Achlorhydria

Overview 
Theory 
Diagnosis 
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Achlorhydria is usually a silent incidental finding that, on its own, does not require diagnostic work-up or therapeutic intervention. It should be suspected in patients with the following:

Signs and symptoms of anaemia due to cobalamin (vitamin B12) or iron deficiency
Signs and symptoms of calcium deficiency
Enteric infection
Decreased efficacy and/or drug levels of certain medications such as thyroxine, ketoconazole, itraconazole, atazanavir, cefpodoxime, enoxacin, and dipyridamole
Hypergastrinaemia
Endoscopic findings of thinning of the oxyntic mucosa in the fundus and corpus (body) of the stomach with decreased rugae (gastric folds) and increased visualisation of submucosal vessels[67]
Gastric neuroendocrine tumour; carcinoid tumours.

All patients with signs or symptoms suggestive of a gastric hypersecretory disorder or endocrine tumour of the pancreas are recommended to have a serum gastrin performed to diagnose Zollinger-Ellison syndrome. In patients with low haemoglobin, achlorhydria should be suspected as acid facilitates non-haem iron absorption, and intrinsic factor (secreted by parietal cells) is necessary for cobalamin absorption.[68][69][70][71]

Biopsy of corpus and/or fundus of stomach is the diagnostic standard, and it may be performed when a differential diagnosis of achlorhydria is entertained based on history, physical exam, and/or laboratory findings.[5][6][7][9]

Patients with hypergastrinaemia require evaluation of luminal gastric pH via oesophagogastroduodenoscopy (OGD or upper endoscopy) to rule out achlorhydria as aetiology prior to embarking on a diagnostic search for Zollinger-Ellison syndrome.

Because Helicobacter pylori, an infection considered carcinogenic by the World Health Organization, plays a role in the pathogenesis of most cases of atrophic gastritis, it is reasonable to test for the organism and, if present, eradicate it.[23][72][73]

Laboratory findings

A number of laboratory investigations are recommended or merit consideration.

Serum gastrin

Hypergastrinaemia is a physiological response to achlorhydria or hypochlorhydria.[Figure caption and citation for the preceding image starts]: Model illustrating physiological regulation of gastric acid secretion by gastrin, histamine, somatostatin (SST), and luminal acid. Gastrin, released from antral G cells, is the main hormonal stimulant of acid secretion during meal ingestion. Gastrin acts directly on the acid-secreting parietal cells and, more importantly, indirectly by stimulating histamine secretion from enterochromaffin-like (ECL) cells. Histamine diffuses to adjacent parietal cells, where it binds to histamine H2 receptors coupled to stimulation of acid secretion. In the interdigestive phase, somatostatin (SST), released from antral D cells in response to luminal acid, tonically inhibits gastrin secretion from G cells, thereby maintaining acid secretion at an economically low level.From the collection of Professor Mitchell L. Schubert, with the acknowledgement of Mary Beatty-Brooks (medical illustrator) [Citation ends]. com.bmj.content.model.Caption@2787ac92 [Figure caption and citation for the preceding image starts]: Model illustrating pathophysiology of achlorhydria and the development of gastric carcinoid tumours. With achlorhydria, the stimulatory effect of luminal acid on SST is lost. Consequently, SST secretion is decreased and its inhibitory restraint on gastrin secretion attenuated (disinhibition), resulting in hypergastrinaemia. Gastrin is not only a secretagogue but also a trophic hormone that induces growth of the oxyntic mucosa. If hypergastrinaemia is sustained for days, ECL cells will hypertrophy; if sustained for weeks to months, ECL cells become hyperplastic, dysplastic, and, in some patients, become carcinoid tumours.From the collection of Professor Mitchell L. Schubert, with the acknowledgement of Mary Beatty-Brooks (medical illustrator) [Citation ends]. com.bmj.content.model.Caption@28fc5e1

Fasting serum gastrin concentrations in healthy individuals are generally <150 picograms/mL. In patients with achlorhydria, gastrin concentrations are generally >400 picograms/mL and are often >1000 picograms/mL.[74][75]

A serum gastrin test should be performed during fasting, and if markedly elevated a gastric pH should be obtained to rule out Zollinger-Ellison syndrome (gastrinoma) as the aetiology of the hypergastrinaemia.[76] Other causes of hypergastrinaemia include anti-secretory medications (5% of patients on long-term proton-pump inhibitors may have serum gastrin levels exceeding 400 picograms/mL), retained gastric antrum in duodenal limb after antrectomy, renal insufficiency, massive small bowel resection, and gastric outlet obstruction with marked distension.[77]

Intragastric pH

This test may be performed using a pH electrode or by using pH paper. It is more useful in ruling out achlorhydria than in establishing the diagnosis, since reflux of alkaline duodenal contents, in the absence of achlorhydria, can increase the pH of gastric juice to >6.

Intragastric pH testing is often used in hypergastrinaemic patients.[76]

Haemoglobin

Haemoglobin is decreased due to cobalamin (vitamin B12) and/or iron deficiency. As intrinsic factor (IF), which is secreted from parietal cells, is essential for cobalamin absorption, atrophic gastritis is the most common cause of cobalamin deficiency.[15][78][79]

About 25% of achlorhydric patients develop iron-deficiency anaemia.[68][69][70][71][80] Haem iron (Fe2+), found mainly in the haemoglobin and myoglobin of meat products, represents only 10% to 15% of total dietary iron intake. However, it is particularly well absorbed, and contributes 40% to total iron absorbed. Non-haem iron (Fe3+), found in vegetable products, is soluble only at an acidic pH and precipitates at pH >4. Because gastric acid releases Fe3+ from food and reduces it to ferrous iron (Fe2+), achlorhydria reduces iron absorption.

Pernicious anaemia describes cobalamin deficiency that results from impaired secretion of intrinsic factor due to atrophy of the oxyntic mucosa.[81] Pernicious anaemia is considered an autoimmune disorder due to the frequent presence of gastric autoantibodies directed against IF and parietal cells.

Intrinsic factor antibodies

Intrinsic factor (IF), a glycoprotein secreted by parietal cells and, to a lesser degree, chief cells, is necessary for the absorption of cobalamin (vitamin B12).[15] Because cobalamin body stores are 1000-fold the daily requirement, it takes many years for a patient with gastric atrophy to develop cobalamin deficiency.[78][79] Over 70% of patients with gastric atrophy and/or autoimmune gastritis have antibodies directed against the parietal cell hydrogen-potassium-stimulated adenosine triphosphatase (H+/K+ ATPase) and/or IF.[31][36][37][38] IF antibodies are >95% specific and 50% to 85% sensitive for pernicious anaemia.[78][82][83][84]

Parietal cell antibodies

Parietal cell antibodies, directed against the alpha and beta subunits of the parietal cell H+/K+ ATPase, are present in up to 90% of patients with pernicious anaemia.

Parietal cell antibodies may be acquired due to molecular mimicry between Helicobacter pylori lipopolysaccharide and H+/K+ ATPase, both of which contain Lewis epitopes.[59] With progression of the gastritis, the incidence of the antibodies may decrease to about 55% to 80%, presumably because of the loss of antigenic drive.[30][31][36][37][38] In one study, combining IF antibody and parietal cell antibody testing yielded a 60% sensitivity for gastric atrophy and 73% sensitivity for pernicious anaemia.[52]

Gastric acid secretory test (gastric analysis)

Gastric acid secretory testing is the definitive test for the diagnosis of achlorhydria, but is not widely available or performed.[85][86] It may be considered (in specialised centres) when the diagnosis remains in doubt after less invasive testing.

The test is performed by placing a nasogastric tube into the most dependent portion of the stomach during fasting, and aspirating gastric juice by suction. Proper positioning may be verified fluoroscopically or by recovery of >90 mL after injection of 100 mL water.

The H+ concentration in a sample of gastric juice is determined either by back-titration to pH 7.0 using a base (e.g., sodium hydroxide) or by measuring the pH of the sample with an electrode and converting this to concentration using a table of activity coefficients for H+ in gastric juice. Once the H+ concentration of the sample in mmol per litre is determined, it is multiplied by the volume of the sample in litres to determine the acid output during the collection period.

Basal acid output (BAO) estimates resting acid secretion and is expressed as the sum of the measured acid output, expressed as mmol H+ per hour, for 4 consecutive 15-minute periods. Maximal acid output (MAO) and peak acid output (PAO) estimate the acid secretory response to an exogenous secretagogue. MAO is the sum of acid output of 4 consecutive 15-minute periods, and PAO is calculated by multiplying by 2 the sum of the 2 highest outputs recorded in the four 15-minute test periods.

Biopsy of corpus and/or fundus of stomach

There is poor correlation between the endoscopic visual determination of gastric atrophy and the histological diagnosis of achlorhydria.[67] The diagnosis of gastric atrophy with achlorhydria is most often made by the finding of atrophic gastritis on biopsy of the oxyntic mucosa at time of oesophagogastroduodenoscopy (OGD or upper endoscopy) together with the finding of a pH >6 on gastric fluid aspirated during OGD and/or hypergastrinaemia.

Gastric atrophy is characterised by loss of glands and parietal cells, with a decreased ratio of the area occupied by glands to the total mucosa area.[87]

Gastric atrophy is usually associated with gastric intestinal metaplasia (IM), the latter may be spotty and hence missed with limited endoscopic biopsies. Because gastric atrophy and gastric IM usually occur on a background of chronic gastritis, some use the term 'atrophic gastritis'.[5][6][7][9]

Autoimmune atrophic gastritis is characterised by lymphocytic infiltration into the epithelium (98%), muscularis mucosa thickening (93%), gland shortening and branching (87%), basal lymphoid aggregates (83%), eosinophil infiltration (46%), and neutrophil infiltration (44%).[88]

Post-histological diagnosis of gastric IM

Multiple biopsies (two from the antrum [at lesser and greater curvature], two from the corpus [at lesser and greater curvature], and one from the incisura) should be obtained.[89] Labelling of the areas biopsied is essential as it helps differentiate normal antral mucosa from pseudopyloric metaplasia of the corpus. Antral and corpus samples, as well as tissue from abnormal mucosa and normal-appearing mucosa, should be placed in separate containers for histopathological preparation and analysis.[89]

Helicobacter pylori infection

H pylori infection is probably the most important contributory factor for the development of chronic atrophic gastritis with achlorhydria, even though most patients harbouring the organism are not achlorhydric. Although there are few data to support the premise that eradication of the organism once atrophy and IM develop will either cease or reverse the process or prevent the development of adenocarcinoma, most gastroenterologists specialising in this field would recommend eradication of the organism if it is still present.[72][90][91][92][93][94]

The American Gastroenterological Association reports that H pylorieradication among individuals with or without gastric IM is associated with a 32% risk reduction for gastric cancer.[76] However, there was a lack of data on the impact of H pylorieradication in those with confirmed gastric IM, and most enrolled patients were from an indigenous Chinese population with an increased risk for gastric cancer.

Diagnostic tests for H pylori infection

Diagnostic tests for H pylori infection, each with >90% sensitivity and >90% specificity, include histology with immunohistochemical stain, urea breath test, rapid urease test on biopsy samples, polymerase chain reaction, fluorescence in situ hybridisation, and stool antigen test.[90][95][96][97][98][99]

Serology, although >90% sensitive, is <80% specific for active infection, since antibodies may remain detectable years after the organism is eradicated.[9][97][98] Consequently, serology should not be used to document eradication of infection.

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