The Etiology of Pernicious Anemia

The work of Minot and Murphy is today recognized as a most laudable achievement. The value of liver feeding in the treatment of pernicious anemia is unquestionably established. Recently the observation was made that equally good results were obtainable when the lining of the hog’s stomach was included in the pernicious anemia patient’s diet. Today a dried liver extract, fairly palatable, is on the market. Little is known concerning its chemical structure, except that it is not a protein. So, again, we see the strange phenomenon which has so often spread itself over the pages of medical history that a new remedy, rather accidentally found, had its worth proven by clinical application, the scientific explanation still remainIng an enigma.

When we stay in the realms of inorganic chemistry, it is often simple to solve chemical riddles. Not so concerning colloid chemistry! For instance, take a celery stem or the stem of the red beet; both are extremely rich in colloid sodium salts, especially sodium chloride, but when the raw stem is tasted, salt seems so entirely lacking that the custom is to dip it in salt to make it palatable. When these stems are boiled in water, the salt tang is more noticeable, but when they are baked in dry heat at oven temperature until they are dry and brittle, and then tasted, the tongue detects an intense saltiness. They are then too salty to be palatable. Here is the best example of chemical difference between colloid and crystalloid sodium chloride: the difference between a living man and the ashes following cremation. Plants get their nourishment from the minerals in the soil and the gas from the air; animals from plants or directly, from eating other animals. Animal and vegetable foods are colloidal compounds.

If it is granted that colloidal sodium chloride, as it is found in nature in the various fruits and vegetables and in animal tissues, is the only form in which sodium chloride can be used in the body chemistry, the question follows, what becomes of all the inorganic table salt that we eat? And why do we eat so much of it? Man certainly does not need it, for the healthiest specimens of men known are the Eskimos, who never use it. Neither do many of the tribes of interior China. Benjamin Rush noted that the American Indians, whose health was a by-word until the white man’s peculiar ways of eating decimated them, never used salt.

One of the principal reasons why we eat salt is because we are mineral-starved and need a substitute for the colloidal sodium chloride that is so sadly lacking in the ordinary diet. Moreover, it is a stimulant. Animals like it for the same reason.

Metabolism of Sodium Chloride

Most authorities agree that an excess of sodium chloride is harmful to the human body, in that it predisposes to kidney impairment. When sodium chloride is eaten in larger quantities than it can be eliminated through the kidney and skin, an excess must be present. What does the body do with this excess? Experiments have shown that different tissues of the body will retain the salt excess. Padtberg¹ demonstrated that, if a dog received an intravenous injection of sodium chloride, 28 to 77 percent of the saline retained by the body accumulated in the skin. Mary Whelan² showed that, during an injection of hypertonic sodium chloride solution, blood taken from veins on the opposite side of the body showed no significant quantitative changes or increase of sodium chloride. Just what tissues held the excess she did not say. J. Hamilton Crawford³ of Edinburgh, says:

“When one compares the water excretion with the salt excretion (after giving one liter of water or sodium chloride solution), it is seen that only a small amount of the salt taken was excreted, while the urine volume was only slightly reduced, Sult must thus have been retained in the body without the retention of the amount of water which would be necessary to reduce it to isotonicity. Probably most of it was stored in the issues.”

Blum and Broun⁴ measured the chlorine and the sodium in organs from twelve patients dead from uremia. Retention of chlorine was manifest in various organs, especially in the brain. It was doubled or trebled in the white matter and increased from four to seven times in the gray matter. They also believe that chemical changes, such as an increase of sodium chloride in the cerebral tissue, play an important, if not a predominant, part in the pathogenesis of uremia.

Muller and Quinke⁵ found that there was a great increase in the percentage of chlorides in the skeletal muscles in tuberculosis Since they had previously ascertained that there was a decrease of chlorides in the blood in tuberculosis, it would appear that the chlorides have been sidetracked from the blood to the muscles. Butts and Hoff⁶ showed that neoplastic tissue contains excess sodium chloride, as tested by dynamic surface tension of solutions and also by spectroscopic examination. Haden and Orr⁷ have suggested that low plasma chloride in intestinal obstruction is due to migration of chlorides to the tissues, as part of a protective mechanism. It is my belief that the chlorides are sidetracked to enhance the kidney function for the more rapid and efficient elimination of protein waste products from the obstructed and degenerating bowel.

It is doubtful whether the kidneys ever do normally excrete sodium chloride. Harris A. Houghton⁸ believes that sodium chloride is an irritant to the renal epithelium. He has shown that the kidneys refuse to excrete it into the urine under normal circumstances, when the concentration in the plasma is less than 563 mgm. per 100 cc. of plasma. When the plasma content increases, sodium chloride is forced through the kidney-filtering apparatus under pressure. Often, to make this elimination possible, the blood pressure actually rises, and when salt is eliminated from the diet and the plasma sodium chloride decreases, the blood pressure also decreases. This is a well known fact.

When the plasma sodium chloride is increased, it is sometimes sidetracked into the cerebrospinal fluid, where its irritating effect may cause convulsions. That sodium chloride, even in isotonic solution, when used to irrigate the ventricles of the brain, is a very violent irritant, causing insanity and paralysis in cats, has been ably demonstrated by Weed and Wegeforth.⁹ Thus we see that sodium chloride can be sidetracked, not only into various body tissues, but that, when it reaches certain concentrations in those tissues, it can, even cause marked local disturbances. It is my belief that the sidetracking of sodium chloride into the bone marrow, where it not only interferes with the production of crythrocyytcs, but also causes hemolysis,¹⁰ gives a clue to the etiology of pernicious anemia. But before proceeding with this explanation, a few words must be said concerning the elimination of sodium chloride through vicarious channels.

Elimination of Sodium Chloride

Erben and Rumpf,¹¹ who each made most careful chemical examinations of the blood in pernicious anemia, showed “an excessively large proportion of sodium chloride.”

It is my belief that, long before pernicious anemia can be clinically recognized, this increased sodium chloride in the patient’s plasma tries to gain an outlet vicariously. First we have catarrh of the nasopharynx, with very salty mucus. One has only to taste the mucus to confirm this fact. The corrosive action of this mucus causes atrophy and paleness of the mucus membrane. Finally the catarrh disappears, because of the atrophy.¹² Here we have an illustration of glandular tissue destroyed by excess sodium chloride.

In the stomach the example is even more interesting. Early in the case, often during adolescence, we get the history of heartburn, acid eructations and belching of gas. At this time, due to the high sodium chloride in the plasma, the gastric cells are secreting more than the normal amount of hydrochloric acid. It is a well known fact that the source of the chlorine of the hydrochloric acid in the gastric juice is the plasma sodium chloride. It is of interest here to note that Talbert and Rosenburg¹³ showed that, during sweating (rapid elimination of plasma sodium chloride through the skin), there is a more or less sudden decline in the gastric acidity. In control experiments, in which sweating was omitted, a more sustained acidity was present until the end of digestion.

Osler noted that pernicious anemia was very rare in the tropics, where sweating is common. But in most pernicious anemia patients the skin is dry and thin and even a mild degree of sweating is the exception This throws upon the mucous membrane of the stomach the burden of trying to eliminate excess sodium chloride from the plasma, resulting in a more or less constant hyperchlorhydria. This incessant hyperchlorhydria has a devastating effect on the hydrochloric-acid-secreting cells, as well as upsetting digestion. Gradually atrophy occurs, similar to that seen in the nasal mucous membrane; and with atrophy comes achylia, which often precedes, by years, the actual state of pernicious anemia. In fact, the case need not necessarily progress to pernicious anemia. Death may supervene from other causes (a sidetracking of sodium chloride into some vital organ), the bone marrow having been spared.

There are many interesting hypotheses explaining why salt is craved to excess. Besides its stimulating effect on the glands of internal secretion, it serves to maintain a normal osmotic balance between the cells and the circulation. But there is a great difference between the normal, colloidal sodium chloride compounds and simple inorganic sodium chloride, which is nothing more nor less than an embalming fluid.

Sodium Chloride in the Organs

ln the illustrations (Fig. I) are shown, diagrammatically, two cells. That on the left is a normal cell, its chlorides being in the form of organic colloidal chlorides. On the right is pictured another cell, the colloid chloride compounds having been replaced by inorganic sodium chloride, which changes the state of turgescence of the cell, shrivels it somewhat, while at the same time it contains loosely-bound water (edema), in order to maintain a normal osmotic balance. The cell on the left is physiologic while that on the right is pathologic. When the inorganic sodium chloride is replaced by the organic chloride compounds, the cell is again normal. When inorganic sodium chloride invades the body, certain tissues become fixed with it before others. According to Munk and Rocnstein¹⁴ the following table represents the percentage of inorganic sodium chloride in the tissues listed:

 

Cartilage Fibrous tissue Brain Muscle Spleen Liver

0.90 0.70 0.20 0.08 0.04 0.02

Although the liver is very poor in inorganic sodium chloride, the bile contains many of the sodium salts, such as those of glycocholic and taurocholic acids and many other very complex and little-understood colloidal sodium compounds. It is, therefore, my belief that inorganic sodium chloride would tend to interfere greatly with the liver function and would be sidetracked into less vital tissues or organs first, thus giving the liver a chance to function normally; also that the liver is the great storehouse of colloidal sodium compounds of the body and, being especially rich in that element, would be the ideal food to replace organic sodium chloride in cases such as pernicious anemia. That this element is present in the non-protein, potent liver extracts that are beneficial in pernicious anemia seems logically reasonable.

There is also another tissue which we would expect to find rich in organic sodium. That is the mucous membrane of the stomach. For the secretion of physiologic hydrochloric acid, the following equation may hold:

 

NaCl (plasma) + H (colloid) → HCl + Na (colloid)

 

So here, again, we have a tissue rich in colloidal sodium, probably similar to that in the liver. It is a well known fact today that the lining of the pig’s stomach is especially efficacious in pernicious anemia. After the feeding of liver, liver extract or pig’s stomach (especially raw), the amount of inorganic sodium chloride excreted in the urine increases very greatly, sometimes enough to irritate and inflame the bladder. It is my belief that the organic colloidal chloride has been substituted for the inorganic sodium chloride, which is rapidly excreted; sometimes too rapidly for the wellbeing of the patient’s kidneys and bladder.

In pernicious anemia, where the function of the bone marrow is greatly interfered with, the restoration of colloidal sodium by liver or stomach feeding should, theoretically, allow for a restoration of hematopoietic function. Clinically we know that this actually happens. lt is my belief that it is just as important to exclude inorganic sodium chloride from the diet of the pernicious anemia patient as it is to feed him liver. F. M. Allen,¹⁵ in a notable paper says:

“We observed distinct and positive benefits, the majority ol pernicious anemia cases, on a salt-free diet, before we ever used liver, and it seems reasonable to employ every means that affords any reasonable help. Especially in the simple anemia cases, we have the impression that the diet with exclusion of salt gives better results than are obtained with only liver feeding.”

It would be of interest at this point to quote a few statements from the recent publication, Quantitative Clinical Chemistry:¹⁶

“Chlorides are found in all the tissues of the organism. It has generally been assumed that all the chloride in the body is inorganic. Hanke and Donovan, however, in a report at present accessible only in abstract form, find that from 10 to 50 percent of the chloride in the different tissues is in combination with hypoid substances soluble in organic solvents. The estimate that probably 15 to 20 percent of the total chlorine of the body is in that organic form. In the liver and the mucosa of the gastric fundus half the chlorine was found to be organic, in the pyloric and duodenal mucosa about a third, and in the blood 12 percent. The chloro-lipoids readily form suspensions in water which undergo slow hydrolysis, splitting off HCI and reducing the pH to 2.5.-3.5. It appears possible that the CI may replace one of the OH groups of the glycerol in one or more lipoid molecules, and that hydrolysis of such chloroesters in the gastric mucosa may produce the gastric HCA.

“Sunderman, F. W.,(personal communication), by extraction and other procedures, has secured more direct chemical evidence that organic chlorine compounds occur in certain sera.”

“From the fact that chlorides have been found in all! the cells and fluids of the body it has been inferred that cell boundaries are, in general, pervious to the chloride ion. In the lymph and serous fluids the CI concentration is a few percent higher than in the blood plasma. In the blood cells it is only about half as high, and in the muscles less than one third as high as in the plasma. The causes of the fact that the chloride distribution is so unequal, despite the ready divisibility of the chloride anion, were studied in the cases of blood cells and plasma.”

One of the explanations offered is that an excess NCI would greatly interfere with the alkali-binding powers of the protein colloids. In other words, a “salting out” process could occur rendering certain protein colloids useless to the body metabolism. It is possible that these “salted out” colloids compose the toxic NaCI colloids that are sidetracked into the bone marrow and result in a paralysis of the hematopoietic function, giving the clinical and laboratory picture of pernicious anemia.

Conclusion

My conclusion is that pernicious anemia is the result of a chronic sodium chloride poisoning of the hematopoietic system.

The great Mackenzie wrote:

“The first appearance of disease in the human body is invariably insidious, with little disturbance of the economy and no visible signs of its presence. By and by the patient becomes conscious that all is not well with him: there is a loss of that feeling of wellbeing which accompanies the healthy state. Disagreeable sensations arise, at first vague, but later becoming more definite, and these may become so urgent that he seeks advice. Still no evident sign of disease may be perceived on the most careful examination. By and by the disease, being situated in some organ or tissue, changes the constitution of that part, so that its presence is now recognized.by a physical sign, when the clinical methods usually employed reveal its character.”

It is only by careful chemical examination of secretions, such as mucus, tears, gastric juice, urine, joint fluids, spinal fluid and blood, that we can arrive at early diagnosis of salt poisoning. This has been emphasized by me once before.¹⁷ Our figures for the normal blood chlorides are all too high, since most of the so-called normal cases are early cases of salt retention.

Again to quote Mackenzie: “There are evidences which would surely indicate the nature of the disease in its earliest stages, were we capable of detecting them.” If we are ever to be able to detect these evidences, we must look for them as chemical pathologists.