Investigation of patients with achlorhydria or pernicious anemia

 

Diagnosis of gastrinoma; basal and secretin-stimulated serum

gastrin measurements are the best laboratory tests for gastrinoma

Gastrin is a peptide hormone produced by mucosal G cells of the

gastric antrum. It is synthesized as preprogastrin, cleaved to

progastrin, which undergoes several posttranslational modifications,

in particular sulfation, and is finally processed into the mature 34

amino acid, gastrin-34. Gastrin-34 may be cleaved further into the

shorter 17 amino acid, gastrin-17. Either may be secreted as a

c-terminal amidated or un-amidated isoform. A number of additional,

smaller gastrin fragments, as well as gastrin molecules with atypical

posttranslational modifications (eg, absent sulfation), may also be

secreted in small quantities. Gastrin half-life is short, 5 minutes for

amidated gastrin-17, and 20 to 25 minutes for amidated gastrin-34.

Elimination occurs through peptidase cleavage and renal excretion.

 

Gastrin-17 I (nonsulfated form) and gastrin-17 II (sulfated) appear

equipotent. Their biological effects are chiefly associated with the

amidated isoforms and consist of promotion of gastric epithelial

cell proliferation and differentiation to acid-secreting cells, direct

promotion of acid secretion, and indirect stimulation of acid production

through histamine release. In addition, gastrin stimulates gastric

motility and release of pepsin and intrinsic factor. Most gastrin

isoforms with atypical posttranslational modifications and most

small gastrin fragments display reduced or absent bioactivity.

This assay measures predominately gastrin-17. Larger precursors

and smaller fragments have little or no cross-reactivity in the assay.

 

Intraluminal stomach pH is the main factor regulating gastrin

production and secretion. Rising gastric pH levels result in increasing

serum gastrin levels, while falling pH levels are associated with

mounting somatostatin production in gastric D cells. Somatostatin,

in turn, down-regulates gastrin synthesis and release. Other, weaker

factors that stimulate gastrin secretion are gastric distention, protein-

rich foods, and elevated secretin or serum calcium levels.

 

Gastrin levels may be pathologically increased due to hypersecretion

by gastrin-producing neuroendocrine tumors, chiefly gastrinomas,

25% of which occur as part of the multiple endocrine neoplasia type 1

(MEN 1) syndrome and, rarely, foregut carcinoid tumors. The chronic

hypergastrinemia in these conditions results in continuous gastric acid

oversecretion, leading to recurrent duodenal and gastric ulcers.

Serum gastrin levels may also be elevated in gastric distention due to

gastric outlet obstruction, and in a variety of conditions that lead to

real or functional gastric hypo- or achlorhydria (gastrin is secreted in

an attempted compensatory response to achlorhydria). These include

atrophic gastritis with or without pernicious anemia, a disorder

characterized by destruction of acid-secreting (parietal) cells of the

stomach, gastric dumping syndrome, and surgically excluded gastric

antrum. In atrophic gastritis, the chronic cell-proliferative stimulus of the

secondary hypergastrinemia may contribute to the increased gastric

cancer risk observed in this condition.

<100 pg/mL

There is no evidence that fasting serum gastrin levels

differ between adults and children. Although 8-hour fasts

are difficult or impossible to enforce in small children,

serum gastrin levels after shorter fasting periods (3-8 hours)

may be 50-60% higher than the 8-hour fasting value.

Achlorhydria is the most common cause of elevated serum gastrin

levels. The most common cause for achlorhydria is treatment of

gastroduodenal ulcers, nonulcer dyspepsia, or gastroesophageal

reflux with proton pump inhibitors (substituted benzimidazoles, eg,

omeprazole). Other causes of hypo- and achlorhydria include chronic

atrophic gastritis with or without pernicious anemia, gastric ulcer,

gastric carcinoma, and previous surgical or traumatic vagotomy.

 

If serum B12 levels are significantly low (<150 ng/L), even if the

intrinsic factor blocking antibody tests are negative, a serum gastrin

level above the reference range makes it likely the patient is

nonetheless suffering from pernicious anemia.

 

Hypergastrinemia with normal or increased gastric acid secretion is

suspicious of a gastrinoma. Gastrin levels <100 pg/mL are observed

so uncommonly in untreated gastrinoma patients with intact upper

gastrointestinal anatomy, as to virtually exclude the diagnosis. The

majority (>60%) of patients with gastrinoma have very significantly

elevated serum gastrin levels (>400 pg/mL). Levels of >1,000 pg/mL

in a gastric- or duodenal ulcer patient without previous gastric surgery,

on no drugs, who has a basal gastric acid output of >15 mmol/hour

(>5 mmol/hour in patients with prior acid-reducing surgery) are

considered diagnostic of gastrinoma. If there are any doubts about

gastric acid output, an infusion of 0.1 N HCl into the stomach reduces

the serum gastrin in patients with achlorhydria, but not in those with

gastrinoma.

 

Other conditions that may be associated with hypergastrinemia in

the face of normal or increased gastric acid secretion include

gastric and, rarely, duodenal ulcers, gastric outlet obstruction,

bypassed gastric antrum, and gastric dumping. Occasionally,

diabetes mellitus, autonomic neuropathy with gastroparesis,

pheochromocytoma, rheumatoid arthritis, thyrotoxicosis, and

paraneoplastic syndromes can also result in hypergastrinemia

with normal acid secretion. None of these conditions tends to be

associated with fasting serum gastrin levels >400 pg/mL, and

levels >1,000 pg/mL are virtually never observed.

 

Several provocative tests can be used to distinguish these patients

from individuals with gastrinomas. Patients with gastrinoma, who

have normal or only mildly-to-modestly increased fasting serum

gastrin levels, respond with exaggerated serum gastrin increases

to intravenous infusions of secretin or calcium. Because of its

greater safety, secretin infusion is preferred. The best validated

protocol calls for a baseline fasting gastrin measurement, followed

by an injection of 2 clinical units of secretin per kg body-weight

(0.4 microgram/kg) over 1 minute and further serum gastrin

specimens at 5-, 10-, 15-, 20-, and 30-minutes postinjection. A peak-

gastrin increase of >200 pg/mL above the baseline value has >85%

sensitivity and near-100% specificity for gastrinoma. Secretin or

calcium infusion tests are not carried out in the clinical laboratory,

but are usually performed at gastroenterology or endocrine testing

units under the supervision of a physician. They are progressively

being replaced (or supplemented) by imaging procedures, particularly

duodenal and pancreatic endoscopic ultrasound.

 

All patients with confirmed gastrinoma should be evaluated for possible

MEN 1, which is the underlying cause in approximately 25% of cases.

If clinical, biochemical or genetic testing confirms MEN 1, other family

members need to be screened.

Isolated serum gastrin levels can only be interpreted in fasting

patients; nonfasting specimens are uninterpretable.

 

Drugs that interfere with gastric acid secretion, in particular proton

pump inhibitors (eg, omeprazole), should be discontinued, if feasible,

for at least 1 week before serum gastrin measurement. Drugs that

interfere with gastrointestinal motility (eg, opioids) should also be

discontinued for at least 5 drug half-lives before serum gastrin testing.

 

Artifactual hypergastrinemia may be observed in fasting patients

who have undergone procedures that result in temporary gastric

distention or dysmotility (eg, after gastroscopy).

 

Renal failure prolongs the serum half-life of gastrin and is associated

with increased serum gastrin levels.

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