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.
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 the 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:
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]
Achlorhydria may develop as a result of the conditions discussed below.
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 the 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.
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]
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.
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]
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 on 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]
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.
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.
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.
Obtain an appropriate history in patients suspected of having achlorhydria. Elicit risk factors for achlorhydria, including prior gastric bypass surgery, history of chronic H pylori infection, chronic PPI use, and autoimmune conditions (eg, diabetes, autoimmune thyroid disease).
Irrespective of the cause, achlorhydria can result in complications such as bacterial overgrowth, intestinal metaplasia, and hip fracture. Therefore, a history of abdominal discomfort, early satiety, weight loss, bowel movement frequency, reflux symptoms, and abdominal bloating should be taken. Since acidic pH facilitates the absorption of iron, achlorhydric patients often develop iron deficiency anemia.[16] Therefore, patients should be assessed for symptoms of anemia.
Bacterial overgrowth can cause micronutrient deficiencies that result in various clinical neurological manifestations. A complete neurological history, including history of visual changes, paresthesias, ataxia, limb weakness, gait disturbance, memory defects, hallucinations, and personality and mood changes, should also be obtained.
Achlorhydria is not associated with any characteristic physical findings.
Although not all patients with suspected achlorhydria need documentary evidence of a lack of acid production, the most important study to prove the presence of the condition is measurement of basal acid secretion.
For practical purposes, gastric pH at endoscopy should be done in patients with suspected achlorhydria. Older testing methods using fluid aspiration through a nasogastric tube can be done. These procedures can cause significant patient discomfort and are less efficient in obtaining a diagnosis. It has been proposed that fasting gastric pH can be predicted noninvasively using an equation based on the serum pepsinogen I level and the presence/absence of H pylori.
See Procedures.
Antiparietal cell antibody testing should be ordered because a strong association exists between achlorhydria and so-called autoimmune conditions. If achlorhydria is confirmed, patients should have a hydrogen breath test to check for bacterial overgrowth. Iron indices, calcium, prothrombin time, vitamin B-12, vitamin D, and thiamine levels should be checked to exclude deficiencies. Complete blood count with indices and peripheral smears can be examined to exclude anemia. Elevation of serum folate is suggestive of small bowel bacterial overgrowth. Indeed, bacterial folate can be absorbed into the circulation.
H pylori infection can be inferred from the presence of immunoglobulin G (IgG) antibodies directed against H pylori. If endoscopy is performed, the most convenient biopsy-based test is the urease enzyme test, which is based on a change in color of an indicator dye due to urea degradation. Histologic examination of the biopsy specimens is the most sensitive test, provided that a special stain (eg, a modified Giemsa or silver stain) permitting optimal visualization of H pylori is used. Culture of H pylori is the most specific test but is difficult.
A complete profile of gastric acid secretion is best obtained during a 24-hour gastric pH study.
Achlorhydria may also be documented by measurements of extremely low serum levels of pepsinogen A (PgA) (< 17 mcg/L).
High serum gastrin levels (>500-1000 pg/mL) may support a diagnosis of achlorhydria.
Litmus paper is readily available to examine the pH of gastric secretions and, in contrast to the pH electrode, is less expensive while providing equally reliable results.
To exclude gastric carcinoids at the time of diagnosis, an upper GI endoscopy may be indicated. Extensive literature examines the utility of upper GI endoscopy to screen patients with diabetes mellitus and antiparietal cell antibodies for gastric carcinoid tumors. Because of the low incidence of gastric carcinoid tumors, there is no evidence that upper GI endoscopy in screening these patients is of clinical benefit.
Gastric acid output measurement consists of a timed collection of acid production; results are reported in mEq/h.
The patient is placed in the left lateral decubitus position. A nasogastric tube is passed into the antrum of the stomach after an overnight fast. Fluoroscopy can be used to guide accurate tube placement.
The initial aspirated fluid is discarded. A specimen is collected for 1 hour (at 15-min intervals) to assess fasting basal acid output (reference range, 1-6 mEq/h). Acid secretion is then stimulated by the administration of intravenous pentagastrin (2 U/kg). Four subsequent specimens in 15-minute aliquots are collected to determine maximal acid output (reference range, < 40 mEq/h).
Acidity is measured either by titration with the chemical indicator methyl red or by the use of a pH electrode. Patients with achlorhydria do not respond with an increase of acid output after pentagastrin stimulation.
Intragastric pH measurements during endoscopy may be a valuable screening method.
A pH electrode for titration of H+ is passed through the biopsy channel of the endoscope. If the pH is found to be 4.0 or higher (and if no further decrease in pH occurs over time), patients may undergo a pentagastrin stimulation test.
More than 50% of patients whose initial stomach pH is 4.0 or higher are hypochlorhydric or achlorhydric.
Gastric atrophy leads to achlorhydria. The subsequent increase of blood gastrin levels may lead to enterochromaffin hyperplasia with the possible, though rare, development of carcinoid tumors after achlorhydria. Patients with multiple endocrine neoplasia type 1 syndrome may develop carcinoids at some stage of their disease.
Another consequence resulting from gastric atrophy includes the development of benign gastric polyps. Conversely, patients who have gastric polyps have a high incidence of otherwise unsuspected achlorhydria and of unsuspected vitamin B-12 malabsorption (50%). In addition, gastric atrophy is considered a predisposing condition for adenocarcinoma of the stomach, especially in those patients who develop intestinal metaplasia.
Treatments for achlorhydria and the physiologic consequences of this condition are discussed in this section.
Achlorhydria associated with H pylori infection may respond to H pylori eradication therapy, although resumption of gastric acid secretion may only be partial.
The standard, first-line therapy for gastric H pylori is as follows: PPI (20 mg bid) plus clarithromycin (500 mg bid) plus amoxicillin (1 g bid). For patients who are allergic to penicillin, amoxicillin can be replaced by levofloxacin (250 mg bid).
There is some minor disagreement on the duration of treatment. US guidelines recommend a 14-day course, while in Europe, a 7-day course is considered to be sufficient. A meta-analysis reveals a 12% advantage for a longer course of treatment, but this is at an added expense and a greater risk of adverse effects. Patient compliance is also more difficult with a longer course of treatment (ie, 14 d vs 7 d).
In immune-mediated diseases (eg, pernicious anemia), acid secretion cannot be restored after destruction of the gastric secretory mucosa.
Treatment of gastritis that leads to pernicious anemia consists of parenteral vitamin B-12 injection. It is not clear whether intranasal vitamin B-12 therapy is adequate in individuals who have been diagnosed with pernicious anemia. Parenteral vitamin B-12 treatment may reverse the hematologic abnormalities. However, it may have little effect on preexisting neurologic abnormalities. This treatment does not affect the underlying gastric atrophy, inflammation, or the possible development of gastric carcinoma and should be followed with these risks in mind.
Associated immune-mediated conditions (eg, insulin dependent diabetes mellitus, autoimmune thyroiditis) should also be treated. However, treatment of these disorders has no known beneficial effect on achlorhydria.
The normal indigenous intestinal microflora consists of about 1015 bacteria that mainly reside in the lower gut. Bacterial overgrowth implies abnormal bacterial colonization of greater than 100,000/mL in the upper gut.
Small intestinal bacterial overgrowth can result in recurrent diarrhea with malabsorption, D-lactic acidosis, and an increased risk of endogenous infection. Other conditions associated with small bowel bacterial overgrowth include steatorrhea, macrocytic anemia, and, less commonly, protein-losing enteropathy.
Microecologic changes are accompanied by vitamin B-12 deficiency anemia, hypovitaminosis, protein deficiency, translocation of bacteria and their toxins from the intestine into the bloodstream, emergence of endotoxinemia, and possible generalization of infection. Bacterial overgrowth is diagnosed by the concentration of hydrogen in expiratory flow (glucose-hydrogen breath test) or by bacteriological study of aspirate from the proximal part of the small intestine.
Antimicrobial agents, including metronidazole, amoxicillin/clavulanate potassium, ciprofloxacin, and rifaximin, can be used to treat bacterial overgrowth.
Achlorhydria resulting from long-term proton pump inhibitor (PPI) use may be treated by dose reduction or withdrawal of the PPI.
Achlorhydria from PPI use may also be corrected by administration of hydrochloric acid supplements. More recently, betaine hydrochloride (BHCl) has been used as a gastric acid supplement and is available over the counter as a nutraceutical. In healthy volunteers with pharmacologically induced hypochlorhydria, BHCl has been shown to temporarily reduce the gastric pH, but cessation of PPI therapy is often enough to correct medication-induced achlorhydria.[18]
Hypergastrinemia due to achlorhydria secondary to PPI therapy or resection of the gastric fundus is known to cause ECL cell hyperplasia and gastric carcinoids. Surgery is the only potentially curative therapy for carcinoid tumors.[19]
Surgical antrectomy results in normalization of serum gastrin levels and disappearance of multicentric gastric carcinoids. In a study by Hirschowitz et al, antrectomy resulted in normalization of serum gastrin levels within 8 hours and disappearance of carcinoids in 6-16 weeks.[20]
Gladdy et al examined the efficacy of endoscopic surveillance versus surgical resection in the treatment of patients with type I GI carcinoid tumors.[19] In the study, 46 patients underwent endoscopic surveillance with polypectomy, while 19 patients were treated with gastric resection. (The latter treatment was used in patients with larger-sized tumors, increased depth of invasion, and solitary tumors.) The 5-year recurrence-free survival rate was 75% in the surgical resection patients, but the disease-specific survival rate was 100% in both patient groups. Concomitant adenocarcinoma was found in 4 of the patients who underwent resection, with the detection made through preoperative biopsy in 2 of these individuals. (The carcinoid tumors were bigger and the carcinoid disease was more advanced in all patients with coexisting gastric adenocarcinoma.)
The authors recommended that resection be considered for patients with more advanced carcinoid disease, owing to the increased adenocarcinoma risk associated with the advanced disorder. They also concluded that endoscopic surveillance is appropriate for determining the status of carcinoid tumors and for the assessment of the dysplasia or adenocarcinoma that can arise in association with type I GI carcinoid tumors.
Patients with achlorhydria may develop ECL cell hyperplasia and gastric carcinoids. However, most experts believe that regular upper endoscopic surveillance is not justified.
Achlorhydria leads to hypergastrinemia. The trophic effect of gastrin leading to colorectal adenocarcinoma has been observed in knockout mouse models.
Patients on long-term PPI treatment may develop drug-induced achlorhydria. These patients have been observed to have reduced serum vitamin B-12 (cobalamin) levels. Vitamin B-12 injections may be indicated in this subgroup.
Bacterial overgrowth and subsequent micronutrient deficiencies can occur in patients with achlorhydria. Patients with a history of gastric bypass surgery or long-term PPI use are predisposed to bacterial overgrowth. These patients should be tested for various nutrient deficiencies, including thiamine levels and calcium levels. Patients should undergo hydrogen breath testing. If the test results are positive, these patients should be treated with antimicrobial therapy for bacterial overgrowth. The patients should receive appropriate supplements to correct deficient nutrients. However, this supplementation may not be sufficient to maintain adequate nutrient levels without the treatment of the bacterial overgrowth.
Achlorhydria may be associated with vitamin B-12 deficiency in the setting of pernicious anemia. Parenteral vitamin B-12 may be important in selected patients.
Achlorhydria is associated with thiamine deficiency in the setting of bacterial overgrowth. Bacterial overgrowth is commonly treated with the following antimicrobials: metronidazole, amoxicillin-clavulanate potassium, ciprofloxacin, or rifaximin.
H pylori infection can be treated with 3 drugs: PPI, clarithromycin, and amoxicillin. Levofloxacin can be used in place of amoxicillin for patients who are allergic to penicillin.
Clinical Context: Deoxyadenosylcobalamin and hydroxocobalamin are the active forms of vitamin B-12 in humans. Vitamin B-12 is synthesized by microbes but not by humans or plants. Vitamin B-12 deficiency may result from intrinsic factor deficiency (pernicious anemia), partial or total gastrectomy, or diseases of the distal ileum.
Clinical Context: Used for thiamine deficiency syndromes.
Vitamin B-12 (cobalamin) deficiency initially and typically manifests as macrocytic anemia, although neurologic symptoms may be present.
Clinical Context: Component of drug combination therapy that effectively treats duodenal ulcer or gastric ulcer associated with H pylori infection. Active against various anaerobic bacteria and protozoa. Appears to be absorbed into cells. Intermediate-metabolized compounds are formed which bind DNA and inhibit protein synthesis, causing cell death.
Antibiotics and other agents are used as adjuvants to treat duodenal ulcer disease associated with H pylori.
Clinical Context: Semisynthetic macrolide antibiotic that reversibly binds to the P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating the dissociation of peptidyl t-RNA from ribosomes, causing bacterial growth inhibition.
If H pylori is identified as the underlying cause of gastritis, subsequent eradication now is almost generally an accepted practice. Protocols for H pylori eradication require a combination of antimicrobial agents and antisecretory agents, such as PPIs, ranitidine bismuth citrate (RBC), or bismuth subsalicylate. Despite the combinatorial effect of drugs in regimens used to treat H pylori infection, cure rates remain, at best, 80%-95%.
Clinical Context: S (-) enantiomer of ofloxacin. Inhibits DNA gyrase in susceptible organisms and thereby inhibits the relaxation of supercoiled DNA and promotes breakage of DNA strands.
Clinical Context: Fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth, by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Has no activity against anaerobes. Continue treatment for at least 2 d (7-14 d typical) after the signs and symptoms have disappeared.
Clinical Context: Nonabsorbed (< 0.4%), broad-spectrum antibiotic specific for enteric pathogens of the GI tract (ie, gram-positive, gram-negative, aerobic, anaerobic). Rifampin structural analog. Binds to beta-subunit of bacterial DNA-dependent RNA polymerase, thereby inhibiting RNA synthesis. Indicated for E coli (enterotoxigenic and enteroaggregative strains) associated with travelers' diarrhea.
Clinical Context: Amoxicillin inhibits bacterial cell wall synthesis by binding to penicillin-binding proteins. Addition of clavulanate inhibits beta-lactamase producing bacteria.
Good alternative antibiotic for patients allergic or intolerant to the macrolide class. Usually is well tolerated and provides good coverage to most infectious agents. Not effective against mycoplasmal and legionella species. The half-life of oral dosage form is 1-1.3 h. Has good tissue penetration but does not enter the cerebrospinal fluid.
For children >3 months, base the dosing protocol on amoxicillin content. Due to different amoxicillin/clavulanic acid ratios in 250-mg tab (250/125) vs 250-mg chewable tab (250/62.5), do not use 250-mg tab until the child weighs >40 kg.
Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.
Clinical Context: S-isomer of omeprazole. Inhibits gastric acid secretion by inhibiting H+/K+-ATPase enzyme system at the secretory surface of gastric parietal cells.
Used in severe cases and in patients not responding to H2 antagonist therapy.
Used for up to 4 wk to treat and relieve symptoms of active duodenal ulcers; may be used up to 8 wk to treat all grades of erosive esophagitis.
Inhibit gastric acid secretion by inhibition of the H+/K+/ATP-ase enzyme system in the gastric parietal cells. These agents are used in cases of severe esophagitis and in patients not responding to H2-antagonist therapy.