Achlorhydria

Gastric acid is the fluid secreted by the stomach. It is composed of hydrochloric acid, potassium chloride, and sodium chloride. Hydrochloric acid plays an integral part in the digestion of food and protects our body against pathogens ingested with food or water. The parietal cells lining the stomach are mainly involved in its production. Achlorhydria or hypochlorhydria refer to conditions in which production of hydrochloric acid in the stomach is respectively absent or reduced. It is usually secondary to an underlying medical condition.[1][2]

Multiple disorders can cause achlorhydria. [3][4][5]

• Pernicious anemia (anti-parietal and anti-intrinsic factor antibodies): It is an autoimmune phenomenon in which antibodies are formed. These autoantibodies cause the autoimmune destruction of parietal cells leading to atrophic gastritis.
• Use of antisecretory medications: Short-term standard dose treatment with PPI has been shown to have low risk, but long-term use of PPI has been linked to hypochlorhydria.
• Helicobacter pylori infection: Acute H. pylori infection of gastric epithelial cells represses H-K-ATPase alpha subunit gene expression leading to transient hypochlorhydria and supporting H. pylori proliferation. This growth of H. pylori may even initiate a pathological process causing gastric cancer.
• Gastric bypass: Gastric bypass is a gastric exclusion operation performed in patients with massive obesity to reduce food intake. Studies show that the acid secretion unbuffered by the food in the excluded stomach results in lowered gastrin secretion hence leading to achlorhydria in such patients.
• VIPomas: VIPoma is an endocrine tumor that usually arises from beta-pancreatic cells and secretes Vasoactive intestinal peptide. It may be associated with MEN1. The massive amounts of VIP secretion cause watery diarrhea, hypokalemia, achlorhydria, vasodilation, hypercalcemia, and hyperglycemia.
• Hypothyroidism: Thyroid hormone plays a role in hydrochloric acid secretion hence hypothyroidism can lead to achlorhydria.
• Radiation to stomach: Radiation to stomach has also been reported to cause achlorhydria.
• Gastric cancer: Animal studies have shown evidence of achlorhydria in gastric cancer.

A study conducted in healthy people and patients with gastrointestinal (GI) diseases showed an increased incidence of achlorhydria and hypochlorhydria in women, but the results were not significant. In patients younger than 60 years of age, the incidence of achlorhydria and hypochlorhydria were 2.3% and 2% respectively; whereas, in older patients, it increased to 5%. That is an increase of almost 3-fold. Another study on autoimmune causes showed an age-related incidence of parietal cell autoantibodies. Their prevalence increases with age, for example, from 2.5% in the third decade to 12% in the eighth decade. Autoimmune gastritis is frequently found in association with other autoimmune conditions. It is also a component of autoimmune polyglandular syndrome type 3. No association has been found between pernicious anemia and HLA types.[6][7][8]

Parietal cells lining the stomach wall are vital in maintaining the acidic pH of the stomach. They do this with the help of hydrogen potassium ATPase pump (HKA pump) which pushes potassium out and hydrogen back into the stomach. To keep the pump working, potassium ions must enter back into the stomach through the apical membrane. The apical membrane is lined with potassium-selective channels that are responsible for potassium ion efflux. These are called inward rectifier channels (Kir). A study conducted on knock out mice showed genetic evidence of one such channel: KCNE2-KCNQ1. KCNQ1 a transmembrane voltage-gated, homotetrameric potassium-selective channel. KCNE2 alters the voltage dependence of KCNQ1, converting it to a voltage-independent gate that has increased current conduction at low pH. KCNE2 and KCNQ1 are often found at the apical membrane of parietal cells. Targetted gene deletion of either of these subunits was found to result in achlorhydria. This study showed that these play an essential role in gastric acid secretion by maintaining the supply of luminal potassium to keep the HK-ATPase pump functional. In the same study, dysfunction of KCNQ1 also caused the development of gastric neoplasia independent of H. Pylori infection (secondary to achlorhydria).

Thus any insult to parietal cells by any means (antibodies, surgery, drugs) can lead to achlorhydria which further activates multiple cascades of events that can lead to bacterial proliferation, GI symptoms, and even gastric cancer.

Studies have shown evidence of changes in oxyntic mucosa in longstanding autoimmune gastritis. The oxyntic mucosa is mainly composed of parietal cell, activation of which increases acid production in the stomach. The oxyntic mucosa undergoes four distinctive yet overlapping histological changes:

• In the early phase, the plasma cells and lymphocytes migrate into the lamina propria, patchy destruction of oxyntic cells may be seen. 
• The lymphocytes and plasma cells then form dense infiltrate in the lamina propria. A metaplastic process is observed in the oxyntic cells; the large pale staining oxyntic cells are replaced by a new phenotype of clear cells also known as pseudo-pyloric metaplasia.
• Then follows intestinal metaplasia of gastric glands which can later lead to malignancy.
• In advanced gastritis, atrophy of oxyntic mucosa is seen. There can also be fibrosis, polyp formation, hyperplasia of muscularis mucosae and/or enterochromaffin-like cells.