Why is B 12 deficiency epidemic

Given the dangers of B12 deficiency, it would be natural to assume that doctors put the disorder high on their list of suspects when they see patients with weakness, dizziness, nerve pain or numbness, mental illness, falls, dementia, multiple sclerosis-like symptoms, chronic fatigue, infertility, or other medical problems that can stem from B12 deficiency. You'd probably guess, too, that they automatically screen children with developmental delays or failure to thrive to determine if B12 deficiency is to blame. And you'd assume that they routinely screen patients in the highest-risk age group of sixty and over, and especially patients with unexplained Alzheimer's-like symptoms.

These assumptions, however, are wrong. In reality, most doctors frequently fail to diagnose people with B12 deficiency, mistakenly ascribing c-\

Most doctors frequently fail to diagnose people with B]2

deficiency, mistakenly ascribing their symptoms to pre-existing

^conditions.__, their symptoms to pre-existing conditions, other diseases, aging, heavy drinking (even when patients deny this), or mental illness—and the results can be catastrophic.

A few years ago, a fifty-four-year-old woman named Rebecca arrived at the hospital in a near-coma after suffering a fall. The description on her chart was "unresponsive," but an equally accurate description would be "victim of an unresponsive medical system."

Why? Because throughout Rebecca's life, her body offered up clue after clue of her Bu deficiency, but no one noticed. Her mother died at an early age of stomach cancer, a rare cancer in the Western world, but one that often targets people with pernicious anemia. Three of Rebecca's children died shortly after birth—also a red flag for Bu deficiency. Rebecca received numerous blood transfusions over the years for anemia, but her doctors never discovered the cause of that anemia. She'd undergone a complete hysterectomy at a relatively early age, possibly as a result of abnormal cells in the cervix and uterus—also a phenomenon that can occur in B^-deficient women. In middle age, she'd begun experiencing excruciating headaches, and she complained of left-side weakness and pains in her arms and legs. She also found it increasingly hard to walk because of her worsening dizziness, and she frequently fell. (The subdural hematoma—bleeding between the brain and the brain's lining—that doctors detected in the emergency room resulted from a fall and from repeated blows to her head over the previous few months, which occurred when she lost her balance trying to get into their truck.) In recent months, according to her daughter, Rebecca's memory and personality had changed. All of these problems—weakness, leg and arm pains, dizziness, loss of balance, mental changes—are classic symptoms that can occur when Bu deficiency progressively damages the brain and nervous system.

The proximate cause of Rebecca's near-coma when she arrived in the emergency department was a subdural hematoma resulting from hitting her head in repeated falls. The real cause, however, was the dizziness, weakness, and imbalance that made her fall—problems that stemmed directly from her Bu deficiency.

Rebecca was severely anemic and required multiple blood transfusions. Her serum Bu level was very low and her red blood cells were very enlarged. (You'll remember that enlarged red blood cells are a classic sign of Bu deficiency.) In addition, her platelets were dangerously low, which made it difficult for her blood to clot.

Doctors diagnosed Rebecca with pernicious anemia and a subdural hematoma. Before giving her blood transfusions, they ordered additional tests for Bn deficiency. (These tests measure levels of methylmalonic acid and homocysteine, explained later in this book). The test results came back several days later and were also grossly abnormal. Rebecca survived emergency brain surgery, but her hematoma enlarged dangerously afterward, and, as a result of the ensuing damage to her brain, she is now in a vegetative state and will never recover.

Rebecca's descent into a permanent coma at the age of only fifty-four, as a result of chronically misdiagnosed vitamin Bu deficiency, is a tragedy and unacceptable. But it's only one in a string of tragedies resulting from her misdiagnosis. Rebecca lost years of her life to debilitating vitamin Bu deficiency, and it's a virtual certainty that all three of her babies who died at birth or in infancy were victims of her disorder, because Rebecca's depleted stores couldn't nourish them during pregnancy or breast-feeding. (The babies, too, may have suffered from an inherited—and easily detectable and treatable—form of Bu deficiency [see Chapter 6].) Simply by testing for Bu deficiency, Rebecca's doctors would have uncovered her problem, and early treatment would have prevented the damage her body suffered for years. Almost undoubtedly, a correct diagnosis also would have saved the lives of Rebecca's babies. But nobody ordered the tests because none of the physicians Rebecca encountered were knowledgeable about vitamin Bu deficiency.

As medical professionals, we see cases like Rebecca's on a regular basis. Most of the patients with undiagnosed B12 deficiency that we encounter aren't at death's door, but a few are—and the majority have suffered terribly, both physically and emotionally, from symptoms that are destroying their health and quality of life.

How can something as simple as a vitamin deficiency cause so much suffering? One explanation is that doctors receive surprisingly little training (much of which is outdated) in the diagnosis and prevention of B12 deficiency.

In general, doctors are trained to recognize only the blood abnormalities associated with B12 deficiency. In particular, they're trained to look for evidence of macrocytosis, or the presence of large, immature red blood cells, a classic sign of B12 deficiency anemia. (Anemia, which causes extreme fatigue and weakness, occurs when your red blood cells don't have enough hemoglobin—the substance that ferries oxygen throughout your body. "Macrocytic" or "megaloblastic" anemia, in which the red blood cells are enlarged, stems from too little B12 or folic acid.) In addition, many doctors who treat severely anemic patients give these patients blood transfusions before ordering sensitive tests to rule out underlying B12 deficiency. When doctors order these tests later, the healthy donor blood may mask the abnormalities in the patient's blood or make serum

B12 levels appear normal. Doctors who look only for classic blood abnormalities (macrocytic anemia) can misdiagnose the neurological abnormalities that stem from B12 deficiency, including tingling or "pins and needles" sensations in the hands and feet, memory loss, depression, personality changes, dizziness and loss of balance, or even outright dementia. These nervous system symptoms often precede classic blood abnormalities by many years—and the neurologic damage that underlies them can be permanent by the time tests for the blood abnormalities traditionally associated with B12 deficiency begin to come back abnormal.

Many doctors also fail to recognize that high levels of another B vitamin, folic acid (folate), can make the complete blood count (CBC) test results appear normal even when a B12 deficiency exists. In 1998, new U.S. government rules mandated the fortification of grains with folic acid, increasing the likelihood of missing B12 deficiency due to high folate levels, which normalize the size of blood cells that otherwise would appear enlarged. Enriching foods with folic acid is a good idea because it helps prevent spina bifida and related birth defects linked to low folic acid levels; but ironically, the same enrichment that protects many babies from harm also endangers other babies and adults whose doctors rely solely on a complete blood count to detect B12 deficiency. New studies reveal B12 is also essential to prevent spina bifida (see Chapter 6).

B12 deficiency mimics many other diseases, so your doctor can't know if you're low in B12 simply by analyzing your symptoms. Also, your doctor can't determine if you're deficient or not simply by ordering a blood count or smear (a test for anemia, enlarged red blood cells and abnormal white

B]2 deficiency mimics many other diseases, so your doctor can't know if you're low in B]2 simply by analyzing

, your symptoms.

Types of Tests for B12 Deficiency

Serum Vitamin B12 Test

Measures the level of vitamin B12 in your blood serum. There is much controversy as to what constitutes a normal result for this test (see discussion later in this box). Because of this controversy, this test is often used in conjunction with other markers of B12 deficiency (MMA, Hcy, and more recently the holoTC).

However, it appears that these markers demonstrate B12 deficiency primarily in patients whose serum B12 is in the "gray zone" (a serum B12 result between 200 pg/ml and 450 pg/ml). We believe that the "normal" serum B12 threshold needs to be raised from 200 pg/ml to at least 450 pg/ml because deficiencies begin to appear in the cerebral spinal fluid (CSF) below 550 pg/ml.10' "' 12

At this time, we believe normal serum B12 levels should be greater than 550pg/ml. For brain and nervous system health and prevention of disease in older adults, serum B12 levels should be maintained near or above 1,000 pg/ml.

We commonly see patients with clinical signs of B12 deficiency who are not being tested. Others who are being tested are not being treated because their serum B12 falls in the gray zone. ^his error results in delayed diagnosis and an increased incidence of injury.

Moreover, of the total serum B12, only about 20% is transcobalamin II—the biologically active form. The other two proteins (I and III) are thought to be inactive, but will be included in the total serum B12 result, yielding higher results and giving false assurance that a patient's B12 status is fine. This is yet another reason why the serum B12 lower end range must be raised. (See more below in the HoloTC test section.)

Methylmalonic Acid (MMA) Test

Measures the amount of MMA in the urine or blood. Elevated levels of MMA indicate B12 deficiency (see Chapter 11). According to Dr. Eric Norman of Norman Clinical Lab, Inc., MMA is 40 times more concentrated in the urine than in the blood, and the urinary MMA (uMMA) is the preferred test over the serum MMA. The urinary MMA can be helpful in ruling out B12 deficiency, especially since our current lower limit range for B12 deficiency is much too low (typically less than 200pg/ml). (See above.)

However, after reviewing past and present literature as well as thousands of patients' results over a ten year period, we believe it does not make sense to use the MMA test to identify B12 deficiency when the serum B12 can do the job in the majority of cases if doctors use an updated threshold (greater than 450pg/ml), along with a clinical exam. We often see symptomatic patients whose serum B12 is low or in the "gray zone" and whose MMA is normal—and these patient often respond well to B12 treatment. It would be dangerous not to treat these patients because their MMA is normal, or to wait for the MMA to become abnormal and the serum B12 to fall further—resulting in poor health or worse yet, permanent neurologic injury.

Moreover, the serum MMA also has limitations and can cause false positives and false negatives. The specificity of these tests is debated.13' 14, 15 We have seen symptomatic patients denied treatment because their serum B12 was in the "gray zone" and their urinary MMA, serum MMA, and/or homocysteine (see next section) was normal, only for these patients to return many months later in worse shape and with tests showing deficiency.

In addition, MMA values can be normal in Bi2-deficient patients receiving antibiotics, which can eradicate the intestinal flora needed to synthesize propionic acid/6

Homocysteine (Hcy) Test

Measures the level of homocysteine in the plasma. Elevated levels of Hcy can indicate vitamin B12, vitamin Ba, or folate deficiency. Hcy may also be elevated in a few other medical conditions (see Chapter 11). The Hcy test is not necessary to diagnose B12 deficiency, but is a valuable adjunct to the serum B12 test, because the higher your Hcy level, the higher your risk of cardiovascular disease (see Chapter 5). Patients with vascular disease should always have their Hcy, serum B12, and RBC-folate levels measured to determine if B vitamin deficiencies are causing or contributing to their health problems. As with the MMA tests, we have seen many Bi2-deficient patients with normal Hcy levels who were symptomatic and either had a serum B12 level less than 200 pg/ml or were in the gray zone.

Holotranscobalamin (HoloTC) Test

Vitamin B12 in serum is bound to two proteins, transcobalamin and haptocorrin. The transcobalamin-cobalamin complex is named holotranscobalamin (HoloTC) or "active-Bi2." Only around 20% of total serum B12 is in the active form our bodies use, and the HoloTC test measures this fraction. The test detects active-Bi2 or holotranscobalamin (HoloTC), which may be a helpful way of determining vitamin B12 deficiency. The test has been available for decades, but has been termed investigational until recently. Coverage for this test will depend on individual insurance policies. As with the MMA test, this test would most likely not be necessary if we raised the lower limit for the serum B12 test and used updated clinical exams. A group of researchers concluded that the HoloTC and the serum B12 test had equal diagnostic accuracy in screening for metabolic B12 deficiency. They found that both tests used in combination provided a better screen than either assay alone.17 (See "Reference Ranges for Diagnostic Tests" on page 14 for ranges considered acceptable for these tests.)

As you read through all of these tests, remember this bottom line: If we simply raised the lower limit of serum B12, the expensive and "presumably more sensitive" tests (MMA, Hcy, and holo-TC) would not be needed to diagnose B12 deficiency in the majority of people with this problem.

What we see is that when a patient is severely B12 deficient, typically all lab results agree with one another. The serum B12 is low, the MMA is elevated, and the Hcy is elevated. When these three laboratory tests all agree with one another, the patient has been B12 deficient for a long time and is being diagnosed in the later stages of B12 deficiency (in which damage often is permanent). This is why the current lower-end normal range for the serum B12 test must be raised, and why we need to educate clinicians that symptomatic patients with a serum B12 between 200pg/ml and 450pg/ml almost certainly have a B12 deficiency that must be addressed. We have seen cases of severe clinical B12 deficiency where the serum MMA was normal, the B12 was very low, and the Hcy was very high (renal function and RBC-folate levels normal). For our part, we advocate treating all patients who are symptomatic and have serum B12 levels under 450pg/ml, regardless of what the MMA, Hcy, and HoloTC results are. In addition, we advocate treating symptomatic patients with normal serum B12 but elevated urinary/serum MMA or Hcy, and/or low HoloTC.

Also, be aware that when it comes to B12 deficiency, many physicians tend to treat the paper laboratory report rather than the patient. Numerous times in our experience, a symptomatic patient's serum B12 was between 200 pg/ml and 300 pg/ml and the doctor told the patient, "You do not have a B12 deficiency." Given the remarkable safety of B12 treatment and the horrific consequences of ignoring a deficiency, it is always best to err on the side of treatment.

While raising the lower limit for B12 is the most crucial step in accurate diagnosis, we also want to be clear that there are times when the additional markers for B12 deficiency (urinary MMA, Hcy, HoloTC) are needed and may be useful. (You'll find more on this in chapters 3, 11, and 12).

blood cells [neutrophils] seen in some clear-cut cases of B12 deficiency). The major problem—indeed, the most important factor—is that most physicians fail to contemplate B12 deficiency, are poorly educated about it, and therefore fail to test for it.

Also, the serum B12 test will uncover many cases of B12 deficiency, but it's possible to have a B12 deficiency and still have "normal" lab results because of the accepted normal range used in the U.S. and world-wide. Most doctors don't understand that a serum B12 result in the gray zone (200 pg/ml-450pg/ml) can most certainly be a B12 deficiency, and choose not to treat patients in this range or order additional B12 tests (see box page 14). The accepted normal range, created many decades ago, is based on hematologic (blood) changes and not neurologic changes, and thus contributes significantly to late diagnosis.

The urinary MMA test described above costs insurance companies or patients around $150 to $256, which isn't much money, especially when you compare it to thousands of dollars for CT scans, MRIs, and other tests that doctors routinely order. Moreover, the MMA and Hcy tests are covered by insurance, but not all doctors know this. The unfortunate result of this lack of awareness is that many physicians forgo these tests in situations where they are indicated, and also forgo treating patients in the "gray zone" who are symptomatic, thus condemning these patients to ill health and unknowingly setting them up for neurologic injury and poor outcomes in the near future.

Reference Ranges for Diagnostic Tests

Common Reference Ranges for the Serum B12 Test Serum B12: 211-911 pg/ml 180-914 pg/ml 200-1,100 pg/ml

Example serum B 12 reference ranges from a hospital with guidelines stronger than the ranges above:

Deficient: < 200 pg/ml Borderline: 200-270 pg/ml Normal: 271-870 pg/ml

As you can see, a few institutions are making physicians aware that a serum B12 between 200 and 270 pg/ml is problematic, using the term "borderline." This gives a hint to the doctor that the patient's B12 needs to be higher.

Serum B12 Gray Zone: 200-450 pg/ml (We advocate B12 treatment in all symptomatic patients with serum B12 below 450 pg/ml). Urinary MMA: < 3.8 ^g MMA/mg creatinine (3.6 ^mole/mmole creatinine) Serum MMA: 0.04-0.27 |imol/L or 70-270 nmol/L 0.07-0.40 umol/L or 70-400 nmol/L Homocysteine (plasma): 4.0-12.0 ^mol/L

HoloTC (Active-Bi2): 35-101 pmol/L (Specialty Laboratories in Santa Monica, California, currently performs this test)

Ironically, this misplaced concern over the expense of B12 testing costs the medical system far more than it saves, because B12 deficiency is remarkably simple to detect and even easier to treat. Patients treated in the early stages of the disease usually experience complete recovery, with even severe symptoms such as vision loss, agonizing leg pains, paralysis, multiple sclerosis-like symptoms, psychosis, and dementia often receding in months or even weeks. Moreover, unlike many medical problems, B12 deficiency is very inexpensive to treat. Treatment for one year involving bi-monthly injections and a series of six initial daily injections costs $36 per year when patients or family members administer the injections (which are similar to the insulin shots diabetics give themselves).

An alternate option, high-dose methyl-Bi2 lozenges (2,000 mcg), costs around $48 to $72 per year depending on the brand used. Compare this to the cost of giving a depressed or demented patient with undiagnosed B12 deficiency unnecessary antidepressants or dementia drugs, which can run over $1,000 a year—or to the cost of caring for a B12 deficient patient misdiagnosed as having Alzheimer's, multiple sclerosis, or developmental disability, an expense that can run $60,000 a year or more for decades. The cost in human terms, of course, is far greater. There is no price one can place on the pain of individuals whose undiagnosed B12 deficiency leads to severe, irreversible physical and mental disability. Here are a few examples:

In 2000, a fifty-year-old Illinois woman, Vicki Lambert, received a $3 million out-of-court settlement from two hospitals and two physician groups. Lambert charged doctors at each of these institutions failed to diagnose her Bu deficiency, leaving her permanently crippled. She suffers from chronic painful neuropathy, uses specialized crutches to walk, and has irreversible cognitive deficits. She is unable to work as a nurse because of her disability and has moved to a one-story home because she could no longer go up and down stairs.

"Unless someone were in my shoes, you can't imagine," Lambert told a newspaper reporter. "I remember lying in bed and feeling death would be better because I was so sick."18

In a similar 1999 case, a sixty-four-year-old Georgia woman was awarded $3.1 million after a missed diagnosis of Bu deficiency. The woman now requires a wheelchair as a result of permanent nerve damage due to her doctors'failure to identify her condition.19

In December 2007, the Toronto Sun reported the case of a 12-year-old boy named J.J. who suffered great neurologic injury due to misdiagnosed vitamin Bu deficiency. J.J. was in and out of the Hospital for Sick Children for more than eight months, slowly losing his ability to walk, write, and draw. J.J's neurologic status continued to deteriorate to the point where he needed a wheelchair, and none of his doctors could figure out why. He then became jaundiced, and his pediatrician worried that J.J.'s organs were shutting down.

"I was watching my son dying in front of my eyes and no one would do anything," his mother said. "Later I overheard the doctors saying that when we brought him in, he was close to death. He stumped everyone, he hit the medical history books because no one has been as bad as him."

J.J. didn't have a bizarre or rare disorder; he simply had vitamin Bu deficiency. Yet none of his doctors knew the signs or symptoms, despite J.J's classic presentation.20 (More on J.J. in Chapter 6.)

Two cases of severe Bu deficiency were reported in Madison, Wisconsin, in the American Journal of Emergency Medicine (2007). Both patients were diagnosed in the emergency department (ED) rather than by their primary care doctors or neurologists. Both had prolonged and progressive symptoms and "had had rather extensive outpatient workups without diagnosis." Their previous doctors and specialists never contemplated vitamin Bu deficiency as the cause of their progressive neurologic decline. The diagnosis was only suggested when blood abnormalities were found in the ED. These blood changes (severe anemia and macrocytosis) are very late signs of Bu deficiency.

The first woman was fifty years old and presented to the ED complaining of progressive weakness and increasing numbness of her arms, feet and legs. Her serum Bu was critically low at 72 pg/ml, despite the fact that she was on a multi-vitamin. Her neurologic signs and symptoms were slightly improved at a one-week follow-up.

The second woman was twenty-five years of age and came to the ED complaining of increasing weakness. She had a six-month history of decline which led to her using a walker for three months. Later, she began to use a wheelchair because she was too unstable to use the walker. Her serum B12 was undetectable in lab tests, and she was severely anemic and required four blood transfusions. However, she was not macrocytic. Two months after starting Bu treatment, her sensory abnormalities improved, but her motor deficits were unchanged and she continues to use a wheelchair.

Prior to this woman's arrival in the ED, it was reported, her own doctors ordered tests including an MRI of her brain and spine and even an electro-myogram (EMG). But they didn't contemplate or investigate vitamin Bn deficiency, even though her signs and symptoms were obvious as well as numerous. As a result, this young woman will have a life-long disability and her physicians may have a costly malpractice suit.21

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