Achlorhydria 

  • Author: Jennifer (Zone-En) Lee, MD; Chief Editor: Julian Katz, MD   more...
 
Updated: Aug 18, 2011
 

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.

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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.

The relationship between parietal cell function and achlorhydria is illustrated using genetic knockout mice models, as follows:

  • The absence of the H+/K+ -ATPase is chronically associated with achlorhydria and mucosal hyperplasia but with no histological evidence for neoplasia.
  • In a gastrin knockout model, achlorhydria is present because of the inactivation of enterochromaffinlike (ECL) cells and parietal cells. This model leads to intestinal metaplasia, bacterial overgrowth, and, in some instances, gastric tumors.
  • In the Kcne2 potassium channel ancillary subunit knockout model, disruption of this gene induces achlorhydria and is related to reduced parietal cell protein secretion and abnormal parietal cell morphology. Disruption of this channel is a possible risk factor for gastric neoplasia.[1]
  • Genetic ablation of a Na+/H+ exchanger (NHE2), which is expressed in the stomach at high levels, leads to a decrease in gastric acid secretion, along with decreased viability of parietal cells, severe metaplasia, and hyperplasia of gastric mucosa.[2]
  • Other mouse models have shown that a hypochloric stomach environment leads to enteric bacterial overgrowth, which may play a role in gastric atrophy, metaplasia, and cancer.[3]
  • Of late, much attention has been given to sonic hedgehog (Shh), a morphogen protein that has been studied in the mouse stomach. Shh acts as a signaling molecule in the stomach epithelial patterning, and loss of Shh results in defective parietal cells, leading to hypochlorhydria and subsequent hypergastrinemia.[4, 5]

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 defective TRPML1 (Ca2+ -permeable TRP channel) causes reduced levels and mislocalization of the gastric proton pump and alters the secretory canaliculi, causing hypochlorhydria and hypergastrinemia.[6]

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Epidemiology

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.[7] 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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Contributor Information and Disclosures
Author

Jennifer (Zone-En) Lee, MD  Fellow, Section of Gastroenterology, Georgetown University School of Medicine, Washington Hospital Center

Jennifer (Zone-En) Lee, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, and American Society of Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Coauthor(s)

Timothy R Koch, MD  Professor of Medicine (Gastroenterology), Georgetown University School of Medicine

Timothy R Koch, MD is a member of the following medical societies: American College of Gastroenterology, American Gastroenterological Association, and American Physiological Society

Disclosure: Nothing to disclose.

Hiral Shah, MD  Chief Resident, Department of Internal Medicine, Georgetown University Hospital at Washington Hospital Center

Hiral Shah, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, and American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

David Greenwald, MD  Associate Professor of Clinical Medicine, Fellowship Program Director, Department of Medicine, Division of Gastroenterology, Montefiore Medical Center, Albert Einstein College of Medicine

David Greenwald, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy, and New York Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

James L Achord, MD  Professor Emeritus, Department of Medicine, Division of Digestive Diseases, University of Mississippi School of Medicine

James L Achord, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Medical Association, American Society for Gastrointestinal Endoscopy, Mississippi State Medical Association, New York Academy of Sciences, Sigma Xi, and Southern Medical Association

Disclosure: Nothing to disclose.

Alex J Mechaber, MD, FACP  Senior Associate Dean for Undergraduate Medical Education, Associate Professor of Medicine, University of Miami Miller School of Medicine

Alex J Mechaber, MD, FACP is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians-American Society of Internal Medicine, and Society of General Internal Medicine

Disclosure: Nothing to disclose.

Chief Editor

Julian Katz, MD  Clinical Professor of Medicine, Drexel University College of Medicine

Julian Katz, MD is a member of the following medical societies: American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Geriatrics Society, American Medical Association, American Society for Gastrointestinal Endoscopy, American Society of Law, Medicine & Ethics, American Trauma Society, Association of American Medical Colleges, and Physicians for Social Responsibility

Disclosure: Nothing to disclose.

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