The Autoimmune Connection: Essential Information for Women on Diagnosis, Treatment, and Getting On With Your Life (36 page)

Celiac disease can cause special complications for women, including delayed puberty and menarche, menstrual irregularities, miscarriages, infertility, and premature menopause. In childhood, the complications are due to delayed development, but it’s not clear how celiac can cause reproductive problems, says Dr. Green.

While celiac can show itself at any time, diagnosis in adults seems to peak around age 50. And the irritability and depression of celiac may even be mistaken for symptoms of menopause.

Celiac poses the threat of osteoporosis for women of all ages. But if a woman is diagnosed with low bone density during her forties or fifties, the underlying cause is often assumed to be estrogen loss, and the standard treatment of bisphosphonates (
Fosamax, Actonel
) to prevent bone resorption may create problems. “Potentially, if the osteoporosis is due to malabsorption of calcium, and a woman is actually maintaining a normal serum calcium, the calcium is being leached out of bones because it is not being absorbed from the gut,” he explains. “If people have osteoporosis due to celiac disease and are just put on Fosamax, the body would not be able to remove calcium from the bones, and serum calcium could potentially drop to dangerous levels. So we don’t recommend that people with osteoporosis and celiac disease be put straight on Fosamax, because we have to increase their calcium absorption first. And that must be done through a gluten-free diet.”

Malabsorption of calcium can also lead to
secondary hyperparathyroidism
; about 20 percent of women with osteoporosis and celiac disease will develop this problem. The four tiny parathyroid glands are buried in the thyroid and
produce
parathyroid hormone (PTH)
, needed along with calcitonin (produced by the thyroid gland) and vitamin D to regulate the balance of calcium in the body. If there’s too little calcium in the blood, the parathyroid glands secrete more PTH, taking calcium from the bones to correct the imbalance. In celiac disease, calcium isn’t properly absorbed and passes out of the body. Vitamin D isn’t being absorbed, either. So the parathyroid produces more PTH. Chronic low levels of calcium can cause the gland to become overactive, causing even more calcium to be removed from the bones.

Hyperparathyroidism is diagnosed by measuring levels of PTH, urinary calcium, and vitamin D. In hyperparathyroidism, PTH is elevated, as is one form of vitamin D (1,25-dihydroxy vitamin D), and urinary calcium is high (signaling malabsorption). Hyperparathyroidism is treated by surgically removing abnormal parathyroid tissue and giving oral calcium and
1,25-dihydroxy vitamin D
supplements (
Calcitriol
) to normalize calcium.

An autoimmune disease common in women over age 60 is
pernicious anemia
. It results from an autoimmune attack on the parietal cells lining the stomach, which secrete a chemical called
intrinsic factor (IF)
that binds to vitamin B
₁₂
and helps it absorb in the small intestine. The destruction of the parietal cells impairs production of intrinsic factor, and autoantibodies against IF prevent it from binding to vitamin B
₁₂
, so the vitamin can’t be absorbed.

The resulting vitamin deficiency can cause atrophy of the surface of the tongue (
atrophic glossitis
), producing a red, smooth appearance; diarrhea; and nerve damage (
peripheral neuropathy
) that leads to tingling and numbness. Nerve damage is a result of lesions caused by autoantibodies, and in severe cases lesions can develop in the brain, leading to memory loss and even psychosis (in some cases, it may even be mistaken for Alzheimer’s disease). It can also occur in women with celiac disease and other autoimmune diseases.

Pernicious anemia is diagnosed with blood tests to measure vitamin B
₁₂
and levels of
folate
, another B vitamin. Red blood cells become enlarged in pernicious anemia (they’re called
megaloblasts
). More than 90 percent of women will have autoantibodies to parietal cells; nearly half of patients have autoantibodies to intrinsic factor.

The treatment is simple: monthly injections of 100 micrograms (mcg) of vitamin B
₁₂
. This remedies the anemia and, in many cases, corrects the nerve-related complications.

In some elderly people, the lining of the stomach may atrophy, and a daily supplement of 25 micrograms of vitamin B
₁₂
is recommended to prevent deficiency.

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Myelin is usually compared to the insulation around electrical wires that helps electrical transmission and protects the wires from being damaged and shorting out. But it’s not really like the single, smooth layer of rubber found on electrical wires. The
myelin sheath
is a membrane made up of layers of a fatty substance manufactured by specialized cells called
oligodendrocytes
that coils around nerve fibers (
axons
), more like multiple wrappings of electrical tape.
Myelinated axons
are commonly called white matter.

Both myelin and oligodendrocytes find themselves under attack in MS. Autoantibodies reacting to proteins in myelin (including
myelin basic protein
) and other toxic products of immune cells eat away one or more layers of the
myelin sheath and the cells producing it. MS also damages nerve cell bodies, found in the brain’s “gray matter.”
²

Since a single oligodendrocyte may spin out myelin for 50 to 100 axons, an attack on one of these cells can result in problems for multiple axons, notes Anthony T. Reder, MD, professor of neurology at the University of Chicago and director of the Neurology and Inflammatory Disease Infusion Center at UC.

However, because there are so many layers of myelin, it may take a while for the damage to produce symptoms. And myelin may regenerate over a period of months in the beginning (the brain may even reorganize some of its circuits to compensate for minor damage). But the new myelin is not as stable, and eventually spots along the sheath are totally eaten away (
demyelination
). Inflammation of the sheath at areas of demyelination, which may come in cycles or bursts of activity, is believed to be responsible for MS flares. Immune attacks and inflammation can occur in any area of the
central nervous system (CNS)
—the brain, the spinal cord, or the optic nerve—but early on, most of this damage may occur silently.

As myelin is eaten away, messages between nerve cells are increasingly disrupted. When the axon is exposed, it can become damaged or even severed. Accumulated damage to axons can be widespread, eventually leading to irreversible loss of function and permanent disability. It’s now known that brain atrophy can occur early in the disease process.
³

As myelin is stripped away, it’s replaced by scar (
sclerotic
) tissue, which forms
plaques
that build up at numerous spots around the central nervous system—hence the name multiple sclerosis. Plaques and inflammation show up as white spots on
magnetic resonance imaging (MRI)
. MRI is an important diagnostic tool because it reveals plaques even when there are no symptoms. The number of myelin-producing cells is reduced (or they’re absent altogether) within the plaques. The use of contrast-enhancing agents like
gadolinium
makes MRI even more accurate, often pinpointing abnormalities in white and gray matter even when there’s no focal inflammation.
³

Symptoms of MS depend on the severity of the immune reaction as well as the location and extent of the plaques, which primarily appear in the brain stem, cerebellum, spinal cord, optic nerves, and the white matter of the brain around the brain
ventricles
(fluid-filled spaces inside of the brain).
²

One theory that generated a lot of attention involves a condition dubbed
chronic cerebrospinal venous insufficiency (CCSVI)
. The idea, first put forth by an Italian researcher in 2009, is that obstructions in the
cerebrospinal veins
(located in the head and neck) cause iron deposits that may lead to MS. However, imaging studies of these veins done with ultrasound and
magnetic resonance venography
show that CCSVI does not appear to be related to MS.
⁴
And small clinical trials of
percutaneous transluminal venous angioplasty
to surgically improve blood flow had no significant benefits.
⁵
While the Italian Multiple Sclerosis Society and others have dismissed CCSVI, some research continues.

For all of the newfound knowledge about the underlying process of MS damage, it’s still unclear what triggers it in the first place.

Faulty genes may predispose people to the most common form of MS. Up to 20 percent of MS patients have at least one relative with the disease. While there’s no evidence that MS itself can be inherited, having certain genes may also make people vulnerable to environmental toxins or viruses. Some MS experts believe female hormones may protect nerve cells to some extent.

The agents of destruction in MS are thought to be cell-killing (
cytotoxic
) T cells, activated as if to rout a foreign invader, along with hordes of scavenger macrophages attracted by chemicals released by the activated T cells. In fact, there may be an invader hidden in the nerves themselves. Some viruses can infect the body and then remain dormant in nerve trunks. To T cells, those viruses may look similar to proteins in myelin (
molecular mimicry
). There are dozens of
suspects—including
Epstein-Barr virus
(
EBV
, which causes infectious mononucleosis), the respiratory virus
Haemophilus influenzae
, the mumps and measles viruses, and a herpes virus that causes the childhood illness
roseola
. We’ve all been exposed to them, but it’s unclear whether they actually trigger the initial MS attack.
⁶

Antibodies
to these viruses (evidence the body has reacted to an infection) are elevated in people with MS; antibodies have also been found in
cerebral spinal fluid (CSF)
.

Evidence of viral infections in the central nervous system and in MS plaques has also been detected. EBV antibodies are increased in MS, and during MS exacerbations, notes Dr. Reder. “One out of every three upper respiratory viruses triggers an MS attack, probably caused by the activation of the immune system.” Respiratory infections are known to prompt MS relapses (probably through a reaction in “memory cells” programmed by a previous encounter with a virus). But so far there’s no direct evidence that viruses actually cause MS.

Almost all of us have been exposed to EBV at some point, so other factors must be involved in MS, such as genetic predisposition, the age at which a woman is infected, or even infection with other microbes, the researchers speculate.

But how would the destructive T cells get through the blood-brain barrier that protects our brain from toxins? New research indicates that cells in the tough brain membrane (
endothelial cells
in the veins of the brain) somehow become activated and secrete chemicals that attract T cells, then literally pull them through the cells, crossing the normally impervious barrier, says Dr. Reder.

These chemicals are called
adhesion molecules
, because they act like glue. Once inside the brain, myelin-reactive T cells multiply and likely release chemicals that bring more inflammatory cells into the area to cause damage.
⁶

MS is more common in people who live in northern climates farthest from the equator, such as Scandinavia, where there’s less (and less intense) year-round ultraviolet light from the sun to manufacture natural vitamin D in the skin. So many scientists believe that low vitamin D levels may be related to the development and disease progression in MS. This appears to be especially true in people who lived in such areas until age 15.
⁷

Animal research suggests vitamin D may prevent formation of adhesion molecules, which allow immune cells to cross the blood-brain barrier.
⁸
Recent
research shows vitamin D levels may be lower in those with progressive MS than in
relapsing-remitting MS (RRMS).
⁶

A relationship has also been found between vitamin D levels and the degree of disability in a subgroup of people with RRMS. In patients in one drug study, as vitamin D levels decreased, the number of new, active MS lesions increased, and this held true even in those considered to have adequate levels of vitamin D.
^7
,
9

A five-year international study later analyzed by researchers from Harvard suggests that blood concentration of
25-hydroxyvitamin D
, abbreviated
25(OH)D
, a marker of vitamin D status, is associated with disease activity in MS. The study used
magnetic resonance imaging
to follow 465 patients being treated after an initial episode suggestive of MS. Increases in vitamin D levels within the first year were associated with a 57 percent lower risk of new active brain lesions on MRI and a 57 percent lower risk of relapse.
⁹

These studies, intriguing as they are, are not conclusive. So consult your doctor before you start taking extra vitamin D.

The first symptom I had was actually vision loss in one eye. I went to an ophthalmologist who suspected that I had MS and wrote in my file that he suspected nerve damage, but he told me it was “only optic neuritis” and that it would go away. I immediately went and looked up optic neuritis in the encyclopedia, and it scared me because it said it was inflammation of nerves. And that led me to believe it wasn’t going to stop. And I became very frightened and thought I was going to be completely blind, but I decided to ignore it.

I went on for about six years with various symptoms that were not really conclusive enough to make a diagnosis, which I know now . . . I didn’t realize that fatigue was a part of MS, and I had other symptoms as well . . . like problems with my bladder, and dizziness if I sat down and stood up too fast. But the symptoms of MS are things everyone has at one time or another, but they’re just more magnified and chronic. Everyone has the tingling hand or the limb that falls asleep, everyone’s been tired and fatigued.

So I could easily chalk up all of my symptoms to other problems. I didn’t even think about pulling all this together. I was in my early twenties, I was going to college, I had a lot going on, and I chose to ignore it. I saw various doctors, but no one could make a definitive diagnosis.

M
ARIANA
, 39

MS can be sneaky—the first symptoms can come and go, and like Marianna you might not pay much attention to them. A mild tingling in one leg, a little trouble with your eyes. Perhaps some fatigue, joint pain, or trouble remembering things. Sometimes these symptoms last a few days and may include balance problems, slurred speech, and stiffness. Symptoms can resemble other conditions, including Lyme disease, which may also delay a diagnosis.

The most common symptom is actually fatigue, reported by up to 92 percent of MS patients.
³
“MS fatigue is very distinctive. It’s not a function of physical disability, or of not sleeping, but if you don’t sleep well that can aggravate it. These women sleep eight hours and wake up feeling like they are just drained. It’s generally made worse with heat, and generally gets worse later in the day,” says Barbara S. Giesser, MD, a professor of neurology and clinical director of the MS Program at the David Geffen School of Medicine at the University of California, Los Angeles.

Unlike other autoimmune diseases,
chronic fatigue syndrome (CFS)
, and
fibromyalgia
are not usually fellow travelers with MS. “However, I certainly have had patients who were initially erroneously diagnosed with fibromyalgia or CFS and turned out to have MS,” Dr. Giesser adds.

Depression is actually the second most common symptom of MS, reported by 50 to 70 percent of patients at some point during the course of their illness.
³
One study suggests that depression may be more common among African Americans and Latinas with MS than among Caucasian women.
¹⁰

Some women may experience wide mood swings, unprovoked and uncontrollable euphoria followed by extreme depression. In fact, Dr. Reder speculates that sometimes these mood swings, which may be attributed to
bipolar depression
(also called
manic depression
), could be an early symptom of MS. No brain lesions are found in manic depression, but they can be seen in early MS.

Depression in MS may be due to brain lesions or immune dysregulation; depression may also induce abnormalities of immune function that may contribute to MS. One recent study found that treating depression is accompanied by a reduction in
interferon-gamma
production, one of the inflammatory proteins associated with MS.
¹¹

Vision problems are very common, especially
optic neuritis
. This can take the form of blurred or hazy vision, usually in the central area, or even a
complete loss of vision. Problems can come on gradually or suddenly, and resolve quickly. Pain around the eyes may precede loss of vision, sometimes by a few hours, sometimes by a few days. An eye exam may reveal paleness at the back of the eye, indicating optic nerve damage.

Motor symptoms can include a vague feeling of weakness or heaviness in the legs (one leg may tend to drag), as well as a tendency to trip or fall. Five percent of MS patients present with a tremor, while 2 percent may suffer from nerve pain that affects the jaw called
trigeminal neuralgia
, notes Dr. Reder. Some women may have trouble swallowing or experience facial twitches or intense itching.

The most common cognitive changes are slowed thinking and visual tracking and memory retrieval, especially short-term memory. Corresponding brain changes may even be seen, such as thinning of the
corpus callosum
, which connects the two hemispheres of the brain, caused by degeneration of nerve fibers.

Some of the sensory changes experienced in MS include tingling, numbness, or feelings similar to small electrical shocks in the limbs or other areas of the body. Some women may experience vertigo or clumsiness. Five percent of women may initially experience bladder problems, a sense of urinary urgency along with more frequent urination, or incontinence. In some women, the bladder may not empty completely, and they may have frequent urinary tract infections. Bladder or urinary problems may be the only initial symptoms of MS. Heat can cause a worsening of symptoms, making it even harder for damaged neurons to communicate.

The four types of multiple sclerosis are based on general patterns of symptoms
¹²
:

• Relapsing-remitting MS (RRMS).
  This is the most common type of MS, in which symptoms flare and then go into remission. This respite may be due to bursts of inflammation that subside or to the regeneration of myelin. That inflammation can be seen on MRI using a special contrast agent. Up to 75 percent of people with MS have the relapsing-remitting type.
  
• Primary progressive MS (PPMS).
  In this type of MS, there are continual attacks on nerves and inflammation with no remissions, causing increasing disability; about 10 percent of patients
  have primary progressive MS. (This is actually more common in men.)
  
• Secondary progressive MS (SPMS).
  About two-thirds of people with the milder relapsing-remitting MS evolve into a secondary progressive form. This can occur with or without occasional flares, minor remissions, and even long plateaus of stability in the disease. But eventually the disease keeps worsening, with a progressive loss of axons.
  
• Progressive-relapsing (PRMS).
  This is relatively rare, occurring in about 5 percent of patients. In this type of MS, there’s a steady worsening of disease from the start, but with distinct flare-ups that may or may not get better. There’s continued disease progression in between flare-ups.
  

Ana’s story continues:

I’d had a cold and sinus infection the winter before I was diagnosed. It seemed like it would never go away. And I had started to feel dizzy. / felt dizzy all the time. I figured it was from the sinus infection, so I went to see an ear, nose, and throat doctor. I was tested for Lyme disease, which came back negative. I had all kinds of other tests, but nothing showed up. The doctor was concerned about the dizziness, and sent me to a balance function center. I went through a whole set of tests. But they couldn’t determine what was wrong. I was eventually sent for a brain scan, and that’s when they saw small lesions. I also had a spinal tap. That’s when I was told I probably had MS for some time. I was lucky to be diagnosed so quickly.