**5. Atrophic gastritis**

#### **5.1 Background**

14 Autoimmune Disorders – Current Concepts and Advances from Bedside to Mechanistic Insights

The treatment of autoimmune thyroid follows the guidelines of congenital hypothyroidism. If the TSH level is greater than 10 μU/ml, L-thyroxin is the drug of choice. The initial dose is related on patient's age and on patient's clinical status from 25 μg/day to 100-150 μg/day. The therapy required periodic reevaluation, in particular when prominent nodules persist despite suppressive therapy, because there is a greater risk of cancer in patients with

Graves' disease is the most important cause of thyrotoxicosis in pediatrics and affects about 0.02% in children and adolescents. Its frequency increases with age: it is rare before the four years, gradually rises, reaching a peak during adolescence, with a preponderance for female gender (Kaguelidou et al, 2009). The aim of therapy is to reduce the excessive hormone production. First, this can be done with anti-thyroid drugs, as tionamides, with side effects especially after long-term therapy. Secondly, can be used thyroidectomy; however this surgical procedure may be complicated by several problems, such as hypoparathyroidism or recurrent nerve injury. Third method, is based on the use of radioiodine, that has not been yet universally accepted in children. Initial treatment, is medication and in the second instance, surgery or radioiodine. The goal of treatment is to maintain euthyroidism for a period at least 24 month and then discontinue the medical therapy. The positive results, with pharmacological treatment alone reaches 25% of cases. In *adults* the disease control is accomplished through the use of radioactive iodine or with drug for short periods. In *children*, however, use the medication for long periods, and then radioiodine, is just as an alternative option. The average age of onset is at 11 years (from 2.5 to 19 years), with preponderance in girls and with more cases of exophthalmos, low BMI, and higher height SDS. The goal of treatment is to limit the biosynthesis of thyroid hormones and maintain euthyroidism by maintaining a check on lab tests. Adverse effects are recorded in 5-32% of cases with skin rashes, transient neutropenia and agranulocytosis. Children have more adverse effects but less severe, often reversible spontaneously or with therapy change. Alternatively, using radioiodine in patients with hyperthyroidism resistant to drug treatment of 4.5 years, there was more remission (about 25% between 2-4 years of follow up). Most side-effect of the therapy is a permanent hypothyroidism, which can be treated with replacement therapy. The problem of this method is a potential carcinogenic risk (thyroid cancer and leukaemia), that declines with age, genetic damage, and a possible damage to reproduction. Radioiodine for safety, low cost and morbidity, could be the definitive treatment of Graves' disease in older children and young adolescents, but no in

children younger than 5 years old (Gruneiro-Papendich et al, 2003).

Autoimmune thyroid disease is frequently reported in patients with type 1 diabetes mellitus, sometimes associated with celiac disease (Ergur et al, 2010). Serological screening studies aimed to evaluate the prevalence of thyroid involvement have gained momentum in recent years (Kadiyala et al. 2010). The prevalence of thyroid autoimmunity in patients with type 1 diabetes has been reported to be two to four times more frequent than in control

**4.3 Autoimmune thyroid disease and type 1 diabetes** 

population.

**4.1.6 Treatment** 

lymphocitic thyroiditis.

**4.2 Graves' disease** 

While the association between type 1 diabetes and celiac disease and/or thyroid autoimmunity is clearly documented, particularly in young patients, few data are available about the frequency of other autoimmune diseases, like autoimmune gastritis and pernicious anemia.

Autoimmune Disorders Associated to Type 1 Diabetes Mellitus in Children and Adolescents 17

Diagnosis of AG requires gastroscopy with at least two biopsies from gastric antrum and gastric body. Atrophy of the gastric body mucosa is defined as focal or complete oxyntic gland loss and/or replacement by metaplastic pylori or intestinal glands. To each graded variable, the scores usually employed are: 0 = absence; 1 = mild; 2 = moderate; 3 = severe

Therapy of autoimmune gastritis includes supplementation of iron or vitamin B12 or removal of pre-malignant gastric lesions. Patients with PCA antibodies and high gastrin

Determining risk factors for and early diagnosis of autoimmune gastritis is mandatory to prevent and treat iron-deficiency anemia, pernicious anemia and pre-malignant gastric lesions. In all PCA positive patients gastroscopy with multiple biopsies should be

Autoimmune gastritis is rarely encountered in children and adolescents with type 1 diabetes, since the prevalence of parietal cell antibodies increases with age and with longer duration of disease. It is noteworthy that even young patients with type 1 diabetes are positive for parietal cell antibodies, with a frequency about 4%, which is higher than in controls (1.9%) (De Block et al., 2008). On the other hand, autoimmune gastritis is more

performed and subsequent clinical and endoscopic close follow-up are mandatory.

frequent in children and adolescents with autoimmune thyroid disorder (Fig. 3 ).

Fig. 3. Atrophic gastritis and sessile antral polyp with signs of esophageal candidiasis

(Bordi et al., 1997).

levels should undergo endoscopy with biopsies.

**5.5 Autoimmune gastritis and type 1 diabetes** 

**5.4 Treatment** 

(personal data)

Autoimmune gastritis, firstly described by Thomas Addison in 1849, is characterized by autoantibodies directed against gastric parietal cells, atrophy of gastric corpus and fundus, hypochlorhydria/achlorhydria, hypergastrinemia, iron deficiency anemia and pernicious anemia.

In *adult* general population the frequency of autoimmune gastritis is about 1-2%, and is 3-5 fold increased in patients with type 1 diabetes (De Block et al, 2008). As regards *children*, *adolescents* and *young adults* with type 1 diabetes, the frequency of parietal cells antibodies is 15.8%, with a close association with older age and duration of disease (De Block et al, 2008, Warncke et al, 2010). Female gender association is controversial.

#### **5.2 Pathogenesis**

Antibodies against parietal cells (PCA) and their secretory product Intrinsic Factor (AIF) are serological markers for autoimmune gastritis and are targeted towards H+, K+-ATPase of gastric parietal cells and denote autoimmune gastritis, characterized by atrophy of corpus and fundus. The chronic auto-aggression to the proton pump exerts in hypochlorhydria/achlorhydria and hypergastrinemia and iron-deficiency anemia as a consequence of impaired gastric secretion and iron absorption. Moreover PCA are responsible for the reduced intrinsic factor secretion with subsequent pernicious anemia due to vitamin 12 deficiency. PCA and AIF are detectable not only in serum, but also in gastric juice. PCA titer is positively related to severity of gastric atrophy and negatively related to concentration of parietal cells. Low serum levels of pepsinogen I, as a consequence of chief cell destruction, represent another early marker of autoimmune gastritis and pernicious anemia. Both pernicious anemia and autoimmune gastritis may predispose to gastric cancer. Gastric adenocarcinomas are reported on 1-10 % of adult patients with autoimmune gastritis through intestinal meta/dysplasia. (De Block et al., 2003) Helicobacter Pylori infection has been reported as a risk factor for autoimmune gastritis, by stimulating granulocytes to produce oxygen radicals, which are mutagenic and lead to corpus atrophy (D'Elios et al., 2004). Molecular mimicry and/or T-helper l-induced expression of HLA-class II and costimulatory molecules on gastric epithelial cells are considered as pathogenic mechanisms for Helicobacter Pylori induced autoimmunity (Lahner et al., 2011). The evidence of a link between pernicious anemia and particular HLA haplo/genotypes is not strong. As regards type 1 diabetes, a weak association between PCA positivity and the HLA-DQA1\*0501- B1\*0301 haplotype, linked to HLA-DR5, has been observed. In mouse models, four distinct genetic regions that confer susceptibility to autoimmune gastritis have been identified: two loci, located on distal chromosome 4, are called *Gasa1* and *Gasa2*; two other loci, located on chromosome 6, are called *Gasa3* and *Gasa4,* respectively. Interestingly, three out of these four susceptibility loci are non-major histocompatibility complex genes which co-localize with those of type 1 diabetes. This is the strongest concordance identified between any two autoimmune disease so far (De Block et al., 2008).

#### **5.3 Diagnosis**

Parietal cell antibodies are measured using immunoblotting or enzyme linked immunoassay (ELISA), which are more sensitive than indirect immunofluorescence technique. Iron deficiency anemia is defined as microcytic hypochromic anemia with a transferrine saturation of less than 20% and low iron and ferritin levels. Pernicious anemia is defined as macrocytic anemia with subnormal vitamin B12 levels and positive levels of PCAs Diagnosis of AG requires gastroscopy with at least two biopsies from gastric antrum and gastric body. Atrophy of the gastric body mucosa is defined as focal or complete oxyntic gland loss and/or replacement by metaplastic pylori or intestinal glands. To each graded variable, the scores usually employed are: 0 = absence; 1 = mild; 2 = moderate; 3 = severe (Bordi et al., 1997).
