AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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.

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.

Three animal models address the relationship between parietal cell function and achlorhydria using murine gene knockout models. First, the absence of the H⁺/K⁺-ATPase is chronically associated with achlorhydria and mucosal hyperplasia but with no histological evidence for neoplasia. Second, in a gastrin knockout model, achlorhydria is present because of the inactivation of enterochromaffin-like (ECL) cells and parietal cells. This model leads to intestinal metaplasia, bacterial overgrowth, and, in some instances, gastric tumors. Third, in the KCNE2 potassium channel ancillary subunit knockout model, disruption of this gene in a murine model induces achlorhydria and is related to reduced parietal cell protein secretion and abnormal parietal cell morphology.

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 protein critical for vacuolar trafficking between the cytoplasm and the apical membrane is defective, resulting in parietal cells that are only partially active.

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.³³ 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.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

History

An appropriate history should be taken in patients suspected of having achlorhydria. 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), should be elicited.

Irrespective of the cause, achlorhydria can result as known complications of 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.

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.

Physical

Achlorhydria is not associated with any characteristic physical findings.

Causes

Achlorhydria may develop as a result of the following conditions:

• Antiparietal cell antibodies
•  
  • Antibodies directed against gastric intrinsic factor results in cobalamin deficiency; this is called pernicious anemia.
  • The 2 types of anti-intrinsic factor antibodies are as follows: (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.
  • Pernicious anemia occurs in association with other autoimmune disorders. 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.
  • Chronic gastric H pylori infection produces gastritis, most prominently in the body of the stomach, and leads to profound suppression of gastric acid secretion.
• 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 have 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.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Mucolipidosis type IV

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• While 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. 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 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.

Other Tests

• 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.

Procedures

• 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 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 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 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.

Histologic Findings

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.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

Achlorhydria and the physiologic consequences of this condition have the following treatments.

• 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 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 effect in the treatment of 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.
  
  
  
  • Microecological 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 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 PPI use may be treated by dose reduction or withdrawal of the PPI.

Surgical Care

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.

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.¹⁶

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Achlorhydria may be associated with vitamin B-12 deficiency in the setting of pernicious anemia.

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.

Drug Category: Vitamins

Vitamin B-12 (cobalamin) deficiency initially and typically manifests as macrocytic anemia, although neurologic symptoms may be present.

Drug Name	Thiamine
Description	Used for thiamine deficiency syndromes.
Adult Dose	Severe complication of thiamine deficiency: 150 mg slow IV qd 100 mg IM qd for 3 d or 100 mg PO bid for 3 d, then 100 mg PO qd/bid for maintenance
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Sensitivity reactions can occur (intradermal test dose recommended in suspected sensitivity); deaths have resulted from IV use; sudden onset or worsening of Wernicke encephalopathy, following glucose, may occur in thiamine deficient patients; administer before or together with dextrose-containing fluids in suspected thiamine deficiency

Drug Category: Antibiotics

Empiric antimicrobial therapy must be comprehensive and should cover all likely pathogens in the context of the clinical setting.

Drug Name	Clarithromycin (Biaxin)
Description	Semisynthetic macrolide antibiotic that reversibly binds to P site of 50S ribosomal subunit of susceptible organisms and may inhibit RNA-dependent protein synthesis by stimulating 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 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%.
Adult Dose	250-500 mg PO bid for 7-14 d
Pediatric Dose	<20 months: Not recommended >20 months: Not established
Contraindications	Documented hypersensitivity; coadministration of pimozide
Interactions	Toxicity increases with coadministration of fluconazole and pimozide; effects decrease and GI adverse effects may increase with coadministration of rifabutin or rifampin; may increase toxicity of anticoagulants, cyclosporine, tacrolimus, digoxin, carbamazepine, ergot alkaloids, triazolam, HMG-CoA reductase inhibitors; plasma levels of certain benzodiazepines may increase, prolonging CNS depression; arrhythmias and increases in QTc intervals occur with disopyramide; coadministration with omeprazole may increase plasma levels of both agents; decreases metabolism of repaglinide, thus increasing serum levels and effects
Pregnancy	C - Safety for use during pregnancy has not been established
Precautions	Coadministration with ranitidine or bismuth citrate is not recommended with CrCl <25 mL/min; give half dose or increase dosing interval if CrCl <30 mL/min; diarrhea may be sign of pseudomembranous colitis; superinfections may occur with prolonged or repeated antibiotic therapies

Drug Name	Levofloxacin (Levaquin)
Description	S (-) enantiomer of ofloxacin. Inhibits DNA gyrase in susceptible organisms thereby inhibits relaxation of supercoiled DNA and promotes breakage of DNA strands.
Adult Dose	250 mg PO bid for 7-14 d
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity
Interactions	Antacids, iron salts, and zinc salts may reduce serum levels; administer antacids 2-4 h before or after taking fluoroquinolones; cimetidine may interfere with metabolism of fluoroquinolones; levofloxacin reduces therapeutic effects of phenytoin; probenecid may increase levofloxacin serum concentrations
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy

Drug Name	Ciprofloxacin (Cipro, Cipro XR)
Description	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 signs and symptoms have disappeared.
Adult Dose	250-500 mg PO bid for 7-14 d
Pediatric Dose	<18 years: Not recommended >18 years: Administer as in adults
Contraindications	Documented hypersensitivity; coadministration with steroid combinations after uncomplicated removal of a foreign body from cornea
Interactions	None reported
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Dosage adjustments (adult adjustments) CrCl (mL/min) <10: 50% of PO or IV dose q12h HD: 0.25-0.5 g PO or 0.2-0.4 g IV q12h During peritoneal dialysis: 0.25-0.5 g PO or 0.2-0.4 g IV q8h In prolonged therapy, perform periodic evaluations of organ system functions (eg, renal, hepatic, hematopoietic); adjust dose in renal function impairment; superinfections may occur with prolonged or repeated antibiotic therapy Not drug of first choice in pediatrics due to increased incidence of adverse events compared to controls, including arthropathy; no data exist for dose for pediatric patients with renal impairment (ie, CrCl <50 mL/min)

Drug Name	Rifaximin (Xifaxan)
Description	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.
Adult Dose	200-400 mg PO tid for 7 d
Pediatric Dose	<12 years: Not established >12 years: Administer as in adults
Contraindications	Documented hypersensitivity to rifaximin or rifamycin antimicrobial agents (eg, rifampin)
Interactions	Induces CYP450 3A4 in vitro; limited data exist; no significant interactions shown in single dose studies with midazolam and oral contraceptives
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Discontinue if diarrhea persists more than 24-48 h or worsens; seek immediate medical care if fever and/or bloody stools emerge (tablets not effective); not effective for travelers' diarrhea due to suspected pathogens other than E coli; postmarketing reports include allergic dermatitis, rash, angioneurotic edema, urticaria, and pruritus

Drug Name	Amoxicillin-clavulanate potassium (Augmentin)
Description	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 cerebrospinal fluid. For children >3 months, base 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 child weighs >40 kg.
Adult Dose	500-875 mg PO q12h or 250-500 mg PO q8h for 7-10 d
Pediatric Dose	<3 mo: 125 mg/5mL PO susp; 30 mg/kg/d (based on amoxicillin component) divided bid for 7-10 d >3 mo: If using 200 mg/5 mL or 400 mg/5 mL susp, 45 mg/kg/d PO divided q12h; if using 125 mg/5 mL or 250 mg/5 mL suspension, 40 mg/kg/d PO divided bid for 7-10 d >40 kg: Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Coadministration with warfarin or heparin, increases risk of bleeding; may act synergistically against selected microorganisms when coadministered with aminoglycosides; coadministration with allopurinol may increase incidence of amoxicillin rash; may decrease efficacy of oral contraceptives when administered concomitantly
Pregnancy	B - Usually safe but benefits must outweigh the risks.
Precautions	Hepatic impairment may occur with prolonged treatment in the elderly; diarrhea may occur; adjust dose in renal impairment; cross allergy may occur with other beta-lactams and cephalosporins

Drug Category: Proton Pump Inhibitors

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.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Outpatient Care

• 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.

In/Out Patient Meds

• Parenteral vitamin B-12 may be important in selected patients.

Complications

• Atrophic gastritis (and associated achlorhydria) has been considered to be a potential precursor to gastric carcinoma.

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.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Long-term PPI therapy has been associated with the following 2 major complications: (1) as described previously, there is an association with hip fractures in patients with achlorhydria on PPI therapy, and (2) current use of gastric acid suppressive therapy has been associated with an increased risk of community-acquired pneumonia.



• Sustained achlorhydria has been observed after PPI treatment in a patient with Zollinger-Ellison syndrome, starting soon after treatment began and becoming complete within 6 months.
  


• Gastric resection, leading to surgically induced achlorhydria, has been associated with severe postoperative infections. It has been observed in humans that the lack of an acidic environment may favor bacterial overgrowth. This, in turn, can lead to various nutrient deficiencies with significant clinical manifestation.
  


• According to a study from the Netherlands by Janssen et al, patients with achlorhydria who take nonsteroidal anti-inflammatory drugs (NSAIDs) develop upper GI ulcers during NSAID use in a similar fashion as patients who produce acid normally.²⁰
  


• Drug-induced achlorhydria is a particularly important situation in elderly patients, in whom it may be associated with secondary bacterial overgrowth.
  


• Patients with pernicious anemia and achlorhydria may demonstrate impaired absorption of iron and may be screened for iron deficiency.

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

1. Andersen J, Strom M. A technique for screening of achlorhydria and hypochlorhydria during upper gastrointestinal endoscopy. Scand J Gastroenterol. Oct 1990;25(10):1084-8. [Medline].
2. Andersen J, Strom M. Pentagastrin given during upper gastrointestinal endoscopy: a simple screening method for hypo- and achlorhydria. Gastrointest Endosc. Jan-Feb 1992;38(1):47-8. [Medline].
3. Attila T, Santharam R, Blom D, Komorowski R, Koch TR. Multifocal gastric carcinoid tumor in a patient with pernicious anemia receiving lansoprazole. Dig Dis Sci. Mar 2005;50(3):509-13. [Medline].
4. Banerjee S, Ardill JE, Beattie AD, McColl KE. Effect of omeprazole and feeding on plasma gastrin in patients with achlorhydria. Aliment Pharmacol Ther. Oct 1995;9(5):507-12. [Medline].
5. Centanni M, Marignani M, Gargano L, Corleto VD, Casini A, Delle Fave G, et al. Atrophic body gastritis in patients with autoimmune thyroid disease: an underdiagnosed association. Arch Intern Med. Aug 9-23 1999;159(15):1726-30. [Medline].
6. De Block CE, Colpin G, Thielemans K, Coopmans W, Bogers JJ, Pelckmans PA, et al. Neuroendocrine tumor markers and enterochromaffin-like cell hyper/dysplasia in type 1 diabetes. Diabetes care. Jun 2004;27 (6):1387-93. [Medline].
7. Demiroglu H, Dundar S. Pernicious anaemia patients should be screened for iron deficiency during follow up. N Z Med J. Apr 25 1997;110(1042):147-8. [Medline].
8. Drake WM, Innes DF. Primary gastric lymphoma presenting with vitamin B12 deficiency and achlorhydria. Am J Gastroenterol. Dec 1996;91(12):2605-6. [Medline].
9. El-Omar EM, Oien K, El-Nujumi A, Gillen D, Wirz A, Dahill S, et al. Helicobacter pylori infection and chronic gastric acid hyposecretion. Gastroenterology. Jul 1997;113(1):15-24. [Medline].
10. Elphick HL, Elphick DA, Sanders DS. Small bowel bacterial overgrowth. An underrecognized cause of malnutrition in older adults. Geriatrics. Sep 2006;61(9):21-6. [Medline].
11. Feldman M, Barnett C. Fasting gastric pH and its relationship to true hypochlorhydria in humans. Dig Dis Sci. Jul 1991;36(7):866-9. [Medline].
12. Freston JW. Long-term acid control and proton pump inhibitors: interactions and safety issues in perspective. Am J Gastroenterol. Apr 1997;92(4 Suppl):51S-55S; discussion 55S-57S. [Medline].
13. Friss-Hansen L. Achlorhydria is associated with gastric microbial overgrowth and development of cancer: lessons learned from the gastrin knockout mouse. Scandanavian Journal of Clinical Lab Investigation. 2006;66(7):607-621.
14. Griffith JL, Cummings OW, Hirschowitz BI. Development of sustained achlorhydria in a patient with the Zollinger- Ellison syndrome treated with omeprazole [published erratum appears in Gastroenterology 1992 Mar;102(3):1096]. Gastroenterology. Jul 1991;101(1):242-6. [Medline].
15. Haboubi NY, Montgomery RD. Small-bowel bacterial overgrowth in elderly people: clinical significance and response to treatment. Age Ageing. Jan 1992;21(1):13-9. [Medline].
16. Hirschowitz BI, Griffith J, Pellegrin D, Cummings OW. Rapid regression of enterochromaffinlike cell gastric carcinoids in pernicious anemia after antrectomy. Gastroenterology. Apr 1992;102(4 Pt 1):1409-18. [Medline].
17. Howden CW. Vitamin B12 levels during prolonged treatment with proton pump inhibitors. J Clin Gastroenterol. Jan 2000;30(1):29-33. [Medline].
18. Hurwitz A, Brady DA, Schaal SE, Samloff IM, Dedon J, Ruhl CE. Gastric acidity in older adults. JAMA. Aug 27 1997;278(8):659-62. [Medline].
19. Husebye E. The pathogenesis of gastrointestinal bacterial overgrowth. Chemotherapy. 2005;51 Suppl 1:1-22. [Medline].
20. Janssen M, Dijkmans BA, Vandenbroucke JP, Biemond I, Lamers CB. Achlorhydria does not protect against benign upper gastrointestinal ulcers during NSAID use. Dig Dis Sci. Feb 1994;39(2):362-5. [Medline].
21. Jensen RT. Consequences of long-term proton pump blockade: insights from studies of patients with gastrinomas. Basic Clinical Pharmacology and Toxicology. Jan 2006;98(1):4-19. [Medline].
22. Laheij RJ, Sturkenboom MC, Hassing RJ, Dieleman J, Stricker BH, Jansen JB. Risk of community-acquired pneumonia and use of gastric acid-suppressive drugs. JAMA. Oct 27 2004;292(16):1955-60. [Medline].
23. Lanfranchi J, Sachs RN, Beaudet B, Deblock C, Tellier P. [Study of dilated cardiomyopathies using gallium 67 myocardial scintigraphy]. Ann Med Interne (Paris). 1989;140(6):486-8. [Medline].
24. Lehy T, Roucayrol AM, Mignon M. Histomorphological characteristics of gastric mucosa in patients with Zollinger-Ellison syndrome or autoimmune gastric atrophy: role of gastrin and atrophying gastritis. Microsc Res Tech. Mar 15 2000;48(6):327-38. [Medline].
25. Moncur PH, Heatley RV. Safety of proton-pump inhibitors: the acid test. Eur J Gastroenterol Hepatol. Feb 2000;12(2):145-7. [Medline].
26. Pereira SP, Gainsborough N, Dowling RH. Drug-induced hypochlorhydria causes high duodenal bacterial counts in the elderly. Aliment Pharmacol Ther. Jan 1998;12(1):99-104. [Medline].
27. Prinz C, Zanner R, Gratzl M. Physiology of gastric enterochromaffin-like cells. Annu Rev Physiol. 2003;65:371-82. [Medline].
28. Rantala A, Ovaska J. Association between medically induced achlorhydria of the stomach and a severe postoperative infection? A report of two cases. Ann Chir Gynaecol. 1994;83(3):268-70. [Medline].
29. Roepke TK, Anantharam A, Kirchhoff P, Busque SM, Young JB, Geibel JP, et al. The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion. J Biol Chem. Aug 18 2006;281(33):23740-7. [Medline].
30. Schiffmann R, Dwyer NK, Lubensky IA, Tsokos M, Sutliff VE, Latimer JS, et al. Constitutive achlorhydria in mucolipidosis type IV. Proc Natl Acad Sci U S A. Feb 3 1998;95(3):1207-12. [Medline].
31. Schubert ML. Gastric secretion. Curr Opin Gastroenterol. Nov 2002;18(6):639-49.
32. Seery JP. Achlorhydria and gastric carcinogenesis. Lancet. Dec 14 1991;338(8781):1508-9. [Medline].
33. Segal HL, Samloff IM. Gastric cancer--increased frequency in patients with achlorhydria. Am J Dig Dis. Apr 1973;18(4):295-9. [Medline].
34. Singh VV, Toskes PP. Small bowel bacterial overgrowth: presentation, diagnosis, and treatment. Curr Gastroenterol Rep. Oct 2003;5(5):365-72. [Medline].
35. Williams C, McColl KE. Review article: proton pump inhibitors and bacterial overgrowth. Aliment Pharmacol Ther. Jan 1 2006;23(1):3-10. [Medline].
36. Wormsley KG. Therapeutic achlorhydria and risk of gastric cancer. Gastroenterol Jpn. Oct 1989;24(5):585-96. [Medline].
37. Yang YX, Lewis JD, Epstein S, Metz DC. long-term proton pump inhibitor therapy and risk of hip fracture. JAMA. Dec 27 2006;296:2947-2953. [Medline].

Article Last Updated: Jun 6, 2007