Abstract
Achlorhydria is a gastrointestinal disorder where the parietal cells no longer function and acid secretion does not occur. We report on a case where the therapeutic use of inositol hexaniacinate (IHN) was effective for the treatment of achlorhydria. The patient presented to the Robert Schad Naturopathic Clinic with complaints of bloating, intermittent diarrhea, gas, chronic throat irritation, perianal swelling and back pain related to maldigestion. The patient's initial fasting gastric pH was 7, indicative of achlorhydria. The patient was instructed to take 650mg three times daily of IHN, a form of niacin (nicotinic acid). After approximately three weeks of use, the pH returned to 1, which is considered normal. A little more than three weeks later, the gastric pH continued to be within the normal range, but did increase to a 3. IHN might enhance the production of hydrochloric acid (HCl) in a manner that cannot be explained by it simply being an acid. The benefits of IHN might be due, in part, to its stress-moderating properties upon the central nervous system. We further postulate that IHN works by priming the parietal cells for the production of mitochondrial adenosine triphosphate (ATP). This priming action provides the cellular energy necessary to drive the process of generating HCl from the parietal cells. These mechanisms of action might be responsible for the therapeutic change in gastric acidity as demonstrated by repeated fasting gastric pH measurements, and by the relief of gastrointestinal symptoms as noted by the patient.

Introduction
Hypochlorhydria is a condition where the parietal cells of the stomach secrete insufficient amounts of hydrochloric acid (HCl). Achlorhydria is simply a more severe form of hypochlorhydria where the parietal cells no longer function and acid secretion does not occur. The consequences of hypo- and achlorhydria include an increased susceptibility to gastric bacterial overgrowth,¹ enteric infections,^2,3 hypergastrinemia that might lead to enterochromaffin-like cell hyperplasia and neoplasia,^4-7 and malabsorption of various nutrients (e.g., calcium, iron and zinc) and amino acids.^8,9 The proper production of HCl is therefore essential for optimal health. It renders the stomach sterile against pathogens, prevents fungal and bacterial overgrowth of the small intestine, facilitates the flow of bile and pancreatic enzymes, and enables the proper absorption of protein and a variety of nutrients. When HCl production is insufficient or absent, the gastric pH will not be sufficiently acidic, digestion will be impaired, and numerous signs and symptoms develop. Table 1 lists the most common signs and symptoms associated with deficient or absent HCl production.

Table 1 here in our print magazine

We report on a case where the therapeutic use of inositol hexaniacinate (IHN), a form of niacin (nicotinic acid), was effective for the treatment of achlorhydria. A previous report by Prousky,¹⁰ and a subsequent report by Prousky & Kerwin¹¹ demonstrate that niacin is potentially an effective nutraceutical for the treatment of hypochlorhydria and achlorhydria. The strength of these reports might have been diminished, in part, for the following two reasons. First, niacin is an effective anti-stress agent¹² and therefore any reduction in gastrointestinal symptoms might simply be due to stress reduction rather than through the augmentation of gastric acid secretion. Second, niacin is itself an acid. Its acidic properties alone might be the reason for any improvement in gastrointestinal symptoms, especially, if they were initially related to a deficiency in gastric acid secretion.

We evaluated the effects that IHN has upon the gastric system by repeatedly using the Gastro-Test^®, a non-invasive diagnostic test for the immediate determination of gastric pH.¹³ The Gastro-Test^® compares well with gastric intubation in pH determination and in the diagnosis of achlorhydria.^13,14 We administered the Gastro-Test^® under fasting conditions since fasting gastric pH is a reliable indicator of hypochlorhydria and achlorhydria.^15,16 As will be demonstrated in this patient report, IHN does appear to enhance the production of HCl in a manner that cannot fully be explained by it simply being an acid.

Materials and Methods
The Gastro-Test^® indicates the presence of low acid (hypochlorhydria), no acid (achlorhydria) and bleeding (esophageal or gastric). The test consists of a weighted gelatin capsule with 70cm of highly absorbent cotton floss attached within the capsule. The floss is attached to one end of the capsule. The test kit also includes a surface marking pH stick and a pH color chart.

The patient was instructed to fast for eight to twelve hours prior to the administration of the Gastro-Test^®. Water, but not food, was allowed anytime during the fast. The patient was seated and the floss-filled capsule was placed in the patient's mouth. The protruding string, attached to the end of the capsule, was taped to the patient's cheek. The patient then drank one-to-two cups (approximately 240-480 ml) of water and swallowed the capsule.

The patient then lay on his left side for ten minutes. Lying down allows for maximal contact between the floss and the gastric pool. After ten minutes, the patient was instructed to sit in a comfortable chair with his head slightly extended. The tape was removed from the cheek and the floss withdrawn from the mouth. The floss was then placed on a piece of white exam paper to augment visualization of the color change. The pH stick was rubbed along the moist end of the string and the resultant color change was then compared to the pH color chart. A pH of 3 or less on any part of the distal half of the floss indicates that the stomach is secreting hydrochloric acid properly. A pH greater than 3 indicates hypochlorhydria, whereas a pH of 5 or above indicates achlorhydria.

This procedure was performed three times on 8-27-02, once on 9-17-02, and again on 10-09-02. No complications were seen or reported during and after the administration of the Gastro-Test^®.

Case
A 39-year old Caucasian male presented to The Robert Schad Naturopathic Clinic (RSNC) on 8-18-02 with chief complaints of bloating, intermittent diarrhea, gas, chronic throat irritation, perianal swelling, and back pain related to maldigestion. The gastrointestinal complaints had persisted for the previous 10 years, reaching a peak 4 years ago. At this time the patient quit smoking and regular coffee drinking. These dietary changes improved his symptoms but did not completely resolve them. The patient currently works as a custodian at a church and reports that there is little stress in his life. He has no family history of gastrointestinal disease. He had seen numerous family physicians for his complaints, but was never prescribed any medications. Physical examination revealed a well-nourished male, with normal vital signs and normal heart sounds. His skin was dry and pale, most notably along his face, upper thorax and legs. There was also mild right-lower quadrant tenderness without rigidity or rebound signs.

The patient returned 1-week later, 8-27-02, for three consecutive fasting Gastro-Tests^®. Each test administered 15 minutes apart. The first test revealed a fasting gastric pH of 7, indicating marked achlorhydria. A second Gastro-Test^® was administered following a challenge with 500mg of non-sustained release niacin (Jamieson Laboratories). The distal 5cm of the string showed a pH of 3. A change of 4 pH points since the first Gastro-Test^® clearly indicates that gastric pH can be made more acidic by taking oral niacin. A third Gastro-Test^® was performed with an additional 1000mg of non-sustained release niacin. This time the result, once again, demonstrated a pH of 7. It is unclear why the pH reverted to a 7. Perhaps the parietal cells could no longer respond to the addition of more acid with the third Gastro-Test^®.

The patient was then prescribed 1000mg of non-sustained release niacin (Jamieson Laboratories) three times each day. It was also recommended that he reduce his intake of fried foods, especially bacon and fast-food hamburgers. He was further instructed to have one salad daily in addition to increasing his intake of fruits and vegetables (no exact amount was specified).

Two days after commencing the dietary and niacin treatment the patient felt a sense of well being, increased energy, with significant improvement in his throat irritation and perianal swelling. However, by the end of the first two days of treatment the patient experienced a superficial rash with swelling and pruritis along the upper thorax, with the axilla and inner thighs being the areas most affected. He went to the emergency room of a local hospital and was given an oral antihistamine. He was also told to discontinue the niacin. Within 24 hours the superficial rash completely cleared.

The patient resumed his niacin treatment the next day, but was switched to the IHN form to reduce the potential for flushing. Each IHN capsule contains 150mg of inositol and 500mg of niacin. He was instructed to take one capsule three times daily. He came back to the RSNC on 9-17-02 for a fasting Gastro-Test^®. The patient fasted seven hours and during the day of the test did not take any IHN. He drank as much water as he desired during the fast, but did not consume any food. The Gastro-Test^® showed a pH of 1 at the distal 8cm of the string. The patient noticed a reduction in gastrointestinal bloating and claimed to have better-formed stools. The patient also reported an increase in energy. Objectively, the patient appeared more upbeat and his skin had less dryness and more of a pinkish color compared to our initial evaluation. The patient also remarked that his skin looked better.

The patient returned to the RSNC on 10-09-02 for a repeat Gastro-Test^®. The patient fasted six hours and during the day of the test did not take any IHN. The Gastro-Test^® showed a pH of 3 at the distal 6cm of the string. The patient once again remarked on his improved health and almost complete absence of gastrointestinal symptoms. A summary of the Gastro-Test^® results for the three office visits are listed in Table 2.

Table 2 here in our print magazine

Discussion
By using the Gastro-Test^® we were able to demonstrate that IHN might play a role in both the reduction of achlorhydria-related symptoms and in augmenting gastric acid secretion.

One question that was posed concerning IHN's role in changing gastric acidity was whether or not the decrease in gastric pH could be accounted for solely by niacin’s inherent acidity. We referred to one of the basic chemistry equations, the Henderson-Hasselbach equation. This equation relates pH to the dissociation constant of an acid, the pKa, and the log of the concentration of the protonated acid, [HA] to its deprotonated conjugate base, [A-]. This is dependent on the amount of acid and on the volume in which the acid is in solution.

In effect, the greater the pKa, the weaker the acid. To illustrate, the pKa of HCl, a very strong acid, is -7 whereas, the pKa of niacin is 4.85, a relatively weak acid.^17,18 Niacin has acidic properties because the hydrogen from the carboxylic acid group can dissociate in solution.

Niacin is a much weaker acid than HCl, and therefore, we expected that it would not have much effect in directly increasing stomach acidity. However, it did appear to have a significant effect in this one patient. A 1-gram dose of niacin when hypothetically administered under fasting conditions was compared to a 1-gram dose of niacin when hypothetically administered under a non-fasting state. In a fasting state the stomach lumen volume is approximately 50ml, and with the addition of 1-gram of niacin calculated without any HCl present, the pH would drop to approximately 2.8.¹⁹ If someone had taken 1-gram of niacin with a large meal (stomach lumen volume approximately 1L or 1000ml), again calculated without HCl being present, the pH would drop to 3.8.¹⁹ The calculations for the fasting and non-fasting pH can be found in Table 3.

Table 3 here in our print magazine

In the case report, the patient was instructed to fast prior to the administration of the Gastro-Test^®. On at least two occasions, the Gastro-Test^® was administered without any niacin being present in the stomach lumen. Therefore, any change in overall gastric acidity could not be accounted for by the direct acidifying effect of niacin. The beneficial change in gastric acidity appears to have been the result of IHN's biochemical role in acting as a substrate for the parietal-cell mitochondria production of adenosine triphosphate (ATP). Half the parietal cell volume is occupied by mitochondria,²⁰ making the parietal cells the largest storehouse of mitochondria among all eukaryotic cells.²¹A report by Spenney,²⁰ elucidating the mechanisms of HCl secretion, has shown it to be an ATP-dependent process. The ATP synthesized from mitochondrial energy, once stimulated to breakdown mediates HCl secretion, and provides the necessary fuel that facilitates the exchange of K+ for H+ occurring within the canalicular membrane of the parietal cell.²⁰ Two additional reports postulated that niacin derived NADH is essential for optimal mitochondrial functioning, leading to the production of ATP that drives the generation of HCl from the parietal cells.^10,11

Additional support for niacin's unique biochemical role in energetically stimulating the parietal cells has to do with the form of niacin used. Initially, the patient was prescribed non-sustained release niacin. However, due to an unpleasant reaction the patient was instructed to switch to IHN. When we contrast IHN to that of niacin, there will essentially be no immediate acidifying effect in the stomach. IHN is composed of six niacin molecules ester bonded with one central inositol molecule. The IHN is absorbed essentially intact, and, unlike niacin, it does not act as an acid in the stomach. Therefore, there is no mechanism by which IHN can directly acidify the stomach. However, as we have seen clinically in this patient, IHN does appear to cause a lowering of gastric pH with continual daily use.

Even though our patient did not present with anxiety or neurasthenic symptoms, the ability of IHN to moderate stress might explain some of the observed clinical changes in both the gastric pH and in the patient’s reported improvements. Studies have delineated the role of the central nervous system (CNS) in conducting and processing visceral signals and suggest that alteration in brain processes involving perception and affective responses play key factors in the pathogenesis of functional gastrointestinal symptoms.^22,23 Thus, the ability of IHN to lower gastric pH to normal might also, in part, be due to its known moderating effects upon the CNS.

The niacin, contained within the larger IHN molecule, converts to the nicotinamide nucleotide coenzymes within the liver and also converts to niacinamide, the amide form of niacin.²⁴ Studies with niacinamide demonstrate pharmacological effects similar to the benzodiazepine medications,^25,26 supporting the putative role of IHN in CNS modulation.

The inositol part of the IHN molecule also has beneficial effects upon the CNS as shown in previous double-blind studies on depression,^27,28 panic disorder,²⁹ and obsessive-compulsive disorder.³⁰ The daily amount of inositol used by our patient, 450mg/day, was well below the 12g or more per day used in the cited clinical studies.^27-30 However, this small amount of inositol, combined with a larger amount of niacin, might still be able to moderate stress levels and favorably impact the gastric system by influencing the CNS.

Although not proven, IHN might favorably impact the CNS in such a way as to reduce the patient's perception of bloating as well as other gastrointestinal symptoms. IHN might also moderate afferent nervous transmissions from the gastric mucosa itself. Another possible effect might be the stimulation and/or normalization of parasympathetic tone. The overall net effect of these possible CNS (i.e., brain-gut) interactions would be improved gastric function since a relaxed state facilitates optimal gastric acid release.

Evaluation & Management Strategy
We propose a clinical model (Table 4) to help the clinician evaluate and treat upper gastrointestinal symptoms that might be due to deficient or absent HCl production.

Table 4 here in our print magazine.

Conclusion
Niacin does have an immediate acidifying effect in the stomach. However, this effect is probably not significant enough to account for the continuous increase in gastric acidity as seen clinically in this case. The patient switched to the IHN form of niacin after just two days of use. After approximately three weeks of taking 650mg of IHN three times daily, the patient's gastric acidity reverted to normal. His gastric acid, as measured by the Gastro-Test^®, remained normal even after he had fasted for 7 hours. Therefore, the moderating effects that IHN has upon the CNS and its priming of the parietal cells for the production of mitochondrial ATP, might be the central reasons that explain the therapeutic change in gastric acidity and the relief of symptoms as noted by the patient.

Acknowledgements
The authors would like to thank David Lescheid, PhD, ND, and Nick DeGroot, BSc, ND for their assistance and thorough review of this manuscript. Additional thanks goes to Jamieson Laboratories for their donation of non-sustained release niacin tablets and HDC Corporation for their donation of the Gastro-Test^® kits. These companies did not pay for this published case report nor did they influence/oversee any of the data contained within the case report. Written consent was obtained from the patient for publication of this study.

Correspondence:
J. Prousky, ND, FRSH, CCNM
1255 Sheppard Ave. E.
Toronto, Ontario M2K 1E2 Canada
jprousky@ccnm.edu

Dr. Prousky is the Associate Naturopathic Medical Officer and an Assistant Professor of Clinical Nutrition at The Canadian College of Naturopathic Medicine. Dugald Seely is a fourth-year Clinical Intern at The Canadian College of Naturopathic Medicine.

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