Micronodular Hyperplasia Research Articles

Omeprazole Therapy in Resistant Reflux Disease

Letters1 February 1995Omeprazole Therapy in Resistant Reflux DiseaseHelge L. Waldum, MD and Eiliv Brenna, MDHelge L. Waldum, MDSearch for more papers by this author and Eiliv Brenna, MDSearch for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-122-3-199502010-00019 SectionsAboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail TO THE EDITOR:We read with interest the article by Klinkenberg-Knol and coworkers [1] on omeprazole safety and the accompanying editorial by Freston [2]. Although the report by Klinkenberg-Knol and colleagues [1] offered a well-balanced description of gastrin values and micronodular neuroendocrine cell hyperplasia in the oxyntic mucosa of many patients receiving omeprazole maintenance treatment, the editorial [2] tended to underestimate the risks for hypergastrinemia. Thus, it was not considered that the maximal functional and trophic effects of gastrin in the rat and in humans on the enterochromaffin-like (ECL) cell are reached at a concentration of less than 500 pM ...

Long-Term Treatment with Omeprazole for Refractory Reflux Esophagitis: Efficacy and Safety

To evaluate the long-term efficacy and safety of omeprazole in patients with gastroesophageal reflux disease resistant to treatment with histamine-2 (H2)-receptor antagonists. Cohort analytic study with a mean follow-up of 48 months (range, 36 to 64 months). Patients receiving ambulatory care from referral centers. 91 patients with gastroesophageal reflux disease resistant to treatment with an H2-receptor antagonist but subsequently responsive to 40 mg of omeprazole daily. Open maintenance therapy consisting of 20 mg of omeprazole daily in 86 patients and 40 mg daily in 5 patients. Endoscopy to assess healing; side effects, laboratory values, fasting serum gastrin level, and gastric corpus biopsies to assess safety. Esophagitis recurred in 47% of the patients receiving 20 mg of omeprazole daily, but all rehealed after the dose was doubled. Seven of 40 patients (18%) had a second relapse after a mean follow-up time of 24 months (range, 9 to 36 months) that was successfully treated with a further 20-mg dose increment for a mean period of 36 months (range, 6 to 39 months). Median gastrin levels increased initially from 60 ng/L before study entry to 162 ng/L (P < 0.01) with treatment and reached a plateau during maintenance treatment. Very high gastrin levels (> 500 ng/L) were observed in a subgroup (11%) of patients. The incidence of micronodular hyperplasia increased from 2.5% of the patients at first biopsy to 20% at the last biopsy (P = 0.001), with a corresponding progression of gastritis to subatrophic or atrophic gastritis from less than 1% to 25% (P < 0.001), which was more pronounced in patients with very high serum gastrin levels. Maintenance therapy with omeprazole was effective for at least 5 years in patients with gastroesophageal reflux disease resistant to treatment with H2-receptor antagonists. Treatment was accompanied by a persistent increase in serum gastrin levels and an increase of micronodular argyrophil cell hyperplasia and subatrophic or atrophic gastritis.

Hyperplastic manifestations of enterochromaffin-like cells in the stomach of rats with congenital moderate hypergastrinemia.

The effect of moderate congenital hypergastrinemia on the enterochromaffin-like (ECL) cells was investigated in Zucker rats 4 and 18 months of age by combining autoradiography after tritiated thymidine injection and selective immunocytochemistry. In both age groups the serum gastrin concentration was 200% higher in obese (fa/fa) than in lean (Fa/Fa; Fa/fa) littermates. In 4-month-old obese rats there was a 120% increase (p < 0.05) in the ECL cell labeling index and also a moderate increase in the ECL cell density (p < 0.05) compared with lean controls. In 18-month-old obese rats the hyperplasia was quantitatively more prominent, with both linear and micronodular ECL cell hyperplasia. At this stage, the ECL cell labeling indices in obese and in lean animals were similar. These data support the hypothesis that moderate hypergastrinemia initially accelerates the ECL cell proliferation rate, leading to diffuse ECL cell hyperplasia. In similar conditions, at the latter stage, linear and micronodular ECL cell hyperplasia also develop in most of the hypergastrinemic animals.

Risk-Benefit Assessment of Omeprazole in the Treatment of Gastrointestinal Disorders

For the treatment of duodenal and gastric ulcer and reflux oesophagitis, especially erosive oesophagitis, omeprazole has an advantage over histamine H2-receptor antagonists because it heals significantly more patients significantly faster. Adverse effects have been observed during short term treatment with the same frequency as during treatment with H2-antagonists. Also, maintenance treatment with omeprazole of reflux oesophagitis is significantly superior to H2-antagonist therapy. During long term treatment for up to 8 years no further drug-related adverse effects have been observed. Moderate hypergastrinaemia occurs in some patients, especially if an omeprazole dosage of 40 mg/day is needed. A slight increase of the agyrophil (endocrine) cell volume density and an extension of micronodular hyperplasia in the oxyntic mucosa after several years of omeprazole treatment seem to be related to the severity of the corpus gastritis and not to drug-induced hypergastrinaemia, because similar changes have been observed in equal frequency in patients not receiving anti-secretory drugs. Theoretical arguments against long term treatment with potent acid-suppressing drugs, such as the possible consequences of gastric bacterial overgrowth or hypergastrinaemia, are not supported by clinical observations and epidemiological data and are, therefore, speculative.

Evaluation of Diagnostic Tests in the Differential Diagnosis of Primary Aldosteronism: Unilateral Adenoma Versus Bilateral Micronodular Hyperplasia

Effective management of primary aldosteronism is dependent upon correct localization of excessive aldosterone production. We report our results of localization studies in patients with biochemically and pathologically confirmed primary aldosteronism. Retrospective chart review identified 69 patients with unilateral adrenal adenoma and 11 with adrenal hyperplasia. Correct unilateral versus bilateral localization of excessive aldosterone production was predicted in 70% versus 71%, respectively, by adrenal venography, 100% versus 63% by adrenal vein hormone sampling, 46% versus 56% by adrenal nuclear scanning and 69% versus 13% by anomalous postural decline of aldosterone. Adrenal computerized tomography appeared to localize correctly 86% versus 80% of the lesions. Unilateral adrenalectomy normalized blood pressure in 79% of the patients with unilateral adenomas versus only 18% of those with adrenal hyperplasia. Once primary aldosteronism is confirmed, localization by adrenal vein sampling, adrenal venography and adrenal computerized tomography is most effective in directing antihypertensive therapy.

Primary hyperaldosteronism–evaluation of procedures for diagnosis and localization

We have reviewed the clinical, investigative and pathological findings in 16 patients with primary hyperaldosteronism, 6 with idiopathic adrenal hyperplasia and 10 with an aldosterone-producing adenoma. The ratio of serum aldosterone to plasma renin activity was > 1400 pmol/micrograms/l/h in all patients when measured supine on a normal salt diet, negating the need for salt loading to confirm primary hyperaldosteronism. Postural changes in serum aldosterone confirmed the presence of an aldosterone-producing adenoma in all but one patient when results on normal and high salt intakes were reviewed together. Nevertheless, the need for salt loading for discrimination is questioned, as the combination of postural changes in serum aldosterone on normal salt intake combined with CT confirmed and localized all aldosterone-producing adenomas. Urinary aldosterone measurements were of little value. Localizing procedures consisting of CT and isotopic scanning using 75Se-seleno-methyl-cholesterol proved most useful; adrenal venous sampling yielded less useful information. The latter may be due to the high predominance of patients (8) showing a background of micronodular hyperplasia with a dominant aldosterone-producing tumour. Only three of these patients have remained normotensive and normokalaemic on no medication. The presence of micronodular background suggests the need for life-long monitoring of such patients.

Long-term omeprazole therapy in peptic ulcer disease: Gastrin, endocrine cell growth, and gastritis

Background: The effects of chronic drug-induced hypergastrinemia on the exocrine and endocrine stomach are still incompletely understood. Chronic hypergastrinemia in rats and humans is associated with gastric argyrophil cell hyperplasia. Methods: Seventy-four patients with chronic ranitidine-resistant ulcerations were treated chronically with omeprazole (median observation period 48 [6–84] months). Results: Median fasting serum gastrin levels increased from a pretreatment value of 74–145 pg/mL after 3 months. No further increase was observed thereafter. The finding of atrophic gastritis increased from 1.8% to 20.8% after 5 years. A doubling of the mean argyrophil cell volume density (0.36% vs. 0.74% after 5 years; P < 0.01%) was paralleled by a decrease in the normal endocrine cell growth pattern from 64.3% to 33.3% and an increase in micronodular hyperplasia (8.9% vs. 16.7%). These changes correlated with the severity of corpus gastritis and seemed to be more disease- than drug-related. No statistically significant changes were observed in the antral G- and D-cell volume densities under therapy. Conclusions: Long-term omeprazole therapy in humans results in moderate hypergastrinemia and a significant argyrophil cell hyperplasia, which are correlated to the grade of corpus gastritis. Because hypergastrinemia and gastritis are closely related, it is difficult to quantitatively assess their respective role in this process.

Proton pump inhibitors, enterochromaffin-like cell growth and Helicobacter pylori gastritis.

In both rodents and humans the development of gastrin-promoted gastric argyrophil enterochromaffin-like cell carcinoids requires the involvement of a genetic factor inherent to multiple endocrine neoplasia syndrome or of type A autoimmune chronic atrophic gastritis. Prolonged severe hypergastrinaemia acting on non-gastritic mucosa, as in Zollinger-Ellison syndrome patients, results in diffuse argyrophil enterochromaffin-like cell hyperplasia but, as a rule, does not produce tumours. Combination of chronic atrophic gastritis (mostly related to Helicobacter pylori infection) with hypergastrinaemia frequently causes linear and micronodular hyperplasia of argyrophil cells, whereas carcinoids are exceptional. No tumours or pre-neoplastic lesions have been observed in patients treated long-term with proton pump inhibitors, apart from rare cases in patients with combined Zollinger-Ellison and multiple endocrine neoplasia syndromes. A moderate increase in the incidence of argyrophil cell clustering, with or without hyperplasia, probably results from the parallel evolution of ulcer-associated Helicobacter gastritis into chronic atrophic gastritis. Eradication of H. pylori with a combination of proton pump inhibitors and antibiotics suppresses gastritis and prevents ulcer recurrence.

Hypercortisolism with non-pigmented micronodular adrenal hyperplasia: transition from pituitary-dependent to adrenal-dependent Cushing's syndrome

We report on a female patient with Cushing's syndrome in whom we observed the transition from pituitary dependency to adrenal dependency. Basal ACTH and cortisol values, the CRH test, the dexamethasone suppression test as well as CT of the pituitary and the adrenal gland all reflected pituitary-dependent Cushing's disease in 1985. The patient refused treatment, but presented again five years later. At that time ACTH was suppressed before and after CRH injection. Plasma cortisol did not respond to CRH. After ketoconazole therapy, ACTH was within the high normal range. The patient underwent bilateral adrenalectomy. The adrenals exhibited a bilateral micronodular hyperplasia of the zona fasciculata. In vitro examination of adrenal cells revealed a maintained ACTH response. Some weeks postoperatively, the patient died from pneumonia. Histological examination later showed a chromophobe pituitary microadenoma; ACTH was demonstrated immunohistologically in the adenoma. We postulate that some cases of pituitary Cushing's disease initially exhibit a bilateral homogeneous adrenal hyperplasia which then develops into a nodular hyperplasia; in the next stage of the disease, single micronodules may become autonomous and elevated cortisol levels suppress ACTH secretion of the pituitary adenoma.

Direct inhibitory effect of etomidate on corticosteroid secretion in human pathologic adrenocortical cells

Etomidate has been shown to inhibit corticosteroid secretion in the normal adrenal gland, but its direct effect in human pathologic adrenals has not been clearly established. In the present study the effect of varying doses of etomidate (10 −11 –10 −5 M) was investigated on basal and adrenocorticotrophic hormone (ACTH)-stimulated corticosteroid secretions in isolated adrenocortical cells obtained from two patients with primary aldosteronism (adenoma and micronodular hyperplasia) and in those from a patient with Cushing's syndrome (adenoma). In cells from primary aldosteronism, increasing concentrations etomidate (10 −11 –10 −5 M) produced a dose-dependent decrease of basal and ACTH-stimulated cortisol, aldosterone, 18-hydroxycorticosterone, and corticosterone secretions (ED 50: 10 −8 M for each of these corticosteroids). In the same cells, the secretions of 11-deoxycortisol and deoxycorticosterone were increased in the presence of low (10 −9 – 10 −7 M) but not high doses of etomidate (10 −6 –10 −5 M). In cells from Cushing's syndrome the changes in costicosteroid secretion were similar to those found in primary aldosteronism except that aldosterone and 18-hydroxycorticosterone could not be determined due to their low levels. Thus the potent inhibition of corticosteroids in human pathologic adrenocortical cells in the presence of low concentrations of etomidate may be predominantly due to inhibition of the 11β-hydroxylase enzyme, whereas higher doses of the drug may inhibit earlier steps of the corticosteroid biosynthetic pathway. (Steroids 58:64–68, 1993)

Cushing's syndrome induced by hypersecretion of cortisol from only one of bilateral adrenocortical tumors

A case of Cushing's syndrome induced by the unilateral (right side) dominance of cortisol secretion in the face of bilateral adrenal tumors is reported. The adrenal tumor resected on the right side was a so-called black adenoma and histologically without any findings of nodular hyperplasia. After resection of the adrenal adenoma, no findings of cortisol hypersecretion from the remaining adrenal tumor on the left side were observed until the present, suggesting that the tumor of the left adrenal gland is a nonfunctioning adenoma. These data imply that the adrenal adenomas have primarily developed from the adrenal gland itself, rather than from micronodular hyperplasia by corticotropin stimulation, and that one of these tumors produces excess hormones initially by corticotropin stimulation, but the other remains in cell proliferation.

Gastric Endocrine Cells and Gastritis in Patients Receiving Long-Term Omeprazole Treatment

Both argyrophil endocrine cells and gastritis were investigated in 2,120 biopsies of gastric corpus mucosa from 443 out of 448 patients receiving long-term (for periods ranging from several months to 4 years) omeprazole treatment. None of the patients showed neoplasia or dysplasia, either endocrine or non-endocrine. In 123 out of 443 patients (27.8%), endocrine hyperplasia of diffuse (9.3%), linear (4.1%) or micronodular (14.4%) type was detected either before or at some time during treatment. Chronic atrophic gastritis was found in 45 (10.2%) patients, 60% of whom also showed micronodular hyperplasia. In patients with chronic atrophic gastritis, micronodular hyperplasia occurred in 49% of 96 biopsies, compared with 6% of 1,083 biopsies from patients with non-atrophic chronic gastritis and 2% of 941 biopsies from patients with no evidence of gastritis. In 202 patients treated with omeprazole for at least 330 days, the incidence of micronodular hyperplasia increased from 2.5% at the first biopsy to 10.4% at the final biopsy, while the incidence of chronic atrophic gastritis increased from 1.0% to 13.0%. The present and parallel studies suggest that progression of gastritis is inherent in the natural history of acid-related diseases, while endocrine cell changes are mostly secondary to gastritis-related gland atrophy and have no tumorigenic potential.

Inter-Relationship between Serum Gastrin Levels, Gastric Mucosal Histology and Gastric Endocrine Cell Growth

The development of gastric enterochromaffin-like (ECL)-cell hyperplasia in humans may be associated with extreme hypergastrinaemia, as occurs in Zollinger-Ellison syndrome (ZES) and pernicious anaemia (type A gastritis). More recently, endocrine cell hyperplasia has been found in all forms of chronic atrophic gastritis and even in cases of focal atrophy. Serum gastrin levels, non-antral gastric endocrine (argyrophil) cell growth, and the severity and type of concomitant gastritis were monitored in 66 unoperated and 8 antrectomized patients with poorly responsive peptic ulcer or reflux oesophagitis during up to 5 years' treatment with high-dose omeprazole, 40 mg daily. A small subgroup of patients (23%) had serum gastrin concentrations of more than four times the normal upper limit. These patients also had hyperplasia of the gastric argyrophil cells. More importantly, the same subgroup of patients had high-grade (atrophic) gastritis. Micronodular hyperplasia of argyrophil cells was significantly more frequent in biopsies showing atrophic gastritis (48%) than in biopsies showing only superficial gastritis (3.6%). It is concluded that, as previously demonstrated in untreated patients with gastric ulcer, the argyrophil cell hyperplasia observed during high-dose omeprazole therapy is related to the progression of chronic atrophic gastritis rather than to serum gastrin levels.

Micronodular hyperplasia of type II pneumocytes-a new lung lesion associated with tuberous sclerosis

Open lung biopsy in a 38-year-old female with Pringle-Bourneville syndrome and recurrent pneumothorax revealed a micronodular pneumocyte II hyperplasia, a new entity probably associated with the tuberous sclerosis syndrome. The lesion caused an obstruction of the alveolar lymphatic vessels and alveolar ducts, resulting in an emphysema-like picture. This cystic dilation of alveoli and draining lymphatics followed by rupture caused the recurrent pneumothorax. The epithelial pneumocytic nature of the lesion was confirmed by immunohistochemistry and electronmicroscopy.

Argyrophil Cell Hyperplasia Associated with Chronic Corpus Gastritis in Gastric Ulcer Disease

Argyrophil cell (AC) hyperplasia in corpus mucosa was investigated in 53 patients with chronic gastric ulcer disease not previously treated with antisecretory drugs. Mucosal biopsies were taken stepwise from the posterior wall in the corpus area of the stomach. Of 117 biopsy sites, 28 showed gastritis without atrophy, 85 showed chronic atrophic gastritis of varying degrees while 4 biopsies showed a normal mucosa. About one third (38%) showed a normal AC pattern. Of the remaining two thirds (62%), 45% had simple AC hyperplasia, 18% had linear and 37% had micronodular AC hyperplasia. A strong association was found between focal (linear/micronodular) AC hyperplasia and chronic atrophic gastritis. It is concluded that focal AC hyperplasia is a common phenomenon in gastric ulcer patients and is inherently related to the spontaneous development of atrophy in the corpus mucosa of these patients.

Continuous Dexamethasone Infusion for Seven Hours in Patients with the Cushing Syndrome

To determine the usefulness of the continuous intravenous dexamethasone suppression test in the differential diagnosis of patients with the Cushing syndrome. Comparison of the results of this test with those of other tests in the study population and with data from the literature. Referral-based endocrine division in a university hospital. One hundred and twenty-one patients with the Cushing syndrome were evaluated: corticotropin (ACTH)-secreting pituitary tumors, 90 cases; adrenal adenoma, 13; adrenal carcinoma, 9; ectopic ACTH-secreting tumors, 6; corticotropin-releasing-hormone (CRH)-secreting tumors, 2; and autonomous bilateral micronodular adrenal hyperplasia, 1. The continuous intravenous dexamethasone suppression test was done in 101 patients. Dexamethasone (1 mg/h) was administered intravenously for 7 hours. A cortisol decrease of at least 190 nmol/L was defined as a positive response. In identification of patients with ACTH-secreting pituitary adenomas, this test had a sensitivity of 100% (95% CI, 95% to 100%), a specificity of 90% (CI, 70% to 99%), and a diagnostic accuracy of 98% (CI, 93% to 100%). Only two patients had false test results. They both had CRH-secreting tumors. Cortisol secretion was also shown to be sensitive for feedback control in other tests, however. The continuous intravenous dexamethasone suppression test has better diagnostic accuracy than other tests that are currently used in the differential diagnosis of the Cushing syndrome, and this test is very convenient. The only false test results were found in patients with CRH-secreting tumors.

Cushing’s Syndrome

Cushing's syndrome remains one of the great diagnostic challenges to internists and endocrinologists. Urologists have the primary role in the treatment of many of the forms of Cushing's syndrome, especially adrenal tumors and micronodular hyperplasia. As we continue to gain experience with Cushing's disease treated with pituitary surgery and with etopic ACTH syndrome and the other forms of Cushing's syndrome, urologists are likely to become even more involved in the therapy of all types of Cushing's syndrome.

Qualitative Studies of Gastric Endocrine Cells in Patients Treated Long-term with Omeprazole

A total of 543 endoscopic biopsies (a mean of three tissue samples each) were taken from the gastric oxyntic mucosa of 122 patients suffering from reflux oesophagitis or peptic ulcer resistant to H2-receptor antagonist therapy. All were treated with omeprazole, 40 mg/day, until healing and then assigned to 20 mg/day for a mean of 13 months. Proliferative changes of endocrine cells were evaluated according to an internationally agreed classification and the paraffin sections were stained with haematoxylin-eosin and Sevier-Munger silver. Only hyperplastic (no dysplastic or neoplastic) lesions of endocrine cells were observed in 11-19% of patients examined, the incidence and severity of these lesions being unaffected by treatment. A relationship between linear and/or micronodular hyperplasia and chronic gastritis was observed.

Gastric carcinoid associated with the syndrome of hypergastrinemic atrophic gastritis. A prospective analysis of 11 cases.

The prevalence of gastric carcinoid in fundic atrophic gastritis is probably greater than previously recognized. To help elucidate the clinicopathology of this syndrome, we report a series of 11 patients with solitary or multicentric carcinoid tumors. In these patients, basal gastrin levels and density of fundic mucosal endocrine cells were greater than that for patients with uncomplicated fundic atrophic gastritis (p = 0.02 and p = 0.002, respectively). The polypoid tumors, of which the largest measured 30 mm, frequently showed characteristic endoscopic features. They were all situated in the fundic mucosa, which showed micronodular endocrine cell hyperplasia. Small, endoscopically evident tumorlets, or "early carcinoids," limited to the lamina propria were observed in some patients. These lesions may represent intermediate stages between micronodules and invasive carcinoids, all of which infiltrated at least into the muscularis mucosae of the gastric wall. Although some consistent characteristics features were noted, there were structural variations. The cells were argyrophil but nonargentaffin and did not stain with conventional mucus stains. They did not stain significantly for carcinoembryonic antigen (CEA). The secretory product of these tumors remains to be identified. Ultrastructurally, some tumors were mainly composed of enterochromaffinlike (ECL) cells, but in other tumors most of the cells could not be classified.

Adrenocortical Micronodular Dysplasia, Cardiac Myxomas, Lentigines, and Spindle Cell Tumors

In a family encompassing three generations, six of 11 evaluated members have two or three elements of a triad comprising adrenocortical micronodular dysplasia, mucocutaneous lentigines, and cardiac myxomas. Evaluation of the adrenals in affected members revealed characteristic pathologic lesions of micronodular adrenal hyperplasia and corticotropin-independent steroidogenesis that correlated with age, suggesting a progressive lesion that begins in early childhood. Since all subjects with micronodular hyperplasia and/or cardiac myxomas also had mucocutaneous lentigines, the skin lesions were markers for affected subjects. This family is one of the larger reported with this syndrome. Of special note was the finding of rare visceral tumors in affected family members, including melanocytic schwannomas and a fibrolamellar hepatoma, signaling another feature of the syndrome. Since 60% of this family encompassing three contiguous generations were affected, the syndrome appears to be inherited as an autosomal or X-linked dominant gene.