Excerpt from Achlorhydria

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Background

Achlorhydria has been defined by multiple separate systems in reference to gastric acid secretion.

First, achlorhydria has been defined by a peak acid output in response to a maximally effective stimulus that results in an intragastric pH of greater than 5.09 in men and greater than 6.81 in women. Second, achlorhydria has been defined by a maximal acid output of less than 6.9 m/mole/h in men and less than 5.0 m/mole/h in women. Third, achlorhydria has been defined as a ratio of serum pepsinogen I/pepsinogen II of less than 2.9.

Several medical conditions and specific gastric surgery can lead to achlorhydria; all of which are described in this article.

Pathophysiology

Acid secretion by gastric epithelial cells is related to the physiologic function of oxyntic cells, which are called parietal cells. Parietal cells are mainly present in the gastric corpus and fundus, although complete mapping in the human stomach is not fully known. Parietal cells are responsible for secretion of hydrochloric acid and also produce intrinsic factor. Parietal cells have large mitochondria with short microvilli and a cytoplasmic canaliculi system in contact with the lumen. The H⁺/K⁺-ATPase responsible for acid secretion resides in the apical microvillus membrane.

Three animal models address the relationship between parietal cell function and achlorhydria using murine gene knockout models. First, the absence of the H⁺/K⁺-ATPase is chronically associated with achlorhydria and mucosal hyperplasia but with no histological evidence for neoplasia. Second, in a gastrin knockout model, achlorhydria is present because of the inactivation of enterochromaffin-like (ECL) cells and parietal cells. This model leads to intestinal metaplasia, bacterial overgrowth, and, in some instances, gastric tumors. Third, in the KCNE2 potassium channel ancillary subunit knockout model, disruption of this gene in a murine model induces achlorhydria and is related to reduced parietal cell protein secretion and abnormal parietal cell morphology.

In clinical conditions, parietal cell dysfunction can be induced by antiparietal cell antibodies. In addition, abnormal hormone secretion can alter parietal cell function. Chronic inflammatory changes related to gastric Helicobacter pylori infection can also induce parietal cell changes.

Among the origins of achlorhydria that are related to medical care, medications that block H⁺/K⁺-ATPase activity can induce achlorhydria.

Two major gastric surgeries also lead to achlorhydria. First, the Roux-en-Y gastric bypass surgery involves formation of a 15- to 30-mL fundal pouch. Second, antrectomy with vagotomy is an older surgical procedure that is designed to block acid secretion regulated by gastrin release from the antrum and acetylcholine release from the vagus nerve.

Patients with mucolipidosis type IV, an autosomal recessive lysosomal storage disease, may be constitutively achlorhydric. In this condition, a protein critical for vacuolar trafficking between the cytoplasm and the apical membrane is defective, resulting in parietal cells that are only partially active.

Frequency

United States

A clear association of increased age and achlorhydria has been established. However, the age-related incidence of this condition has not been reported.

Mortality/Morbidity

Several conditions associated with achlorhydria lead to increased mortality and morbidity. Specifically, achlorhydria has been associated with the following major sequelae: gastric cancer, hip fracture, and bacterial overgrowth.

• Carcinoid tumors
  • Achlorhydria is an important cause of hypergastrinemia, which can subsequently lead to the development of GI carcinoid tumors.
  
  
  
  • In a report from the American Cancer Society, approximately 5000 carcinoid tumors are diagnosed each year in the United States. Statistics from the National Cancer Institute demonstrate that approximately 74% of these tumors originate in the GI tract, while 8.7% of all enteric carcinoid tumors originate in the stomach.
    
  
  
  • Mortality specific to gastric carcinoid tumor has previously been studied and is as follows: 5-year survival is 64% with localized disease, 40% with regional disease, and 10% with distant disease spread.


• Hip fracture
  • Long-term proton pump inhibitor (PPI) therapy, particularly at high doses, is associated with an increased risk of hip fracture. The mortality rate during the first year after a hip fracture is 20%. Among those who survive, 1 in 5 patients require nursing home care.
    
  
  
  • These findings suggest an association between achlorhydria related to PPI use and hip fracture. Several potential mechanisms may explain this association. Significant hypochlorhydria, particularly among the elderly, who may have a higher prevalence of H pylori infection, could result in calcium malabsorption secondary to small bowel bacterial overgrowth. Limited animal and human studies have shown that PPI therapy may decrease insoluble calcium absorption or bone density. In addition, in vitro data suggests that PPI therapy may inhibit osteoclastic vacuolar H⁺/K⁺-ATPase and result decrease bone resorption.

• Bacterial overgrowth
  • Bacterial overgrowth is underrecognized. It is the most common cause of malabsorption among older adults. Competition between bacteria and the human host for ingested nutrients leads to malabsorption and considerable morbidity due to micronutrient deficiency.
    
  
  
  • Clinical symptoms, including chronic diarrhea, steatorrhea, macrocytic anemia, weight loss, and protein-losing enteropathy, can be seen in these patients.

Race

Achlorhydria has not been reported to affect various races differently.

The relative prevalence of H pylori in individuals of different socioeconomic backgrounds could alter this association.

Sex

Achlorhydria has not been reported to affect men and women differently.

Age

Many studies have pointed to impaired acid secretion in relation to increased age. This relationship is mainly seen in people with GI symptoms. According to a report by Segal et al of 1590 patients, the incidence of achlorhydria was 19% in the fifth decade of life and 69% in the eighth decade of life.³³ The increased rate of achlorhydria was also associated with a rise in the frequency of gastric cancer. These findings may be explained by the higher prevalence of H pylori in older individuals.

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