Macrocytosis

What Is Macrocytosis?

[dropcap]M[/dropcap]acrocytosis is a blood cell disorder characterized by altered blood cell formation that results in abnormally large erythrocytes (red blood cells) circulating in the bloodstream.

The mean corpuscular volume (MCV), which is a measure of the size of red blood cells in the bloodstream, is greater than 100 fL as shown in a complete blood count (CBC) laboratory analysis report.

Macrocytosis produces macrocytic anemias that are classified as megaloblastic or non-megaloblastic:

1. Megaloblastic anemias result from disorders of DNA synthesis of red blood cell precursors (megaloblasts) in bone marrow due to B vitamin deficiency demonstrated by macro-ovalocytes and hypersegmented neutrophils.¹
2. Non-megaloblastic anemias are or those caused primarily by alcoholism, liver disease and hypothyroidism.²

What Is Macrocytosis In Celiac Disease and/or Gluten Sensitivity?

• Relationship between macrocytosis and celiac disease. Macrocytosis is a classic sign of celiac disease.
• Relationship between macrocytosis and vitamin deficiencies. Macrocytosis in celiac disease results from chronic deficiencies of folate and/or vitamin B12. These B vitamins are required for normal red blood cell production in bone marrow.
• Relationship between macrocytosis and symptoms. Initial evaluation should include a carefully taken history and physical examination along with a complete hematologic (blood) profile, reticulocyte count, and peripheral blood smear. Serum vitamin B12 and red cell folate determinations and other studies may then be undertaken as appropriate.³

How Prevalent Is Macrocytosis In Celiac Disease and/or Gluten Sensitivity?

Macrocytosis is a common serology (blood test) finding in untreated celiac disease patients.⁴

What Are The Symptoms Of Macrocytosis?

Macrocytosis is marked by anemia causing tissue hypoxia (not enough oxygen to the body) including:

• Fatigue.
• Weakness.
• Headache.
• Lightheadedness.
• Angina.
• Dyspnea.
• Pallor.
• Tachycardia (fast heart rate).
• Curly graying hair.
• Increased skin color (hyperpigmentation).
• Worsening of heart disease.

How Does Macrocytosis In Celiac Disease and/or Gluten Sensitivity Develop?

• Macrocytosis results from folic acid and/or vitamin B12 deficiencies induced by celiac disease.⁴

Does  Macrocytosis Respond To Gluten-Free Diet?

Yes. Celiac disease-related macrocytosis responds to gluten free diet.⁵

6 Steps To Improve Macrocytosis In Celiac Disease and/or Gluten Sensitivity:

• [dropcap]1[/dropcap]Remove the Trigger. Maintain a Strict, Nutritious Gluten Free Diet:

[box type=”shadow” ]Treatment. This condition responds to the complete elimination of gluten, which is the required treatment that improves both macrocytosis and gut health.

• Gut health is the foundation to restore ALL health. Restored health will enable you to maintain a strict gluten free diet, just as other life tasks will be easier.
• A strict gluten free diet means removing 100% of wheat, barley, rye and oats from the diet.
• Cutting out bread and other obvious sources of gluten is not good enough for recovery. Even 1/8th teaspoon of flour or bread crumb is enough to sustain the inflammation that is damaging your small intestine, causing increased permeability (leaky gut) and allowing undigested gluten to enter your body where it can damage structures and function, and instigate immune inflammatory responses.

Correct Your Individual Nutritional Needs.

• Eat foods that can replenish missing nutrients. Find them under NUTRIENT DEFICIENCIES.
• Take nutritional supplements as needed. Find them under NUTRIENT DEFICIENCIES.

Recovery. You should begin to feel better within a week and notice more energy as inflammation subsides and the  absorbing cells that make up the surface lining of your small intestine are better able to function.

• Intestinal lining cells are replaced every 5 days. The healing process is like sunburn where the damaged surface layer of skin sloughs off and is replaced with new normal cells.
• Leaky gut normally resolves in two month after starting a gluten free diet and brings about a big improvement in health. Improvement in intestinal permeability precedes morphometric recovery (cell appearance and structure) of the small intestine in celiac disease.⁶
• The intestinal lining may take up to a year to heal.[/box]

 

• [dropcap]2[/dropcap] Reduce Inflammation. Foods to Eat and Foods Not to Eat:

Because gluten is inflammatory, eliminate OTHER inflammatory foods from your diet to reduce an additive effect to gluten. At the same time, try to eat foods that reduce inflammation (anti-inflammatory).

[box type=”shadow” ]Here Are Major Inflammatory Food Types That Reduce Healing:

• Damaging Foods. In susceptible persons, includes corn, dairy (cow), and soy. Lactose, the sugar in any animal milk disrupts intestinal permeability causing leaky gut.⁷
• Allergenic Foods. Includes foods that trigger the immune sytem to produce IgE antibodies. Allergy testing is the usual way to discover these offending foods.
• Shelf Stable Processed Foods. Includes any that contain additives and preservatives. Look for them on the nutrition label of the box or package. Additives and preservatives also disrupt intestinal permeability causing leaky gut.⁷
• Fats. Limit deep fried foods, trans-fats, saturated fats (animal fat/butter), and EXCESSIVE omega-6 fatty acid oils like corn oil. Rancid fats, sodium caprate (a medium chain fat), and sucrose monester fatty acid (a food grade surfactant) induce significant disruption of the intestinal barrier that causes leaky gut.⁷.
• Excessive Refined White Flours (bran layer removed). Includes products made from them such as cookies, bread, cakes, pies. Bran contains the vitamins and minerals that metabolize grains and slows the otherwise rapid entry of sugar from their digestion into the bloodstream. Also disrupt intestinal permeability causing leaky gut.⁷
• Refined Sugars.  Includes white sugar, corn fructose and high fructose corn syrup.
• Certain Spices. Includes paprika and cayenne pepper which disrupt intestinal permeability causing leaky gut.⁷
• Alcohol and Caffeine. Disrupt intestinal permeability causing leaky gut.⁷[/box]

[box type=”shadow” ]Here Are Important Anti-Inflammatory Food Types to Promote Health:

• Fruits. Contain ample amounts of vitamins, minerals and phytochemicals which are naturally occuring components in plants that detoxify toxins, carcinogens (reducing the risk by 50%) and mutagens.
• Non-Starchy Vegetables. Support intestinal integrity and provide ample amounts of vitamins, minerals and phytochemicals. Includes lettuce, kale, onion, broccoli, garlic, and others.
• High Quality Complex Carbohydrates. Provide vitamins, minerals, and fiber while boosting serotonin levels to help you relax and feel calm. Includes whole grains, legumes, and root vegetables such as carrots, parsnips, sweet potatoes, turnips, red beets, and others.
• Antioxidants. Protect the body from inflammatory oxidant molecules that continually occur and help us handle stress and reduce irritability. Includes vitamin C-containing foods such as lemon, grapefruit, apricot, Brussels sprouts and strawberries, and others. Also, includes vitamin E-containing foods such as nuts, seeds, avocado, olive oil, and others. Cocoa is good, too.
• Omega-3 Fatty Acids. Balance opposing omega-6 fatty acids and bad fats. Fish sources includes tuna, salmon, cod, and others. Plants sources include flax, chia seeds, canola oil, and others.
• Probiotics. Supply normal microbes needed for colon health and health of the body such as these fermented foods: yogurt, kefir, and unpasteurized apple cider vinegar.
• Prebiotics/ High Fiber Foods.  Food with fiber keeps our population of colonic microbes healthy.
• Protective Herbs and Spices.  See below #6 below for examples.[/box]

• [dropcap]3[/dropcap] Information Sheet You Can Take to Your Doctor or Other Health Professional:

Click here.

 

• [dropcap]4[/dropcap] Manage Your Medications Safely:

[box type=”shadow” ]

Certain prescription drugs can cause nutritional deficiencies that promote macrocytosis. Ask your doctor or pharmacist about this possible adverse effect. Do not stop without supervision – this is mandatory:

FEMALE HORMONES disrupt intestinal permeability.

• Oral Contraceptives (Norinyl®, Ortho-Novum®, Triphasil®, and others) deplete Vitamin B12, Folic Acid.
• Oral Estrogen/Hormone Replacement (Evista®, Prempro®, Premarin®, Estratab® and others) deplete Vitamin B12, Folic Acid.

DIURETICS

• Potassium Sparing Diuretics (Midamor®, Aldactone®, Dyrenium® and others) deplete Folic Acid.

DIABETIC DRUGS 

• Metformin® depletes Folic acid, Vitamin B12.

ANTI-INFLAMMATORIES – Disrupt Intestinal permeability.

• Corticosteroids (Prednisone, Medrol®, Aristocort®, Decadron) deplete Vitamin B12, Folic Acid.
• NSAIDS (Motrin®, Aleve®, Advil®, Anaprox®, Dolobid®, Feldene®, Naprosyn® and others) deplete Folic acid.
• Aspirin and Salicylates deplete Folic acid.

ANTICONVULSANTS

• Phenobarbital and Barbituates; and Dilantin®, Tegretol®, Mysoline®, Depakane/Depacon® deplete Folic Acid, Vitamin B12.

MAJOR TRAQUILIZERS  

• Thorazine®, Mellaril®, Prolixin®, Serentil® and others deplete Vitamin B12.

ANTIBIOTICS  disrupt intestinal permeability.

• Gentomycin, Neomycin, Streptomycin, Cephalosporins, Penicillins deplete B Vitamins.

ANTACIDS / ULCER MEDICATIONS

• Pepcid®, Tagamet®, Zantac® deplete Folic Acid, Vitamin B12.
• Magnesium and Aluminum Antacid preparations (Gaviscon®, Maalox®, Mylanta®) deplete Folic Acid, Vitamin B12.
• Prevacid®, Prilosec® depleteVitamin B12.
• Alka Seltzer®, Baking Soda deplete Folic Acid.

CHOLESTEROL DRUGS

• Colestid® and Questran® Folic acid, Vitamin B12.

ANTIVIRAL AGENTS

• Zidovudine (Retrovir®, AZT and other related drugs) deplete Vitamin B12.

ANTI-DEPRESSANTS

• Adapin®, Aventyl®, Elavil®, Pamelor®, and others deplete these nutrients: Vitamin B12.[/box]

• [dropcap]5[/dropcap]Nutritional Supplements To Help Correct Deficiencies:

[box type=”shadow” ]

The type and quantity of nutritional supplements that may be needed depend on which nutrients are deficient.

• Multivitamin/mineral combination once a day is useful to improve overall nutrient levels. This is a safe dose, but always check with your doctor to avoid interactions with medications.
• 100% of the B vitamins, or as prescribed by a doctor. About B Vitamin Complex supplements:  some labeling can be confusing, for example, “B 100” does not mean 100%. If the ingredient list shows  an excessive amount like 3000% or more, look for another brand because this excessive amount will cause the loss of mineral in the urine.
• Vitamin B12 by mouth or if not absorbed by the intestines, sublingually or by injection as prescribed following blood test for status.

Storage Note: Store container tightly sealed, away from heat, moisture and direct light to avoid loss of potency. That is, in a safe kitchen cabinet – not in the bathroom or on the kitchen table. [/box]

• [dropcap]6[/dropcap]Manage Natural Remedies: 

[box type=”shadow” ]Hydration:

• Eight glasses of water are recommended per day unless there is a contraindication such as kidney or heart disease. The Institute of Medicine recommends approximately 2.7 liters (91 ounces) of total water, from all beverages and foods, each day for women and 3.7 liters (125 ounces) daily of total water for men.
• If you are thirsty, drink water. Add fresh, squeezed lemon to water. Lemon is anti-inflammatory, alkalizing and provides vitamin C.
• Hydration Test: Urine should be pale yellow. Fingertips should be plump, without pruning but this may not be reliable when fingers are swollen with edema. Lips should be plump, without puckering. The feeling of thirst can be unreliable.
• What is wrong with soda, coffee, tea, and alcohol? These drinks are dehydrating, increase acid, and deplete nutrients.[/box]

[box type=”shadow” ]Carminatives. The following  anti-inflammatory plant sources called carminitives help heal the digestive tract. They also tone the digestive muscles which improves peristalsis, thus aiding in the expulsion of gas from the stomach and intestine to relieve digestive colic and gastric discomfort.

Carminative Food Remedies:

• Raspberry.
• Carrot is also a cleansing digestive tonic.
• Grape is also bile stimulating and a cleansing remedy for sluggish digestion and laxative.
• Redbeets also stimulate and improve digestion and are easily digested.
• Cabbage also stimulates and improves digestion and is also a liver decongestant.
• Lettuce also stimulates and improves digestion and is also an alterative, meaning it improves the function of organs involved with the digestion and excretion of waste products to bring about a gradual change.
• Potatoes are antispasmodic (due to atropine like properties) and a liver remedy.

Carminative Herb Remedies:

• Sage is also a digestive, astringent, bile stimulant and energy tonic that heals the mucosa.  Drink as tea or use in cooking.
• Chamomile, lemon balm, and fennel, (as a tea) also help relieve nervous tension.
• Parsley also relieves indigestion.
• Rosemary as a tea and in cooking also is a nervous system tonic for stress and fatigue, bile stimulant, and can relieve headaches and indigestion.
• Thyme is also soothing remedy useful for stimulating digestion of rich, fatty foods.

Carminative Spice Remedies:

• Cloves are also antispasmodic.
• Nutmeg is also useful for indigestion.
• Ginger.[/box]

[box type=”shadow” ]Exercise Helps:

Gentle exercise improves circulation and rids the body of toxins. Exercise only up to the point of pain to prevent tissue damage from lack of oxygen.

• Walking is aerobic exercise that reconditions the whole body to improve stamina. Read more about Exercise and Fitness.
• Weight training builds muscle. Read more about Exercise and Fitness.
• Stretching improves flexibilty. Read more about Exercise and Fitness.

Note: Exercise is important, but the amount and type of exercise undertaken depends on your health. Your first priority is to heal. [/box]

 

What Do Medical Research Studies Tell About Macrocytosis In Celiac Disease and/or Gluten Sensitivity?

RESEARCH STUDY SUMMARIES

“Anemia in celiac disease is multifactorial in etiology.” This study assessed the characteristics of anemia from a cohort of patients seen at a hospital care center for celiac disease. Hematological parameters measured less than 3 months of diagnosis and degree of villous atrophy from 405 patients diagnosed after 1995 was analyzed. Folate deficiency was seen in approximately 12% of the total sample. Macrocytic anemia with concurrent folate deficiency was 3%.⁸

“Vitamin B12 deficiency in untreated celiac disease.” This study investigating the prevalence of vitamin B12 deficiency in patients with celiac disease demonstrated that vitamin B12 deficiency is common in patients with untreated celiac disease and concentration should be measured routinely before hematinic replacement.⁹

“Serum folates in man.” This study investigating folate compounds and their breakdown compounds demonstrated that 5-ethyltetrahydrofolate is poorly absorbed by patients with celiac disease and the availability for biological utilization of the major dietary folate compounds will depend on the amount of gastric acidity and of the ascorbate in the intestinal chyme. Many folate compounds may be unavailable for metabolic utilization in the body.¹⁰

CASE REPORT SUMMARIES

“Carpopedal spasm in an elderly man: an unusual presentation of celiac disease.” This case report describes diagnosis of celiac disease in a 68-year-old single Caucasian man admitted to the hospital with a 24-hour history of carpopedal spasm of both hands. Apart from generalized weakness, he reported no other symptoms. Physical examination revealed carpopedal spasm, clubbing of fingers and cachexia (body mass index 14 kg/m2). This patient was found to have several unusual features of celiac disease, including macrocytosis [low folate and vitamin B12 levels], severe hypocalcemia and electrolyte disturbances as the initial manifestations, minimal gastrointestinal symptoms, and negative tTG-antibodies.

Blood tests showed severe hypocalcemia, with a total serum calcium of 1.06 mmol/L (normal range [NR] 2.05-2.55 mmol/L). He also had low serum potassium (2.8 mmol/L; NR 3.5-5.5 mmol/L) and magnesium (0.36 mmol/L; NR 0.65-1.05 mmol/L). Other significant results included hemoglobin 10.6 g/dL (NR 13-18 g/dL), mean corpuscular volume 98.1 fl (NR 82-98 fl), vitamin B12 157 ng/L (NR > 165 ng/L), folate 2.8 g/L (NR 3.1-17.5 μg/L), ferritin 252 μg/L (NR 30-250 μg/L), prothrombin time 20 s (NR 11-14 s), thyroid stimulating hormone 0.87 mu/L (NR 0.35-4.5 mu/L), phosphate 0.57 mmol/L (NR 0.8-1.45 mmol/L), albumin 32 g/L (NR 34-48 g/L) and alkaline phosphatase 313 IU/L (NR 47-141 IU/L). Subsequent results revealed vitamin D deficiency with a low serum 25-OH vitamin D of < 7 μg/L (NR 7-40 μg/L), a low 24-hour urinary calcium excretion of 0.9 mmol (NR 2.5-7.5 mmol) and a raised serum parathyroid hormone of 22.7 pmol/L (NR 1.6-6.9 pmol/L). Serology for tissue transglutaminase (tTG) antibodies was negative, and a serum IgA level of 4.95 g/L (NR 0.8-4.0 g/L) excluded selective IgA deficiency. Electrocardiograph at admission showed prolonged QT interval.

In view of cachexia, clubbing and negative tTG-antibodies, he was further investigated for an occult malignancy. Barium meal and follow through showed dilated proximal bowel loops and absence of normal feathery pattern of the jejunum, features suggestive of a malabsorptive state. Upper gastroscopic examination was normal; however, the duodenal biopsy showed partial and subtotal villous atrophy with increased intra-epithelial lymphocyte infiltration, consistent with the diagnosis of coeliac disease.¹¹

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2. Davenport J. Macrocytic anemia. Am Fam Physician. 1996 Jan;53(1):155-62. [↩]
3. Brigden ML. A systematic approach to macrocytosis. Sorting out the causes. Postgraduate Medicine. May 1995; 97(5):171-2,175-7,181-4 passim. [↩]
4. Murray JA, the widening spectrum of celiac disease. American Journal of Clinical Nutrition. Mar 1999; 69(3):354-365. [↩] [↩]
5. Murray JA, the widening spectrum of celiac disease. American Journal of Clinical Nutrition. Mar 1999; 69(3):354-365. [↩]
6. Cummins AG, Thompson FM, Butler RN, et al. Improvement in intestinal permeability precedes morphometric recovery of the small intestine in coeliac disease. Clinical Science. Apr 2001;100(4):379-86. [↩]
7. Farhadi A, Banan A, Fields J, Keshavarzian A. Intestinal barrier: an interface between health and disease. Journal of Gastroenterology and Hepatology. 2003;18:479-91. [↩] [↩] [↩] [↩] [↩] [↩]
8. Harper JW, Holleran SF, Ramakrishnan R, Bhagat G, Green PH. Anemia in celiac disease is multifactorial in etiology. Am J Hematol. 2007 Nov; 82(11):996-1000. [↩]
9. Dahele A, Ghosh S. Vitamin B12. deficiency in untreated celiac disease. American Journal of Gastroenterology. Mar 2001; 96(3):745-50. [↩]
10. Thien KR, Blair JA, Leeming RJ, Cooke WT, Melikan V. Serum folates in man. Journal of Clinical Pathology. Mat 1977; 30(5):438-48. [↩]
11. Schmidt K, Powari M, Shirazi T, Vaidya B. Carpopedal spasm in an elderly man: an unusual presentation of coeliac disease. J R Soc Med. 2007 Nov;100(11):524-5. [↩]