Encyclopedia
Please note this is a comparison between Version 1 by Rinaldo Pellicano and Version 2 by Amina Yu.
Celiac disease (CD) is a chronic, small-intestinal, immune-mediated enteropathy due to gluten exposition in genetically predisposed individuals. It occurs in about 1% of the population and often remains an underdiagnosed condition. This could be due to the fact that the adult population often lacks the classical signs and symptoms of CD, manifesting only atypical symptoms.
- celiac disease
- extraintestinal
- diagnosis
- clinical presentation
- gluten-free diet
1. Neurological Manifestations
The relationship between CD and neurologic disorders was first described in 1966, by Cooke and Smith [1][20], who observed evidence of cerebellar ataxia and peripheral neuropathies in some CD patients. Nowadays, although gluten neuropathy and ataxia remain the most common [2][21], many other neurologic disorders have been correlated to CD, such as headache, epilepsy, and cognitive impairment [3][22].
Overall, it has been estimated that one-fifth of CD patients suffer from neurological manifestations [4][3]. A recent study by Hadjivassiliou et al. [5][23] observed that at the time of diagnosis, 67% of patients already have signs of neurologic dysfunction.
However, the precise pathophysiological process of neurological involvement in CD remains partially unclear. Certainly, the nervous system undergoes many gluten-mediated mechanisms, including cross-reacting antibodies, immune-complex deposition, direct toxicity and gut–microbiota–brain axis alteration [6][24]. In recent years, some authors have also hypothesized that neurologic disorders could be a consequence of an abnormal brain perfusion [3][7][22,25]. Using single-photon emission computed tomography, they noted the presence of cerebral hypoperfusion in CD patients, which might be related to intestinal hyperemia and/or perivascular inflammation [3][22].
1.1. Ataxia
Cerebellar ataxia (CA), also called gluten ataxia, is one of the first neurologic symptoms and one of the most frequent in patients with CD [1][20]. A recent systematic review estimated the prevalence of gluten ataxia to be 0–6% among CD patients and observed that ataxia accounts for a higher percentage of neurological manifestations in CD adults compared to children [3][22].
CA could be the only and first clinical manifestation of CD. It usually appears in late mean age (55 years old) and without any other associated gastrointestinal symptoms [8][26].
In most cases (69%), symptoms are mild and include difficulty with arm and leg control, altered movements of eyes and poor coordination. However, in one-third of patients CA leads to a progressive impairment of stability with moderate/severe gait manifestations which require walking support or even wheelchair use [9][27].
From a histological point of view, patients with gluten ataxia show a particular type of neurologic deficit consisting of the loss of Purkinje cells. This damage was firstly attributed to vitamins deficiencies, such as B1, B3, B6, and B12, which were well-known causes of neurological disorders [10][28]. However, later findings demonstrated an immune-mediated pathogenesis [10][28]. In fact, AGA and anti-tTG (particularly tTG6) have shown reactivity with the deep cerebellar nuclei brainstem and cortical neurons, which bring to a cross-reaction with Purkinje cells and their consequent damage [2][5][10][21,23,28]. So, it is not surprising that the prevalence of circulating AGAs and/or tTG6 antibodies was found to be higher in CD patients with CA rather than in those without neurological problems (73% vs. 40%) [5][23].
Diet seems to be effective on gluten ataxia—the higher the adherence to a strict GFD, the better are the improvements in cerebellar function and clinical manifestations [10][28]. These effects are probably due to the positive impact of gluten exclusion on autoimmunity mechanisms. However, ataxic symptom relief with a GFD has been proven only in adult CD patients. Hence, its usefulness is unclear among children [2][21].
1.2. Peripheral Neuropathy
Peripheral neuropathy is the second-most-common neurological manifestation reported in CD patients [1][2][20,21]. Its prevalence ranges from 2% to 23%, with higher rates among females and older patients [2][5][11][21,23,29].
The presence of peripheral neuropathy is often discovered from mild sub-clinical manifestations such as lower sensibility to pain threshold, warm or skin contact, feeling of numbness or tingling, and writing difficulty [1][12][20,30]. It is usually described as a symmetric neuropathy, so it involves both the arms and legs, and it can progressively lead to gait instability.
1.3. Headache, Epilepsy, and Cognitive Impairment
Other neurological manifestations correlated to CD are headache, epilepsy, and cognitive impairment [3][22].
In the early 2000s, Cicarelli et al. observed a higher prevalence of headache among CD patients and used, for the first time, the term “gluten encephalopathy” [14][32]. This condition is characterized by episodic headache attacks, which are similar to migraine and affect about 26% of celiac population [15][33].
From a histological point of view, CD patients with headache show some white manner alterations at magnetic resonance neurography (MRN). These lesions seem to be correlated not so much to demyelination as to a vascular inflammation process [12][30].
Adherence to a GFD is effective for symptom improvement and leads to total resolution of headaches in up to 75% of patients. The precise mechanism of this effect remains unclear, but it is probably due to inflammation reduction. Nevertheless, a GFD is not able to resolve white matter abnormalities [15][16][33,34].
Instead, Pfaender et al. collected a series of cases in which children with biopsy-confirmed CD had epilepsy and bilateral occipital calcifications [17][35]. This association was also described by other authors [18][19][36,37], who suggested that HLA genotypes predisposing to CD could be the same as those predisposing to bilateral occipital calcifications and epilepsy [17][35].
The risk of epilepsy in CD population is increased of 1.4 times, with a prevalence of 1–6%. However, neither the etiopathogenesis nor the correlation between CD and epileptic crisis are completely understood [20][38]. Some researchers have associated the presence of cerebral calcifications to a gluten-toxicity process [21][22][39,40].
Manifestations of CD crisis are very similar to those of epileptic syndrome, including blurred vision and colored dots’ view, and they are usually well controlled by antiepileptic medications [12][30].
The effect of a GFD is evident in most patients, in whom it determines better seizure control, decreased drug use, and even complete resolution. Moreover, a GFD seems to arrest cerebral calcification development [18][21][36,39].
CD can also cause cognitive function damage. The presence of cognitive impairment in celiac patients was first reported by Kinney et al. [23][41]. Since then, many studies have confirmed the correlation between CD and cognitive impairment, but its real prevalence remains difficult to define. In fact, symptoms are non-specific and variable, in both severity and duration. Usually, they are mild and transient, and include difficulties in concentration, inattention, struggling to find words, and episodic memory deficits. The condition of slight cognitive alteration, that is known as “brain fog”, is the most common symptom among CD patients [24][42]. However, in some cases, cognitive impairment gets worse and may lead to confusion, disorientation, and even dementia [24][42].
Several mechanisms have been proposed to explain the gluten-induced deleterious process. Nowadays, two hypotheses are the most accredited. The first attributes cognitive damage to systemic inflammation caused by CD, which also favors cerebral inflammation and consequent reduction in neuronal transmission speed. The second blames gluten for indirectly reducing brain serotonin levels [24][25][42,43].
2. Neuropsychiatric Manifestations
The relationship between CD and psychiatric disorders is known, but it is not yet fully recognized and understood. Depression, anxiety, attention deficit/hyperactivity disorder (ADHD), and autism are the most frequent neuropsychiatric manifestations in celiac patients [27][45].
The precise pathophysiological mechanism of gluten-induced psychiatric involvement is unclear. However, both biological and social factors might be involved. Biological explanations include inflammation processes, autoimmunity activity, microbiota composition, and the gut–brain axis relationship, but evidence in this regard is scarce especially due to small sample sizes of the studies [27][45]. Instead, social implications are easier to guess. They include all the possible negative consequences of GFD introduction, such as social isolation or avoiding going out because of difficult meal management and contamination risk [27][28][45,46].
2.1. Depression
Smith et al. observed that depressive disturbance was more common and more severe among adult CD subjects [29][47]. According to a recent systematic review, the risk of depression development is higher in this cohort, with a mean prevalence of 3.5% [27][45].
The increased risk has been explained by various biological hypotheses, such as low levels of serotonin due to tryptophan malabsorption, concomitant presence of hypothyroidism, and increased hypothalamic–pituitary–adrenal axis activity [27][28][45,46]. On the other hand, adherence to a strict dietary regimen can induce patients to avoid social situations involving food, and to have higher levels of stress because of meal difficulties and worries. All these psycho–social conditions certainly contribute to depression onset and progression [28][46].
As diet stress is one of the possible contributing causes of depressive manifestations, the role of a GFD is controversial. Some studies observed improvement with GFD adherence, especially after long-term administration [30][48], while others even reported the worsening of depressive symptoms [27][31][45,49].
2.2. Anxiety, ADHD, and Autism
Anxiety states are more common among new-diagnosed CD patients. In fact, the introduction of a GFD leads the subject to make many changes in eating habits and lifestyle, which can result in agitation and feelings of stress [28][46]. However, this condition usually ameliorates after 1 year of GFD [31][49].
ADHD affects about 1.4% of CD patients, whose risk is higher compared to the general population [28][46]. A preliminary study by Niederhofer et al. found an “overexpression” of ADHD symptoms in a group of celiac subjects, which improved in the majority of them (74%) after 6 months of a GFD [32][50].
A significant increase in risk development has also been observed for autistic spectrum disorders, in which an appropriate compliance to a GFD seems to improve behavioral symptoms [28][46].
Although the correlation of anxiety, ADHD, autism, and CD is often described, precise etiological mechanisms and specific biological explanations of GFD effectiveness remain unclear and need further investigation.
2.3. Other Psychiatric Disorders
Evidence concerning correlation between CD and other psychiatric disorders is very limited and mainly published as case reports.
Some researchers recently hypothesized that CD patients are at higher risk of having eating disorders. However, only a few studies have investigated the impact of a GFD on them [27][45].
Many surveys have evidenced symptom improvement in schizophrenic subjects after the introduction of a GFD. This has stimulated scientists to investigate the possible association between CD and schizophrenia, also through research on genetic similarities [33][34][51,52]. However, recent studies challenged this theory and showed no significant correlations [27][45].
3. Liver Manifestations
It is not rare that CD is included in the history of illness signs of hepatic injury.
Liver damage can be due to a dysmetabolic condition, such as non-alcoholic fatty liver disease [35][53], or to a concomitant autoimmune disease, such as autoimmune hepatitis [36][54]. However, recent studies showed elevated aminotransferase levels in celiac patients without known causes of liver disease [37][38][55,56]. This condition has been called “gluten-induced hepatitis”, with a prevalence of 4–9% reported by recent studies [39][57].
Usually, hepatic injury is mild and easily reversible, leading to liver failure on rare occasions. Behind the physio-pathological mechanism of the hepatotoxicity, there is the alteration of gut permeability, which leads to an increased exposure to hepatotoxins in the portal circulation [37][55]. Moreover, a few studies have reported histological evidence of tTG2 autoantibody deposits in liver biopsies from CD patients, suggesting their direct involvement in hepatocellular damage [4][3].
So, the search for CD should be performed in subjects who present no symptoms of chronic liver disease nor other reasons for high transaminase levels [37][55]. The severity of the hypertransaminasemia has been associated with the presence of malabsorption, high titer of celiac autoantibodies and severe duodenal lesions [40][12]. When a liver biopsy is performed, generally in patients who show persistently high liver enzyme levels, a minimal grade steatosis or a reactive nonspecific hepatitis can be observed [37][55].
In celiac patients, liver condition is generally benign and reversible—GFD usually leads to injury resolution and transaminases normalization within 6–12 months [39][57].
Since it may often occur as an isolated hypertransaminasemia in the absence of other gastrointestinal symptoms, it must be included in hepatitis differential diagnosis [38][56]. Only where CD is unrecognized or untreated and the liver involvement is subclinical, is progression of the hepatic involvement to be feared. Surprisingly, as a few studies have demonstrated, GFD allows a clinical improvement even in these more severe conditions [38][41][56,58].
4. Reproductive Manifestations
It is known that CD can cause inflammation and malabsorption. Both these conditions might be responsible, or at least partially contribute, to infertility [42][59]. However, some researchers have also proposed the possible role of autoimmunity, suggesting that anti-tTG antibodies may be responsible for the inhibition of endometrial angiogenesis [43][60]. Whatever the cause, GFD seems to be effective. In fact, celiac women undergoing a GFD have a fertility which is comparable to healthy ones [44][45][61,62], whereas women who do not follow a GFD can manifest several conditions such as late menarche, secondary amenorrhea, early menopause, miscarriages, preterm pregnancy, and low birth weight of the newborn [45][46][47][48][62,63,64,65]. Specifically, the risk of recurrent miscarriages is eight to nine times higher in celiac women who do not follow a GFD than in the general population [49][66]. As observed by Fortunato et al. [50][67], prevalence of reproductive disorders is higher in patients with CD compared to the general population, suggesting how it may be useful to test for CD in women presenting changes during pregnancy or infertility [50][67].
Thus, CD can be considered as a risk factor for infertility. The favorable response to a GFD can justify the serological screening for CD among women with infertility of unknown origin [48][51][65,68]
Nevertheless, not all the studies agree with this theory. In a recent meta-analysis, the authors reported that using a more stringent definition of CD (confirmed by biopsy requiring a Marsh type III villous atrophy), the prevalence of this condition in women with infertility should be similar to that observed in the general population [51][68]. This stands in contrast to the meta-analyses by Castano et al. and Singh et al. who instead found a higher prevalence of infertility in patients with CD [52][53][69,70]. One of the reasons why this difference can be observed may be found in the definition of CD—some studies have considered Marsh type I as sufficient for the diagnosis of disease while others have not even used Marsh’s criteria for diagnosis. In the meta-analysis by Glimberg et al., CD diagnosis had to be verified by a biopsy that confirmed a Marsh type III and excluded couples in which the underlying problem was male infertility. In a second analysis, studies were evaluated in which, for the definition of CD, the presence of IgA tTG was sufficient [54][71]. However, the authors highlight how the lack of fertile women used as control can be a limitation as well as the low number of participants in the majority of the studies [54][71]. Further cohort studies are needed to better understand the correlation between CD and infertility.
Focusing on the male population, sperm abnormalities both in terms of morphology and motility can be observed in CD patients [55][56][72,73]. From a strictly biochemical point of view, some studies reported a condition of androgen resistance, which means high testosterone levels and high LH values [55][56][72,73]. However, androgen resistance seems to respond to a GFD. In fact, a study conducted on 41 CD males with androgen resistance showed that a GFD determined the normalization of biochemical alterations [56][73].
