Currently, the diagnosis of gastritis has no commonly accepted classification. The classification called the Sydney System is still used by physicians, and it was developed in 1990. The first detailed classification occurred after the discovery of Helicobacter pylori, a bacteria involved in the etiology of gastritis. In 1994, scientists made further distinctions between atrophic and non-atrophic gastritis.
The updated Sydney System breaks down atrophic gastritis further into multifocal (H. pylori, specific diet, environmental factors) and corpus-predominant (autoimmune). Frequently, metaplasia plays a part in autoimmune gastritis, thus the word has been added in the classification for autoimmune metaplastic atrophic gastritis (AMAG). Let’s take a further look at the causes, manifestations, and treatment of AMAG, for which H. pylori is the most common cause for the development of gastritis worldwide.
Epidemiology
Pernicious anemia (PA) is a key manifestation of AMAG. Physicians used to believe that PA was a disease that affected only elderly females of Northern European descent. However, it is now recognized that the prevalence is similar across all populations. Like other autoimmune disorders, AMAG is more common in females than in males with a 3:1 ratio. Scientists believe that both AMAG and PA are significantly underdiagnosed around the globe. One explanation may be that doctors treat microcytic and macrocytic anemia with iron, folic acid, and cobalamin without identifying the cause of the anemia.
Pathogenesis
Researchers are still working to understand how AMAG develops as a disease. This is due to several reasons, notably the low prevalence of AMAG, coexisting H. pylori-induced gastritis, and very limited symptoms during the early stages. Still, they have identified both genetic and environmental factors that are key to the development of autoimmune gastritis. Genes have been identified that make an individual susceptible to AMAG, and they are located close to diabetes mellitus susceptibility genes in mice. This may explain the strong association between AMAG and diabetes mellitus.
Despite the lack of in-depth knowledge about how AMAG develops, scientists have identified some features like the infiltration of oxyntic mucosa by plasma cells and lymphocytes. The random destruction of parietal cells leaves small “islands” of normal oxyntic mucosa. This phenomenon is known as gastric pseudopolyposis, and it is similar to lesions in patients with ulcerative colitis. The result includes hypochlorhydria, which is a loss or decrease of hydrochloric acid secretion, which sets off a chain of events. This can lead to spasmolytic polypeptide-expressing metaplasia (SPEM). Inflammatory and hyperplastic polyps develop in the later stages of AMAG. Oxyntic mucosa can be completely absent in the advanced stages of AMAG.
Association with H. pylori
Scientists have established that H. pylori can cause atrophic gastritis by itself. Many patients with AMAG have a coexisting infection with H. Pylori. Researchers suggest that some H. pylori-induced gastritis may progress to AMAG. Many patients with H. pylori develop a wide spectrum of antibodies, which includes antifoveolar, anticanalicular, and the classic APCA.
The factors that help doctors differentiated between AMAG and H. pylori gastritis are 1) ECL hyperplasia (more common in AMAG), 2) parietal cell pseudohypertrophy (in AMAG; can be seen in H. pylori infection secondary to proton pump inhibitor use) and 3) oxyntic gland involvement (more common in AMAG).
Association with other autoimmune disorders
AMAG occurs more frequently in patients with other autoimmune conditions. Approximately 33% of patients with autoimmune thyroid disease and 10% of patients with type 1 diabetes have AMAG as well. Other autoimmune disorders with higher rates of AMAG include polyglandular autoimmune syndrome, vitiligo, Addison’s disease, myasthenia gravis, and perioral cutaneous autoimmune conditions.
Clinical manifestations
The symptoms of atrophic gastritis develop slowly with the early stages showing no symptoms. Frequently, it is difficult to diagnose either AMAG or PA based solely on clinical manifestations.
The affected patient may present with a variety of signs and symptoms ranging from weakness to severe neurological manifestations such as paranoia. That is why among doctors, PA is also known as a “great pretender”.
Hematological manifestations
Iron-deficiency anemia (IDA) is one of the earliest presentations of AMAG that develops due to achlorhydria from oxyntic atrophy. Several studies suggest that refractory or unexplained IDA should be examined more closely by a physician, both in adults and children. PA is the most common cause of cobalamin deficiency, although scientists don’t know why.
The asymptomatic increase in mean corpuscular volume and hypersegmented neutrophils are typically the initial laboratory findings in PA. As the disease progresses, the patients may experience weakness, light-headedness, palpitations, symptoms of angina, and congestive heart failure. Lab tests may detect thrombocytopenia, increased levels of LDH, and bilirubin (signs of hemolysis). Rare cases may have symptoms that mimic serious conditions like disseminated intravascular coagulopathy (DIC) or thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS).
Neurological manifestations
Neurological manifestations of cobalamin deficiency include demyelination, axonal damage, and neuronal death. The neurological symptoms also include subacute combined degeneration involving the cervical and thoracic segments of the spinal cord. This causes sensory abnormalities. In advanced stages, the corticospinal tract may be affected. The neurological damage is irreversible. However, time is of the essence. Failure to treat these patients in a timely manner may lead to paresthesia and numbness in the lower extremities. Doctors may find it difficult to distinguish between SCD and peripheral neuropathy because both are asymptomatic.
Neuropsychiatric conditions associated with PA include mania, depression, obsessive-compulsive disorder (OCD), psychosis, and dementia. Research has shown that using high doses of vitamins B12, B6, and folic acid slows the shrinkage of the whole brain as well as reduces cerebral atrophy in patients with Alzheimer’s disease.
Gastrointestinal manifestations
It may seem odd, however, AMAG rarely results in gastrointestinal symptoms. This may be due to the fact that most of the upper gastrointestinal-related complaints are secondary to an increased level of hydrochloric acid. Individuals with AMAG typically present with vague dyspeptic symptoms like bloating, early satiety, and epigastric discomfort.
Neoplastic complications
The incidence of gastric neoplasms is higher in patients with AMAG compared to the general population. Overall, AMAG is linked with the development of two types of gastric neoplasms: intestinal-type GC and type I gastric carcinoid (TIGC).
Intestinal-type gastric cancer
A coexisting infection with H. pylori and intestinal metaplasia (IM) are two main factors in the occurrence of gastric cancer in patients with AMAG. However, eradication of H. pylori with precancerous lesions does not lower the incidence of gastric cancer. The “Correa Cascade” describes the progression: 1) normal gastric mucosa, 2) non-atrophic gastritis, 3) multiple atrophic gastritis without (initially) and with (later) IM, 4) dysplasia progressing from low grade to high grade and 5) gastric cancer.
AMAG with no coexisting H. pylori infection does not follow the Correa Cascade. Not all individuals with H. pylori-induced gastritis develop gastric cancer. The risks are higher when certain virulence factors are present For instance, CagA-positive strains of H. pylori have been shown to have a significantly higher risk of the development of peptic ulcer and GC compared to CagA-negative strains.
Type I gastric carcinoid
While researchers have linked AMAG with a higher risk of TIGC, the incidence rate is not known. There are three known types of gastric carcinoids: type I is associated with AMAG, type II can be present in patients with multiple endocrine neoplasias (MEN) I and Zollinger-Ellison syndrome, and type III, the most aggressive variant, usually occurs sporadically. Serum gastrin levels vary depending on the type of gastric carcinoid: types I and II – high, and type III – normal. The loss of negative feedback by parietal cells on gastrin secretion induces the pathologic changes in TIGC. Then, hypo-/achlorhydria leads to hypergastrinemia, which has trophic effects on ECL cells.
ECL hyperplasia followed by ECL dysplasia is considered to be precancerous lesions and over time can progress to T1GC. The detection of body polyps during endoscopy in patients with AMAG is strongly associated with the presence of TIGC. Patients with TIGC are usually asymptomatic, although symptoms of dyspepsia and IDA can be present. That is why the diagnosis is usually made during gastroscopy.
Treatment
The management and treatment for AMAG and PA depend on their clinical manifestations, lab tests, and imaging results. Treatment for AMAG with supplements of iron, folic acid, and cobalamin is common during the early stages before the condition progresses to PA. An oral dose of vitamin B12 is often recommended because 1% of free vitamin B12 is absorbed in the small intestine through passive diffusion. However, in patients with neurological manifestations, parenteral administration of vitamin B12 is currently recommended. Because AMAG is associated with other autoimmune disorders, doctors should carefully investigate other conditions like autoimmune thyroiditis and TIDM.
In addition, it’s crucial to identify and treat an H. pylori infection because of the higher risks associated with the coinfection. Several studies show that H. pylori can induce an autoimmune process in the gastric lining including oxyntic mucosa. Therefore, eradication of the bacteria is crucial to lowering the levels of antibodies associated with AMAG. This treatment has been proven effective to cure the early stages of autoimmune gastritis.
Type 1 gastric cancer has an excellent prognosis, and a variety of options may be available like polypectomy, surveillance, and antrectomy. One of the potential treatments for TIGC has been recently introduced. Netazepide, a gastrin receptor antagonist, has been shown to decrease the plasma level of CgA along with tumor number and size. Another treatment option is to consider using somatostatin analogs. One study showed that the use of somatostatin analogs resulted in a reduction in median gastrin and CgA levels and thus should be considered as an effective therapy.
A new and emerging form of therapy for the treatment of neuroendocrine tumors is the use of peptide receptor radiotherapy (PRRT). However, this therapy is new and has not been studied for atrophic gastritis.