Not all patients with myasthenia gravis are grave

Myasthenia gravis (MG) is another autoimmune disease in that the body is tricked to think acetylcholine receptor, an important component in the nerve conduction, is ‘foreign’ and dutifully attacks it.

There is a gap between nerves or between nerve and muscle, through which the conduction of impulse depends on chemical substances called neurotransmitters, in the case of MG, it is acetylcholine between nerve and muscle.

There are two clinical forms of myasthenia gravis: (1) ocular form (affects the eyes only)  and (2) generalized form (may affect any skeletal muscles on the whole body) Myasthenia means “muscle debility”; Latin gravis means “serious” and having a generalized form of myasthenia gravis is indeed serious (grave); but this dreaded name makes the more limited ocular form seem more serious than it actually is.

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About half (50%) of patients with purely ocular MG are seropositive (i.e. has acetylcholine antibody in the blood).  About 85% of patients with generalized form, and virtually all patients (98-100%) with MG and thymoma (tumor in thymus) have this antibody.

About 10-15% of MG patients have thymoma, and about 85% have thymic hyperplasia (i.e. thymus gland overgrow, but there is no tumor) It is postulated that all patients with myasthenia gravis have B cells that produces acetylcholine antibody.

Most experts feel it is beneficial to surgically remove thymus gland (whether thymic hyperplasia or thymoma) and it may take many years to see the benefit of thymectomy (surgical removal of thymus).

It is well known that a given disease may present with a widely varying severity and course.  Another example is amyotrophic lateral sclerosis (better known as Lou Gehrig’s disease in the U.S.) in which the motor neurons are destroyed.  Lou Gehrig succumbed to it less than two years after he proclaimed that he was “the luckiest man on the face of the Earth.” in his touching farewell address at Yankee Stadium.  And yet Stephen Hawking has lived with this disease for more than 40 years and is still going on ‘strong’ in his quest in the fields of cosmology and quantum gravity.

Pernicious anemia is no longer pernicious

The once invariably fatal pernicious anemia is nowadays easily treated with a monthly injection of vitamin B₁₂.  Vitamin B₁₂ (cobalamin) is only present in animal products (meat and dairy products).  Cobalamin is required in making blood; without proper supplement, the strict vegetarians are in danger of developing megaloblastic anemia.
 
The cobalamin we take in needs intrinsic factor (secreted by parietal cells lining the stomach) to carry it to the small intestine (terminal ileum) to be absorbed.  Pernicious anemia is one of the numerous autoimmune diseases that plagues us.  The body somehow treats the intrinsic factor (IF) as ‘foreign’ and attacks it, rendering it useless.  This is why pernicious anemia has to be treated with injection of cobalamin, and taking it orally wouldn’t work.

Recent discovery that there is second back up transport system for cobalamin, lower efficiency though it may be, that does not require intrinsic factor or a functional terminal ileum.  But, it requires taking megadose (at least 1,000 to 2,000 μg (1-2 mg) orally a day. (for injection 1,000 μg or even 100 μg a month is more than enough.)

The word ‘pernicious’ means highly destructive or exceedingly harmful; Shakespeare used it in Henry VI (part 2), “Pernicious blood-sucker of sleeping men!” its Latin root “nex” means ‘violent death’.  English physician Thomas Addison first described it in 1855 and German physician Anton Biermer coined the name of “pernicious anemia” in 1872.

Pernicious anemia was still invariably fatal in 1930s when three physicians (two from Harvard) were honored with Nobel Prizes in Medicine (1934) for their using liver-rich diet in successfully treating patients with pernicious anemia.  I read the following in the presentation speech in 1934 Nobel Prize in Medicine,

“I propose to say a little about pernicious anemia.  As the name tells us, it is a fateful disease, which, previous to the labours of our prize-winners, almost invariably, with only a few exceptions, ended fatally in the course of a few years, or in a still shorter time, a few months.  Its cause is unknown. . .”

Of note, vitamin B₁₂ was not isolated until 1948 and they didn’t have any idea of what actually helped; medical science was not always exact, even for the Nobel-Prize work, in those days.  And those improved upon this diet probably did not have true pernicious anemia, in which 70% would have antibody against intrinsic factor (IF) and would require vitamin B₁₂ injections to get better.

Many elderly have atrophic gastritis leading to decline in IF production, in which cases, antibodies are directly against the gastric parietal cells that produce IF.  The inadequacy of IF can be compensated by the realtively large amount of vitamin B₁₂ in the diet, otherwise, these three physicians wouldn't succeed and became laureates.

Medical students learn Structure and Function in their first year schooling before they plunge into the Scientific Basis of Medicine the second year.  Using X ray crystallography technique; Dorothy Crawfoot Hodgkin labored, coupled with high intellect and intuition, from 1948 to 1956, and figured out the structure of vitamin B₁₂, a very large and complex biomolecule—a tremendous feat that earned her the Nobel Prize in Chemistry in 1964.  I believe that the Iron Lady, Margaret Thatcher once studied under Dorothy Hodgkin at Oxford.
 
Elucidation of the structure of vitamin B₁₂ opened the door of the understanding of the metabolism, synthesis, and function of vitamin B₁₂ that we have come to know.  And the name of pernicious anemia stays only for sentimental reason.

Exubera never brought exuberance to Pfizer

It was touted as a revolutionary new delivery system for insulin since it was developed some 80 years ago when Exubera, an inhaled insulin, was approved for adults with types 1 or 2 diabetes in January 2006.

Unfortunately it never took off, failing to gain the acceptance of patients and physicians and Pfizer announced on October 18, 2007 that it will end the marketing of Exubera, phasing it out over the next three months.

It was a business decision and there was no issue of safety or efficacy.  But FDA has warned on April 10, 2008 that more cases of lung cancers have been reported in patients treated with Exubera than in controls in clinical trials. FDA added that “too few cases to determine whether the emergence of these events is related to Exubera” and all patients diagnosed with lung cancer had a history of cigarette smoking.

Having a ‘philosophy’ of “never be the first one to use the new medicine o.r the last one to discard the old medicine,” I somehow never prescribed Exubera.