Blood losses due to menstruation and haemorrhage are a common cause of iron-deficiency anaemia, and our patient's medical history included menorrhagia. Therefore, the initial diagnosis was microcytic anaemia due to iron deficiency with a subsequent cytoplasmic maturation defect and ineffective erythropoiesis.1 2
Our patient also had subclinical hypothyroidism, which leads to reduced thyroid hormone stimulation of the bone marrow and erythropoietin deficiency.3
However, our patient's iron-deficiency anaemia was refractory to supplemental iron and thyroxine treatment and only partially responsive to parenteral iron administration. Therefore, on the basis of the well-known major role played by gastric hydrochloric acid, we measured gastrin levels to investigate the state of the mucosa in the gastric corpus.
The finding of gastrin levels >100 pg/ml was compatible with a diagnosis of hypergastrinaemia—a condition frequently associated with the administration of histamine type-2 receptor antagonists or proton pump inhibitors, peptic ulcer disease, chronic gastritis (types A and B), gastric carcinoma without antral involvement, gastric carcinoid tumours (types 1 and 2), highly selective truncal vagotomy, Zollinger–Ellison syndrome, gastric-outlet obstruction, Billroth II gastrectomy with antral exclusion and massive small bowel resection.4
High plasma chromogranin A levels are also common in these conditions and in patients with neuroendocrine tumours (pheochromocytoma, oat-cell carcinoma of the lung, neuroblastoma, gastrointestinal and pancreatic tumours). Moreover, enterochromaffin-like cell hyperplasia secondary to hypergastrinaemia is a well-known cause of elevated blood levels of chromogranin A.
Our patient had no history of long-term treatment with proton pump inhibitors or histamine type-2 receptor antagonists, and she had never had surgery. Immunological tests revealed positive titres of antigastric mucosa antibodies and the endoscopic evaluation supported the diagnosis of autoimmune gastritis. The normalisation of the haemoglobin level value with subcontinuous intravenous iron replacement confirms that the cause of the anaemia was impaired duodenal and proximal jejunal absorption secondary to hypochlorhydria caused by autoimmune gastritis. Dikey et al5
were the first to observe that autoimmune gastritis can present with iron-deficiency anaemia. Their findings were confirmed by Marignani et al6
and Annibale et al
who observed that in 19.5–26% of patients with refractory iron-deficiency anaemia and no gastrointestinal symptoms the anaemia is caused by autoimmune gastritis.7
Therefore, in the work-up of patients with unexplained iron-deficiency anaemia an autoimmune origin for the anaemia should always be suspected. Moreover, in the presence of immune-mediated failure of non-endocrine organs (stomach, skin) and several endocrine glands (thyroid) we should always consider a rare polyendocrinopathy known as APS. In 1980, Neufeld and Blizzard distinguished four main types of APS on the basis of clinical features.8
APS-1 is an autosomal recessive disorder diagnosed during childhood or early adolescence and is caused by mutations of a single gene located on chromosome 21 (autoimmune regulator gene or AIRE
). It is characterised by the presence of at least two of the following conditions: chronic candidiasis, chronic hypoparathyroidism and Addison's disease.9
APS-2 is an autosomal dominant disorder with incomplete penetrance and generally strikes women 20–40 years of age. Addison's disease is almost always present and is associated with autoimmune thyroid diseases and/or type 1 diabetes mellitus. APS-2 is associated with the HLA DR3/4 haplotype.
APS-3 is characterised by the presence of autoimmune thyroid disease (Hashimoto's thyroiditis, idiopathic myxedema, Graves' disease, asymptomatic thyroiditis or endocrine exophthalmus) and another autoimmune disease, excluding Addison's disease. Betterle and Zanchetta distinguish four subtypes (A, B, C and D) on the basis of the different organ-specific and non-organ-specific autoimmune disease associated, excluding Addison's disease and/or hypoparathyroidism.10
The only case of APS type 3B+C was described by Amerio et al
It involved a 36-year-old woman with a 20-year history of generalised vitiligo, chronic autoimmune thyroiditis and autoimmune gastritis with high titres of antiparietal cell antibodies and pernicious anaemia.
APS-4 is a rare syndrome, which comprises all the clinical combinations not included in the other APS subtypes.
As for the pathogenesis of the APSs, it has been recently suggested that some external agents share one or more epitopes with an antigen common to several endocrine tissues (eg, those derived from the same germ layer).12
Thus, exposure to such agents would trigger an autoimmune response directed against the germ-layer-specific antigen.
In conclusion, we believe that this case offers some important clues to the differential diagnosis and management of iron-deficiency anaemia and also to the identification of APS. First, in a premenopausal woman reporting menorrhagia, hypothyroidism and a history of refractory iron-deficiency anaemia—even if there are no gastrointestinal symptoms and fecal occult blood tests are negative—it is important to consider gastrointestinal diseases that impair iron absorption, not only celiac disease and H pylori
gastritis, but also less common conditions such as autoimmune involvement of the gastric corpus.13
Therefore, in the work-up of patients with unexplained iron-deficiency anaemia, screening for atrophic gastritis of the corpus based on measurement of gastrin and chromogranin levels and antigastric mucosa antibody titres might be carried out before the endoscopic biopsy procedure. Moreover, chronically high serum gastrin levels can cause the proliferation of enterochromaffin-like cells.14–16
Indeed, up to 10% of patients with autoimmune gastritis develop gastric carcinoid tumours or adenocarcinomas. Thus, regular gastroscopic surveillance should be offered to all patients with autoimmune gastritis.
Second, in patients with specific autoimmune disease of multiple non-endocrine organs (such as vitiligo, autoimmune gastritis, alopecia, celiac disease, rheumatoid arthritis, myasthenia gravis and pernicious anaemia), the possibility of multiple endocrine gland insufficiency (autoimmune thyroiditis, diabetes mellitus, Addison disease) should also be considered to exclude an APS. In contrast, patients with monoglandular endocrinopathies need to be screened for organ-specific autoantibodies to identify those at risk for developing APS in the future.
- In the presence of chronic refractory iron-deficiency anaemia associated with a long-term history of two different autoimmune diseases, an autoimmune origin for the anaemia should always be suspected and investigated.
- All patients with autoimmune gastritis should undergo regular gastroscopic surveillance because of the risk to develop carcinoid tumours or adenocarcinomas (up to 10%).
- In patients with a single or multiple endocrine gland, insufficiency associated to an autoimmune disease of multiple non-endocrine organs should be considered to exclude an APS.