.

UIBC, or unbound iron binding capacity, has an optimal range of 175-350 ug/dL. Lower levels mean higher iron.

Transferrin saturation: our preferred functional range is 17-45% with optimal being 25-35%

Elevated transferrin saturation (TS) stimulates hepcidin, which we’ll talk about next. In turn, hepcidin downregulates iron absorption and increases storage of iron in ferritin. TS is more sensitive than ferritin because TS is what causes ferritin to increase in response to high iron. It’s also more specific to iron status than ferritin, which is influenced by many other factors like inflammation, which we discussed earlier.

Hemoglobin (Hg): 

Hemoglobin is the iron-containing portion of a red blood cell that transports ozxygen from lungs to tissues. Depleted or excessive amounts of hemoglobin can point to imbalanced iron levels.

Mean Corpuscular Volume (MCV):

MCV is a measure of the average volume of red blood cells. Anemias are often referred to in reference to the size of the red blood cell. There is microcytic anemia (low MCV and often is caused by low iron), normocytic anemia (normal MCV), and macrocytic anemia (high MCV – also called pernicious anemia – often caused by low B12 and/or folate levels).

Gamma Glutamyl Tranferase (GGT):

GGT is a liver enzyme that has traditionally been used to primarily look for liver issues. Recently, it has become clear that GGT elevation (even high-normal values) can be associated with increased risk for metabolic syndrome. Levels greater than the lowest 25% of the population are associated with metabolic abnormalities, cardiovascular disease risk, and more.

Hepcidin:

Sometimes referred to as “The Iron Regulatory Hormone,” hepcidin is the master coordinator of iron. High iron hepcidin downregulates iron absorption and directs free iron to be sequestered in ferritin. Hepcidin responds to threats like an infection via inflammation which could use free iron for its own proliferation. Hepcidin also has antimicrobial properties; in fact its name comes from the its location of synthesis, the liver (hep-), and its antimicrobial effects (-cidin) (23).

hsCRP: our functional range is 0-1 mg/L

We talked about hsCRP and inflammation earlier. Inflammation, as measured by high sensitivity C-Reactive Protein (hsCRP) can lead to false normal or even elevated ferritin in the presence of anemia. Anemia of chronic disease results in low absorption and high storage as ferritin, so high ferritin and iron deficiency can exist simultaneously because the small amount of iron that is absorbed is directed into storage instead of hemoglobin synthesis in an effort to sequester it away from pathogenic invaders. hsCRP isn’t an iron marker per se, but it can be useful to confirm or rule out inflammation that may be elevating ferritin.

Now that we have a better understanding of these markers and how to use them to evaluate iron deficiency, let’s review some iron-rich foods before closing. Also be sure to keep an eye out for our upcoming post on iron overload and hemochromatosis.

Iron foods

  • Clams
  • Liver / organ meat
  • Red meat – lamb, beef
  • Prunes
  • Beets
  • Venison
  • Kidney
  • Octopus
  • Oysters
  • Sardines
  • Blackstrap molasses

In Conclusion

Iron is a critical nutrient and iron is the most common deficiency worldwide. Furthermore, iron deficiency anemia is the most common form of anemia, and it impacts every cell of the body because of its role in ATP production. It’s easy to see why resolving iron deficiency is a critical piece for anyone whom is affected by it. Stay tuned for an upcoming post on the other side of the coin from iron deficiency – iron overload and hemochromatosis!

For those low in iron, here are strategies that can help increase iron stores:

  • Make sure low iron is based on lab testing, as iron can be toxic when in excessive quantities
  • Increase iron containing foods (especially those with heme iron like animal products)
  • Add vitamin C with meals (500-1000mg)
  • Contain calcium-containing foods and/or supplements to 1 meal per day (calcium blocks iron absorption)
  • Iron supplementation under the guidance of a functional medicine doctor / practitioner
  • Stop donating blood temporarily until iron stores are back up
  • Avoid chelating substances or protocols intended to chelate metals
  • Be sure you re-test labs so that you know when levels are normal and you can simply maintain
  • If you do not have success with basic practices, see a functional medicine doctor / practitioner to identify root cause issues that might be preventing iron absorption

References

  1. Cassat JE, Skaar EP. Iron in Infection and Immunity. Cell host & microbe. 2013;13(5):509-519. doi:10.1016/j.chom.2013.04.010.
  2. Galleano, M. “Nitric Oxide and Iron: Effect of Iron Overload on Nitric Oxide Production in Endotoxemia.” Molecular Aspects of Medicine, vol. 25, no. 1-2, 2004, pp. 141–154., doi:10.1016/j.mam.2004.02.015.
  3. Kadiiska, Maria B., et al. “A Comparison of Cobalt(II) and Iron(II) Hydroxyl and Superoxide Free Radical Formation.” Archives of Biochemistry and Biophysics, vol. 275, no. 1, 1989, pp. 98–111., doi:10.1016/0003-9861(89)90354-8.
  4. West AR, Oates PS. Mechanisms of heme iron absorption: Current questions and controversies. World Journal of Gastroenterology : WJG. 2008;14(26):4101-4110. doi:10.3748/wjg.14.4101.
  5. Teucher, et al. “Enhancers of Iron Absorption: Ascorbic Acid and Other Organic Acids.”International Journal for Vitamin and Nutrition Research, vol. 74, no. 6, 2004, pp. 403–419., doi:10.1024/0300-9831.74.6.403.
  6. Lynch, Sean R. “The Effect of Calcium on Iron Absorption.” Nutrition Research Reviews, vol. 13, no. 02, 2000, p. 141., doi:10.1079/095442200108729043.
  7. Hisano, M, et al. “Vitamin B6 Deficiency and Anemia in Pregnancy.” European Journal of Clinical Nutrition, vol. 64, no. 2, 2009, pp. 221–223., doi:10.1038/ejcn.2009.125.
  8. Chan, W Y, and O M Rennert. “The Role of Copper in Iron Metabolism.” Annals of Clinical and Laboratory Science, vol. 10, no. 4, 1980, pp. 338–44.
  9. Sharp, Paul. “The Molecular Basis of Copper and Iron Interactions.” Proceedings of the Nutrition Society, vol. 63, no. 04, 2004, pp. 563–569., doi:10.1079/pns2004386.
  10. Walsh, W, et al. “Elevated Blood Copper/Zinc Ratios in Assaultive Young Males1.” Physiology & Behavior, vol. 62, no. 2, 1997, pp. 327–329., doi:10.1016/s0031-9384(97)88988-3.
  11. “Micronutrient Deficiencies.” WHO, World Health Organization, www.who.int/nutrition/topics/ida/en/.
  12. Clenin, G E. “The Treatment of Iron Deficiency without Anaemia (in Otherwise Healthy Persons).” Swiss Medical Weekly, vol. 147, no. 2324, 2017, doi:10.4414/smw.2017.14434.
  13. Guo EL, Katta R. Diet and hair loss: effects of nutrient deficiency and supplement use. Dermatology Practical & Conceptual. 2017;7(1):1-10. doi:10.5826/dpc.0701a01.
  14. Allen, Richard P., and Christopher J. Earley. “The Role of Iron in Restless Legs Syndrome.”Movement Disorders, vol. 22, no. S18, 2007, doi:10.1002/mds.21607.
  15. Allen, Richard P., et al. “The Prevalence and Impact of Restless Legs Syndrome on Patients with Iron Deficiency Anemia.” American Journal of Hematology, vol. 88, no. 4, Dec. 2013, pp. 261–264., doi:10.1002/ajh.23397.
  16. Uchida, T, and Y Kawati. “Pagophagia in Iron Deficiency Anemia.” The Japanese Journal of Clinical Hematology, vol. 55, no. 4, 2014, pp. 436–9.
  17. Nanami, M. “Tumor Necrosis Factor- -Induced Iron Sequestration and Oxidative Stress in Human Endothelial Cells.” Arteriosclerosis, Thrombosis, and Vascular Biology, vol. 25, no. 12, Jan. 2005, pp. 2495–2501., doi:10.1161/01.atv.0000190610.63878.20.
  18. Evans PC. The influence of sulforaphane on vascular health and its relevance to nutritional approaches to prevent cardiovascular disease. The EPMA Journal. 2011;2(1):9-14. doi:10.1007/s13167-011-0064-3.
  19. Hutchinson C, Bomford A, Geissler CA. The iron-chelating potential of silybin in patients with hereditary haemochromatosis. European journal of clinical nutrition. 2010;64(10):1239-1241. doi:10.1038/ejcn.2010.136.
  20. Toolsee NA, Aruoma OI, Gunness TK, et al. Effectiveness of Green Tea in a Randomized Human Cohort: Relevance to Diabetes and Its Complications. BioMed Research International. 2013;2013:412379. doi:10.1155/2013/412379.
  21. Theil EC. Ferritin iron minerals are chelator targets, antioxidants, and coated, dietary iron. Annals of the New York Academy of Sciences. 2010;1202:197-204. doi:10.1111/j.1749-6632.2010.05575.x.
  22. Rouault, Tracey A. “How Mammals Acquire and Distribute Iron Needed for Oxygen-Based Metabolism.” PLoS Biology, vol. 1, no. 3, 2003, doi:10.1371/journal.pbio.0000079.
  23. Rossi E. Hepcidin – the Iron Regulatory Hormone. Clinical Biochemist Reviews. 2005;26(3):47-49.
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December 29, 2017

Diagnosing Anemia with Functional Medicine

anemia

by Aaron Mello, CNTP, MNT and Dr. Miles Nichols, DAOM, MS, LAc

Anemia is a complex and varied condition characterized by low levels of erythrocytes (red blood cells) and hemoglobin. There are many types of anemia. In a recent post on B12 injections, we talked about B12 deficiency anemia. In this post we’ll expand on the anemia piece and talk more about different types of anemia including iron deficiency anemia, hemolytic anemia and sickle cell anemia. We’ll also delve into some of the lab markers that are used to distinguish different types of anemia.

Anemia is a large topic so we’ll get to as much as we can in this post, and expand in future posts. We’ll also touch on ways that anemia can interact with other conditions like Small Intestine Bacterial Overgrowth (SIBO) and chronic inflammation. In addition, we’ll talk about iron and iron deficiency anemia, especially as it relates to vegan and strict vegetarian diets, which are often deficient in heme iron as well as vitamin B12. There is a lot to cover and you’re bound to learn something new, like how B12 analogues from spirulina can actually block B12 absorption! Keep reading to learn more.

Definition of anemia

For a quick recap, anemia is a deficiency of erythrocytes, or red blood cells (RBCs), which transport oxygen to all the cells of the body where it is used to fuel the mitochondria. Erythropoesis, or manufacture of RBCs, takes place in the bone marrow. The RBCs are then transported to the bloodstream where they live for about 120 days in a healthy individual. Depressed hemoglobin levels can also cause anemia.

Generally speaking, most anemia has one of two broad causes:

  1. Decreased production of RBCs and/or hemoglobin
  2. Increased loss or destruction of RBCs, such as a bleeding disorder (1)

RBCs are the most abundant blood cell by far and make up 40-45% of the blood by volume. Even though RBCs live about four months, the body must manufacture an astonishing two million erythrocytes every second to keep up with the equally high rate of RBC destruction. The anatomy of RBCs is highly specialized to provide optimal oxygen transportation abilities.

Symptoms of anemia

Because depressed RBCs negatively affect the body’s ability to fuel its cells with oxygen, many of the symptoms of anemia revolve around difficulty supplying cells with enough oxygen such as low energy levels and shortness of breath.

Symptoms of anemia include: 

  • Fatigue
  • Weakness
  • Pale or yellowish skin
  • Irregular heartbeats
  • Shortness of breath
  • Dizziness or lightheadedness
  • Chest pain
  • Cold hands and feet
  • Headache (1)

Now that we know what anemia is and what the symptoms are, let’s look more in depth at how RBCs carry oxygen and get into more detail about the etiology of anemia, as well as different forms. One of the most important components of RBCs is hemoglobin, which is the iron-containing component of erythrocytes.

Hemoglobin & Iron

Each RBC contains about 280 million hemoglobin molecules and each hemoglobin molecule contains four heme, nonprotein pigments that contain iron ion (Fe2+) which are able to reversibly combine with oxygen molecules, making oxygen transport possible. Hemoglobin also transports about 23% of carbon dioxide, a metabolic waste product, for excretion (2).

Because the iron in hemoglobin binds oxygen for transport by RBCs, a deficiency of iron can lead to iron deficiency anemia, the most common form. We’ll talk about iron-deficiency more shortly. Now that we’ve reviewed relevant erythrocyte anatomy and physiology, let’s move on to the different forms of anemia.

Forms of anemia

Primary or secondary anemia can result from many different causes. In this section we’ll review some of the most common kinds.

Iron deficiency anemia

We touched on this form of anemia earlier. Iron is critical for the manufacture and proper function of RBCs. Iron deficiency primarily results from inadequate intake or absorption, excessive loss through bleeding, or increased iron demand, and it is the most common form of anemia. Individuals eating a strict vegetarian or vegan diet are among the most likely to have inadequate iron intake (3). Iron malabsorption is common with gastric ulcer, parasites, H. pylori infection (4), hypochlorhydria, and in digestive disorders like Crohn’s and celiac disease (5).

Increased iron loss is common in women with heavy menses and in cases of internal bleeding (6). The presence of blood in the stool, especially dried blood that resembles coffee grounds is a strong indication of intestinal bleeding. An occult blood test can also identify blood in the stool that is not visible. When diagnosing iron deficiency anemia, we include more serum markers than with some other forms of anemia, like megaloblastic anemia. An anemia panel for iron deficiency that we use in our clinic includes ferritin, serum iron, UIBC, transferrin saturation, and an CBC w/ differential (at a minimum for comprehensive diagnosis…we sometimes include other markers as well).

Megaloblastic anemia

Megaloblastic anemia is also known as “B12 deficiency anemia” because it is caused by a lack of vitamin B12 and/or folate. Both of these B vitamins are required for erythropoesis, or RBC synthesis. Pernicious anemia (PA) is a common cause of B12 deficiency and megaloblastic anemia, and results from an inability to produce intrinsic factor, which binds to B12 in the stomach and makes absorption in the small intestine possible. PA can also be autoimmune and is confirmed with a positive intrinsic factor antibody blood test. To learn more about megaloblastic anemia, refer back to our recent post on B12 injections.

As we discussed in that post, another common underlying cause of B12 deficiency is a strict vegetarian or vegan diet that does not include any fish or shellfish. Microalgae like spirulina are often believed to contain B12, but instead mostly contain B12 analogues that not only are inactive in the body, they actually block the absorption of usable B12! We don’t recommend spirulina for B12, as it can actually contribute to deficiency by blocking absorption of active B12 (7).

Another interesting aspect of megaloblastic anemia we have observed clinically is a relationship between Small Intestine Bacterial Overgrowth (SIBO) and megaloblastic anemia. It’s fairly well known that SIBO can push B12 low by preventing absorption, and it can also increase folate (8). Some of the SIBO bacteria produce folate, and what we have observed clinically is that sometimes after treating SIBO,  B12 comes back up and folate levels drop, so it can be worth retesting both of these B vitamins after treating SIBO in cases of anemia, as both can change significantly with successful SIBO treatment.

Anemia of chronic inflammation

This type of anemia is secondary to chronic inflammation and is initiated by the activation of inflammatory cytokines like interleuken-6 (IL-6). Anemia that presents with elevated inflammatory cytokines may indicate anemia secondary to inflammation. The spike in cytokines leads to inflammation by several mechanisms:

  • Increases hepatic production and secretion of hepcidin, a peptide which inhibits iron transport and absorption
  • Hepicidin also prevents the stores from being released and utilized
  • Suppresses erythroid precursor proliferation in the bone marrow
  • Inhibits erythropoietin from the kidney
  • Shortens lifespan of RBCs (9)

Chronic disease can also produce a similar type of anemia. Chronically increased WBC production to support an elevated immune response can come at the expense of RBC production and lead to decreased erythropoesis.

Hemolytic anemia

In hemolytic anemia, RBC plasma membranes rupture prematurely and release hemoglobin into the bloodstream. This can overload and damage the glomeruli units in the kidneys that filter blood. Hemolytic anemia can result from many different causes, including inherited defects like altered RBC enzymes, or from exogenous influences like parasites and toxins (10).

Thalassemia is a related group of hereditary hemolytic anemias, which are characterized by deficient synthesis of hemoglobin. In thalassemia, RBCs are small (microcytic), pale (hypochromic) and short-lived. We’ll get into terms for the size and color of RBCs shortly.

Sickle cell disease

Sickle cell anemia is characterized by misshapen RBCs that contain an abnormal kind of hemoglobin and as a result become long, sickle-shaped and unable to carry oxygen. As a result of their abnormal shape, sickle cells rupture easily and die prematurely, resulting in low RBCs. Sickle cells also clump together and can cause blockages in blood vessels (11).

Describing anemic RBCs

Different types of anemia are described in terms of the size and color of the RBCs.

  • Size: 
    • Large – macrocytic
    • Medium – normocytic
    • Small – microcytic
  • Color:
    • High – hyperchromic (or megaloblastic)
    • Medium – normochromic
    • Low – hypochromic

We can see how the types of anemia already discussed can fall into these categories:

  • Mirocytic hypochromic:
    • Iron deficiency
    • Anemia of blood loss
    • Anemia of chronic inflammation / disease
    • Thalassemia
  • Normocytic normochromic:
    • Anemia of chronic inflammation / disease
    • Anemia of acute blood loss
    • Hemolytic anemia
    • Sickle cell
  • Megaloblastic:
    • B12/folate deficiency
    • Pernicious anemia

These distinctions will come into play into the next section on lab testing. One primary way different types of anemia are distinguished from each other is by looking at color and size of the RBCs.

Lab testing for anemia

There are many anemia patterns, as anemia can have many different etiologies. These manifest differently on labwork. Anemia is primarily diagnosed through the RBC section of the Complete Blood Chemistry (CBC). We’ll go over those in this section, discuss some patterns and also a few other markers that can be useful to run.

Anemia in general is identified by depressed RBCs, hemoglobin (HGB) and hematocrit (HCT). From there we look first at Mean Corpuscular Volume (MCV), Mean Corpuscular Hemoglobin (MCH) and Mean Corpuscular Hemoglobin Concentration (MCHC) to begin to distinguish different types. Red Blood Cell Distribution Width (RDW) is also useful, especially when mixed anemia is present.

  • Anemia is defined as:                                                            ideal ranges
    • Low RBCs (below the following ideal range)           (M) 4.4-4.9         (F) 3.9-4.5
    • Low HGB (below the following ideal range)            (M) 14-15 g/dL   (F) 13.5-14.5 g/dL
    • Low HCT (below the following ideal range)            (M) 39-55%        (F) 37-44%
  • MCV looks at cell size:                   defined as
    • Depressed – microcytic          <80 fL
    • Normal – normocytic             80-100 fL
    • Elevated – macrocytic            >100 fL
  • MCH & MCHC look at cell color:            defined as
    • Depressed – hypochromic     MCH <85 pg          MCHC <32 g/dL
    • Normal – normochromic       MCH 85-92 pg      MCHC 32-36 g/dL
    • Elevated – hyperchromic       MCH >92 pg          MCHC >36 g/dL

Let’s look at these markers in a little more detail before moving on to other important anemia markers.

  • RBCs: the absolute number of cells per liter of blood, which if low may indicate deficient synthesis, increased destruction, or excessive blood loss. High RBCs are associated with high altitude, dehydration, bone marrow disorders or renal disorders.
  • Hemoglobin (HGB): The main iron-containing oxygen-transport metalloprotein in RBCs which carries oxygen to the cells and carbon dioxide to the lungs for expiration.
  • Hematocrit (HCT): A measurement of the RBC-containing fraction of whole blood.
  • Mean Corpuscular Volume (MCV): The average volume of an RBC, which is used to distinguish microcytic, normocytic and macrocytic anemia from each other.
  • Mean Corpuscular Hemoglobin (MCH): The average mass of hemoglobin per RBC.
  • Mean Corpuscular Hemoglobin Concentration (MCHC): The average concentration of hemoglobin in the cells. This is used to distinguish between hypochromic, normochromic and megaloblastic (hyperchromic) anemia.
  • Red Blood Cell Distribution Width (RDW): This is a measure of the variation in RBC size. High RDW may indicate a mixed anemia like concurrent microcytic and macrocytic or early stage anemia when there is more variation in the size of RBCs being produced.

Next, we’ll talk about how iron status can impact the presentation of anemia before talking about how to correctly identify and treat the root cause.

Iron markers and disorders

Because of the crucial role iron plays in oxygen transport and anemia, iron disorders overlap with anemia quite a bit. Iron analysis markers are useful in classifying some types of anemia and distinguishing anemia from non-anemia iron disorders. Iron is also essential for erythropoiesis (RBC creation) and DNA synthesis (12). Iron disorders are a large subject all on their own, which we may cover in a future post. We’ll just discuss iron here briefly as it relates to anemia.

Iron-deficiency anemia is a form of microcytic hypochromic anemia characterized by depressed ferritin, serum iron and iron saturation and elevated TIBC and transferrin. There can be many causes of iron-deficiency anemia, many of which involve either reduced iron intake or absorption, or increased blood loss, or both.

Common causes of iron-deficiency anemia:

  • Reduced iron intake:
    • Evaluate diet for iron intake, vegetarian/veganism
    • Heme iron vs non-heme iron
  • Reduced iron absorption:
    • H. pylori
    • Hypochlorhydria
    • Celiac disease
    • Parasites (hookworms, roundworms, pinworms)
  • Increased blood loss:
    • Gastric ulcer
    • Internal bleeding
    • Heavy menses
    • Occult blood in stool

One thing we often see in our office is vegetarians and vegans who are deficient in iron, despite making a concerted effort to eat iron-rich vegetable sources like spinach. Vegetable sources of iron contain non-heme iron, which must be converted into heme iron to be utilized in the body. In contrast, animal sources of iron are much higher in heme iron. One of the best sources is red meat. As we discussed in our previous post on B12 injections, plant foods do not contain B12. Consequently, strict vegans and vegetarians who do not eat any fish or shellfish are at increased risk of B12 deficiency, as well as iron deficiency.

Because iron status is such a large subject on its own, we will continue the iron discussion in a future post with information on iron overload, non-anemia iron deficiency and hereditary hemochromatosis. Now that we’ve covered some of the common markers, let’s emphasize focusing on root-cause diagnosis before putting it all together with some anemia patterns.

What’s the root cause?

As we have seen in many other cases, it’s critical to correctly identify the underlying root cause of anemia. For example, just within the category of iron deficiency anemia, it is important to identify if a person is anemic because of a yet undaignosed H. pylori infection, or the anemia could be secondary to heavy menses that are depleting iron. These are just two of many possible root causes of iron deficiency.

Lab testing to order

The markers we talked about earlier like RBCs, HCT, MCV, MCH, MCHC and RDW are all part of a standard CBC. That is a great starting point. Other important markers to consider are iron status markers like ferritin, serum iron, UIBC, and transferrin saturation if iron deficiency anemia is suspected. We will go into these more in our upcoming post on iron. If, on the other hand megaloblastic anemia is suspected, markers of B12 and folate status are important (such as serum B12, serum folate, RBC folate, homocysteine, Methylmalonic Acid (MMA), and possibly holotranscobalamin if available in your area. Pernicious anemia can be confirmed with a positive intrinsic factor antibody in cases of suspected pernicious anemia.

Getting started

Start with the RBC breakdown on the CBC to determine whether the anemia is micro-, normo- or macrocytic and hypo-, normo- or hyperchromic. Once you’ve identified the type, look at possible underlying causes and order further testing as appropriate, whether it’s a SIBO breath test, an iron panel, inflammatory cytokines or MMA and folate. Getting a serum B12, homocysteine, and ferritin value are also standard orders for nearly every patient in our clinic (on top of a CBC with differential).

If you are vegan or strictly vegetarian, you may need to supplement with vitamin B12, iron, zinc, and possibly other trace minerals (best to check and confirm deficiencies as excessive amounts of some nutrients like iron or zinc can be toxic. B12 is generally considered to be safe with low chances for toxicity even with excessive doses). Some people decide to become vegetarian or vegan for health reasons. While there are conditions that can improve from various diets, vegetarian and vegan diets included, there are times when the health benefits can be exaggerated or the negative health impacts can be ignored. An example is the “What the Health” documentary. This movie has been the subject of several of our patients who have inquired about whether they should be eliminating animal products from their diet.

Unfortunately, this movie does a great job of touching into peoples emotions, but is very poor in citing any well-done, peer-reviewed research (although some people watching it think that it must be valid evidence). It is our professional opinion that the research cited in this movie is of poor quality and that the perspective was biased without considering both sides of the issue. We do not generally recommend vegetarian or vegan diets for health reasons in most cases. However, we completely understand ethical / religious reasons for choosing these kinds of diets and support clients who consciously choose these kinds of diets with recommendations for how to avoid nutrient deficiencies (especially by supplementing with some of the nutrients listed above and choosing certain foods that are rich in nutrients that are commonly deficient). For pescatarians (or vegetarians that are comfortable eating things that do not have faces), clams are a fantastic source of vitamin B12 and iron (plus other minerals). Oysters are the highest source of zinc. Just one or two servings of clams per week can correct some of the nutrient deficiencies that are common in vegetarians / vegans who are willing to eat shellfish.

If you struggle with some or all of:

  • Fatigue
  • Weakness
  • Dizziness
  • Pale skin

Plus you have some of the risk factors like:

  • Vegan diet
  • Excessive bleeding
  • Gastrointestinal (gut) infections
  • Extreme exercise

It is worth getting lab testing from a functional medicine doctor who can assess for functional ranges and help identify the root cause(s) behind anemia or other conditions that can also cause some of the same kinds of symptoms.

Check back soon for our future posts which will expand this information. We’ll get more detailed about iron markers and other anemia patterns.

References

  1. National Institute on Health. “Anemia: Symptoms – National Library of Medicine – PubMed Health.” National Center for Biotechnology Information, U.S. National Library of Medicine, www.ncbi.nlm.nih.gov/pubmedhealth/PMHT0022311/.
  2. Tortora GJ. and Grabowski SR. (1993) Principles of Anatomy and Physiology. Harper Collins College Publishers.
  3. Pawlak R, Lester SE, Babatunde T. The prevalence of cobalamin deficiency among vegetarians assessed by serum vitamin B12: a review of literature. Eur J Clin Nutr. 2014;68(5):541-8.
  4. Ciacci C, Sabbatini F, Cavallaro R, et al. Helicobacter pylori impairs iron absorption in infected individuals. Dig Liver Dis. 2004;36(7):455-60.
  5. Saboor M, Zehra A, Qamar K, Moinuddin. Disorders associated with malabsorption of iron: A critical review. Pakistan Journal of Medical Sciences. 2015;31(6):1549-1553. doi:10.12669/pjms.316.8125.
  6. Moschonis G, Papandreou D, Mavrogianni C, et al. Association of Iron Depletion with Menstruation and Dietary Intake Indices in Pubertal Girls: The Healthy Growth Study. BioMed Research International. 2013;2013:423263. doi:10.1155/2013/423263.
  7. Watanabe F, Katsura H, Takenaka S, et al. Pseudovitamin B(12) is the predominant cobamide of an algal health food, spirulina tablets. J Agric Food Chem. 1999;47(11):4736-41.
  8. Dukowicz AC, Lacy BE, Levine GM. Small Intestinal Bacterial Overgrowth: A Comprehensive Review. Gastroenterology & Hepatology. 2007;3(2):112-122.
  9. Nemeth E, Rivera S, Gabayan V, et al. IL-6 mediates hypoferremia of inflammation by inducing the synthesis of the iron regulatory hormone hepcidin. Journal of Clinical Investigation. 2004;113(9):1271-1276. doi:10.1172/JCI200420945.
  10. Dhaliwal G, Cornett PA, Tierney LM. Hemolytic anemia. Am Fam Physician. 2004;69(11):2599-606.
  11. Dubert M, Elion J, Tolo A, et al. Degree of anemia, indirect markers of hemolysis, and vascular complications of sickle cell disease in Africa. Blood. 2017;130(20):2215-2223.
  12. Wu CJ, Krishnamurti L, Kutok JL, et al. Evidence for ineffective erythropoiesis in severe sickle cell disease. Blood. 2005;106(10):3639-3645. doi:10.1182/blood-2005-04-1376.
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December 11, 2017

Does Acupuncture Really Work? Researched Benefits of Acupuncture

Benefits of Acupuncture

by Aaron Mello, CNTP, MNT and Dr. Miles Nichols, DAOM, MS, LAc

Acupuncture is a treatment that has been used in China for thousands of years. More recently, the practice has become popular in the United States and other Western countries. Despite its long history of use, acupuncture has only begun to be formally researched in the last few decades. Only in the last 10-20 years have researchers begun conducting more rigorous, quality trials to evaluate the benefits of acupuncture. That being said, clearly acupuncture has withstood the test of time and is one of the oldest forms of medicine that has withstood the test of time and remains an important part of medicine not only in China, but all over the world. In addition to research, it is important to also consider longevity of a system because those systems that become outdated and do not work tend to fade away at least out of larger medical systems. The test of time clearly shows that acupuncture is safe and popular. In this blog, we will explore whether it is also proven to be effective from a research-based perspective.

In this blog post we will change gears a bit from some recent posts on herbs and nutraceuticals and review the research and see what benefits of acupuncture are supported by well performed research. Lately we’ve been writing about B12 injections, pyroluria, multitasking and heart health. Acupuncture is a powerful complementary modality that works on an energetic level which can work synergistically with other “physical” approaches like nutrition and herbal remedies.

Acupuncture is effective for a wide range of conditions. In this article we will review research on the benefits of acupuncture for insomnia, neck pain, migraine, low back pain, chronic pain and depression. There are many other conditions acupuncture is used to treat. We use acupuncture extensively in our office. Dr. Diane Mueller, Dr. Miles Nichols, and Dr. Melati Olivia (docs in our clinic) are all Doctors of Acupuncture and Oriental Medicine (in addition to functional medicine). We’re excited that new, better performed research is being performed to bring more understanding to the ancient practice of acupuncture!

A brief history of acupuncture

Acupuncture probably originated in China, possibly as long ago as 6000 BCE – about 8000 years ago. The first known document that describes a system of diagnosis and treatment is the The Yellow Emperor’s Classic of Internal Medicine, which dates back to about 100 BCE. It describes the concept of energy meridians through which Qi flows, a concept which is still found in modern acupuncture. Since that time, acupuncture has continued to evolve.

By the time of the Ming Dynasty (1368 – 1644 AD) these concepts had been consolidated into The Great Compendium of Acupuncture and Moxibustion. This text forms the basis of modern acupuncture. In the 19th century, interest in acupuncture declined and it was outlawed for about 20 years in 1929 on the grounds that it was superstitious. Acupuncture came back into favor when the Communist government rose to power in 1949, and divergent strands of acupuncture and herbal medicine were combined into Traditional Chinese Medicine (TCM), which is how it is known today (1).

How acupuncture works

Acupuncture treatment involves the stimulation of “acupuncture points” with very thin needles which are found along energy meridians in the body. As such, it is an energy-based practice. The TCM philosophy of health revolves around the relationship between Yin and Yang, and Qi and blood. Qi is life force. Without Qi, there would be no life. Qi infusing all living things. Yang represents the active, ascending, subtle, expansive pole of Qi. Yin represents the nurturing, receptive, earthly, restful pole of Qi. Blood is said to be yin and nourishing in nature, serving the function to nourish the cells of the body. Diseases develop when Yin and Yang become out of balance. When this happens, Qi and blood become stagnant and do not flow properly.

The benefits of acupuncture result from balancing energy in the body through the stimulation of acupuncture points, which correspond to major organs of the body. The points are selected by a qualified practitioner after making a diagnosis and treatment strategy. Some Western practitioners propose a different mechanism of action and suggest that acupuncture works by stimulating nerves, muscles and connective tissue, which may in turn increase blood flow and the release of natural endorphins. Regardless of the mechanism, we will be focused mostly on exploring the benefits that research supports from the procedure of acupuncture.

Safety of acupuncture

Acupuncture is generally very safe. The main risks are usually minor and include infection, bleeding, hematoma, pain, and mild bruising. One large German study looked at the incidence of adverse reactions in a cohort of almost 230,000 patients who received an average of about 10 treatments each. In all, 8.6% of patients reported an adverse event and 2.2% of those required treatment (2). Compared to the risks associated with many medications and surgical procedures, acupuncture appears quite safe.

Another large study, this one in Britain, evaluated the number of adverse events in a pool of 34,407 treatments over a four week period. Practitioners were asked to report incidents they considered to be significant, defined as “unusual, novel, dangerous, significantly inconvenient, or requiring further information.” There were no serious adverse events requiring hospital admission, leading to permanent disability or death. A small number of cases, less than 2% reported mild bruising, pain and bleeding at the site of needle placement (3).

The safety of acupuncture is considered to be significant enough for it to be common practice to use acupuncture with women who are pregnant. This is incredibly important because there are many medications and other procedures that have not been shown to be safe during pregnancy. Acupuncture may be one of the best choices for pregnant women to receive relief from pain or other problems that arise during pregnancy. Acupuncture has been time tested with a long history of safe use with pregnancy.

Research is difficult

The benefits of acupuncture are somewhat difficult to study accurately. One main problem is that, unlike many drug and nutritional supplement studies, placebos are difficult to utilize. Patients can easily tell whether a needle is inserted or not, so many studies that attempt to use a placebo utilize what is called “sham acupuncture,” which usually involves needling points that are either not known acupuncture points or points that are unrelated to the condition being treated. Some research has found that “true acupuncture” is no more effective than “sham acupuncture,” which may suggest that the placebo effect may account for most, if not all of the benefit (4).

However, this research is actually doing acupuncture despite trying to look for a placebo effect. In truth, non-meridian points that are used in studies are used in the practice of acupuncture also (acupuncturists will use what are called “ashi” points to needle any area of the body that is painful or might benefit the person). Thus, the argument that acupuncture is ineffective because you can needle non-meridian points to get a similar effect is actually really implicating that acupuncture is effective, just that staying on meridians may not be necessary for that benefit.

Another difficulty is that a double blind structure is nearly impossible to achieve. The acupuncturist administering treatment will know whether the points s/he is needling are valid or “non points,” making bias hard to avoid. It is possible for the treatment to be designed and administered by different acupuncturists if using points irrelevant to the patient’s symptoms or disease. But in this case, there may still be some benefit or effect from needling active points, even if they do not appear to relate directly to a patient’s symptoms or disease etiology. Furthermore, a treatment plan of randomly placed acupuncture points that do not form a coherent treatment would be obvious to most trained acupuncturists, affecting bias.

In addition, acupuncturists are trained to use unique point combinations for each individual (not the same set of points for different people that have the same condition). Much of the research requires needling the same set of points for different people with the same condition which goes against acupuncture training (because there might be several different reasons why a condition arose from acupuncture theory). This makes it difficult to evaluate whether acupuncture for a given condition is effective, as different acupuncturists may be using different approaches and even the same acupuncturist will use a different treatment plan for different patients with the same condition. We of course know that even in Western medicine, similar symptoms may result from much different causes.

Finally, in addition to the above issues, much of the research has been of low quality. There is not an abundance of funding for such research because there are not potential drugs to patent that may result from the research. Consequently, many trials on the benefits of acupuncture have not been well constructed and are subject to bias. With all that being said, there have been some better constructed trials in recent years. This is clearly evidenced by the US Army’s use of acupuncture for pain relief (with significantly lower pain medication use from injured soldiers using acupuncture). Let’s go on next to review the research we do have.

Benefits of acupuncture

In this section we’ll review research which has demonstrated significant benefits of acupuncture for various conditions. We’ll include conditions, symptoms and diseases that are the best researched and focus on meta-analyses, which each include many studies, and often thousands of participants. Meta-analyses are considered the gold standard of research because in addition to including a large sample size, they typically exclude poorly designed studies. We also focus on studies that have a sham acupuncture group because blinding is not possible in research that compares acupuncture to no treatment. In the next section we’ll go through the research we found for each disease or condition.

Insomnia

One fairly large meta-analysis of 46 randomized trails comprising 3811 patients compared the benefits of acupuncture to no treatment, sham acupuncture and sleeping medication. The acupuncture showed a beneficial effect of acupuncture as compared to both no treatment and sham acupuncture. In addition, acupuncture was superior to medications for increasing sleep duration for more than three hours, and provided comparable increases in average sleep duration. Acupuncture plus medication was also superior to medication alone, and no serious adverse effects resulted from acupuncture in the included trials (5).

Neck pain

We found another large meta analysis which included about 10,000 participants with various types of neck pain. The most common conditions evaluated were subacute or chronic neck pain and chronic non-specific neck pain. Researchers evaluated the benefits on several metrics and found that compared to sham acupuncture, real acupuncture was beneficial for reducing pain intensity and disability. This study only looked at short-term outcomes and did not evaluate whether repeated sessions would be successful. This study echoed the safety of the previous one on insomnia and found that adverse were minor, adding also that the treatments were cost-effective (6).

Migraine

A 2016 Cochrane review paper evaluated 22 trials including almost 5000 participants who suffer from migraine and compared acupuncture to no treatment, sham acupuncture and prophylactic drug treatment. Compared to no treatment, acupuncture was associated with a moderate reduction of headache frequency. Compared to sham acupuncture, acupuncture resulted in a small by statistically significant reduction in frequency of headaches. And in the final category, acupuncture reduced migraine frequency significantly more than drug treatment after treatment, but this did not continue at the follow-up session. All the same, the acupuncture groups reported small but significant reductions in headache frequency at three and six months, as compared to the drug treatment groups.

Regarding safety, this meta-analysis on the benefits of acupuncture for migraines also found adverse effects of be rare. The number of adverse effects did not differ significantly between the real acupuncture and sham acupuncture groups. And in the drug treatment comparison groups, acupuncture treatment participants were less likely to report adverse effects and less likely to drop out due to them. The authors conclude that acupuncture results in a small but significant reduction in frequency of migraine headaches compared to sham acupuncture, and that acupuncture may be at least similarly effective to drug treatment (7).

Low back pain

Low back pain is an extremely common problem that most people experience at some point during their life (8). It represents a major problem that is often treated with opiate painkillers, which can lead to addiction over time. The research on the benefits of acupuncture for low back pain is somewhat mixed and many studies cite the prevalence of low quality research. One meta-analysis of 11 RCTs compared acupuncture to NSAIDs and found that “acupuncture may more effectively improve symptoms of acute LBP.” Researchers also noted that acupuncture was more effective at reducing pain than sham acupuncture (8).

Another meta-analysis of 33 RCTs found that acupuncture was significantly more effective than sham treatment at providing short-term relief of chronic back pain (10). Both this study and another found move evidence to support acupuncture for chronic lower back pain than acute (9). Several of the studies cited conflicting results in some cases and an overall low quality of evidence. Hopefully future research will clarify this issue for us.

Chronic pain

The benefits of acupuncture for the treatment of chronic pain is fairly well established. A large JAMA meta-analysis of 29 RCTs comprised of almost 18,000 participants evaluated the effects of acupuncture on four categories of chronic pain – back and neck pain, osteoarthritis, chronic headache and shoulder pain. They found acupuncture to be “superior to both shame and no-acupuncture control for each pain condition.” The effect sizes were similar across all pain conditions. The authors note that although the differences were relatively modest, there was a significant difference between real and sham acupuncture, indicating a clear effect in addition to placebo (10).

Depression

Acupuncture also appears to improve symptoms of depression, and may also reduce side effects of antidepressant medications. One review found that acupuncture is a generally beneficial, well-tolerated and safe way to treat depression (11). Some other studies find conflicting results and have concluded that acupuncture does not provide a clear benefit over sham acupuncture. As an example, a large Cochrane review study failed to find a consistent beneficial effect of acupuncture as compared to sham acupuncture or a wait list.

Interestingly, the authors also noted that most of the included trails found no benefit between acupuncture and antidepressant medication (12). The authors do not appear to attempt to reconcile how medication, an accepted primary treatment for depression, did not differ in efficacy from acupuncture, which they conclude lacks sufficient evidence to support its clinical application. Other research has found that as much as 80% of the benefit of SSRI antidepressants results from the placebo effect (13).

When it comes to depression, the evidence is mixed. Some studies pointed out that depression is hard to treat in general, and that recurrence of symptoms is common. We have had good luck treating depression in our office with acupuncture especially by focusing on a root-cause evaluation. We often think of depression as being a symptom of an upstream root cause and work to identify and treat whatever is leading to the depression.

In conclusion

Research on the benefits of acupuncture is limited and somewhat difficult to perform in a double-blind placebo-controlled manner, which is the gold standard for research at this point. There is a moderate body of research at this point to support the use of acupuncture for the treatment of insomnia, neck pain, migraine, low back pain, chronic pain and depression. It is our hope that more well-devised research studies will continue to illuminate the conditions acupuncture is effective in treating, and provide more detail on which modalities and treatment approaches are the most effective for a given affliction or condition.

Does this mean that acupuncture isn’t good for digestive issues, fatigue, menstrual problems, or infertility? Absolutely not! Lack of ample quality research is not evidence against effectiveness. There are plenty of subjective reports of success with these and more issues. Whether acupuncture helps in a significant way on average for most people remains to be seen. There is some limited research for some of these conditions with positive implications. More research is needed, though, to draw stronger conclusions.

One thing is clear: acupuncture has withstood the test of time and is generally regarded as very safe. For those with conditions not responding to other treatments, acupuncture may be worth a go.

References

  1. A. White, E. Ernst; A brief history of acupuncture, Rheumatology, Volume 43, Issue 5, 1 May 2004, Pages 662–663, https://doi.org/10.1093/rheumatology/keg005
  2. Witt, Claudia M., et al. “Safety of Acupuncture: Results of a Prospective Observational Study with 229,230 Patients and Introduction of a Medical Information and Consent Form.”Complementary Medicine Research, vol. 16, no. 2, 2009, pp. 91–97., doi:10.1159/000209315.
  3. Macpherson, H., et al. “The York Acupuncture Safety Study: Prospective Survey of 34 000 Treatments by Traditional Acupuncturists.” British Medical Journal, vol. 323, no. 7311, Jan. 2001, pp. 486–487., doi:10.1136/bmj.323.7311.486.
  4. Moffet, Howard H. “Sham Acupuncture May Be as Efficacious as True Acupuncture: A Systematic Review of Clinical Trials.” The Journal of Alternative and Complementary Medicine, vol. 15, no. 3, 2009, pp. 213–216., doi:10.1089/acm.2008.0356.
  5. Cao H, Pan X, Li H, Liu J. Acupuncture for Treatment of Insomnia: A Systematic Review of Randomized Controlled Trials. Journal of Alternative and Complementary Medicine. 2009;15(11):1171-1186. doi:10.1089/acm.2009.0041.
  6. Trinh, Kien, et al. “Acupuncture for Neck Disorders.” Cochrane Database of Systematic Reviews, Apr. 2016, doi:10.1002/14651858.cd004870.pub4.
  7. Linde, Klaus, et al. “Acupuncture for the Prevention of Episodic Migraine.” Cochrane Database of Systematic Reviews, 2016, doi:10.1002/14651858.cd001218.pub3.
  8. Lee, Jun-Hwan, et al. “Acupuncture for Acute Low Back Pain.” The Clinical Journal of Pain, vol. 29, no. 2, 2013, pp. 172–185., doi:10.1097/ajp.0b013e31824909f9.
  9. Liu L, Skinner M, McDonough S, Mabire L, Baxter GD. Acupuncture for Low Back Pain: An Overview of Systematic Reviews. Evidence-based Complementary and Alternative Medicine : eCAM. 2015;2015:328196. doi:10.1155/2015/328196.
  10. Vickers, Andrew J., et al. “Acupuncture for Chronic Pain.” Archives of Internal Medicine, vol. 172, no. 19, 2012, p. 1444., doi:10.1001/archinternmed.2012.3654.
  11. Wu, Junmei, et al. “Acupuncture for Depression: A Review of Clinical Applications.” The Canadian Journal of Psychiatry, vol. 57, no. 7, 2012, pp. 397–405., doi:10.1177/070674371205700702.
  12. Smith, Caroline A, et al. “Acupuncture for Depression.” Cochrane Database of Systematic Reviews, 2010, doi:10.1002/14651858.cd004046.pub3.
  13. Kirsch, Irving. “The Emperor’s New Drugs: Medication and Placebo in the Treatment of Depression.” Placebo Handbook of Experimental Pharmacology, 2014, pp. 291–303., doi:10.1007/978-3-662-44519-8_16.

 

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December 11, 2017

10 Recommendations to Maintain Gut Health this Holiday Season

holidays gut health

holidays gut health

It’s no secret that a lot of people let their health habits slip during the holidays. We understand the excitement, stress, and time constraints of this season: Sometimes it’s hard to put your gut health at the forefront. But, neglecting your gut health during the holidays is not a good gift to give yourself. Here are 10 recommendations on how to focus on gut health during the holidays:

1) Continue eating prebiotic foods. Everyone talks about probiotics. Probiotics are important yes, but they cannot survive unless we feed them. The food for the healthy bacteria in our body are called prebiotics. Foods that are prebiotics include lentils, dandelion greens, green bananas, green plantains, onions (can be cooked, but need to still be crunchy), and potatoes (must be cooked and cooled for 24 hours and eaten cold).

2) Pick “treat” days around the holidays. The holidays are a time for a little extra indulgence. In health, our bodies can handle some indulgences. The trouble lies where we start having indulgences on a regular basis. So look at your calendar, pick 1-2 days/week and designate them treat days. Participate in treats on these days and say no the rest of the time. It will help both your gut AND your waist line!

3) Zinc Carnosine: Zinc carnosine is a form of zinc that helps to heal the gut lining and keep the intestinal cells happy.

4) Alcohol: Womens can pretty safely detox one drink/day and men can detox two. Any more than this can impact the health of the gut and can contribute to leaky gut. Therefore, make it your holiday goal not to have more than these recommendations.

5) Since sugar is an unavoidable part of the holiday season, pick healthy sugars. If you are going to a party, make a paleo version of a recipe. Or substitute cookies with buckwheat flour and coconut sugar for healthier versions.

6) Gluten is another food that is hard to avoid around the holidays. Gluten causes leaky gut EVEN in those who are not sensitive or allergic. Therefore, we should all minimize or eliminate gluten even if we do not notice it. Substitute buckwheat flour, cassava flour, coconut flour or other gluten free flours for wheat. The website Paleo Mom has great recipes.

7) No matter how much we plan in advance, the holidays can be stressful. So much family, parties and traveling on top of our normal life activities leave many people pretty exhausted. Make a point to take 10 minutes for yourself every day to practice meditation or a mindfulness based stress activity. UCLA has great free guided meditations that can be found here: http://marc.ucla.edu/mindful-meditations. Put it in your calendar so that you remember!

8) Take an adrenal based product to help with stress around the holidays. See your functional medicine practitioner to know which adrenal product is right for your unique health condition.

9) Make a point to not sacrifice sleep. Work to make things simpler on yourself such as online shopping to help save time. Ask each family member to make one dish at the holiday season to decrease the work load. Be okay if the house is not as clean as you want. Sleep is your best friend to maintaining healthy weight, lower stress levels and a reduced waist line (yes, sleep deprivation is associated with diabetes and weight gain).

10) Plan a detoxification for after the holidays. There are three phases of gut detoxification. While most people think of the liver for detoxification, one of these phases exists largely in the small intestine. What does this mean? Your intestine is a detox organ! While the holidays are not a great time to detox, they are a great time to plan to start a detox afterwards to allow the body to heal. At Living Love, we offer easy to follow (non starvation) detox programs.

We work with people all around the country for these! Email service@livinglovecommunity.com for more information and receive a 10% discount if you sign up before December 21st.

Book a 15-min Discovery Phone Call!

 

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November 20, 2017

Got Enough B12? Benefits of B12 Injections

B12 Injections

by Aaron Mello, CNTP, MNT and Dr. Miles Nichols, DAOM, MS, LAc

Vitamin B12 is an essential nutrient that is involved in many crucial functions in the body, and B12 injections are a great way to increase your levels. Do you know if you have enough B12? Consequences of B12 deficiency range from fatigue, vision loss and constipation to neurological problems, psychiatric problems and certain types of anemia. Vitamin B12 is found almost exclusively in animal foods, so long-term vegans and vegetarians are at an elevated risk of deficiency. In addition, absorption of this nutrient from food is a somewhat complex process and may be impaired in some people.

In this blog we’ll review the most important functions of Vitamin B12 in the body, which foods are good sources, what conditions and medications interfere with absorption, how to test for Vitamin B12 deficiency and the researched benefits of B12 injections. Because B12 absorption can be impaired even if you’re eating enough, you may be deficient even if you’re eating B12-rich foods. If you’re deficient in B12 despite eating good food, B12 injections are the most effective way to raise B12 levels. Keep reading to learn about the benefits of B12 injections!

Vitamin B12

Also known as cobalamin, vitamin B12 is an essential water-soluble nutrient that is part of the B complex of vitamins. B12 is more complex than the other B vitamins. The name cobalamin comes from the fact that this vitamin contains cobalt. B12 is the only B vitamin which contains this element. Different forms of cobalamin are available in supplement form, including cyanacobalamin, methylcobalamin, and hydroxocobalamin. Different forms of B12 injections are appropriate depending on an individual’s methylation status. Next, we’ll look at the roles B12 plays in the body.

Functions of vitamin B12

Vitamin B12 is required for many functions in the body. People who get B12 injections often cite increased energy as a primary benefit. One main way B12 improves energy levels is its role in the production of erythrocytes (red blood cells), which carry oxygen to the cells, where it is used to fuel energy-producing mitochondria. B12 deficiency leads to a type of anemia called megaloblastic anemia, which is characterized by depressed numbers of erythrocytes that are also immature and large, or macrocytic. Low levels of erythrocytes impair the body’s ability to supply cells with sufficient oxygen, resulting in anemic fatigue.

In addition to helping synthesize erythrocytes, Vitamin B12 is also used for:

  • DNA synthesis
  • Converting homocysteine to methionine
  • Neurotransmitter function
  • Synthesis of hormones
  • Producing the myelin sheath that coats nerves
  • Fetal development during pregnancy (1)

These are just some of the most important known functions of B12 and is certainly not an exhaustive list. Now that we know some of the critical functions of B12 in the body, let’s go on to symptoms of B12 deficiency before getting into the benefits of B12 injections.

Signs and symptoms of B12 deficiency

Because B12 is used for so many processes in the body, there can be many signs and symptoms. Because symptoms can have overlapping causes, these should not be used to diagnose B12 deficiency. With that said, these signs and symptoms may indicate that B12 testing is appropriate.

Here are the main signs and symptoms:

  • Pale or jaundiced skin
  • Weakness and fatigue
  • Peripheral sensation of “pins and needles” in extremities
  • Unsteady gait or trouble balancing
  • Glossitis – red, smooth and swollen tongue
  • Breathlessness or dizziness
  • Disturbed vision
  • Depression and other mood changes

Next, we’ll look at which foods are high in B12.

Food sources of vitamin B12

Vitamin B12 is primarily found in animal foods, so long-term vegans may be at increased risk for B12 deficiency if they are not supplementing or getting B12 injections. One review of 40 studies found that up to 86% of vegans may be deficient in B12 (2). Vegans with low B12 levels may want to consider whether their diet is still serving them. Omnivores may also be deficient, usually due to impaired ability to absorb B12 known as pernicious anemia, which we’ll discuss shortly. We’ll also get into testing to establish whether your B12 levels are adequate.

These foods are best sources of B12:

  • Clam
  • Grass-fed beef liver
  • Sardines
  • Salmon
  • Cod
  • Lamb
  • Oyster
  • Mussels
  • Scallops
  • Shrimp
  • Beef
  • Yogurt
  • Eggs

As you can see, these are all animal and marine sources. The best sources for vegetarians who eat seafood (pescetarians) are shellfish (especially clam), fish like sardines and salmon, eggs and yogurt. Some mushrooms also contain some B12, although it’s disputed whether the amount is significant (3). The same is true for fermented food like tempeh – the bacteria which ferment soybean into tempeh synthesize some B12, but it may be a form that has low affinity for intrinsic factor and is not well absorbed (4).

Consequently, supplementation is especially important for strict vegans. For most people, B12 injections are the best option to raise their B12 levels, whether they vegan, omnivorous or somewhere in the middle. This form bypasses the digestive tract and any problems that may prevent absorption. We’ll talk about absorption problems in the next section.

Inability to absorb B12

Many factors can result in an impaired ability to absorb B12 from food. In contrast to other B vitamins, B12 is more complex and absorption of this nutrient is more complicated. The parietal cells in the stomach secrete hydrochloric stomach acid (hcl) as well as intrinsic factor, which is required to absorb B12. Intrinsic factor binds to B12 and enables its absorption in the small intestine. B12 absorption relies on both intrinsic factor and adequate hcl. Many of the causes of B12 malabsorption are related to impaired hcl and intrinsic factor production.

Some of the most common causes of impaired B12 absorption are:

  • Pernicious anemia – more on this shortly
  • Parasitic infections like fish tapeworm and Giardia lamblia
  • Small Intestine Bacterial Overgrowth (SIBO)
  • Familial factors
  • Hypochlorhydria (low stomach acid)
  • Aging – stomach acid production declines with age
  • Gastrointestinal surgery that removes significant sections of the terminal ileum
  • Digestive disorders like Crohn’s disease or celiac disease
  • Certain medications like oral contraceptives, Metformin, proton pump inhibitors (PPIs) and others (5)

If a person is consuming a reasonable about of B12-rich foods in the diet but B12 levels are still low, this may indicate an issue with B12 absorption. In these cases, oral B12 supplements are unlikely to make much of an impact, as they too must be absorbed in the small intestine. These cases are especially good candidates for B12 injections, since that route of administration bypasses the digestive tract.

If a person is unable to absorb B12, it’s important to treat the root cause for that malabsorption. B12 shots bring levels of this crucial nutrient back up, but they do not resolve the underlying root cause. A B12 deficiency in an individual who’s eating B12-rich foods provides valuable information to indicate an underlying problem. It’s important to work with a qualified functional medicine practitioner to not just correct B12 levels with B12 injections, but also treat the underlying root cause. We’ll go into B12 malabsorption in the next section.

Pernicious anemia

Pernicious anemia (PA) is also known as B12 deficiency anemia, and occurs when the body is unable to absorb B12. We’ve already talked about the role of B12 in anemia and problems with absorption. Pernicious anemia is a common cause of B12 malabsorption and accounts for 20-50% of B12 deficiency in adults. It usually results from an autoimmune attack against either gastric parietal cells which secrete intrinsic factor and hydrochloric acid, or intrinsic factor itself. PA is diagnosed by testing for antibodies against intrinsic factor and/or gastric parietal cells (GPC) (6).

Pernicious anemia was identified in 1855 by Thomas Addison, the English physician best known in the context of Addison’s disease. At that point, PA was often fatal until science discovered that it was a B12 deficiency, hence the name pernicious, which means highly destructive or fatal. Even once the B12 connection was made it was still difficult to treat, as many people with PA are not able to absorb oral B12 supplements or foods high in B12 like liver (7). Happily, today it is easily treated with B12 injections, which bypass the digestive tract.

PA causes a type of anemia known as megaloblastic anemia, which we mentioned briefly earlier. Megaloblastic anemia is a form of macrocytic anemia characterized by large, oversized and immature erythrocytes paired with low overall levels of erythrocytes. Because B12 is required for proper maturation of erythrocytes, a deficiency of this vitamin results in pernicious anemia. Now that we understand the role B12 plays in PA, let’s go on to testing for B12 deficiency.

Testing for B12 deficiency

We use a blood test to diagnose B12 deficiency. In addition to getting serum B12 levels, we also run methylmalonic acid (MMA), which helps to provide more accurate results. The combination of these two markers provides the most accurate picture of B12 levels. MMA is inversely correlated with B12 levels and high MMA levels indicate a B12 deficiency and a need for B12 injections.

B12 is the only cofactor that metabolizes MMA into succinyl-CoA. Consequently, elevated MMA levels indicate there is not enough B12 to make the conversion to succinyl-CoA. MMA is considered a superior marker to serum B12 because that value can change fairly rapidly if B12 has been ingested recently, so B12 by itself can change quickly and be misleading. We like to run both B12 and MMA levels.

Another marker that is useful but not commonly available from US labs is holotranscobalamin II. This marker can detect even early stages of B12 deficiency (stage I and II). MMA detects middle stages, and serum B12 detects later stages. For a functional range on the most common test, we like to see serum B12 at least at 400 pg/ml (evidenced by research and supported in lab ranges in some countries like Japan). We optimally prefer to see 500 pg/ml or higher.

High homocysteine can be an indirect marker / indicator of B12 deficiency. It is also possible that homocysteine can be elevated with low folate or low B6 also. So it is not a guarantee of just B12 since there are other nutrients that can be depleted causing elevated homocysteine levels.

Benefits of B12 injections

If you are deficient in vitamin B12, injections are the most effective way to bring levels back up and alleviate a lot of symptoms. In this section we’ll explain some of the most common benefits.

  • Reduce fatigue:
    • Low B12 levels inhibits production of erythrocytes (red blood cells) and leads to fatigue. Bringing B12 levels back up through injection can significantly improve energy levels.
  • Improve athletic performance:
    • Exercise increases the body’s oxygen needs to fuel the mitochondria. Because B12 deficiency leads to anemia (low erythrocytes) and a reduced ability to carry oxygen to the mitochondria, athletic performance suffers. Bringing B12 levels back up can help improve oxygenation of mitochondria, and as a result, boost athletic performance.
  • Protects the heart by lowering homocysteine:
    • Homocysteine is a recognized risk factor for heart disease. One primary way to reduce homocysteine levels is through a B12-dependent pathway. (8)
    • See also our other recent posts about hawthorn, dan shen and pomegranate, which all support heart health.
  • Prevent cognitive decline associated with dementia:
    • High homocysteine is a risk factor for dementia in addition to heart disease and B12 can lower homocysteine. The benefits directly related to dementia may be limited to those with pernicious anemia who are unable to absorb B12 (9).
  • Reduce symptoms of depression:
    • Depressed patients often have low levels of B12. In addition, B12 and folate are required for S-adenyl methionine (SAMe) production, which donates methyl group that are crucial for proper neurological function (10).
    • We recently wrote about pyroluria, a condition that can cause symptoms of depression, as well as how omega-3s can impact pyroluria.
  • Improve hair, skin and nails:
    • B12 isn’t just used to produce erythrocytes, it’s required for multiple rapidly dividing cell lines including hair, skin and nails. In fact, one common symptoms of B12 deficiency anemia is brittle fingernails (11).
  • Increase sperm count and motility:
    • Vitamin B12 improves semen quality, increases sperm count and improves sperm motility. These benefits probably result from increased reproductive organ functionality, decreased homocysteine toxicity, reduced nitric oxide and reducing oxidative damage to sperm (12).
  • Reduces fetal development problems:
    • B12 is required for proper fetal development and deficiency has been linked to cognitive, motor and growth problems in fetal development (13).
  • Improve B12 deficiency symptoms:
    • We listed symptoms of deficiency earlier, including: Pale or jaundiced skin, weakness and fatigue, peripheral sensation of “pins and needles,” unsteady gait or trouble balancing, glossitis, breathlessness or dizziness and disturbed vision. These all stand to improve after correcting low B12 levels.

In summary

Vitamin B12 is a critical nutrient for many processes in the body, and deficiency can have serious consequences. Some effects of B12 deficiency can result in permanent damage, such as irreversible nerve damage. If you suspect that you may be deficient, it’s important to work with a qualified functional medicine practitioner to properly diagnose the deficiency, correct it with B12 injections and identify what underlying root cause is contributing to the deficiency.

When considering the value of increasing B12 levels:

  • Functional lab testing for serum B12, MMA, Homocysteine, and if possible Holotranscobalamin II can help identify a deficiency
  • Look at dietary sources and for vegans or vegetarians who are willing to have some shellfish, consider a weekly serving or two of clam
  • Consider B12 injections and/or supplementation if there is an absorption issue or if there is a medication being used that is depleting levels
  • Look for methylcobalamin or hydroxocobalamin for supplements and/or injections and avoid cyanocobalamin because of trace amounts of cyanide present in cyanocobalamin
  • Work with a functional medicine practitioner to find underlying root causes for why B12 levels are not sufficient and correct the root causes

References

  1. Black MM. Effects of vitamin B12 and folate deficiency on brain development in children. Food and nutrition bulletin. 2008;29(2 Suppl):S126-S131.
  2. Pawlak, R, et al. “The Prevalence of Cobalamin Deficiency among Vegetarians Assessed by Serum Vitamin B12: a Review of Literature.” European Journal of Clinical Nutrition, vol. 68, no. 5, 2014, pp. 541–548., doi:10.1038/ejcn.2014.46.
  3. Watanabe F, Yabuta Y, Bito T, Teng F. Vitamin B12-Containing Plant Food Sources for Vegetarians. Nutrients. 2014;6(5):1861-1873. doi:10.3390/nu6051861.
  4. O’Leary F, Samman S. Vitamin B12 in Health and Disease. Nutrients. 2010;2(3):299-316. doi:10.3390/nu2030299.
  5. Office of Dietary Supplements. “Vitamin B12.” NIH Office of Dietary Supplements, U.S. Department of Health and Human Services, 24 June 2011, ods.od.nih.gov/factsheets/VitaminB12-Consumer/.
  6. Andres E, Serraj K. Optimal management of pernicious anemia. Journal of Blood Medicine. 2012;3:97-103. doi:10.2147/JBM.S25620.
  7. Chanarin, I. (2000), A history of pernicious anaemia. British Journal of Haematology, 111: 407–415. doi:10.1111/j.1365-2141.2000.02238.x
  8. Verhoef, P., et al. “Homocysteine Metabolism and Risk of Myocardial Infarction: Relation with Vitamins B6, B12, and Folate.” American Journal of Epidemiology, vol. 143, no. 9, Jan. 1996, pp. 845–859., doi:10.1093/oxfordjournals.aje.a008828.
  9. Werder SF. Cobalamin deficiency, hyperhomocysteinemia, and dementia. Neuropsychiatric Disease and Treatment. 2010;6:159-195.
  10. Coppen, Alec, and Christina Bolander-Gouaille. “Treatment of Depression: Time to Consider Folic Acid and Vitamin B12.” Journal of Psychopharmacology, vol. 19, no. 1, 2005, pp. 59–65., doi:10.1177/0269881105048899.
  11. Brescoll, Jennifer, and Steven Daveluy. “A Review of Vitamin B12 in Dermatology.” American Journal of Clinical Dermatology, vol. 16, no. 1, June 2015, pp. 27–33., doi:10.1007/s40257-014-0107-3.
  12. Banihani SA. Vitamin B12 and Semen Quality. Bähler J, ed. Biomolecules. 2017;7(2):42. doi:10.3390/biom7020042.
  13. Pepper, M. Reese, and Maureen M. Black. “B12 In Fetal Development.” Seminars in Cell & Developmental Biology, vol. 22, no. 6, 2011, pp. 619–623., doi:10.1016/j.semcdb.2011.05.005.
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November 18, 2017

The Pyroluria & Omega-3 Paradox

omega-3 & pyroluria

by Aaron Mello, CNTP, MNT and Dr. Miles Nichols, DAOM, MS, LAc

In a recent post we wrote about pyroluria, a genetic condition that is highly implicated in many mental health disorders including depression, anxiety and schizophrenia, as well as addiction and alcoholism. Pyroluria is best known for its tendency to deplete zinc and vitamin B6, which can lead to mood disturbances and inner tension. Although not as widely known, pyroluria also depletes other nutrients.

In this post we will continue the discussion by focusing on the role of omega-3 and omega-6 fatty acids in pyroluria. The omega-3 fatty acids EPA and DHA, mostly commonly found in cold-water fatty fish like salmon, sardines and anchovies are highly touted for their ability to reduce inflammation and positively impact mental health conditions. Omega-3s are now well supported in the research for the treatment of depression and anxiety (1) (2).

But as always, it’s critical to understand the mechanism behind each individual’s symptoms. Many different biochemical causes can lead to symptoms of depression and anxiety, and it’s important to view patients on a case-by-case basis. Pyroluria is a great example of this, because although many depressed and anxious people stand to benefit from increasing their omega-3 consumption if it’s deficient, doing so can actually make some people with pyroluria worse.

Terminology: mauve factor / HPL

As discussed in our previous pyroluria post, the term pyrrole refers to a whole family of chemical compounds. The specific pyrrole implicated in pyroluria is hydroxyhemopyrrolin-2-one (HPL), and researchers are now suggesting that pyroluria be renamed to “mauve factor” or HPL, which is the terminology we’ll use in this post.

Omega-3 and omega-6 balance

Omega-3 and omega-6 fats are both polyunsaturated fatty acids that must remain in balance with each other. It is now well known that the Standard American Diet is often too high in omega-6 fats, which in general tend to be pro-inflammatory, and too low in the anti-inflammatory omega-3 fats EPA and DHA. Mauve factor (pyroluria) adds an extra layer to the story, however, as it can interfere with the synthesis of omega-6 fats.

Without understanding this important caveat, many people who suffer from depression or anxiety supplement with omega-3 fish oil. In some cases, doing so may be counterproductive for people with high mauve / pyroluria. If high mauve is an individual’s underlying root cause, they may unwittingly push the omega-3 and omega-6 ratio too far in favor of omega-3 with high dose supplementation. We’ll see why this is a problem in the next section.

Omega-3s can worsen anxiety

There are reports of omega-3 fish oil actually contributing to symptoms of anxiety in some people. One interesting case study from 2015 relates an instance of a 55-year old man who reports mild panic attacks, general anxiety, shortness of breath and insomnia that result from taking fish oil.

He reports experiencing anxiety and insomnia for several months while taking fish oil supplements, symptoms which he says “largely disappeared” after stopping the fish oil. Several weeks later, he resumed fish oil again and experienced a recurrence of symptoms. After two days, he stopped the fish oil once again and saw his symptoms nearly vanish again. The case study report does not mention mauve factor or pyroluria, so we don’t know whether he was tested or not (3).

This is an area that needs further study. Sadly, there is not a lot of research on high mauve in general, probably because there is no pharmaceutical treatment for the condition. In addition to the case study above, several health websites and online forums report anecdotal cases of fish oil supplements worsening anxiety, such as a comment on this pyroluria blog post by Trudy Scott (4). Of course, these type of anecdotal reports must be taken with a grain of salt if not disregarded entirely, but in the absence of better quality research they are worth mentioning.

To understand why HPL / high mauve can cause low omega-6 fats, let’s look next at the biochemistry of the omega-6 pathway in the body.

Omega-6 fat synthesis

Low levels of omega-6 fats with pyroluria appear to result from a problem with the production of arachidonic acid (AA). This is different from the mechanism behind low vitamin B6 and zinc in high mauve. HPL depletes zinc and B6 by binding to these nutrients, which causes them to be excreted in urine. So it’s not that the omega-6 arachidonic acid is depleted in pyroluria, it’s that its synthesis is inhibited.

This block in AA synthesis appears to result from a problem with delta-6-desaturase, the enzyme which converts the omega-6 precursor linoleic acid into gamma-linoleic acid (GLA), which is then converted into AA. This same enzyme is also required for the synthesis of omega-3 fatty acids, so both omega-3 and -6 PUFA synthesis may be inhibited, but it appears that with high mauve, it’s more common for just the omega-6 eicosanoids to be affected. You can see where the delta-6-desaturase enzyme factors into PUFA synthesis here:

PUFA synthesis pathways

Delta-6 desaturase is required for the synthesis of omega-3 and omega-6 fatty acids

One study from 1986 on schizophrenia proposes a subtype of schizophrenia that is characterized by high linoleic acid, high fasting insulin and elevated urinary pyrroles / HPL. The authors explain this subtype as resulting from blocked delta-6-desaturase, which would yield elevated linoleic acid that is unable to be converted into GLA (5). To understand why the delta-6-desaturase enzyme underperforms, we need to look back at the two nutrients most associated with HPL – zinc and vitamin B6.

Zinc and Vitamin B6

As mentioned previously, zinc and vitamin B6 are the primary nutrients depleted in HPL. The depletion of these nutrients may explain the reduced activity of delta-6-desaturase and resulting deficiency of GLA, arachidonic acid and other downstream omega-6 fatty acids. Both zinc and B6 are cofactors required for the proper function of delta-6-desaturase (6) (7). Reduced omega-6 fatty acid levels may therefore be a secondary deficiency resulting from low zinc and B6.

EPA inhibits omega-6 eicosanoids

It’s interesting to note that EPA itself, a primary constituent of fish oil, inhibits the conversion of arachidonic acid into later stage omega-6 eicosanoids. In addition to zinc and B6 and the role these nutrients play in delta-6-desaturase, EPA itself may be implicated (8). This issue may present different sequelae than issues with D6D, as it comes into play in series 2 prostaglandins, which are synthesized from AA later in the omega-6 pathway than the previous issues. Many of the problems hypothesized to account for schizophrenia related to the omega-6 pathway have to do with prostaglandin E1 (PGE1), a series 1 prostaglandin.

As you can see from the flow chart above, PGE1 is synthesized from DGLA earlier in the pathway from DGLA before the synthesis of arachidonic acid, whereas several other prostaglandins and leukotrienes are synthesized from AA itself. It’s possible that by inhibiting conversion of AA into later stage eicosanoids, EPA may increase levels of other prostaglandins and leukotrienes by increasing levels of AA.

Other omega-6 pathway inhibitors

Alcohol is well known to exacerbate mood issues. Drinking alcohol has also been shown to inhibit both delta-6-desaturase as well as delta-5-desaturase, which catalyzes the conversion of DGLA into AA (9). Consequently, individuals with high mauve and low omega-6 levels would be advised to minimize consumption.

Trans fatty acids inhibit liver D6D activity in animal models and leads to decreased GLA and prostaglandin levels (10).

Fructose has also been shown to depress D6D gene expression in spontaneously hypertensive rats. The rats also had decreased levels ofomega-6 linoleic acid as well as its derivatives. Interestingly, D6D omega-3 gene expression decreased, yet activity of omega-3 D6D increased (11). By decreasing omega-6 D6D activity while increasing omega-3 D6D would lead to omega-3 dominance.

Chronic viral infections may also decrease D6D activity in both the omega-3 and omega-6 pathways. AA and EPA both have antiviral activity, even at low concentrations (12).

Diabetes also inhibits D6D and D5D activity, which is reversed by insulin in rat models (13).

Magnesium deficient rats exhibit decreased D6D activity and a slower conversion of linoleic acid to AA (14).

Now that we know some of the issues that can inhibit the omega-6 pathway and its prostaglandins, let’s move on to more detail about the prostaglandins themselves. Many of the effects of low omega-6 levels are manifested though low levels of its prostaglandins. As mentioned earlier, PGE1 in particular is implicated in schizophrenia.

Prostaglandins and pyroluria

Prostaglandins are classified as eicosanoid hormones and are found in virtually all cells in the body except erythrocytes (red blood cells). They are also involved in platelet activation, vasodilation and constriction and respiration. Other roles include altering glandular secretions, reproductive processes, platelet function and immune response. They also mediate inflammation, fever and pain. NSAIDs work by inhibiting cyclooxygenase (COX), a key enzyme in prostaglandin synthesis (15).

As mentioned earlier, Prostaglandin E1 plays a central role in schizophrenia. It is also relevant to mood disorders and is elevated in mania, the “high” side of bipolar disorder, and low in the depressive state. Another effect of alcohol, which we discussed in the last section, is that consumption stimulates PGE1 while drinking but leads to depressed levels afterwards, contributing to depression (16).

PGE1 also factors into gut health and has been shown to improve intestinal permeability (17). The gut-brain connection and role of intestinal permeability in mood disorders are well established at this point. Because high mauve can interfere with the synthesis of DGLA, which in turn can decrease PGE1, it may contribute to intestinal permeability and secondary symptoms of depression and anxiety.

The many effects of high mauve

As we’ve seen in this post, pyroluria or high mauve is not as simple as a zinc and Vitamin B6 deficiency. There are many other potential sequelae, including inhibited production of omega-6 fatty acids. As a result, PGE1 may be low as well, which has its own consequences for mood. Patients who know about the benefits of omega-3s for depression and anxiety may be supplementing high dose fish oil in an attempt to improve their symptoms. If they have high mauve and don’t know it, they may be unwittingly contributing to their symptoms.

Now that we know how high mauve can affect omega fatty acid balance and some effects of that imbalance, let’s move on to treatment recommendations, supplement recommendations and lab testing.

Treatment recommendations

It’s important to question patients thoroughly about their omega-3 intake from fish oil and cod liver oil as well as food sources like cold-water fish, grass-fed beef, flax seed and walnuts. Weighing benefits against potential issues is key. It can also be useful to question them about when symptoms of anxiety in particular started, how long they’ve been taking fish oil, and whether there is any correlation between the two. Patients may be unaware of the connection.

Supplement recommendations

In addition to the supplement recommendations in our last post, which focus primarily on B6 and zinc, it can be useful to supplement GLA in the form of evening primrose oil (EPO) or borage oil. Another option is to swap out their omega-3 fish oil for a combination product that includes GLA fatty acids as well. If a patient is not already taking adequate zinc and B6 that is the most important area to begin, and getting those levels up may help omega-6 eicosanoids as well because both B6 and zinc are required for proper D6D activity.

Testing options

The most important test when pyroluria, or high mauve is suspected is the urinary pyrrole test which evaluates the presence of HPL in the urine. This is the only way to conclusively diagnose high mauve. This urine test is the best starting point. We like the one from Health Diagnostics Research Institute. A questionnaire like this one by Trudy Scott can also be helpful if you are unsure whether testing is warranted. The questionnaire can also help with buy-in from the patient, as they can see how high their score is.

Another test that’s worth considering is an essential fatty acid test like the Essential & Metabolic Fatty Acid Analysis by Genova. This test reveals levels of omega-3 and omega-6 fatty acids in the blood and can help to identify whether they are out of balance. Another good option is a micronutrient test that looks at levels of zinc and B6 like the Vibrant Wellness Micronutrient Test. It’s also wise to compare zinc and copper levels as the two need to remain in a certain ratio with each other.

In summary

In this post we’ve explored how pyroluria, or high mauve can affect fatty acid balance and potentially lead to low levels of omega-6 fats. We also examined how low levels of these eicosanoids can also affect prostaglandins like PGE1, and how that may contribute to symptoms of depression, anxiety and even schizophrenia. If you have patients with pyroluria who have made incomplete recovery even after supplementing with zinc and B6, it may be worthwhile to look at omega-6 eicosanoids and PGE1. That may be the missing piece!

Ideas for those who have tested for or strongly suspect high mauve / HPL:

  • Cover the bases with zinc and vitamin B6 (see previous post for more details)
  • Limit supplementation with fish oil and moderate cold-water fatty fish intake*
  • Add GLA from evening primrose oil
  • Limit or eliminate alcohol intake
  • Add magnesium glycinate, taurate, and/or l-threonate (total of 400-1000mg daily)
  • Limit fructose consumption (aside from a moderate amount of whole phytonutrient-rich fruits)
  • Test for chronic viral infections and work with a functional medicine practitioner to resolve them

*Fish oil must be weighed with an understanding of benefits and possible issues. There was great cardiovascular promise from early short-term fish oil studies. Later long-term studies did not show significant benefit. There is some concern with high dose fish oil for long-term use for anyone, not just those with high mauve / HPL. That being said, there is of course some anti-inflammatory benefit from a healthy omega 3 : 6 ratio. This must also be considered. In the case of high mauve / HPL, extra attention and care should be taken to observe if a level of omega 3 may be a cause of worsened anxiety and/or depression.

References

  1. Martins, Julian G. “EPA but Not DHA Appears To Be Responsible for the Efficacy of Omega-3 Long Chain Polyunsaturated Fatty Acid Supplementation in Depression: Evidence from a Meta-Analysis of Randomized Controlled Trials.” Journal of the American College of Nutrition, vol. 28, no. 5, 2009, pp. 525–542., doi:10.1080/07315724.2009.10719785.
  2. Bozzatello P, Brignolo E, De Grandi E, Bellino S. Supplementation with Omega-3 Fatty Acids in Psychiatric Disorders: A Review of Literature Data. Brown L, Rauch B, Poudyal H, eds. Journal of Clinical Medicine. 2016;5(8):67. doi:10.3390/jcm5080067.
  3. Blanchard LB, McCarter GC. Insomnia and exacerbation of anxiety associated with high-EPA fish oil supplements after successful treatment of depression. Oxford Medical Case Reports. 2015;2015(3):244-245. doi:10.1093/omcr/omv024.
  4. Scott, Trudy. “The Anxiety Summit: How Zinc and Vitamin B6 Prevent Pyroluria and Social Anxiety.” everywomanover29, Trudy Scott, 31 May 2016, www.everywomanover29.com/blog/anxiety-summit-how-zinc-vitamin-b6-prevent-pyroluria-social-anxiety/.
  5. Heleniak, E.p., and S.w. Lamola. “A New Prostaglandin Disturbance Syndrome in Schizophrenia: Delta-6-Pyroluria.” Medical Hypotheses, vol. 19, no. 4, 1986, pp. 333–338., doi:10.1016/0306-9877(86)90106-4.
  6. Yary, T., et al. “Omega-6 Polyunsaturated Fatty Acids, Serum Zinc, Delta-5- and Delta-6-Desaturase Activities and Incident Metabolic Syndrome.” Journal of Human Nutrition and Dietetics, vol. 30, no. 4, July 2016, pp. 506–514., doi:10.1111/jhn.12437.
  7. Bordoni, A, et al. “Dual Influence of Aging and Vitamin B6 Deficiency on Delta-6-Desaturation of Essential Fatty Acids in Rat Liver Microsomes.” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 58, no. 6, 1998, pp. 417–420., doi:10.1016/s0952-3278(98)90163-6.
  8. Culp, Brenda R., et al. “Inhibition of Prostaglandin Biosynthesis by Eicosapentaenoic Acid.”Prostaglandins and Medicine, vol. 3, no. 5, 1979, pp. 269–278., doi:10.1016/0161-4630(79)90068-5.
  9. Nervi, Anibal Mario, et al. “Effect of Ethanol Administration on Fatty Acid Desaturation.” Lipids, vol. 15, no. 4, 1980, pp. 263–268., doi:10.1007/bf02535837.
  10. Kinsella, J E, et al. “Metabolism of Trans Fatty Acids with Emphasis on the Effects of Trans, Trans-Octadecadienoate on Lipid Composition, Essential Fatty Acid, and Prostaglandins: an Overview.” American Journal of Clinical Nutrition, vol. 34, ser. 10, 1981, pp. 2307–18.10.
  11. Comte, C., et al. “Effects of Streptozotocin and Dietary Fructose on Delta-6 Desaturation in Spontaneously Hypertensive Rat Liver.” Biochimie, vol. 86, no. 11, 2004, pp. 799–806., doi:10.1016/j.biochi.2004.10.002.
  12. Puri, B K. “Long-Chain Polyunsaturated Fatty Acids and the Pathophysiology of Myalgic Encephalomyelitis (Chronic Fatigue Syndrome).” Journal of Clinical Pathology, vol. 60, no. 2, Feb. 2006, pp. 122–124., doi:10.1136/jcp.2006.042424.
  13. Rimoldi, Omar J., et al. “Effects of Diabetes and Insulin on Hepatic Δ6 Desaturase Gene Expression.” Biochemical and Biophysical Research Communications, vol. 283, no. 2, 2001, pp. 323–326., doi:10.1006/bbrc.2001.4785.
  14. Mahfouz, M. M., and F. A. Kummerow. “Effect of Magnesium Deficiency on Δ6 Desaturase Activity and Fatty Acid Composition of Rat Liver Microsomes.” Lipids, vol. 24, no. 8, 1989, pp. 727–732., doi:10.1007/bf02535212.
  15. Tortora, Gerard J., and Bryan Derrickson. Principles of Anatomy & Physiology. John Wiley & Sons, 2012.
  16. Horrobin DF, Manku MS. Possible role of prostaglandin E1 in the affective disorders and in alcoholism. British Medical Journal. 1980;280(6228):1363-1366.
  17. Empey, L.r., and R.n. Fedorak. “Effect of Misoprostol in Preventing Stress-Induced Intestinal Fluid Secretion in Rats.” Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 38, no. 1, 1989, pp. 43–48., doi:10.1016/0952-3278(89)90146-4.
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October 23, 2017

Myth of Multitasking: How to Be More Efficient

Myth of Multitasking

by Aaron Mello, CNTP, MNT and Dr. Miles Nichols, DAOM, MS, LAc

This post will delve into what is becoming known as “the myth of multitasking.” Multitasking is a feat that is glorified in our culture. As many employers will attest, job applicants often list multitasking as a skill on resumes and job applications. As a culture, we believe that doing lots of things at once makes us very productive. Unfortunately, research is beginning to show that for most people, the opposite is true.

It turns out that multitasking is a fallacy and a misnomer, a feat that is not really possible. Adding insult to injury, attempting to multitask may even be counterproductive, resulting in accomplishing less than we would if we instead focus on one task at a time. In this article we’ll explain why multitasking is a myth and provide recommendations on how to become more productive by focusing on one task at a time.

It’s also important to mention that the research on multitasking of course looks at averages. It is likely that there is a very small percentage of the population whose productivity does not decrease during multitasking. However, for the vast majority of us, focusing on one thing at a time is a likely way to gain more time and increase how productive we are.

The myth of multitasking

Multitasking is defined as “simultaneous performance of two discrete tasks,” or attempting perform multiple tasks at once. We think we’re multitasking when we’re typing an email while talking on the phone, or editing a document during a meeting. By working on multiple tasks at once we feel like we’re being more efficient. But as we’ll see shortly, the opposite appears to be true, hence the phrase “the myth of multitasking.”

In reality, the mind can only focus on one task a time. When we attempt to multitask, what we’re really doing is rapidly switching back and forth between tasks (1). As a result, the brain has to refocus every time we switch from one task to another. The net result is increased strain on the mind and less efficient and accurate work.

The effects of rapid task switching

You might be thinking, so what’s the big deal if we’re not really multitasking, anyway? Even if we’re rapidly switching between tasks instead of truly doing multiple things at once, isn’t that just semantics? Even though it doesn’t roll off the tongue as gracefully as multitasking, surely there is something to be said for rapidly switching tasks!

No so, according to new research. It’s called the myth of multitasking for a reason. It turns out that when we attempt to multitask, rather than doing one thing well we end up doing lots of things poorly. There is a cost associated with rapidly switching tasks known as the switching cost.

The switching cost

A 2003 study looked at how the interruption associated with receiving email messages affected employee productivity. They found that on average, employees checked their email every five minutes, and each time an individual stopped the task at hand to read an email it took an average of 64 seconds to resume the original task after reading and/or responding to the email (2).

Based on these numbers, it’s easy to see how quickly the time consumed by switching tasks can add up. In this study, one minute out of every six was spent getting back on task. Over the course of an eight hour work day, this amounts to more than 90 minutes of lost time! And as email becomes increasingly utilized as a preferred method of office communication, that number only stands to increase.

Accuracy also suffers

In addition to the time lost due to switching between tasks, accuracy and quality of work also suffer when attempting to multitask. When we try to rapidly switch between tasks, our ability to perform either one well suffers (3). This lines up with the general theme of this article, which we’ll expand in the recommendations section below: Pick one thing to do and do it well, rather than trying to multitask. Give up on the myth of multitasking!

You can test this for yourself. Grab a piece of paper and a stopwatch, or the timer on your phone. Write out the 26 letters of the alphabet and then write out the numbers 1 though 26. Note how long it takes you to complete the task. Next, attempt to multitask. Alternate between writing numbers and letters so that you write 1 – A – 2 – B – 3 – C, etc.

What were your times? Most people will be able to complete the monotask exercise of writing numbers and then writing letters faster than the multitask version of alternating between the two. How much faster was the monotask exercise than the multitask version? 10%? 20%? This should give you a sense of how much time you can potentially save by focusing on one task at a time.

What’s your priority?

The word priority first entered the English language in the 14th or 15th century, when it was used to refer to a singular thing (4). A person can have one priority, and everything else is not the priority. In contrast, today we talk about having multiple priorities, plural.

It seems we would do well to revert back to the older, original definition of priority, which referred to one singular task or focus. Because we can really only do one thing at a time, we are doing ourselves a disservice by trying to manage multiple simultaneous priorities. It’s helpful to change our mindset from thinking about “all the things I need to do today” to focusing on one task, one priority. Once that priority is accomplished, we establish a new priority.

If everything is a priority, nothing is

Because we can only do thing at once, we don’t do well with having multiple priorities. We get into trouble when we have the mindset, “these are all the things I have to do today.” This makes it tempting to multitask. As we’ll see shortly, simply changing our mindset a bit can make a big difference.

In the next section, we’ll get into those recommendations. But first, let’s clarify one thing.

When multitasking is an option

You might be thinking the assertion that “multitasking is a myth” isn’t always true. After all, it seems like there are some things people can do simultaneously, and do well. After all, you can carry on a conversation while chopping vegetables, or listen to music while driving. And you’re right. The distinction here is that you can’t concentrate on two things at once.

In the above examples of tasks being performed simultaneously, at least one of the tasks in each scenario is an automated behavior or habit. Once we learn how to drive or chop vegetables, those tasks become automatic and don’t require thinking. In fact, as we learned in a previous post about habit change, they often become so automatic that we do them habitually without thinking and it actually takes concentration to reprogram a habitual behavior.

So to be more accurate, although we can perform multiple behaviors at once as long as at least one is an automated habit, we can’t concentrate on two things at once. With that distinction in mind, let’s move on to the next section in which we’ll discuss how to implement better habits to be more efficient (and accurate) with our time by focusing on one task at once.

The benefits of monotasking

Before we get into how to monotask, or focus on one task at a time, let’s quickly review what you stand to gain by doing so:

  • Increased productivity: Focusing on one task at a time increases efficiency, allowing you to get more done
  • Increased accuracy of work: Multitasking leads to mistakes, whereas monotasking increases accuracy
  • Lower frustration: Trying to multitask is tiring and frustrating, as it’s stressful and difficult to rapidly switch between tasks
  • Feeling more in control: With only one task to focus on, we tend to feel more capable and in control of what we’re doing, rather than living on the defensive being pulled in between tasks
  • Sense of accomplishment: When we accomplish a goal, we complete our priority and have a sense of accomplishment, rather than slowly chipping away at multiple projects and ending the day unclear about whether we’ve accomplished anything at all

How to increase efficiency

It seems like multitasking should increase our productivity, but as we’ve seen, the opposite seems to be true. With the above benefits of monotasking in mind, let’s get into how to implement this in our lives. The good news is that people who are the biggest multitaskers make the biggest improvements when making these changes (2)!

Don’t wear busyness as a badge of honor

Our culture reveres being busy, and that feeds the myth of multitasking. We feel like if we’re busy all the time, we must be doing important work. Taken even further, we may conclude that if we’re doing important work, that must mean we are important. If some part of this rings true for you, it may be an idea worth investigating further.

Take time to refine your goal. Is it to appear busy all the time? Or is it to be productive and efficient so you can accomplish more in a shorter amount of time and thus have more down time? The latter seems like a better goal, especially in our culture of overwork. Free time is a precious commodity many of us would like more of.

Mindful meditation

One proven way to improve focus and concentration is to practice mindful meditation, which we wrote about last week. This can help to clear the mind and focus one’s concentration. Mindful meditation can also help reduce rumination and distraction. People sometimes have trouble prioritizing and establishing what needs to be done first, so they end up trying to multitask and work on multiple things at once.

Taking time to meditate and paying attention to what thoughts and feelings arise can help refine focus and establish a priority. If, for example, you think that writing a contract is your priority but nagging thoughts about another project keep popping into your mind while meditating, that may be a clue that you have not identified your priority accurately.

Establish your priority

Set attainable goals for the day and restrict your “to do” list to a manageable number of tasks, ideally one. Identify the one thing you want to get done that day and make that your priority. You can still have other tasks on your list, such as running errands, but think of them in sequence, not parallel.

Budget your time

To avoid the myth of multitasking, once you’re established your priority and other tasks you may need to accomplish, make a plan for your day. It can also be helpful to limit the time you spend on each task, which helps to make more progress during that time. If you know you only have two hours to work on a project you tend to be more motivated to accomplish as much as possible during that time.

This is a good way to manage multiple projects. Your priority can change during the day. Establish a priority for different time blocks and focus entirely on that priority during that time. Budget time in for potential distractions that may come up during the day like responding to emails and phone calls and limit those activities to those times.

Eliminate distractions

While you’re focused on your priority, eliminate distractions. Put your phone on “do not disturb,” close your email application on your computer, and close out other tabs in your browser not directly related to the task at hand. Close your office door and make your intentions to focus known to others in your office.

Weapons of Mass Distraction

Weapons of Mass Distraction

Allow yourself breaks

Rather than working on a priority for hours on end, establish a window of time during which you will focus 100% and then allow yourself a break. It may feel like you don’t have time to take breaks, but you may be surprised how much more time you have when you focus and accomplish a lot during that time.

Be firm but not inflexible

Hold yourself accountable to your schedule, but allow some flexibility as necessary. If you are simply unable to concentrate on the task at hand, maybe that’s a sign that something needs to change. What role is the myth of multitasking playing in your life? Ask yourself some questions:

  • Is there another task that really should be your priority that keeps popping into your head?
  • Are you having trouble concentrating because you’re hungry?
  • Are your goals unrealistic? Maybe you need to adjust and work for shorter periods of time.
  • Do you need to get out for a short walk and some fresh air?
  • Do you need a meditation break?

Meditate mindfully

A great way to focus and be curious about what is preventing you from focusing is to meditate. We already talked about this earlier in the post. Taking a quick 10 or 20 minute mindful meditation break can go a long way to refocus your concentration and help you uncover what thoughts and feelings may be impeding your efforts.

Work on striking a balance between accountability with your plan and being flexible when you need to. If the plan you’ve made is not working, use that as feedback to adjust your plan for tomorrow.

In conclusion

The research shows that we can’t really multitask and that we’re more productive when we establish a priority and focus on that priority while minimizing distractions and eliminating jumping from one task to another. In order to address the myth of multitasking and make your time more productive and fruitful, concentrate on these tips:

  • Don’t wear busyness as a badge of honor
  • Practice mindful meditation
  • Establish a priority
  • Budget your time
  • Eliminate distractions
  • Allow yourself to take breaks
  • Be firm but not inflexible

With these guidelines in mind you can begin to transform your habits to be more productive and less stressed, and even have more downtime! Sometimes less is more, and this is one such case.

Finally, remember to be patient with yourself. It will take time to implement and tweak new habits in your life, so give yourself time to make these changes and recognize that as you practice, you will continue to improve. If you are a person who multitasks a lot, you stand to make the most improvements but you also have the furthest to go!

References

  1. Rubinstein, Joshua, et al. “Executive Control of Cognitive Processes in Task Switching.”PsycEXTRA Dataset, doi:10.1037/e537272012-189.
  2. Jackson, T., Dawson, R. and Wilson, D., 2003. Reducing the effect of email interuption on employees. International Journal of Information Management, 23(1), pp.55-65
  3. Pashler, Harold. “Dual-Task Interference in Simple Tasks: Data and Theory.” Psychological Bulletin, vol. 116, no. 2, 1994, pp. 220–244., doi:10.1037//0033-2909.116.2.220.
  4. “Priority | Origin and Meaning.” Online Etymology Dictionary, www.etymonline.com/word/priority.
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October 9, 2017

Natural Alternatives to Aspirin for Heart Health

natural_asprin_alternatives

by Aaron Mello, CNTP, MNT and Dr. Miles Nichols, DAOM, MS, LAc

In this week’s post we’ll be discussing natural alternatives to aspirin. Aspirin has been used for more than 100 years as a remedy for pain, and headaches in particular. In more recent years, daily low-dose aspirin was recommended as a way to reduce the risk of heart attack and other cardiovascular events. Because aspirin thins the blood, it shows some benefit in preventing heart attack and stroke by preventing platelet aggregation, especially in atherosclerotic individuals.

However, this therapy has its own risks, and the risks are serious. In addition to the risk of excessive bleeding in the event of an injury, others include gastric ulcer, hearing loss, cerebral bleeding, Crohn’s disease, influenza mortality, Reye syndrome and helicobacter pylori (H. pylori) infection. Fortunately, several natural alternatives are available which provide similar, and sometimes superior, cardiovascular protection.

This blog will focus on the risks associated with regular low-dose aspirin consumption and natural alternatives. So to learn more about natural alternatives to aspirin, keep reading!

History of aspirin

Before we get into the knitty-gritty of aspirin and its alternatives, let’s get a little background info on the history of aspirin. Natural forms of salicylic acid, the active ingredient in modern-day aspirin, have been used for thousands of years. Salicylic acid is most commonly found in the leaves and bark of the willow tree, and is also present in jasmine, beans, peas and clover.

Willow bark has been used at least as far back as the ancient Egyptians, who used it as a remedy for aches and pains. Later, Hippocrates wrote about using willow bark and leaves to relieve pain and fevers. Thousands of years after Hippocrates, French pharmacist Henri Leroux isolated salicylic acid in 1829. By the end of the 19th century, Bayer pharmaceutical corporation had begun distributing acetylsalicylic acid as a powder to physicians. The drug was a hit, and in 1915 Bayer began selling aspirin as over-the-counter tablets (1).

Aspirin for heart attack prevention

Today aspirin is no longer used as widely for pain and fever, as more people now reach for acetomenophin (Tylenol), ibuprofen (Advil) and naproxen (Aleve). But in the 1990s, aspirin found a new use as a preventative treatment for heart attack and stroke prevention. But because of the risks associated with even low-dose aspirin, today this preventative measure is only recommended in certain scenarios when directed by a physician (2). Fortunately, several natural substances confer similar, and sometimes superior protective effects without the risks associated with aspirin!

Risks of aspirin use

Even relatively short-term daily use of aspirin has been demonstrated to result in negative side effects. One 2009 study administered either low-dose aspirin or a placebo daily for 14 days to a group of healthy volunteers and found that 80% of the aspirin group developed small bowel pathology, compared to 20% in the control. The authors specify that the difference between the two groups was not significant but conclude that low-dose aspirin was associated with mild inflammation of the small intestine (3).

Natural alternatives to aspirin

Fortunately, several natural alternatives are readily available that provide comparable, and in some cases superior cardiovascular protection, without the risks associated with aspirin. Most of these substances work by reducing platelet aggregation, or the clumping together of platelets in blood to form a blood clot.

Platelet aggregation can lead to stroke, infarction, or other cardiovascular event and is of particular concern in individuals with atherosclerosis. When atherosclerotic plaque narrows blood vessels, platelet aggregation becomes a larger concern, as narrow blood vessels can more easily become blocked by aggregated platelets.

In the following sections we will present research about specific natural substances that have been demonstrated to reduce risk of cardiovascular events by reducing platelet aggregation and supporting the vascular endothelium.

Pycnogenol

Pycnogenol is a standardized extract of maritime French pine bark that has antioxidative and antiinflammatory effects. It is high in phenolic acids, catechin and taxifolin (4). It is hard to spell but quite effective at reducing cardiovascular risk factors.

One study assessed the effects of Pycnogenol and aspirin on platelet function in cigarette smokers, who are at increased risk of cardiovascular disease and hypertension. There were somewhat conflicting results on study groups that used lower doses of Pycnogenol (100-150mg), with some groups demonstrating reduced platelet aggregation and other not at this dose. But high-dose (200mg) Pycnogenol significantly reduced platelet aggregation, compared to subjects taking 100mg or 150mg.

Impressively, a single dose of 200mg of Pycnogenol remained effective at preventing smoking-induced platelet aggregation for six days! Some other study groups showed benefit from either 100-125mg Pycnogenol or 500mg aspirin, when taken after smoking. Although aspirin conferred a similar benefit, one clear benefit of Pycnogenol was that aspirin significantly increased bleeding time, whereas Pycnogenol did not. This observation led the researchers to conclude that Pycnogenol has an advantageous risk-benefit ratio (5).

Policosanol

Policosanol is a great natural alternative to aspirin. It is a a wax extract primarily made from sugar cane that is known for its ability to reduce blood cholesterol levels without the dangerous side-effects of statin drugs. In addition, policosanol inhibits blood clotting as effectively as aspirin, but without the dangerous side-effects. One study compared the effects of policosanol with aspirin in reducing platelet aggregation in 43 healthy volunteers and found similar benefits.

In this clinical trial, policosanol reduced aggregation induced by adenosine diphosphate (ADP), epinephrine and collagen, whereas aspirin was only effective in reducing collagen- and epinephrine-induced aggregation. Aspirin was more effective at reducing collagen-induced aggregation and less effective than policosanol at reducing epinephrine-induced aggregation. Overall, researchers conclude that policosanol at 20mg/day is as effective as 100mg/day at reducing platelet aggregation (6).

Omega-3 Fish Oil

The omega-3 fatty acids in fish oil are also helpful in reducing platelet aggregation. A 2013 study compared the effects of aspirin monotherapy and combined fish oil and aspirin in type 2 diabetics. Researchers found that the addition of 4g of fish oil per day reduced platelet aggregation more than aspirin alone. This study also observed that the addition of fish oil to aspirin treatment further reduced NF-κB compared to aspirin alone, which may result from the ability of DHA to inhibit NF-κB related signal transduction and activation (7).

Another study evaluated the effects of a much lower dose of fish oil, 640mg/day, on platelet aggregation in two group of subjects – a healthy group and a group with cardiovascular disease (CVD). Platelet aggregation was induced by ADP and adrenaline. In the healthy group, the administration of fish oil significantly reduced platelet aggregation in both models. In the CVD arm of the study, platelet aggregation was also reduced, but not as significantly. The authors suggest that higher dose fish oil may deliver more significant results in CVD patients (8).

Turmeric and Curcumin

Curcumin is a primary constituent of the Ayurvedic spice turmeric, and appears to prevent platelet aggregation as well. An in vitro study found that curcumin inhibited platelet aggregation induced by arachidonate, adrenaline and collagen by modulating eicosanoids. The authors suggest that curcumin’s antiinflammatory effects may result, at least in part, from its effects on eicosanoid biosynthesis (9).

Another similar study found similar results. In this research, curcumin preferentially inhibited platelet aggregation induced by platelet-activating factor (PAF) and arachidonic acid (AA). Much higher concentrations of curcumin were required to reduce platelet aggregation induced by collagen, epinephrine and ADP. In addition, curcumin inhibited A-23187-induced mobilization of intracellular Ca2+ as well as the formation of thromboxane A2 (TXA2) by platelets.

In contrast, curcumin did not inhibit aggregation induced by protein kinase C (PKC) activator phorbol myrsitate acetate. These results lead the authors of the study to suggest that curcumin inhibits PAF- and AA-induced platelet aggregation by reducing TXA2 synthesis and Ca2+ signaling, and that PKC is not involved in its effects (10).

Dark Chocolate

In good news for chocolate lovers, the flavonoids in cocoa powder also appear to inhibit platelet aggregation. One study found that cocoa-rich dark chocolate inhibited platelet aggregation induced by collagen but not ADP in healthy volunteers (11). Another similar study evaluated the effects of dark chocolate in a group of otherwise healthy cigarette smokers. Dark chocolate significantly improved flow-mediated dilation two hours after ingestion, and the benefits lasted six hours.

In addition, total antioxidant status increased significantly after dark chocolate consumption. Endothelial and platelet function both significantly improved compared to the control group. In addition, there were no changes observed in glucose or lipid markers. The authors conclude that the benefits are likely due to the antioxidant properties of cocoa flavonoids (12).

It’s interesting to note that both of these studies on dark chocolate used white chocolate, which contains little to no cocoa, as a control. The first study also included a milk chocolate group, which demonstrated a small but statistically insignificant improvement. These data support the hypothesis that the cocoa flavonoids confer the observed benefits, as dark chocolate is high in cocoa, milk chocolate is significantly lower, and white chocolate has little to no cocoa. In other words, the higher the cocoa content, the more impressive the results, so it’s important to stress that patients not substitute milk or white chocolate for dark.

Dan Shen

This powerful Chinese herb also known as Salvia Miltiorrhiza is well known for its cardiovascular benefits, which we have written about previously. To learn about Dan Shen in more detail, check out our previous post. Here we’ll review the high points of how Dan Shen impacts platelet aggregation.

Animal studies show that Dan Shen inhibits platelet aggregation by inhibiting calcium channel mechanisms (13) (14). In addition, the Tanshinones in Dan Shen reduce cerebral infarction and support the vascular endothelium. Tanshinone also has been shown to inhibit platelet aggregation in piglets by modifying eicosanoid mechanisms (15). Several herbs and plants are great alternatives to aspirin, which we’ll cover next.

Coleus Forskohlii

Coleus Forskohlii is an herb in the mint family that is grown in Nepal, Thailand and India. One of the primary active constituents is known as forskolin, which is a diterpene and a potent cAMP stimulator. In animal studies, forskolin has been demonstrated to reduce platelet aggregation (16), which appears to be due to its ability to activate platelet adenylate cyclase (17).

Peony

Two forms of the peony plant, Paeonia Lactiflor and Paeonia Suffruticosa, both positively impact platelet aggregation and blood coagulation (18). Two paeonia constituents, paeonal and paeoniflorin have demonstrated anticoagulant (19) and antiplatelet effects (20). Furthermore, paeonia suffruticosa inhibits fibrosis and thromboxane A2 (TXA2) activation of platelets (21).

In Conclusion

Several natural substances appear to offer similar benefits to reduce the risk of blood clot, stroke and other cardiovascular events, but without the risks associated with daily aspirin consumption. These options are worth keeping in mind for patients who are concerned about their heart health but are concerned about taking low-dose aspirin every day.

When we recommend supplements for reducing platelet aggregation, we look at the ones we’ve reviewed in this article and see whether there are additional reasons why certain ones of these would have additional benefits for other reasons.

For example, pycnogenol (or grape seed extract, which is similar in its activity) is a strong antioxidant. If we suspect oxidative stress on top of wanting to reduce platelet aggregation, we might recommend 100-200mg pycnogenol per day. We would add to that some 80% or greater dark chocolate since that also has antioxidant activity.

If, on the other hand, someone has signs of inflammation, we might instead recommend curcumin in a highly bio-available form (Theracurmin, Meriva, or BCM-95) and Peony root (especially if there is also pain). We may also use omega 3 fish oil, especially if fish intake is less than 1-2 pounds of cold-water fatty fish per day.

If someone has high cholesterol, we might use policosanol 20mg twice daily and possibly also some curcumin.

When blood flow is poor, we would choose Dan Shen together with pycnogenol or grape seed extract.

If there is low testosterone or a goal of weight loss, we might choose Coleus Forskohlii.

In many cases multiple issues are occurring simultaneously and we prefer to use a combination of some of these supplements together with nutrition, lifestyle, stress-management, and mindfulness practices.

Resources

  1. Landau, Elizabeth. “From a Tree, a ‘Miracle’ Called Aspirin.” CNN, Cable News Network, 22 Dec. 2010, www.cnn.com/2010/HEALTH/12/22/aspirin.history/index.html.
  2. “Can an Aspirin a Day Help Prevent a Heart Attack?” U S Food and Drug Administration Home Page, Office of the Commissioner, 16 Feb. 2016, www.fda.gov/ForConsumers/ConsumerUpdates/ucm390539.htm.
  3. Endo, Hiroki, et al. “Incidence of Small Bowel Injury Induced by Low-Dose Aspirin: A Crossover Study Using Capsule Endoscopy in Healthy Volunteers.” Digestion, vol. 79, no. 1, 2009, pp. 44–51., doi:10.1159/000204465.
  4. Rohdewald, Peter Jörg. “Review on Sustained Relief of Osteoarthritis Symptoms with a Proprietary Extract from Pine Bark, Pycnogenol.” Journal of Medicinal Food, 2017, doi:10.1089/jmf.2017.0015.
  5. Pütter, M., et al. “Inhibition of Smoking-Induced Platelet Aggregation by Aspirin and Pycnogenol.” Thrombosis Research, vol. 95, no. 4, 1999, pp. 155–161., doi:10.1016/s0049-3848(99)00030-4.
  6. Arruzazabala, M.l., et al. “Comparative Study Of Policosanol, Aspirin And The Combination Therapy Policosanol-Aspirin On Platelet Aggregation In Healthy Volunteers.”Pharmacological Research, vol. 36, no. 4, 1997, pp. 293–297., doi:10.1006/phrs.1997.0201.
  7. Block RC, Abdolahi A, Smith B, et al. Effects of Low-Dose Aspirin and Fish Oil on Platelet Function and NF-kappaB in Adults with Diabetes Mellitus. Prostaglandins, leukotrienes, and essential fatty acids. 2013;89(1):9-18. doi:10.1016/j.plefa.2013.03.005.
  8. Mcewen, Bradley, et al. “Effects of Omega-3 Polyunsaturated Fatty Acids on Platelet Function in Healthy Subjects and Subjects with Cardiovascular Disease.” Seminars in Thrombosis and Hemostasis, vol. 39, no. 01, 2013, pp. 025–032., doi:10.1055/s-0032-1333309.
  9. Srivastava, K.c., et al. “Curcumin, a Major Component of Food Spice Turmeric (Curcuma Longa) Inhibits Aggregation and Alters Eicosanoid Metabolism in Human Blood Platelets.”Prostaglandins, Leukotrienes and Essential Fatty Acids, vol. 52, no. 4, 1995, pp. 223–227., doi:10.1016/0952-3278(95)90040-3.
  10. Shah, Bukhtiar H, et al. “Inhibitory Effect of Curcumin, a Food Spice from Turmeric, on Platelet-Activating Factor- and Arachidonic Acid-Mediated Platelet Aggregation through Inhibition of Thromboxane Formation and Ca2 Signaling.” Biochemical Pharmacology, vol. 58, no. 7, 1999, pp. 1167–1172., doi:10.1016/s0006-2952(99)00206-3.
  11. Innes, Andrew J., et al. “Dark Chocolate Inhibits Platelet Aggregation in Healthy Volunteers.”Platelets, vol. 14, no. 5, 2003, pp. 325–327., doi:10.1080/0953710031000123681.
  12. Hermann F, Spieker LE, Ruschitzka F, et al. Dark chocolate improves endothelial and platelet function. Heart. 2006;92(1):119-120. doi:10.1136/hrt.2005.063362.
  13. Park JW1, Lee SH, Yang MK, Lee JJ, Song MJ, Ryu SY, Chung HJ, Won HS, Lee CS, Kwon SH, Yun YP, Choi WS, Shin HS. 15,16-dihydrotanshinone I, a major component from Salvia miltiorrhiza Bunge (Dansham), inhibits rabbit platelet aggregation by suppressing intracellular calcium mobilization. Arch Pharm Res. 2008 Jan;31(1):47-53.
  14. Ning Wang’, Hon-wet Luo’2, Masatake Niwa3, and fang: A New Platelet Aggregation Inhibitor from Salvia miltiorrhiza; Department of Phytochemistry, China Pharmaceutical University Received: Nanjing, Jiangsu, People’s Republic of China; April 25, 1988
  15. Jiang-Qin Liua, Tze-Fun Leea, Margaret Miedzyblockib, Godfrey C.F. Chanc, David L. Bigamb, Po-Yin Cheung; Effects of tanshinone IIA, a major component of Salvia miltiorrhiza, on platelet aggregation in healthy newborn piglets; Journal of Ethnopharmacology Volume 137, Issue 1, 1 September 2011, Pages 44–49
  16. Christenson JT1, Thulesius O, Nazzal MM. The effect of forskolin on blood flow, platelet metabolism, aggregation and ATP release. Vasa. 1995;24(1):56-61.
  17. Siegl AM, Daly JW, Smith JB. Inhibition of aggregation and stimulation of cyclic AMP generation in intact human platelets by the diterpene forskolin. Mol Pharmacol 1982;21:680- 687.
  18. Koo YK1, Kim JM, Koo JY, Kang SS, Bae K, Kim YS, Chung JH, Yun-Choi HS. Platelet anti-aggregatory and blood anti-coagulant effects of compounds isolated from Paeonia lactiflora and Paeonia suffruticosa. Pharmazie. 2010 Aug;65(8):624-8.
  19. Akamanchi, K.g., et al. “Synthesis and In-Vitro Evaluation of Platelet Aggregation Inhibitory Activity of Paeonol and Its Analogues.” Pharmacy and Pharmacology Communications, vol. 5, no. 5, Jan. 1999, pp. 323–329., doi:10.1211/146080899128734910.
  20. Zhu M1, Tang Y, Duan JA, Guo J, Guo S, Su S, Shang E, Qian D, Ding A.
    Roles of paeoniflorin and senkyunolide I in SiWu decoction on antiplatelet and anticoagulation activities. J Sep Sci. 2010 Nov;33(21):3335-40. doi: 10.1002/jssc.201000340.
  21. RR Watson; Complementary and Alternative Therapies and the Aging Population: An Evidence-Based Approach, Academic Press April 28, 2011.
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September 9, 2017

Pyroluria, an Underlying Cause of Mental Illness

Pyroluria

by Aaron Mello, CNTP, MNT and Dr. Miles Nichols, DAOM, MS, LAc

The last several weeks I’ve written a lot about cardiovascular disease, with posts on pomegranate, Dan Shen and hawthorn. This week I’m going to shift gears and cover pyroluria, which is a genetic condition that is characterized by elevated excretion of pyrroles in the urine. If you got your hopes up (as I did) the first time I saw the term “pyroluria” thinking it had something to do with fire, you may be disappointed to learn that the “pyro” part of the name comes from the pyrroles which are excreted in high levels in the urine, not the “pyro” prefix of pyromaniac.

All the same, pyroluria is an interesting condition that is seldom discussed in mainstream medicine or psychiatry, despite the fact that it is associated with many psychiatric conditions and autism. As we’ll see in the coming sections, pyroluria depletes the body of several nutrients required for neurotransmitter production and stable mood, namely Vitamin B6 and zinc. Before I get into the details of how these nutrients become depleted, let me first give a brief history of pyroluria.

History of pyroluria

Pyrroles were first discovered in the urine of schizophrenic patients in 1958 by Dr. Abram Hoffer, who was then a Director of Psychiatric Research in Saskatchewan. He originally called pyrroles “mauve factor” because of the color they stained the paper chromatogram, and termed their presence “malvaria.” Dr. Carl Pfeiffer, a pioneer in the field of orthomolecular psychiatry, later renamed this phenomenon “pyroluria.” As we’ll see shortly, even this name is something of a misnomer. The term “pyrrole” is actually somewhat broad and refers to a family of chemical compounds, including but not limited to mauve factor, the specific substance that is implicated in pyroluria.

In the 1960s, some researchers misidentified mauve factor as a similar but distinct substance, kryptopyrrole. This error was published in a high profile scientific journal in 1969 (1), and was repeated in another article in 1970 (2). Subsequent research with improved technology went on to demonstrate that kryptopyrroles are not found in urine at all (3), and mauve factor is a distinct substance from kryptopyrrole. Furthermore, some researchers have argued that the term “pyrrole” lacks specificity as it refers to a whole family of substances that appear in urine, and pyroluria should be renamed.

What is mauve factor?

If kryptopyrrole is not the substance responsible for pyroluria, what is? Improved technology revealed that mauve factor is actually a substance known as hydroxyhemopyrrolin-s-one (HPL), which is the hydroxylactam of hemopyrrole. The two terms “mauve factor” and “hydroxyhemopyrrolin-2-one” (HPL) refer to the same substance and I will use them interchangeably in this article. Newer research uses these terms to replace “kryptopyrrole,” which was used erroneously in older research, and refers to subjects with elevated HPL as “high-mauve.”

Now that we have our terminology straight, I’ll next review symptoms of high mauve, and then explore possible causes, how to test for high mauve, the consequences of this condition, and finally I’ll conclude with treatment options.

Symptoms of pyroluria / high mauve

Many of the signs and symptoms of pyroluria are symptoms of deficiencies of Vitamin B6 and zinc, as those are primary nutrients depleted by the condition. There are many, and they are admittedly not well studied. Here is a list from a review study on pyroluria (4):

  • Poor dream recall (Vitamin B6)
  • Nail spots (zinc)
  • Stretch marks
  • Pale skin/poor tanning
  • Coarse eyebrows
  • Knee and joint pain
  • Acne
  • Allergy
  • Cold hands or feet
  • Abdominal tenderness
  • Stitch in side
  • Constipation
  • Morning nausea
  • Light/sound/odor intolerance
  • Tremor/shaking/spasms
  • Hypoglycemia/glucose intolerance
  • Obesity
  • Migraine
  • Delayed puberty

  • Amenorrhea/irregular periods
  • Impotence
  • Eosinophilia
  • B6-responsive anemia
  • Attention deficit/hyperactivity
  • Crime and delinquency
  • Substance abuse/alcoholism
  • Stress intolerance
  • Explosive anger
  • Anxiety
  • Pessimism
  • Dyslexia
  • Social withdrawal
  • Depression
  • Paranoia
  • Hallucinations
  • Disordered perception
  • Bipolar disorder
  • Autism

Causes of pyroluria / high mauve

Now that we know some of the possible signs and symptoms of pyroluria, let’s examine possible causes. Today, the causes of elevated HPL remain elusive and largely unknown, although several theories have been presented over the years. High mauve may result from dietary sources, altered heme production, porphobilinogen (PBG),  porphyrins, genetic causes and altered gut bacteria.

  • Dietary sources: Some foods contain pyrrole subunits, and ingestion of large amounts has been proposed to increase HPL. Examples include coffee, tea, cola drinks, chlorophyll, tobacco, tryptophan and Vitamin B12. However, a study evaluating high intake of these foods in psychiatric patients did NOT find an increase in HPL excretion (5).
  • Heme: Dr. Carl Pfeiffer suggested that HPL results from breakdown of heme (6), but research that attempted to produce HPL from heme, bilirubin or bile pigments under laboratory conditions was unsuccessful. Furthermore, large doses of hemoglobin from blood sausage produced no effect on HPL excretion (7).
  • Porphobilinogen (PBG): PBG is a pyrrole involved in porphyrin metabolism and is generated by aminolevulinate (ALA). HPL may be a metabolite of PBG or porphyrins from the heme biosynthetic pathway. One study found that a large dose of ALA did double urinary HPL in one subject (8), but in an in vitro experiment researchers were unable to produce HPL from porphyrins (7).
    • Isocoproporphyrin is a porphyrin that is the most homologous to HPL. It is produced from altered heme biosynthesis (9). Isocoproporphyrins are increased by CPOX polymorphism and toxins like mercury (10) and hexachlorobenzene (11).
    • High-mauve schizophrenics exhibited greater coproporphryin concentrations than other schizophrenics (12). and rats injected with HPL increased urinary coproporphyrins (13).
  • Altered gut bacteria: Production of isocoproporphyrin from altered heme biosynthesis involves activity from gut flora. Oral dosing with antibiotics reversibly abolished or sharply reduced urinary HPL in a small cohort study (14).

Consequences of high mauve

As I mentioned in the introduction, HPL binds certain nutrients and causes them to be excreted in urine, leading to deficiencies. The two main nutrients implicated are zinc and Vitamin B6, which are heavily involved in the production of neurotransmitters. Interestingly, although zinc and Vitamin B6 deficiencies appear to result from high mauve, supplementation with these nutrients also reduce levels of HPL in urine in a “chicken and egg” scenario. Clinicians have reported proportionality between symptom severity and mauve excretion (15).

Prevalence of HPL in mental illness

HPL is highly correlated with many forms of mental illness, including down syndrome, depression, anxiety, schizophrenia, bipolar disorder, substance abuse and autism. Because Vitamin B6 and zinc are both required for the synthesis of neurotransmitters like serotonin and dopamine it’s easy to see how deficiencies of these nutrients can lead to mood issues. Disturbances in these neurotransmitters are implicated in many, if not all of the mental health issues I listed above.

High mauve may account for some of these disturbances by reducing levels of Vitamin B6 and zinc, which in turn leads to disturbances in neurotransmitters. Research has illuminated the prevalence of high mauve in the following mental health disorders:

Diagnosis                              % High Mauve

Down syndrome                              71
Schizophrenia, acute                     59-80
Schizophrenia, chronic                  40-50
Bipolar disorder                             47-50
Depression, non schizophrenic       12-46
Autism                                           46-48
Epilepsy                                          44
ADHD                                              40-47
Alcoholism                                      20-84

The numbers are somewhat staggering. It certainly seems from these figures that HPL may play a significant role in many forms of mental illness and addressing it may be a way to provide significant relief to these populations of people.

Vitamin B6 and zinc

Ongoing supplementation with Vitamin B6 and zinc is generally believed to be necessary to suppress HPL and manage symptoms. Dosage requirements are usually proportional to the levels of mauve excreted in urine, and needs may be elevated during certain phases of treatment. Initial levels are often higher than ongoing supplementation requirements, which can be reduced in maintenance doses. In addition, zinc requirements sometimes increase during growth spurts.

In addition to zinc and Vitamin B6, low biotin may also be implicated. In a small, mixed cohort study conducted by the Vitamin Diagnostics Laboratory, 24-hour urinary concentrations of HPL were strongly correlated with biotin deficiency in a group of 24 subjects. Elevated HPL predicted low plasma biotin in 16 out of 16 subjects (discerning mauve pt 1). Biotin deficiency results in neurological disease in animals (16) and humans (17) and is more common than is often believed (18).

Neurotoxicity of HPL

In addition to its role in certain nutrient deficiencies, as discussed in the previous section, HPL itself appears to be neurotoxic. Pyrroles as a class are known to be “nerve poisons” (19) and monopyrroles, of which HPL is an example are well known for biotoxicity (20). Another neurotoxic monopyrrole is batrachotoxin from the poison dart frog (21), which exerts potent effects on the nervous system.

HPL and stress

HPL excretion is not static; it varies over the course of the day and also increases in response to stress. Based on his clinical experience, Dr. Pfeiffer declared that mauve is “a stress-induced factor” (22) and this observation is borne out in research as well (23), which has concluded that symptoms and HPL excretion both increase in response to stress. Furthermore, an unpublished 1992 study on men in the Navy found that urinary HPL increased after volunteers were subjected to cold-water immersion stress. In addition, stress contributes to intestinal inflammation and permeability (24), which I will discuss in the next section.

HPL and the gut

It’s well established at this point that gut health issues are also strongly correlated with mental illness, so it probably should come as no surprise that HPL is associated with gut health issues as well. In addition to neurobehavioral symptoms, high mauve is also associated with abdominal signs and symptoms. A large percentage of high mauve subjects report abdominal tenderness (25). One reason for this phenomenon may have to do with intestinal permeability.

Zinc deficiency results in damage to the small intestinal epithelium and increases permeability due to increased intestinal nitric oxide (15). Because HPL is associated with zinc deficiency, it is probably also associated with increased intestinal permeability. Zinc reduces intestinal permeability in humans (26).

HPL and oxidative stress

Deficiencies of zinc and Vitamin B6 result in increased oxidative stress. Even slightly depressed Vitamin B6 is associated with lower glutathione peroxidase (GSHPx), glutathione (GSH) reductase, reduced/oxidized glutathione ratios and higher lipid peroxide levels and mitochondiral decay (27) (28) (29). In addition, B6 itself is highly vulnerable to damage by reactive oxygen species (30) and P5P, the activated form of B6, protects neurons from oxidative stress (31). Furthermore, zinc supplementation has been shown to decrease oxidized biomolecules (32). Because HPL is a marker for B6 and zinc status, HPL is also a potential biomarker for oxidative stress.

Consequences of pyroluria

As I mentioned earlier, the main consequence of high mauve is the depletion of nutrients. The two most commonly depleted nutrients are zinc and Vitamin B6. Biotin is also depleted in some people. Another nutrient that is impacted is arachidonic acid (AA), an omega-6 fatty acid. This is an interesting deficiency because the Standard American Diet tends to be very high in omega-6 fats and low in omega-3s, which must remain in balance with each other. Omega-3s are commonly supplemented in many cases of mental illness. Individuals with pyroluria may benefit from adding some omega-6 (but not from industrial seed oils like canola oil, sunflower oil, safflower oil, corn oil, soy oil or peanut oil which can be pro-inflammatory — instead from whole seeds, nuts, avocados, olive oil, etc.) in addition to the omega-3s.

Other consequences are downstream from those deficiencies. As I already mentioned, Vitamin B6 and zinc are both needed to synthesize serotonin and other neurotransmitters, so low levels of neurotransmitters may result. In addition, increased intestinal permeability is another possibility because of the role zinc plays in maintaining the integrity of the intestinal lining. High mauve can also contribute to elevated oxidative stress and a reduced ability to respond appropriately to stress. In the next section I’ll review how to test for high mauve, and then conclude with treatment options.

Testing for pyroluria / HPL

HPL is unstable outside the body and is rapidly broken down by heat and light. Urine collection and assay for pyroluria testing, which we now know should be more accurately referred to as HPL, is ideally performed under very dim light. If this method of testing is not available, the problem can be abated somewhat by adding Vitamin C (ascorbic acid) to the urine sample, which helps protect HPL from degradation. Most, if not all laboratories that perform this testing require samples to be frozen and shipped overnight for assay.

We prefer to use the Health Diagnostics Research Institute (HDRI) urine test for pyroluria because they are very careful about avoiding light exposure. Because pyrroles are easily degraded, samples that are exposed to light can result in a false negative test result. We also occasionally use LabCorp as another option for patients, though we are unsure about how careful and promptly the test is being completed and have some concern about validity of results. HDRI provides the following reference range for urinary pyrroles:

Urine level              Diagnosis               Recommendation
< 15 µg/dL                  negative                     no evidence of pyroluria
15-25 µg/dL                elevated                     may benefit from treatment
> 25 µg/dL                  positive                     treatment recommended
> 50 µg/dL                 strongly positive      treatment strongly recommended

Another method of evaluating pyroluria involves using a symptom questionnaire. Several practitioners have made questionnaires. I like the one by Trudy Scott, a nutritionist who (like myself) specializes in nutrition for mental health and works primarily with women dealing with depression and anxiety. Her questionnaire is from her book The Antianxiety Food Solution and an online version is available on her blog. This questionnaire can be useful if a patient either can’t afford the cost of the urine test, or if you’re trying to decide whether the test would be worthwhile. You can use the questionnaire to narrow down where pyroluria is likely based on symptoms.

Treating pyroluria / HPL

The primary treatment approach for high mauve involves supplementing zinc and Vitamin B6. Biotin and omega-6 fatty acids may be necessary also. Research notes that the initial starting doses of Vitamin B6 and zinc are often considerably higher than maintenance doses required long-term. Long-term supplementation is usually necessary. Dosage increases can also be necessary during growth spurts. Progress can be gauged by symptom improvement and completing the questionnaire again. Urine can also be retested. When the zinc and Vitamin B6 dosage is adequate, urine levels of HPL will decrease into normal range.

In summary

Pyroluria, which is more accurately referred to as high mauve or HPL is a condition with causes that are still unknown. It is associated with many forms of mental illness and mood disorders, primarily due to its effects on zinc and Vitamin B6 levels. Treatment options primarily involve long-term supplementation with those nutrients, and potentially also biotin and omega-6 fatty acids. Hopefully in the future science will reveal more about the causes of pyroluria and what can be done to prevent or treat it without the need for long-term supplementation. We suspect other nutrients may also be depleted but need more research to know which nutrients and how significant those depletions are.

But in the meantime, zinc and B6 supplementation, plus the possible addition of biotin, is a relatively simple, safe and inexpensive way to treat symptoms and make significant improvements to people dealing with a whole host of mental illness, including depression, anxiety, bipolar disorder and schizophrenia. Pyroluria, or high mauve goes a long way to explain a biochemical mechanism for mental illness.

Our recommended forms of zinc and vitamin B6:

  • Zinc Carnosine: great for if there are also digestive/stomach issues, H. Pylori, and/or leaky gut. Dose is smaller and more expensive than other zinc supplements, though, so we only recommend this versus other zinc if gut issues are present. A small amount of this can be combined with other forms of zinc for cost-effectiveness.
  • Zinc Sulfate: avoid supplementing with this form. It is not very bioavailable and can cause symptoms.
  • Zinc Acetate, Citrate, Methionine, Picolinate, Glycinate: these are all fine forms to supplement with.
  • Zinc dosage: avoid dosing more than 40mg per day for long-term dosing (from all supplement sources). Consider getting increased zinc from foods like oysters (highest), and red meat like beef and lamb. Short-term dosing (up to 100mg / day) is probably safe for most people for short-term dosing (i.e. for a couple of days when getting sick). Larger short-term dosing in some cases of HPL elevation (>40mg) for a fixed period of time may be therapeutic (please only do this under the supervision of an experienced functional medicine practitioner who knows what they are doing). Also, we suggest adding some copper when supplementing with zinc, especially if in higher doses or for a long period of time. We suggest about a 1:10 ratio of copper:zinc. So take 1/10th the amount of copper as you are zinc. If you are supplementing with higher doses (20mg+ of zinc daily), a low dose of trace minerals (be sure to choose a high-quality brand as some have been contaminated with lead) is recommended to keep a balance of multiple minerals.
  • Vitamin B6: Peroxidal-5-Phosphate (P5P) is the preferred form. 100mg per day for adults is the upper limit recommended for long-term use. If supplementing with more than this, do so temporarily and under the guidance of a skilled functional medicine practitioner. We suggest generally starting with 50mg unless there is a test indicating significant elevation of HPL.

References

  1. Irvine DG, Bayne W, Miyashita H, Majer JR. Identifi cation of kryptopyrrole in human urine and its relation to psychosis. Nature. 1969;224(5221):811-813.
  2. Sohler A, Beck R, Noval JJ. Mauve factor re-identified as 2,4-dimethyl-3-ethyl pyrrole and its sedative effect on the CNS. Nature. 1970;228(5278):1318-1320.
  3. Gendler PL, Duhan HA, Rapoport H. Hemopyrrole and kryptopyrrole are absent from the urine of schizophrenics and normal persons. Clin Chem. 1978;24(2):230-233.
  4. McGinnis, W R, et al. “Discerning the Mauve Factor, Part 1.” Alternative Therapies in Health and Medicine, vol. 14, no. 2, 2008, pp. 40–50.
  5. Irvine DG. Kryptopyrrole in molecular psychiatry. In: Hawkins D, Pauling L, eds. Orthomolecular Psychiatry: Treatment of Schizophrenia. San Francisco: WH Freeman and Company; 1973:146-178.
  6. Pfeiffer CC, Bacchi D. Copper, zinc, manganese, niacin and pyridoxine in the schizophrenias. J Appl Nutr. 1975;27:9-39.
  7. Irvine DG. Clinical, EEG and biochemical correlates of hydroxyhemopyrrolenone excretion. Proceedings of the 22nd Annual Psychiatric Research Meeting, Saskatoon Psychiatric Research Division. Saskatoon, Saskatchewan; May 1977: 59-60.
  8. Hoffer A. The presence of malvaria in some mentally retarded children. Am J Ment Def. 1963;67:730-732.
  9. Irvine DG, Wilson DL. Oxidized monopyrroles in porphyric disorders and related conditions. In: Doss M, ed. Porphyrins in Human Diseases: Proceedings of the International Porphyrin Meeting, 1st, Freiburg, Germany, May, 1975. Basel, Switzerland: Karger Publishers; 1976. pp 217-224.
  10. Heyer NJ, Bittner AC Jr, Echeverria D, Woods JS. A cascade analysis of the interaction of mercury and coproporphyrinogen oxidase (CPOX) polymorphism on the heme biosynthetic pathways and porphyrin production. Toxicol Lett. 2006;161(2):159-166.
  11. Cooper CL, Stob CM, Jones MA, Lash TD. Metabolism of pentacarboxylate porphyrinogens by highly purified human coproporphyrinogen oxidase: further evidence for the existence of an abnormal pathway for heme biosynthesis. Bioorg Med Chem. 2005;13(22):6244-6251.
  12. Pfeiffer CC, Sohler A, Jenney EH, et al. Treatment of pyroluric schizophrenia (malvaria) with large doses of pyridoxine and a dietary supplement of zinc. J Appl Nutr. 1974;26:21-28.
  13. Graham DJM, Thompson GG, Moore MR, Goldberg AA. The effects of selected monopyrroles on various aspects of heme biosynthesis and degradation in the rat. Arch Biochem Biophys. 1979;65(1):132-138.
  14. Irvine DG. Mauve factor and 6-sulfatoxy skatole: two biochemical abnormalities associated with specifi c measures of psychiatric disease. Clin Chem. 1963;9:444-445.
  15. Cui L, Takagi Y, Wasa M, Sando K, Khan J, Okada A. Nitric oxide synthase inhibitor attenuates intestinal damage induced by zinc deficiency in rats. J Nutr. 1999;129(4):792-798.
  16. Bregola G, Muzzolini A, Mazzari S, et al. Biotin deficiency facilitates kindling hyperexciability in rats. Neuroreport. 1996;7(11):1745-1748.
  17. Grünewald S, Champion MP, Leonard JV, Schaper J, Morris AA. Biotinidase deficiency: a treatable leukoencephalopathy. Neuropediatrics. 2004;35(4):211-216.
  18. Mock DM, Henrich CL, Carnell N, Mock NI. Indicators of marginal biotin deficiency and repletion in humans: validation of 3-hydroxyisovaleric acid excretion and a leucine challenge. Am J Clin Nutr. 2002;76(5):1061-1068.
  19. Corwin AM, et al. Encyclopaedia Britannica. 1960;18:801.
  20. Irvine DG. Kryptopyrrole and other monopyrroles in molecular neurobiology. Int Rev Neurobiol. 1974;16(0):145-182.
  21. Dumbacher JP, Wako A, Derrickson SR, Samuelson A, Spande TF, Daly JW. Melryrid beetles (Choresine): putative source for batrachotoxin alkaloids found in poison-dart frogs and toxic passerine birds. Proc Natl Acad Sci U S A. 2004;101(45):15857-15860.
  22. Pfeiffer CC. The schizophrenias ‘76. Biol Psychiatry. 1976;11(6):773-775.
  23. Ward JL. Relationship of kryptopyrrole, zinc and pyridoxine in schizophrenics. J Orthomolec Psychiatr. 1975;4:27-31.
  24. Hart A, Kamm MA. Review article: mechanisms of initiation and perpetuation of gut inflammation by stress. Ailment Pharmacol Ther. 2002;16(12):2017-2028.
  25. McCabe DL. Kryptopyrroles. J Orthomolec Psychiatr. 1983:12:2-18.
  26. Bates CJ, Evans PH, Dardenne M, et al. A trial of zinc supplementation in young rural Gambian children. Br J Nutr. 1993;69(1):243-255.
  27. Cabrini L, Bergami R, Fiorentini D, Marchetti M, Landi L, Tolomelli B. Vitamin B6 deficiency affects antioxidant defences in rat liver and heart. Biochem Mol Biol Int. 1998;46(4):689-697
  28. Park LC, Zhang H, Sheu KF, et al. Metabolic impairment induces oxidative stress, compromises inflammatory responses, and inactivates key mitochondrial enzyme in microglia. J Neurochem. 1999;72(5):1948-1958.
  29. Atamna H, Walter PB, Ames BN. The role of heme and iron-sulfur clusters in mitochondrial biogenesis, maintenance, and decay with age. Archiv Biochem Biophys. 2002;397(2):345-353.
  30. Bilski P, Li MY, Ehrenshaft M, Daub ME, Chignell CF. Vitamin B6 (pyridoxine) and its derivatives are efficient singlet oxygen quenchers and potential fungal antioxidants. Photochem Photobiol. 2000;71(2):129-134.
  31. Yamashima T, Zhao L, Wang XD, Tsukada T, Tonchev AB. Neuroprotective effects of pyridoxal phosphate and pyridoxal against ischemia in monkeys. Nutr Neurosci. 2001;4(5):389-397.
  32. Maret W. Metallothionein/disulfide interactions, oxidatives stress, and the mobilization of cellular zinc. Neurochem Int. 1995;27(1):111-117.
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August 29, 2017

Hawthorn, a Cardioprotective Herb Powerhouse

Hawthorn

by Aaron Mello, CNTP, MNT

This week’s blog post is about the role hawthorn plays in preventing and treating cardiovascular disease (CVD). I’ve written a lot over the last several weeks about natural treatments for CVD and their mechanisms of action, including pomegranate and the Chinese herb Dan Shen. This week I’ll be continuing the conversation about CVD by talking about hawthorn, which is also a powerful cardioprotective herb.

What is hawthorn?

Hawthorn, also known as Crataegus oxycantha is a widely used herb in Chinese medicine, but its use is not limited to China. Hawthorn has also been used for the treatment of heart problems in North American for more than 200 years. Hawthorn is part of a genus of spiny shrubs and trees native to temperate regions of the Northern hemisphere in Europe, Asia and North America (1). A member of the Rosaceae family, hawthorn has bright green leaves, white flowers and bright red berries.

History of hawthorn

Hawthorn has long been used in folk medicine for the treatment of several health conditions, including diarrhea, gallbladder issues, insomnia, and asthma (2). The herb has also been used in Chinese medicine for digestive problems, hyperlipidemia, poor circulation and dyspnea and labored breathing (3). The use of hawthorn for the treatment of cardiovascular disease dates back to the late 1800s (4). Today, it is gaining attention for its potential cardiovascular protective properties (5), especially in the treatment of chronic congestive heart failure (CHF) (6).

As I discussed in the last post on Dan Shen, cardiovascular disease is the leading cause of death worldwide and represents a global health crisis. For this reason, safe and effective treatments for CVD are in high demand and that is why I’m focusing a lot of these articles over the last several weeks on natural treatments for CVD. Fortunately, hawthorn offers a lot of promise in reducing heart disease! In the next section I’ll briefly review the phytochemistry of hawthorn before going on to discuss its mechanisms of action on CVD, before finally giving practical advice for using hawthorn in clinical practice.

Chemical constituents of hawthorn

There are several different species of hawthorn hailing from different regions of the Northern hemisphere. The most common and best researched species appears to be Crataegus oxyacantha, although several other species appear to have similar health benefits. Products sold for health include tinctures, tables, teas and aqueous or alcoholic extracts made from the berries, leaves and flowers of the plant.

Hawthorn contains a variety of pharmacaogically active substances, such as flavonoids including vitexin, hyperoside, rutin and catechin/epicatechin derived oligomeric procyanadins (OPC). Other important constituents include triterpenic acids like ursolic, oleanolic and crataegolic acids, as well as  phenol carboxylic acids such as chlorogenic and caffeic acids and several amines (7). These constituents have many important properties for health such as anti-oxidant and anti-inflammatory benefits, which I will review in more detail in the next section.

Antioxidant activity

Oxidative stress is a primary mechanism implicated in the pathogenesis of many forms of cardiovascular disease, so it follows that therapeutic interventions should possess antioxidant or free radical scavenging activites (8). Hawthorn has several possible mechanisms by which it may exert antioxidant activity, including preventing lipid peroxidation, reducing isoproterenol-induced decrease in antioxidant enzymes in the heart, and increasing the rate of ADP-stimulated oxygen uptake and respiratory coupling ratio (9).

Hawthorn also protects against structural and functional disturbances in heart mitochondria, which is significant because many forms of CVD are associated with mitochondrial dysfunction. One study found that pretreating myocardial infarction-induced rat hearts with an alcoholic extract of hawthorn maintained mitochondrial antioxidant status and prevented both mitochondrial lipid peroxidative damage and decreases in Krebs cycle enzymes induced by isoproterenol (10).

Another study evaluated the effects of hawthorn fruit extracts and some of their isolated flavonoids on mitochondrial membrane potential of isolated rat heart mitochondria. They found that the extract produced positive benefits by decreasing mitochondrial membrane potential. Similar effects were found with isolated hawthorn flavonoids. At high dose the hawthorn extract also slightly reduced the maximal ADP-stimulated and uncoupled respiration (11).

Anti-inflammatory effects

In addition to oxidative stress, a second factor contributing to the pathogenesis of CVD is chronic and uncontrolled inflammation (12). One in vitro study evaluated the effects of the water fraction of hawthorn fruit on LPS-stimulated RAW 264.7 cells. They found that hawthorn suppressed the expression of the inflammatory markers COX-2, TNF-α, IL-1β, and IL-6. The authors suggest that anti-inflammatory effects of hawthorn may result from the downregulation of expression of these inflammatory markers (13).

This conclusion is supported by other research in vivo which evaluated the effects of an alcoholic extract of hawthorn berries on isoproterenol-induced myocardial infarction in a rat model. Researchers observed that isoproterenol significantly increased the release of lactate dehydrogenase (LDH) and creatine kinase (CK) in serum, decreased antioxidant status in the heart and increased lipid peroxidation. In addition, increased nitritive stress and apoptosis were seen in the isoprotereno-induced rat heart. However, pre-treatment with hawthorn extract for 60 days significantly reduced these negative markers and maintained near normal status (14).

Other research found that hawthorn extract inhibited N-formyl-Met-Leu-Phe-induced superoxide anion generation and lipopolysaccharide-induced generation of TNF-α and IL-8. The extract also inhibited intracellular calcium signal and extracellular calcium entry into calcium-depleted neutrophils (15). These findings all speak to various anti-inflammatory effects of hawthorn and how they may confer cardioprotective effects. Next I’ll review some research on positive effects hawthorn has on contractions of the heart muscle.

Positive effects on heart muscle

Another mechanism of action for hawthorn may be a positive inotropic effect, or ability to amplify the contraction of the heart muscle. A special extract of hawthorn leaves and flowers called WS 1442 was used in this study. Researchers evaluated the effect of this extract on human myocardium from patients with congestive heart failure, as well as nonfailing controls. WS 1442 significantly increased the force of contraction and improved the frequency-dependent force generation in both the active and control groups. The authors conclude that their findings suggest a mechanism of action similar to the cAMP-independent positive inotropic action of cardiac glycosides, which are a class of organic compounds that increase the output force of the heart by acting on the sodium-potassium ATPase pump (16).

Preventing cardiac remodeling

In addition to strengthening heart muscle contractions, hawthorn has been demonstrated to prevent changes in heart structure associated with CVD. Also known as cardiac remodeling, these changes negatively influence heart function. In a study on rats subjected to pressure overload-induced cardiac hypertrophy, researchers found that hawthorn markedly reduced left ventricle chamber volumes after aortic constriction and augmented relative wall thickness. These results suggest that hawthorn exerts positive benefits that help to prevent cardiac remodeling associated with cardiac hypertrophy (17).

Vasodilating effects

In addition to the benefits I’ve already listed, hawthorn also protects the vasculature through its vasodilating properties. Hawthorn extract induces NO-mediated vasorelaxation (18). It was also shown to preserve endothelium-dependent relaxation and vascular contraction in streptozotocin- (STZ)-induced diabetes, potentially by reducing iNOS expression in the aorta and by decreasing plasma levels of TNF-α and IL-6, as well as by preventing lipid peroxidation (19). Other research suggests that hawthorn may also serve as a vasodilator by inhibiting the angiotensin-converting enzyme (ACE) (20).

Endothelial protection

Another important factor in atherosclerosis and heart failure is hyperpermeability of the endothelium, and subsequent edema (21). Other research on the effects of the WS 1442 hawthorn extract I mentioned in the previous section found that it protected against key determinants of endothelial permeability. In both in vitro and in vivo experiments, WS 1442 was found to protect against endothelial barrier dysfunction by blocking the Ca(2+)/PKC/RhoA pathway and activating the cAMP/Epac1/Rap1 pathway (22).

Protection against ischemia and reperfusion injury

Impaired blood flow (ischemia) and subsequent restoration of blood flow to an organ or tissue (reperfusion) can injure endothelial cells and contribute to enhanced leukocyte adhesion, increased oxygen free radical production and mast cell degranulation. Therefore, minimizing circulatory disturbances can help protect against the pathogenesis of CVD. Several studies show that hawthorn extract WS 1442 can reduce the deterioration of contractile function and infarct size in rat myocardium exposed to prolonged ischemia and reperfusion (23). It also has been shown to reduce the prevalence of malignant arrhythmias and ventricular tachycardia (24). In addition, hawthorn also protected antioxidant enzyme activity from isoproterenol-induced decrease (9).

Improved lipid markers

Altered lipid markers are associated with an increased risk for CVD and hawthorn appears to improve several of these markers. One study found that hawthorn reduced blood lipids in ApoE gene deficient atherosclerotic mice fed an atherogenic diet. Specifically, hawthorn significantly reduced the LDL : total cholesterol ratio and triglyceride levels (25). Another study found that the flavonoids fraction of hawthorn leaf (Crataegus pinnatifada species) inhibited triglyceride and glucose absorption and accelerated gastrointestinal transit time. It also suppressed the gene expression of C/EBPα, PPARγ, SREBP 1c, aP2 and adiponectin, leading researchers to suggest that hawthorn leaf may be helpful for reducing hyperlipidemia (26).

Human studies

Most of the research I’ve presented so far has been from in vitro and animal studies and has gone into detail about proposed mechanisms of action, but of course petri dish and animal research do not always translate into humans. In this section I’ll present information about randomized, placebo-controlled studies that have been performed in humans.

One 3-year open cohort study of 372 patients with heart failure evaluated the effects of WS 1442 hawthorn extract in addition to standard medications, as compared to standard medications and placebo. They found that maximal workload, left ventricular ejection fraction and pressure-heart rate product increase at 50 W ergometric exercised improved more in active treatment than in placebo patients. In addition, typical symptoms like reduced exercise tolerance, exertional dyspnea (labored breathing), weakness, fatigue and palpitations improved more in active treatment than in the placebo group (27).

Another study of 100 chronic heart failure patients found similar improvements to maximal workload, left ventricular ejection fraction and pressure-heart rate product increase, as well as a significant reduction of systolic blood pressure and heart rate. No severe side effects were observed (28). A final larger randomized, double-blind, placebo-controlled study of 2681 congestive heart failure patients found that WS 1442 reduced sudden cardiac death by 39.7% (29).

Hypertension

Other research has also found anti-hypertensive effects of hawthorn. A trial that involved 79 type 2 diabetic patients found that 1200mg of hawthorn extract daily for 16 weeks resulted in a significant mean diastolic blood pressure reductions as compared to placebo (30). Another study found that hawthorn significantly reduced resting diastolic blood pressure, as well as anxiety after 10 weeks (31).

Clinical application of hawthorn

In most of the studies I found, adverse effects to hawthorn were mild to moderate and oral hawthorn was generally well tolerated. In fact, one systematic review that included 29 clinical studies comprised of 7311 patients found relatively few adverse events were reported. Only 166 such events (2.27%) were reported, the vast majority of which were mild to moderate. Best results appear to occur after about 10 weeks and hawthorn should be used for at least four to eight weeks for full benefit. The recommended dosage depends on the type of hawthorn preparation used (32).

In summary

In conclusion, the benefits of hawthorn supported in research include:

  • Antioxidant effects
  • Antiinflammatory effects
  • Inotropic effect (increasing force of heart beat)
  • Prevents cardiac remodeling
  • Vasodilating effects
  • Endothelial protection
  • Protection against ischemia and reperfusion
  • Improved lipid markers
  • Hawthorn is safe and well tolerated

Hawthorn is well supported in research for its cardioprotective benefits and can be an important part of alleviating the significant cardiovascular disease burden!

References

  1. Dahmer, S, and E Scott. “Health Effects of Hawthorn.” American Family Physician, vol. 81, no. 4, 2010, pp. 465–8.
  2. Farnsworth NR, Beecher CWW, Fong HHS. The NAPPALERT database: linking traditional and modern medicine. Essential Drugs Monitor. 1995;(20):2–3.
  3. Rigelsky, J M, and B V Sweet. “Hawthorn: Pharmacology and Therapeutic Uses.” American Journal of Health-System Pharmacy, vol. 59, no. 5, 2002, pp. 417–22.
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  5. Koch, Egon, and Fathi Malek. “Standardized Extracts from Hawthorn Leaves and Flowers in the Treatment of Cardiovascular Disorders – Preclinical and Clinical Studies.” Planta Medica, vol. 77, no. 11, July 2011, pp. 1123–1128., doi:10.1055/s-0030-1270849.
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  13. Li, Chunmei, and Myeong-Hyeon Wang. “Anti-Inflammatory Effect of the Water Fraction from Hawthorn Fruit on LPS-Stimulated RAW 264.7 Cells.” Nutrition Research and Practice, vol. 5, no. 2, 2011, p. 101., doi:10.4162/nrp.2011.5.2.101.
  14. Vijayan, Navin Alukkathara, et al. “Anti-Inflammatory and Anti-Apoptotic Effects of Crataegus Oxyacantha on Isoproterenol-Induced Myocardial Damage.” Molecular and Cellular Biochemistry, vol. 367, no. 1-2, 2012, pp. 1–8., doi:10.1007/s11010-012-1251-9.
  15. Dalli, E, et al. “Hawthorn Extract Inhibits Human Isolated Neutrophil Functions.”Pharmacological Research, vol. 57, no. 6, 2008, pp. 445–450., doi:10.1016/j.phrs.2008.05.001.
  16. Schwinger, Robert H. G., et al. “Crataegus Special Extract WS 1442 Increases Force of Contraction in Human Myocardium CAMP-Independently.” Journal of Cardiovascular Pharmacology, vol. 35, no. 5, 2000, pp. 700–707., doi:10.1097/00005344-200005000-00004.
  17. Hwang, Hyun Seok, et al. “Effects of Hawthorn on Cardiac Remodeling and Left Ventricular Dysfunction after 1 Month of Pressure Overload-Induced Cardiac Hypertrophy in Rats.”Cardiovascular Drugs and Therapy, vol. 22, no. 1, 2008, pp. 19–28., doi:10.1007/s10557-008-6082-2.
  18. Anselm, Eric, et al. “Crataegus Special Extract WS 1442 Causes Endothelium-Dependent Relaxation via a Redox-Sensitive Src- and Akt-Dependent Activation of Endothelial NO Synthase but Not via Activation of Estrogen Receptors.” Journal of Cardiovascular Pharmacology, vol. 53, no. 3, 2009, pp. 253–260., doi:10.1097/fjc.0b013e31819ccfc9.
  19. Topal, Gökçe, et al. “Effects OfCrataegus Microphyllaon Vascular Dysfunction in Streptozotocin-Induced Diabetic Rats.” Phytotherapy Research, vol. 27, no. 3, 2012, pp. 330–337., doi:10.1002/ptr.4726.
  20. Miller, Lucinda G. “Herbal Medicinals: Selected Clinical Considerations Focusing on Known or Potential Drug-Herb Interactions.” Archives of Internal Medicine, vol. 158, no. 20, Sept. 1998, p. 2200., doi:10.1001/archinte.158.20.2200.
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  22. Bubik, Martin F., et al. “A Novel Approach to Prevent Endothelial Hyperpermeability: The Crataegus Extract WS® 1442 Targets the CAMP/Rap1 Pathway.” Journal of Molecular and Cellular Cardiology, vol. 52, no. 1, 2012, pp. 196–205., doi:10.1016/j.yjmcc.2011.10.020.
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  25. Xu, Hong, et al. “A Study of the Comparative Effects of Hawthorn Fruit Compound and Simvastatin on Lowering Blood Lipid Levels.” The American Journal of Chinese Medicine, vol. 37, no. 05, 2009, pp. 903–908., doi:10.1142/s0192415x09007302.
  26. Wang, Tao, et al. “Regulation Effects Of Crataegus PinnatifidaLeaf on Glucose and Lipids Metabolism.” Journal of Agricultural and Food Chemistry, vol. 59, no. 9, Nov. 2011, pp. 4987–4994., doi:10.1021/jf1049062.
  27. Eggeling, Thomas, et al. “Baseline Severity but Not Gender Modulates Quantified Crataegus Extract Effects in Early Heart Failure – A Pooled Analysis of Clinical Trials.”Phytomedicine, vol. 18, no. 14, 2011, pp. 1214–1219., doi:10.1016/j.phymed.2011.06.022.
  28. Schmidt, U., et al. “Efficacy of the Hawthorn (Crataegus) Preparation LI 132 in 78 Patients with Chronic Congestive Heart Failure Defined as NYHA Functional Class II.”Phytomedicine, vol. 1, no. 1, 1994, pp. 17–24., doi:10.1016/s0944-7113(11)80018-8.
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  30. Belz, G.g., et al. “Camphor-Crataegus Berry Extract Combination Dose-Dependently Reduces Tilt Induced Fall in Blood Pressure in Orthostatic Hypotension.” Phytomedicine, vol. 9, no. 7, 2002, pp. 581–588., doi:10.1078/094471102321616382.
  31. Walker, A F, et al. “Hypotensive Effects of Hawthorn for Patients with Diabetes Taking Prescription Drugs: a Randomised Controlled Trial.” The British Journal of General Practice, vol. 56, no. 527, 2006, pp. 437–43.
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