Continuing Education Activity

Achlorhydria is a condition in which the stomach does not produce hydrochloric acid, one of the components of gastric acid. Hydrochloric acid plays an integral role in the digestion of food and protects the body from pathogens ingested with food or water. This activity reviews the presentation, evaluation, and management of achlorhydria and highlights the role of the interprofessional team in caring for patients affected by it.

Objectives:

• Describe the pathophysiology of achlorhydria.
• Summarize the causes of achlorhydria.
• Review the complications associated with achlorhydria.
• Explain interprofessional team strategies for improving care coordination and communication to advance the evaluation and management of achlorhydria and optimize outcomes.

Introduction

Gastric acid is the fluid secreted by the stomach. It is composed of hydrochloric acid, potassium chloride, and sodium chloride. Hydrochloric acid plays an integral part in the digestion of food and protects our body against pathogens ingested with food or water. The parietal cells lining the stomach are mainly involved in its production. Achlorhydria or hypochlorhydria refer to conditions in which the production of hydrochloric acid in the stomach is respectively absent or reduced. It is usually secondary to an underlying medical condition.[1][2]

Etiology

Multiple disorders can cause achlorhydria.[3][4][5]

• Pernicious anemia (anti-parietal and anti-intrinsic factor antibodies): It is an autoimmune phenomenon in which antibodies are formed. These autoantibodies cause the autoimmune destruction of parietal cells leading to atrophic gastritis.
• Use of antisecretory medications: Short-term standard dose treatment with proton pump inhibitors (PPIs) has been shown to have low risk, but long-term use of PPIs has been linked to hypochlorhydria.
• Helicobacter pylori infection: Acute H. pylori infection of gastric epithelial cells represses H-K-ATPase alpha-subunit gene expression leading to transient hypochlorhydria and supporting H. pylori proliferation. This growth of H. pylori may even initiate a pathological process causing gastric cancer.
• Gastric bypass: Gastric bypass is a gastric exclusion operation performed in patients with morbid obesity to reduce food intake. Studies show that the acid secretion unbuffered by the food in the excluded stomach results in lowered gastrin secretion hence leading to achlorhydria in such patients.
• VIPomas: VIPoma is an endocrine tumor that usually arises from beta-pancreatic cells and secretes vasoactive intestinal peptide (VIP). It may be associated with multiple endocrine neoplasia type 1 (MEN1). The massive amounts of VIP secretion cause watery diarrhea, hypokalemia, achlorhydria, vasodilation, hypercalcemia, and hyperglycemia.
• Hypothyroidism: Thyroid hormone plays a role in hydrochloric acid secretion hence hypothyroidism can lead to achlorhydria.
• Radiation to stomach: Radiation to the stomach has also been reported to cause achlorhydria.
• Gastric cancer: Animal studies have shown evidence of achlorhydria in gastric cancer.

Epidemiology

A study conducted in healthy people and patients with gastrointestinal (GI) diseases showed an increased incidence of achlorhydria and hypochlorhydria in women, but the results were not significant. In patients younger than 60 years of age, the incidence of achlorhydria and hypochlorhydria were 2.3% and 2% respectively; whereas, in older patients, it increased to 5%. That is an increase of almost 3-fold. Another study on autoimmune causes showed an age-related incidence of parietal cell autoantibodies. Their prevalence increases with age, for example, from 2.5% in the third decade to 12% in the eighth decade. Autoimmune gastritis is frequently found in association with other autoimmune conditions. It is also a component of autoimmune polyglandular syndrome type 3. No association has been found between pernicious anemia and HLA types.[6][7][8]

Pathophysiology

Parietal cells lining the stomach wall are vital in maintaining the acidic pH of the stomach. They do this with the help of a hydrogen potassium ATPase pump (HKA pump) which pushes potassium out and hydrogen back into the stomach. To keep the pump working, potassium ions must enter back into the stomach through the apical membrane. The apical membrane is lined with potassium-selective channels that are responsible for potassium ion efflux. These are called inward rectifier channels (Kir). A study conducted on knockout mice showed genetic evidence of one such channel: KCNE2-KCNQ1. KCNQ1 a transmembrane voltage-gated, homotetrameric potassium-selective channel. KCNE2 alters the voltage dependence of KCNQ1, converting it to a voltage-independent gate that has increased current conduction at low pH. KCNE2 and KCNQ1 are often found at the apical membrane of parietal cells. Targetted gene deletion of either of these subunits was found to result in achlorhydria. This study showed that these play an essential role in gastric acid secretion by maintaining the supply of luminal potassium to keep the HK-ATPase pump functional. In the same study, dysfunction of KCNQ1 also caused the development of gastric neoplasia independent of H. Pylori infection (secondary to achlorhydria). Thus any insult to parietal cells by any means (antibodies, surgery, drugs) can lead to achlorhydria which further activates multiple cascades of events that can lead to bacterial proliferation, GI symptoms, and even gastric cancer.

Histopathology

Studies have shown evidence of changes in oxyntic mucosa in longstanding autoimmune gastritis. The oxyntic mucosa is mainly composed of parietal cells, activation of which increases acid production in the stomach. The oxyntic mucosa undergoes four distinctive yet overlapping histological changes:

• In the early phase, the plasma cells and lymphocytes migrate into the lamina propria, patchy destruction of oxyntic cells may be seen. 
• The lymphocytes and plasma cells then form dense infiltrate in the lamina propria. A metaplastic process is observed in the oxyntic cells; the large pale staining oxyntic cells are replaced by a new phenotype of clear cells also known as pseudo-pyloric metaplasia.
• Then follows intestinal metaplasia of gastric glands which can later lead to malignancy.
• In advanced gastritis, atrophy of oxyntic mucosa is seen. There can also be fibrosis, polyp formation, hyperplasia of muscularis mucosae, and/or enterochromaffin-like cells.

History and Physical

Depending on the primary cause, the symptoms of achlorhydria can vary. Generally, patients develop the following symptoms which are listed in order of their prevalence:

• Epigastric pain
• Weight loss
• Heartburn
• Nausea
• Bloating
• Diarrhea
• Abdominal pain
• Acid regurgitation
• Early satiety
• Vomiting
• Postprandial fullness
• Constipation
• Dysphagia
• Glossitis
• Decreased position and vibration sense

Evaluation

When suspecting achlorhydria, multiple tests are conducted to confirm the diagnosis and to find its primary cause:

• Antiparietal and anti-intrinsic factor antibody
• Biopsy of stomach
• Gastric pH monitoring
• Serum pepsinogen level (a low serum pepsinogen level indicates achlorhydria)
• Serum gastrin levels (high serum gastrin levels greater than 500 to 1000 pg/mL may indicate achlorhydria)
• Tests for detecting H. pylori infection (urea breath test, stool antigen test, biopsy, polymerase chain reaction-PCR or fluorescent in situ hybridization [FISH]) 
• Hemoglobin level

Treatment / Management

There is no specific treatment for achlorhydria. Eradication of H. pylori is recommended in patients who are found to have it. Other treatments are targeted at improving the complications of achlorhydria. [9][10][11] These include the replacement of calcium, vitamin D, iron, and vitamin B12. There are no specific guidelines for surveillance, although it is a preneoplastic condition. The Kyoto consensus in 2015 stated that endoscopic surveillance and follow-up should be done in patients who underwent eradication therapy for H. pylori and were found to have a preneoplastic condition.

Differential Diagnosis

• Mucolipidosis type IV
• Pernicious anemia
• VIPomas

Prognosis

Despite having a small risk of developing into gastric adenocarcinoma and gastric carcinoid tumor, achlorhydria has a good prognosis.

Complications

The majority of the complications found in achlorhydria are due to nutrient deficiency. They are also more common as compared to the other complications.

• Iron deficiency
• Vitamin-B12 deficiency
• Vitamin-D and calcium deficiency leading to osteoporosis and bone fracture
• Gastric adenocarcinoma
• Gastric carcinoid tumor
• Small intestinal bacterial overgrowth syndrome

Deterrence and Patient Education

Patients are educated that due to increased gastric pH some drugs will not be absorbed effectively thus such drugs are given in higher doses.

Pearls and Other Issues

• Anything that causes an insult to the parietal cells can lead to the development of achlorhydria.
• KCNE2 and KCNQ1 were found to play a significant role in the functioning of parietal cells by a knockout study conducted in mice.
• Despite leading to some malignant conditions (a rare occurrence) in the stomach, achlorhydria has a good prognosis.
• No specific guidelines have been established for long-term surveillance.
• The treatment varies on the underlying cause and is mainly directed at the replacement of nutrient deficiency.

Enhancing Healthcare Team Outcomes

Achlorhydria is not a very common disorder in clinical practice. Even when it presents, the signs and symptoms are vague. However, in order to avoid the high morbidity, healthcare workers including the primary care provider must consider it in the differential diagnosis when evaluating patients with epigastric discomfort. The pharmacist should assist with pain control. To make the diagnosis of achlorhydria, testing is always required. Once the diagnosis is made, the treatment depends on the cause. Even though there are no current guidelines on screening or monitoring of these patients, the clinician should always be aware that many cases of gastric cancer have been reported in these patients. [Level 5][12][13]