The Changing Clinical Profile of Celiac Disease
The Changing Clinical Profile of Celiac Disease
The annual distribution of CD diagnoses is shown in Figure 1. Of the 770 CD patients, 318 were diagnosed in the first 10 years (1998–2007), whereas 452 were detected in the last five years (2008–2012). The onset of CD was symptomatic in 610 patients (79%), whereas the remaining 160 (21%) showed a subclinical phenotype. Of the 610 symptomatic patients, 210 had the classical phenotype, whereas 400 displayed the non-classical phenotype (Figure 2). In the period 1998–2007 the classical, non-classical and subclinical phenotype were respectively found in 47.2%, 43.1% and 9.7% of CD cases, whereas in the period 2008–2012, the most frequent clinical phenotype was the non-classical (58.2%), followed by the subclinical (28.5%) and by the classical (13.3%). The median age at diagnosis was significantly lower in patients with the subclinical (32 years) than with the symptomatic phenotype (37 years) (P < 0.001). No significant difference was found in the median age at diagnosis between classical and non-classical forms (39 vs. 36 years, P = 0.058). Taking into account all CD patients (n = 770), about half (53%) of them had gastrointestinal symptoms/manifestations, i.e. diarrhea (27%), bloating (20%), aphthous stomatitis (18%), alternating bowel habit (15%), constipation (13%) and gastroesophageal reflux disease (GERD) (12%) (Figure 3A). Extra-intestinal manifestations, alone or in combination with gastrointestinal symptoms, were detected in 45% of CD patients (Figure 3B). Frequent findings were anemia (34%), cryptogenic hypertransaminasemia (29%) and recurrent miscarriages (12%). A few CD patients showed IgE-mediated allergy (9%), often characterized by positivity for specific IgE to graminaceae and mites. A small number of subjects showed headache (5%) and fibromyalgia-like symptoms (2.2%). Iron-deficiency with low levels of ferritin was found in 85% of patients with anemia, which was also related to folic acid malabsorption. Bone densitometry, performed in two-thirds of the 770 CD patients, revealed a condition of osteopenia/osteoporosis in 52% of cases, often associated with 25-OH Vitamin D3 low levels.
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Figure 1.
The annual distribution of CD diagnoses in the referral center of the St. Orsola-Malpighi University Hospital from 1998 to 2012. Of the 770 diagnosed patients, 318 (41.2%) were identified in the first 10 years (1998–2007), whereas the other 452 (58.8%) were diagnosed in the last five years (2008–2012).
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Figure 2.
Prevalence of symptomatic and subclinical phenotypes in the 770 CD patients. Note that 610 patients (79%) were diagnosed as symptomatic, whereas the remaining 160 (21%) were classified as subclinical CD. Of the 610 symptomatic patients, 210 (34%) displayed the classical onset with diarrhea and malabsorption (regardless of extraintestinal manifestations), whereas the other 400 showed the non-classical form with gastrointestinal symptoms (other than diarrhea) and extraintestinal manifestations.
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Figure 3.
Gastrointestinal and extraintestinal symptoms in 770 CD patients. A) Symptoms related to gastrointestinal tract included diarrhea (27%), bloating (20%), aphthous stomatitis (18%), alternate bowel habit (15%), constipation (13%) and gastroesophageal reflux disease (GERD) (12%). B) Extraintestinal manifestations, alone or in combination with gastrointestinal symptoms/signs, included osteopenia/osteoporosis (52%), anemia (34%), cryptogenic hypertransaminasemia (29%), recurrent miscarriages (12%), IgE-mediated allergy (9%), headache (5%) and fibromyalgia-like symptoms (2.2%).
A total of 744 (97%) out of the 770 CD patients were positive for IgA anti-TG2, whereas 91% of the same patients were IgA EmA positive. EmA detection was always coincident with anti-TG2 positivity. Of the 26 patients negative for IgA anti-TG2 and EmA, 15 had selective IgA deficiency and all of them were positive for IgG anti-TG2 or DGP. Only 11 CD patients (9 females) were seronegative. The median age at CD diagnosis was significantly higher in the seronegative vs. seropositive patients (49 vs. 36 years, P < 0.005). Compared to seropositive cases, CD patients testing negative for serology were all characterized by a significantly higher prevalence of classical phenotype (P < 0.001). Four seronegative patients showed a positivity for first generation gliadin antibodies of IgG class (1 case also associated with IgA), nowadays no longer considered serological CD markers (Table 1).
Villous atrophy was found in 670 (87%) of 770 CD patients. Total (3c) and subtotal (3b) villous atrophy were observed in 36% and in 26% of cases, respectively, whereas a partial (3a) atrophy was identified in 25% of patients. The remaining 100 patients (13%) had a histological pattern characterized by an increased number of IEL (lesion type 1). These minor lesions were consistent with a potential CD, confirmed by HLA-DQ2 and/or -DQ8 and IgA anti-TG2 and/or EmA positivity. A high number of potential CD were first-degree relatives of CD and type 1 DM patients. Only symptomatic cases of potential CD started GFD, whereas subclinical cases continued to eat gluten. Five out of the 100 potential CD cases showed disappearance of EmA and anti-TG2 on a gluten containing diet.
Autoimmune thyroiditis was found in 26.3% of CD patients, of whom about half showed hypothyroidism. Dermatitis herpetiformis was found in 4% of CD cases, whereas type 1 DM was detectable in 3% of patients. Other associated diseases included neurological disorders, i.e. gluten ataxia, cryptogenic epilepsy and peripheral neuropathy (all together 2.2%); IgA deficiency (1.9%); autoimmune liver disorders, such as primary biliary cirrhosis and autoimmune hepatitis (1.8%). Finally, connective tissue disorders, mainly Sjögren syndrome and systemic sclerosis were diagnosed in 1.7%. Chromosomal disorders coexisted in 15 CD patients, i.e. 12 Down and 3 Turner syndrome. Only three celiac patients were affected by inflammatory bowel disease (1 case of Crohn's disease ad 2 of ulcerative colitis).
A total of 654 (85%) of the 770 CD patients underwent a clinical and biochemical follow-up every 18 months. The follow-up duration ranged from 18 months to 14 years (mean 5 years). The response to GFD was regarded as good in 514 patients (79%), whereas the remaining 140 CD cases showed a poor response to GFD and were labeled as non-responsive CD. The main causes of non-responsive CD were poor compliance with GFD (40%), irritable bowel syndrome (20%), GERD (15%), lactose intolerance (12%), bacterial overgrowth (9%) and complicated CD (4%).
Six (0.9%) of the 654 CD patients developed complications during the follow-up (Table 2). Three patients had refractory CD type 1, two had small bowel carcinoma and one developed enteropathy associated T cell lymphoma (EATCL). Patients developing complications had a late diagnosis with a median age of CD at diagnosis significantly higher than that of non complicated CD (53.5 vs. 36 years, P < 0.005). The estimated diagnostic delay in complicated CD cases ranged from 5 to 11 years. All complicated CD had a classical phenotype testing positive for HLA-DQ2 (3 cases carried DQ2 in homozygosis). Regarding clinical presentation, classical phenotype was significantly higher in complicated vs. non complicated CD (P < 0.001) (Table 2). Of the 6 complicated patients, 5 are still alive and only 1 with small bowel carcinoma died 2 years after surgery and chemotherapy.
Results
Clinical Data
The annual distribution of CD diagnoses is shown in Figure 1. Of the 770 CD patients, 318 were diagnosed in the first 10 years (1998–2007), whereas 452 were detected in the last five years (2008–2012). The onset of CD was symptomatic in 610 patients (79%), whereas the remaining 160 (21%) showed a subclinical phenotype. Of the 610 symptomatic patients, 210 had the classical phenotype, whereas 400 displayed the non-classical phenotype (Figure 2). In the period 1998–2007 the classical, non-classical and subclinical phenotype were respectively found in 47.2%, 43.1% and 9.7% of CD cases, whereas in the period 2008–2012, the most frequent clinical phenotype was the non-classical (58.2%), followed by the subclinical (28.5%) and by the classical (13.3%). The median age at diagnosis was significantly lower in patients with the subclinical (32 years) than with the symptomatic phenotype (37 years) (P < 0.001). No significant difference was found in the median age at diagnosis between classical and non-classical forms (39 vs. 36 years, P = 0.058). Taking into account all CD patients (n = 770), about half (53%) of them had gastrointestinal symptoms/manifestations, i.e. diarrhea (27%), bloating (20%), aphthous stomatitis (18%), alternating bowel habit (15%), constipation (13%) and gastroesophageal reflux disease (GERD) (12%) (Figure 3A). Extra-intestinal manifestations, alone or in combination with gastrointestinal symptoms, were detected in 45% of CD patients (Figure 3B). Frequent findings were anemia (34%), cryptogenic hypertransaminasemia (29%) and recurrent miscarriages (12%). A few CD patients showed IgE-mediated allergy (9%), often characterized by positivity for specific IgE to graminaceae and mites. A small number of subjects showed headache (5%) and fibromyalgia-like symptoms (2.2%). Iron-deficiency with low levels of ferritin was found in 85% of patients with anemia, which was also related to folic acid malabsorption. Bone densitometry, performed in two-thirds of the 770 CD patients, revealed a condition of osteopenia/osteoporosis in 52% of cases, often associated with 25-OH Vitamin D3 low levels.
(Enlarge Image)
Figure 1.
The annual distribution of CD diagnoses in the referral center of the St. Orsola-Malpighi University Hospital from 1998 to 2012. Of the 770 diagnosed patients, 318 (41.2%) were identified in the first 10 years (1998–2007), whereas the other 452 (58.8%) were diagnosed in the last five years (2008–2012).
(Enlarge Image)
Figure 2.
Prevalence of symptomatic and subclinical phenotypes in the 770 CD patients. Note that 610 patients (79%) were diagnosed as symptomatic, whereas the remaining 160 (21%) were classified as subclinical CD. Of the 610 symptomatic patients, 210 (34%) displayed the classical onset with diarrhea and malabsorption (regardless of extraintestinal manifestations), whereas the other 400 showed the non-classical form with gastrointestinal symptoms (other than diarrhea) and extraintestinal manifestations.
(Enlarge Image)
Figure 3.
Gastrointestinal and extraintestinal symptoms in 770 CD patients. A) Symptoms related to gastrointestinal tract included diarrhea (27%), bloating (20%), aphthous stomatitis (18%), alternate bowel habit (15%), constipation (13%) and gastroesophageal reflux disease (GERD) (12%). B) Extraintestinal manifestations, alone or in combination with gastrointestinal symptoms/signs, included osteopenia/osteoporosis (52%), anemia (34%), cryptogenic hypertransaminasemia (29%), recurrent miscarriages (12%), IgE-mediated allergy (9%), headache (5%) and fibromyalgia-like symptoms (2.2%).
Serological Tests
A total of 744 (97%) out of the 770 CD patients were positive for IgA anti-TG2, whereas 91% of the same patients were IgA EmA positive. EmA detection was always coincident with anti-TG2 positivity. Of the 26 patients negative for IgA anti-TG2 and EmA, 15 had selective IgA deficiency and all of them were positive for IgG anti-TG2 or DGP. Only 11 CD patients (9 females) were seronegative. The median age at CD diagnosis was significantly higher in the seronegative vs. seropositive patients (49 vs. 36 years, P < 0.005). Compared to seropositive cases, CD patients testing negative for serology were all characterized by a significantly higher prevalence of classical phenotype (P < 0.001). Four seronegative patients showed a positivity for first generation gliadin antibodies of IgG class (1 case also associated with IgA), nowadays no longer considered serological CD markers (Table 1).
Duodenal Histology
Villous atrophy was found in 670 (87%) of 770 CD patients. Total (3c) and subtotal (3b) villous atrophy were observed in 36% and in 26% of cases, respectively, whereas a partial (3a) atrophy was identified in 25% of patients. The remaining 100 patients (13%) had a histological pattern characterized by an increased number of IEL (lesion type 1). These minor lesions were consistent with a potential CD, confirmed by HLA-DQ2 and/or -DQ8 and IgA anti-TG2 and/or EmA positivity. A high number of potential CD were first-degree relatives of CD and type 1 DM patients. Only symptomatic cases of potential CD started GFD, whereas subclinical cases continued to eat gluten. Five out of the 100 potential CD cases showed disappearance of EmA and anti-TG2 on a gluten containing diet.
Associated Disorders
Autoimmune thyroiditis was found in 26.3% of CD patients, of whom about half showed hypothyroidism. Dermatitis herpetiformis was found in 4% of CD cases, whereas type 1 DM was detectable in 3% of patients. Other associated diseases included neurological disorders, i.e. gluten ataxia, cryptogenic epilepsy and peripheral neuropathy (all together 2.2%); IgA deficiency (1.9%); autoimmune liver disorders, such as primary biliary cirrhosis and autoimmune hepatitis (1.8%). Finally, connective tissue disorders, mainly Sjögren syndrome and systemic sclerosis were diagnosed in 1.7%. Chromosomal disorders coexisted in 15 CD patients, i.e. 12 Down and 3 Turner syndrome. Only three celiac patients were affected by inflammatory bowel disease (1 case of Crohn's disease ad 2 of ulcerative colitis).
Non-responsive CD
A total of 654 (85%) of the 770 CD patients underwent a clinical and biochemical follow-up every 18 months. The follow-up duration ranged from 18 months to 14 years (mean 5 years). The response to GFD was regarded as good in 514 patients (79%), whereas the remaining 140 CD cases showed a poor response to GFD and were labeled as non-responsive CD. The main causes of non-responsive CD were poor compliance with GFD (40%), irritable bowel syndrome (20%), GERD (15%), lactose intolerance (12%), bacterial overgrowth (9%) and complicated CD (4%).
Complicated CD
Six (0.9%) of the 654 CD patients developed complications during the follow-up (Table 2). Three patients had refractory CD type 1, two had small bowel carcinoma and one developed enteropathy associated T cell lymphoma (EATCL). Patients developing complications had a late diagnosis with a median age of CD at diagnosis significantly higher than that of non complicated CD (53.5 vs. 36 years, P < 0.005). The estimated diagnostic delay in complicated CD cases ranged from 5 to 11 years. All complicated CD had a classical phenotype testing positive for HLA-DQ2 (3 cases carried DQ2 in homozygosis). Regarding clinical presentation, classical phenotype was significantly higher in complicated vs. non complicated CD (P < 0.001) (Table 2). Of the 6 complicated patients, 5 are still alive and only 1 with small bowel carcinoma died 2 years after surgery and chemotherapy.
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