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Achlorhydria

  • Author: Divyanshoo Rai Kohli, MD; Chief Editor: BS Anand, MD  more...
 
Updated: Jul 15, 2016
 

Background

Achlorhydria, in simple terms, means the absence of hydrochloric acid in gastric secretions and 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 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. Achlorhydria is associated with intestinal metaplasia of the gastric mucosa, which may lead to dysplasia, and is hence considered a premalignant condition.

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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]  There are emerging data to suggest that the deletion of this gene may lead to early-onset nonalcoholic fatty liver disease. [2]
  • 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. [3]
  • 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. [4]
  • 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. [5, 6]

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 like proton pump inhibitors 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.[7]

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Etiology

Achlorhydria may develop as a result of the conditions discussed below.

Antiparietal cell antibodies

Antibodies directed against gastric intrinsic factor result in cobalamin deficiency; this is called pernicious anemia.

The two types of anti-intrinsic factor antibodies are (1) antibodies that block attachment of cobalamin to intrinsic factor, and (2) antibodies that block attachment of the intrinsic factor-cobalamin complex to ileal receptors.

Clinically, highly specific anti-intrinsic factor antibodies are found in about 70% of patients with pernicious anemia. A second component of pernicious anemia is chronic atrophic gastritis that leads to a decline in intrinsic factor production. The chronic atrophic gastritis in pernicious anemia is also associated with an increased risk of intestinal gastric cancer and gastric carcinoid tumors. Clinical factors associated with autoimmune gastritis in addition to vitamin B-12 deficiency include celiac disease, neurological symptoms, and a positive family history.[8]

Pernicious anemia occurs in association with other autoimmune disorders.[9]  In one study, autoimmune thyroid disorders were observed in 24% of 162 patients with pernicious anemia. In this condition, fundic histology is characterized by severe gland atrophy. Ninety percent of patients have antibodies directed against the H+/K+ -ATPase pump. In these patients, achlorhydria leads to pronounced hypergastrinemia (>1000 pg/mL) with subsequent hyperplasia of gastric ECL cells. Gastric carcinoid tumors develop in 3-5% of patients.

Parietal cell antibodies are found in 20% of patients with type 1 diabetes, denoting autoimmune gastritis, achlorhydria, and pernicious anemia. This condition may predispose to ECL cell proliferation and gastric carcinoid tumors.

Chronic gastric H pylori infection

ECL cells in the gastric mucosa control acid secretion by releasing histamine from gastrin stimulation. During chronic H pylori infection, proinflammatory cytokines, such as interferon (IFN)-alpha and tumor necrosis factor (TNF)-alpha, are released. This cytokine release can affect ECL cells by impairing their secretory function and lead to achlorhydria and subsequently gastric cancer via ECL hyperplasia by increased gastrin stimulation.[10, 11]

Chronic gastric H pylori infection produces gastritis, most prominently in the body of the stomach, and leads to profound suppression of gastric acid secretion.

Relatively recent studies have demonstrated an association between childhood infection with H pylori and low serum iron and hypochlorhydria.[12]

Proton pump inhibitor therapy

The use of PPIs alters the role of gastrin in maintaining gastric homeostasis and the control of acid secretion. Profound suppression of gastric acid has been associated with bacterial overgrowth, enteric infections, and hypergastrinemia.

Gastric knockout mouse models with inactivated parietal cells subsequently develop achlorhydria. Achlorhydria stimulates antral G cells to release gastrin. Gastrin, in turn, stimulates the oxyntic mucosa, which may ultimately lead to hyperplasia of ECL cells. In these models, bacterial overgrowth and intestinal metaplasia leading to gastric tumors have been observed. Further, perturbation of gastrin (and gastrin precursor) homeostasis leading to colorectal carcinogenesis has been examined in these models.

PPIs should be used in disorders that clearly benefit from this therapy and in patients in whom the benefits outweigh the risks associated with PPI therapy.

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Epidemiology

International data

A clear association between increased age and achlorhydria has been established. Studies from Europe have reported the prevalence of achlorhydria to range from 1-4.7% in healthy subjects.[13, 14]

Race-, sex-, and age-related demographics

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.

Demographic data have reported equivalent prevalence of achlorhydria among men and women.[13, 14]

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.[15] 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.

Similarly, a study from Denmark by Christiansen showed that the incidence of achlorhydria in patients increased rapidly from 1.8% in the fifth decade to 18.5% in the eighth decade.[13]

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Prognosis

Small bowel bacterial overgrowth is a chronic condition. Retreatment may be necessary once every 1-6 months. There are reports of cycling of antibiotics to reduce the risk of antibiotic resistance.

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, whereas 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 in 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 in decreased 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.

Complications

Atrophic gastritis (and associated achlorhydria) has been considered to be a potential precursor to gastric carcinoma. It is also related (given the comorbidities) to hip fracture and osteoporosis.

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Contributor Information and Disclosures
Author

Divyanshoo Rai Kohli, MD Fellow, Department of Gastroenterology, Hepatology and Nutrition, Virginia Commonwealth University School of Medicine

Divyanshoo Rai Kohli, MD is a member of the following medical societies: American College of Physicians

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, American Physiological Society

Disclosure: Nothing to disclose.

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, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Additional Contributors

David Greenwald, MD 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, New York Society for Gastrointestinal Endoscopy, American College of Gastroenterology, American College of Physicians, American Gastroenterological Association, American Society for Gastrointestinal Endoscopy

Disclosure: Nothing to disclose.

Acknowledgements

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.

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