Nutritional Consequences of Celiac Disease and Gluten-Free Diet

Abstract

Celiac disease is an immune-mediated condition triggered by gluten ingestion in genetically predisposed individuals. The global prevalence of celiac disease is significant, affecting approximately 1.4% of women and 0.7% of men, with incidence rates of 17.4 and 7.8 per 100,000 person-years, respectively. The clinical presentation of celiac disease may range from overt diarrhea and malabsorption to more subtle features such as nutritional deficiencies and extraintestinal manifestations. It is the most common cause of global malabsorption in Western countries. A life-long gluten-free diet is the only available treatment for celiac disease. Moreover, a gluten-free diet is often adopted by individuals without celiac disease, either to address non-celiac gluten sensitivity or for other reasons. This review aims to explore the current understandings of the nutritional consequences of untreated celiac disease and the impact of the gluten-free diet itself. Physicians and dietitians specializing in celiac disease should focus on providing a well-rounded nutritional scheme to address deficiencies caused by the disease and prevent the instauration of new nutritional imbalances.

1. Introduction

Celiac disease (CD) is the main cause of malabsorption in Western Countries [1]. Selective malabsorption is the most common presenting feature of CD, with iron deficiency leading to anemia and vitamin D3 deficiency resulting in osteoporosis [2,3]. CD should be regarded as a systemic condition that can be associated with various extraintestinal manifestations [4], including neurological, endocrine, dermatological, and hepatic disorders [5], as well as recently recognized sexual dysfunctions [6] and well-known fertility issues [5,7].

The only validated treatment for CD is a life-long gluten-free diet (GFD) [8], which has been shown to improve small-bowel mucosal health and its absorptive functions [9]. Clinical practice guidelines emphasize the importance of nutritional therapy over other treatment options [10]. The GFD should be initiated as soon as possible in individuals with a confirmed diagnosis of CD, even if they are asymptomatic, to prevent irreversible consequences [11]. A definitive diagnosis before starting therapeutic intervention is essential to avoid complications in management, uncertainties, time-consuming processes, and the gluten challenges [12].

Ongoing follow-up with CD patients is also crucial to ensure adherence to the GFD and to detect persistent nutritional deficiencies, which may indicate the development of serious complications [13]. Regular physical activity supports adequate nutrition [14], but individuals with gastrointestinal disorders often struggle with adherence to it [15]. Additionally, there is growing concern about subtle aspects of the GFD, such as imbalances in macronutrients and excess calorie intake, as well as deficiencies in micronutrients and vitamins due to a restrictive dietary regimen [16].

Starting from these premises, we examined the current knowledge regarding the nutritional implications and shortcomings of CD and the GFD.

2. Nutritional Impairment of CD and Restoration on GFD

2.1. Global Malabsorption

Malabsorption, defined as the failure of normal digestion products to cross the intestinal mucosa into the systemic circulation, can be caused by several gastrointestinal and non-gastrointestinal conditions. The clinical presentation of malabsorption syndrome includes gastrointestinal and extraintestinal manifestations, along with laboratory abnormalities [4], such as diarrhea, weight loss, peripheral edema, anemia, failure to thrive in childhood, and more. CD is the most common enteropathy causing malabsorption syndrome in Western countries [1]. Intestinal damage, primarily characterized by villous atrophy, severely impairs nutrient transport within the enterocytes. Additionally, CD patients may experience compromised intraluminal digestion due to reduced bile and pancreatic secretions and defects in brush border enzymes [4]. Currently, the most common presentation of CD is characterized by more subtle manifestations, if any, often tied to macronutrient and micronutrient deficiencies [17], while the “classical” form with overt malabsorption is less frequently observed [2,18].

Most CD patients show clinical and histological improvement on a GFD within one year of starting the diet. Nonetheless, limited data are available regarding the effect of the GFD on body composition.

Several studies on children [19] have demonstrated significant improvement in fat-free mass, muscle mass, weight, and body mass index (BMI) after at least one year on a GFD. For instance, in a previous study including 80 adult patients on a GFD [20], Corazza et al. observed significant improvements in body weight (as the percentage of an ideal body weight) and muscle mass after a period of 12 ± 6 months, regardless of their clinical presentation at the time of CD diagnosis.

Despite the necessity of a GFD, it may not fully restore important nutritional outcomes. CD patients on a GFD have been shown to have a significantly lower body weight, height and BMI compared to healthy controls [21], as has been observed in autistic patients following a GFD and casein-free diet [22]. Not all studies evaluating the effects of a GFD on growth and nutritional status in CD young patients with associated type 1 diabetes (T1DM) show complete improvements. Some studies found no significant effect on body composition [23] or growth parameters [24]. Indeed, T1DM may have contributed to the apparent lower effectiveness of a GFD in these patients.

It is also worth noting that atypical presentations are not uncommon in both pediatric [2] and adult CD patients [18]. Several reports have documented normal BMI or even overweight/obesity at diagnosis, despite the presence of severe malabsorption. The exact pathogenetic mechanism remains unclear, though some have speculated a compensatory mechanism involving the distal, functionally preserved segments of the intestine.

Overall, substantial evidence supports the positive role of a GFD in improving nutritional status and growth. Nevertheless, some patients may not fully return to normality. Factors beyond the diet itself may influence this outcome, including educational status, employment condition, psychosocial factors, physical activity, and comorbidities [22,25,26].

2.2. Specific Deficiencies in CD and Correction in GFD

2.2.1. Iron Deficiency and Anemia

Iron deficiency, regardless of anemia, is a common clinical feature in untreated CD, with an incidence ranging from 12 to 69% [27,28]. Interestingly, there is no clear difference in incidence between genders or across age groups [28]. The main pathogenic mechanism behind anemia is the reduced absorption of iron in the duodenum, due to the cranio-caudal progression of intestinal lesions. Additional factors include mutations in iron transporter genes, inflammation-related hepcidin upregulation, and decreased erythropoietin production [27,29]. Screening for CD is mandatory at any age when iron deficiency is present [30].

A retrospective Finnish study on 445 newly diagnosed CD children found that anemic subjects had higher transglutaminase antibodies levels, which were less frequently screen-detected (13.4% vs. 34.6%) and had more severe histological damage [31]. This relationship between anemia and histological damage has been confirmed by other randomized clinical trials (RCTs) [32], even in cases of potential CD or partial and subtotal villous atrophy. Interestingly, in ethnic minorities, iron deficiency anemia could have a higher incidence compared to non-Hispanic whites [33].

While a GFD typically resolves iron deficiency anemia, with improvements in hemoglobin and ferritin levels [28], iron supplementation should still be considered, particularly in special populations such as women of childbearing age and pregnant women, who tend to recover more slowly [29,34,35]. In a Finnish trial [32], 92% of anemic children diagnosed with CD recovered from anemia after a median of 1 year on GFD. However, their hemoglobin levels remained significantly lower than those in the non-anemic group (12.5 vs. 13.2 g/dL). In adults, anemia resolved in 77.8% of cases within 6 months of starting a GFD and in 98% of cases within 12 months. However, iron deficiency persisted in 50% of patients after 12 months on a GFD [36], where the GFD was not enough for restoring iron deposits [37].

Interestingly, although oral iron therapy is the first-line treatment, it may upregulate hepcidin levels, requiring parenteral formulations to overcome the deficiency [37].

It is also important to rule out other causes of persistent anemia, such as non-adherence to the GFD, chronic H. pylori infection, vitamin B12 and folate deficiency, atrophic gastritis, or blood loss from mucosal lesions [27,29,30,38,39,40].

2.2.2. Other Anemias

In addition to iron deficiency, deficiencies in folic acid and vitamin B12 may also cause anemia in CD patients, though less frequently. Recent data indicate that folic acid deficiency occurs in 20–30% of newly diagnosed adult CD patients and 15–18% of children, while vitamin B12 deficiency affects 8–41% of adults and 4–8% of children [41,42,43]. The causes of these deficiencies are only partially attributable to global malabsorption, with other factors also playing a role. For example, folic acid deficiency may be due to a reduced intake of dietary fiber (e.g., fruits and vegetables). Vitamin B12 deficiency may be worsened by low red meat intake or by concomitant conditions, particularly autoimmune gastritis [44], as ileal involvement in CD is relatively rare.

The restoration of the intestinal absorptive function through strict adherence to a GFD does not always fully resolve these deficiencies, both in young and adult patients [45,46,47]. A micronutrient deficiency in long-term GFD patients was found in up to 20% of subjects for folic acid and 30% for vitamin B12 [46]. For this reason, the regular monitoring of these nutrients levels is necessary during a GFD, and supplementation should be provided as needed [41,48].

2.2.3. Coagulopathies Due to Malnutrition

Normal levels of both vitamin K-dependent and independent coagulation factors are essential for maintaining proper coagulation function. Vitamin K is a fat-soluble vitamin with a low daily intake requirement, therefore, deficiency due to intestinal malabsorption in CD is relatively rare [49]. A recent review reported 47 cases of CD patients who experienced hemorrhagic events [49]. In about 25% of the cases, hemorrhagic events occurred up to 5 years before the diagnosis of CD. Notably, not all these patients had gastrointestinal symptoms. The main hemorrhagic events reported include gastrointestinal bleeding in 15 cases, hemoptysis in 9, epistaxis in 4, hematuria in 6, and cutaneous hematomas, and petechiae or ecchymoses in 8 cases. Additionally, 15 cases of Lane–Hamilton syndrome (idiopathic pulmonary hemosiderosis associated with CD) were documented.

Excluding cases linked to immune thrombocytopenic purpura, which has been associated with CD, the primary hypothesized pathogenic mechanism is a vitamin K deficiency due to malabsorption. Vitamin K is a crucial cofactor in the hepatic synthesis of coagulation factors and inhibitors. Deficiency of vitamin K can result in prolonged prothrombin time, as seen in routine blood tests, affecting 1% of asymptomatic and 19% of symptomatic untreated adult CD patients.

The prognosis of coagulopathies typically improves with adherence to a GFD [49].

For treating the hemorrhagic events, an intravenous administration of vitamin K was the most commonly reported therapy, followed by oral vitamin K supplementation. However, in patients with long-standing vitamin K deficiency, rapid correction or administration after normalization of prothrombin time should be approached with caution, as it may increase the risk of ischemic events.

2.2.4. Bone Metabolism Impairment

Untreated CD is associated with reduced bone mineral density (BMD) in both adults and children, affecting 7–16% of patients [50], and carries an increased risk of fractures compared to the general population [51]. A recent systematic review found reduced BMD in 4–20% and osteopenia in 10–50% of men and premenopausal women with CD [3]. In this specific setting, the prevalence of bone health issues is particularly high. Rickets, however, is rarely reported and mainly observed in developing countries [10].

Calcium and vitamin D malabsorption are not the sole mechanism behind bone metabolism impairment in CD. Inflammatory mediators and autoimmune processes are also implicated, although the exact mechanisms remain partially understood. These factors may contribute to decreased BMD, even in patients with minor intestinal lesions [52].

Early CD diagnosis is warranted for improving bone health, and CD serology should be conducted in patients presenting with osteoporosis or osteomalacia [51]. It is strongly recommended to test newly diagnosed CD patients for vitamin D3, calcium, and parathormone levels, followed by appropriate supplementation [10,53]. While routine screening for osteoporosis in CD patients under 30 years is not widely supported [54], some guidelines do recommend it [10]. BMD measurement should be considered in patients with a delayed diagnosis or those with severe clinical and histological manifestations at diagnosis [50].

The diagnostic workup for osteoporosis in CD follows standard clinical practice. Risk factors common to the general population, such as age, gender, weight, nutritional status, comorbidities, medications, physical activity, and menopausal status, also apply to CD patients [50]. In individuals with confirmed osteoporosis, bisphosphonate treatment may be preferable [10].

Most studies report significant BMD improvement within 1 year of GFD [55]. Interestingly, children typically achieve full bone health recovery within 2–3 years, whereas adult patients may improve bur rarely normalize their BMD [56]. Since peak bone mass is reached in early adulthood, delayed diagnosis can result in incomplete bone recovery [7].

Fracture risk can remain elevated even after starting a GFD. A Swedish register-based study linked persistent fracture risk to slow histological recovery, possibly due to more severe duodenal damage at diagnosis or poor dietary adherence [57]. In addition to a strict GFD, calcium and vitamin D3 supplementations should be provided, and weight-bearing exercises should be actively encouraged for all age groups, from children to post-menopausal women [26,50,58]. Supplementations should follow general recommended daily intakes based on age and gender [50].

A recent observational study found higher serum vitamin D3 levels in treated CD patients compared to controls, likely due to vitamin supplementation, which was self-reported by one-third of CD subjects [59].

Vitamin D3 levels should be measured at diagnosis, every 3 months until normalized, and annually thereafter [10]. In CD adults without malabsorption, BMD testing might be considered if other risk factors are present [50]. Follow-up BMD testing should occur at 1–2-year intervals if initial results are abnormal, or every 2–3 years if normal at baseline.

If bone loss continues despite adherence to a GFD, dietary compliance should be reassessed, and a repeat intestinal biopsy may be necessary [7]. For patients with persistent osteoporosis after 1–2 years of a strict GFD and adequate supplementation, the use of bisphosphonates, teriparatide, or denosumab should be considered [55].

2.2.5. Neuromyopathies from Nutritional Deficiencies

CD is associated with a wide range of neurological conditions, ranging from mild and transient symptoms like headache and “brain fog” to permanent and severe disorders [7]. These can include central nervous system involvement, such as encephalopathy, myelopathy, tetraplegia/paraplegia, ataxia, psychosis, and seizures [60,61]. Peripheral neuropathy, typically presenting as symmetric acral polyneuropathy, is also common in CD patients [61]. Studies on CD patients reported a prevalence of neuropathy ranging from 4% to 23% in adults, and 0% to 7% in children [61,62]. Restless leg syndrome, often linked to iron deficiency, can also be present. The exact causes and magnitude of the association between CD and neurological disorders remain unclear, and current evidence does not support routine CD screening [62].

Many factors contribute to neuropathy in CD, including autoimmunity and inflammation, as well as nutritional deficiencies, particularly in B-complex vitamins (B1, B6, B7, B9, B12, folic acid), vitamin E, vitamin A, iron, selenium, and copper [62].

Vitamin A deficiency, a common cause of malabsorption-related ocular manifestations in CD, can lead to night blindness, xeropthalmia, keratomalacia, and corneal ulcers [63]. Though often asymptomatic, vitamin A deficiency is observed in 7.5% of newly diagnosed CD patients [41,63]. In the case of nyctalopia and xerophthalmia, artificial tears and vitamin A supplementation are recommended, with generally favorable outcomes [63].

Vitamin B12 levels typically normalize on a GFD alone, but symptomatic patients may still require supplementation [17,48]. While symptoms of peripheral neuropathy tend to improve with adherence to a GFD [1], the diet may not fully prevent neuropathy development, and it does not always completely reverse it [61]. Full recovery from gluten ataxia is rare as well. It is possible that these conditions are part of a spectrum of gluten-related disorders whose mechanisms remain largely unclear [7,62].

2.2.6. Electrolyte Deficiencies

A potentially life-threatening manifestation of undiagnosed CD is known as “celiac crisis”, characterized by acute, massive watery diarrhea, and severe dehydration, requiring urgent hospitalization. This condition is largely under-recognized, with only 48 cases reported in the literature to date [60]. In addition to severe dehydration, patients may present with metabolic acidosis, acute kidney injury, tetraplegia/paraplegia, ataxia, and potential cardiac arrythmias. These complications are due to the critical role of potassium, calcium, and magnesium in regulating cellular excitability. Clinicians should consider “celiac crisis” in the differential diagnosis of severe acute diarrhea accompanied by weight loss.

Despite the acute onset, “celiac crisis” typically lacks the features of complicated CD, and the clinical picture dramatically improves within a few days of the GFD. Fluid resuscitation and GFD remain the cornerstone of the treatment. In some cases, artificial nutrition and corticosteroids may be needed, though these interventions can exacerbate electrolyte depletion and increase the risk of refeeding syndrome [60].

2.2.7. Other Vitamin and Mineral Deficiencies and Their Clinical Consequences

Several proteins and enzymes involved in the thyroid metabolism depend on iron and iodine [64]. However, a systematic review of 57 studies found no significant impact of iron supplementation on thyroid-stimulating hormone (TSH), triiodothyronine (T3), and thyroxine (T4) levels [65]. Growing evidence suggests that vitamin D deficiency may increase susceptibility to respiratory tract infections and autoimmune diseases. Nevertheless, these correlations are still controversial and require further research [64].

Many cutaneous diseases affecting CD patients are primarily mediated by allergic, immune, or inflammatory mechanisms [61,66]. Also, CD-related malabsorption may exacerbate psoriasis due to vitamin D deficiency [67]. Pellagra, characterized by the “3D” syndrome (dermatitis, dementia, and diarrhea), due to severe niacin deficiency [66,67], and scurvy, resulting from severe vitamin C deficiency, have been sporadically reported in CD [68].

Recurrent aphthous stomatitis (RAS) is commonly observed in CD, particularly in cases of silent or undiagnosed CD [69], with an odds ratio of 3.79 compared to the general population. This warrants screening for CD in patients with RAS. The etiopathology of RAS may be related to hematinic deficiencies, such as low serum levels of iron, folic acid, and vitamin B12 [5,66,67]. Other oral manifestations of CD include enamel defects [70], delayed tooth eruption, cheilitis, atrophic glossitis, and burning tongue [66,67], which are often linked to deficiencies in iron, vitamin B6, B2, and B1 [71]. These issues are more frequent and severe in both children and adults with typical gastrointestinal manifestations at diagnosis [69,70].

Low levels of several vitamins are common in untreated CD, including vitamin E (88%), B1 (71%), K (21%), and B6 (12%) [68].

Reproductive health can also be impacted in untreated CD due to altered hormone levels, nutrient deficiencies, and chronic inflammation [1,61]. Delayed puberty, higher age at menarche, infertility, miscarriages, pregnancy complications, and early menopause have been reported in women. While men with CD show comparable fertility rates to controls in some studies, the data are limited [7]. Active screening for CD seems justified in women with unexplained infertility or recurrent miscarriages [7].

Many deficiencies in CD improve with a GFD, following the restoration of the intestinal mucosa trophism. Nevertheless, a GFD may not fully restore Ca, Fe, Mg, and Zn, as these nutrients are often lacking or not well quantified in gluten-free products [72]. A recent meta-analysis showed that women with CD experience improved fertility after starting a GFD, while the risk of miscarriage appears similar to that of non-CD patients. However, studies on outcomes like in vitro fertilization have yielded mixed results. Adverse pregnancy outcomes including stillbirth, intrauterine growth restriction, and prematurity have been reported in both untreated and treated CD, though improvements are noted with a GFD [7]. Additionally, a recent observational study found that sexual dysfunctions- such as low desire, arousal disorder, erectile dysfunction, lubrification disorder, discomfort during intercourse, and difficulty achieving orgasm, are prevalent in up to 50% of both female and male CD patients. Altered BMI was significantly associated with sexual dysfunctions in both sexes. In males, an early age at diagnosis has been identified as a significant predictor of sexual dysfunction. It is important to note that all patients were evaluated while on a GFD, so it remains unclear how much these sexual dysfunctions are attributable to the disease itself versus the effects of the GFD [6]. We synthetized our clinical advices for assessing nutritional deficiencies in

Table 1. Nutritional impairment in CD: clinical advice.

Thoroughly Rule Out Other Causes of Anemia: Conduct a thorough evaluation to exclude other causes of severe or persistent anemia.

Oral Iron Therapy: Recommend oral iron therapy if deficiency persists after initiating a GFD.

Vitamin B12 Supplementation: Supplement vitamin B12 if serum levels are below 350 pg/mL, paying particular attention to pregnant women.

Investigate Hemorrhagic Events: Consider vitamin K deficiency if hemorrhagic events occur in CD patients.

Monitor Vitamin D Levels: Monitor vitamin D levels at diagnosis, especially if there is evidence of a diagnostic delay.

Assess Electrolytes: Check electrolyte levels if acute diarrhea is present at the presentation of the disease.

.

2.2.8. Diabetes Mellitus in CD and Metabolic Control on a GFD

CD and T1DM are the most common pediatric autoimmune disorders. Both conditions are increasing in incidence and frequently coexist, sharing genetic and immunological pathways [23].

CD presentation in children with T1DM is often subtle, with up to one-third being asymptomatic, leading to diagnosis primarily through routine CD screening [7]. In this context, the pros and cons of combined dietary management should be carefully considered, given the added burden on patients.

Conversely, screening CD patients for T1DM is not generally useful, as T1DM-specific antibodies have a low positive predictive value (10–25%) over five years [23].

A landmark 2001 population study by Ventura et al. revealed that the prevalence of autoimmune disorders in CD patients was significantly higher than in controls (14% vs. 2.8%), with age at diagnosis being the only significant predictor of developing another autoimmune disorder [73]. The prevalence of type 2 diabetes in CD patients, however, is comparable to that of the general population [23].

While animal studies suggest a potential link between TDM1 and gluten intake, human studies have been inconclusive. These studies found no significant differences in T1DM autoantibody levels or in the preservation of beta-cell function in high-risk children after 6 to 12 months on a GFD [74,75].

Several studies have assessed the impact of a GFD on metabolic control in children with T1DM, but results are mixed. Some studies suggest that GFD may contribute to normalizing metabolic control [76], while others have not found a significant effect on HbA1c levels [75]. Interestingly, achieving antibody negativity after diagnosis appears to be associated with better metabolic control [77], although only one-third of T1DM patients with CD achieve this, likely due to poor adherence to both diets.

Strict adherence to a GFD is essential for optimal outcomes in CD patients, helping to reduce the risk of complications, mortality [11], and persistent gastrointestinal symptoms [13,34]. However, T1DM itself can influence the course of CD, as it does in other chronic gastrointestinal conditions, such as inflammatory bowel disease (IBD), where a wealth of data exist [78].

In a prospective interventional study, asymptomatic T1DM patients aged 8–45 were screened for CD. Those with biopsy-confirmed CD were randomized to either a GFD or gluten-containing diet and followed for 12 months. No significant differences in HbA1c levels were observed between the groups, although greater postprandial glucose emerged in the GFD group [79].

However, a protective role of the GFD in preventing vascular complications was observed [80].

In conclusion, the effect of a GFD on glycemic control remains debated, though evidence suggests a generally favorable outcome. Thus, screening for CD in both pediatric and adult patients with T1DM is recommended [80,81]. Nevertheless, patients with diabetes are often excluded from interventional studies due to potential confounding factors, limiting the generalizability of these studies to this population.

2.2.9. Pancreatic Exocrine Deficiency

The relationship between CD and pancreatic exocrine function has not been extensively studied [82]. Pancreatic involvement can occur in CD, either as a consequence of small-bowel disease or as a coexisting condition. The primary mechanisms proposed for this association include the impaired release of cholecystokinin and secretin, as well as chronic duodenal inflammation leading to changes in the papillary mucosal area. In some cases, patients also develop chronic idiopathic pancreatitis, which is not directly related to decreased secretin release. Additionally, amino acid malabsorption may reduce the synthesis of pancreatic enzymes [83].

CD is recognized as a less common etiology of pancreatic exocrine insufficiency (PEI). Up to 80% of newly diagnosed CD patients may show impairment of pancreatic exocrine function [84]. Fecal elastase testing is recommended for detecting PEI. In treated CD patients who remain unresponsive to a GFD, PEI should be considered a potential cause of treatment failure [82]. In this group of patients, PEI has been reported in 12–18% of cases [82], although the exact prevalence remains unknown. A recent prospective RCT raised concerns about the effectiveness of pancreatic enzyme supplementation in reliving symptoms in CD patients with PEI, suggesting that enzyme replacement may not always be beneficial [85]. Much of the existing evidence on this topic is based on old studies, highlighting the need for further research. Interestingly, some authors have reported that pancreatic enzyme replacement therapy can be discontinued in patients who experience improvement following the restoration of mucosal architecture with a GFD [83].

2.2.10. Gluten-Induced Hepatitis

Liver damage in untreated CD can arise from coexisting autoimmune conditions, such as autoimmune hepatitis, or metabolic disorders like non-alcoholic fatty liver disease [5]. However, several studies have reported elevated aminotransferase levels in CD patients without other identifiable causes of liver disease [86], a condition known as “gluten-induced hepatitis”. This condition has a prevalence of 4–9%, is typically mild, and usually resolves within 6–12 months after starting a GFD [86]. The mechanisms behind “gluten-induced hepatitis” may involve altered gut permeability, which allows hepatotoxins to enter the portal circulation, potentially contributing to liver inflammation [86]. Additionally, aminotransferase levels have been found to correlate with the clinical severity of malabsorption and of the extent of duodenal lesions in CD patients [87], although this liver damage is not directly related to malnutrition.

3. Nutritional Consequences of a GFD

3.1. Nutritional Excesses in GFD and Cardiovascular Risk

Overweight and obesity have been observed in patients following a GFD [88]. The restoration of intestinal absorptive function can result in an increased energy load for the patient, while poor dietary habits may further contribute to excessive caloric intake [89]. A GFD is associated with higher calorie, sodium, and fat consumption compared to non-celiac controls [90]. Additionally, the global trend toward overweight and obesity may also impact these patients.

A meta-analysis by Potter et al. on the cardiovascular risk associated with a GFD did not draw firm conclusions on the overall risk, though it noted that GFD in CD patients is linked to increased levels of total cholesterol, high-density lipoprotein, fasting blood glucose, and BMI (though still within a healthy weight range) [91]. Another review by Schmucker et al. confirmed the uncertainty surrounding a GFD as a risk factor for cardiovascular diseases [92]. A recent Italian systematic review of 7959 patients across 45 studies concluded that while mean BMI increased significantly on a GFD, only 9% of patients moved into the overweight/obese category [89].

Emerging evidence also suggests a possible link between a GFD and the development of non-alcoholic fatty liver disease, attributed to the increased intake of products rich in saturated fats and carbohydrates [93]. On the other hand, an Asian RCT involving 50 patients showed positive outcomes from an 8-week GFD used as therapeutic tool for metabolic syndrome, with reductions in fasting blood glucose, waist circumference, and serum triglyceride levels [94].

3.2. Induced Deficiencies by a GFD

Nutritional deficiencies acquired during the active phase of CD are gradually reversed once a GFD is started [45]. However, a GFD is typically associated with various nutritional deficiencies. Notably, fiber intake is lower in both CD adults and children compared to their non-celiac peers [95], as are intakes of vegetables and FODMAP-containing foods [43,95,96].

Micronutrients such as zinc, manganese, B vitamins, vitamin E, calcium, and others are also found to be lower in GFD regimes compared to non-GFD regimes. The prevalence of these deficiencies across different cultural settings suggests they are inherently linked to the foods commonly included in a GFD [90,95]. Another notable trend is that patients on a GFD may consume more meat than their non-GFD counterparts [95,96], although their overall protein intake may still be lower [97,98].

An interesting study [44] found that after 2 years of good adherence to a GFD, up to 30% of subjects still have a vitamin B12 deficiency; 40% were deficient in iron, 20% in folic acid, 25% in vitamin D, 40% in zinc; 3.6% of children were deficient in calcium; and 20% were low in magnesium. This suggests that supplementation in CD patients under a GFD may be necessary. In contrast, another study found that individuals with CD following a GFD had higher weekly intakes of vitamin E, vitamin B6, thiamine, and phosphorus, though their intake of polyunsaturated fatty acids was lower [59]. Moreover, in an RCT published in 2009, the supplementation of group B vitamins significantly improved psychological well-being [48].

While some studies indicate that a GFD can improve BMD and overall nutrition in CD patients [99], and that long-term GFD adherents may achieve a similar nutritional status to non-CD individuals, other research suggests the need for diary and calcium-enriched products to avoid deficiencies [43,95,96,97,100]. Calcium-fortified gluten-free products are available for prophylactic and therapeutic purposes. Nonetheless, encouraging the consumption of natural foods that support calcium absorption is recommended [100].

3.3. Dietary Management of the GFD

Inadequate adherence to a GFD is often the cause of various intestinal and extra-intestinal complications, resulting in a poorer quality of life and worse patient outcomes [34]. Therefore, the proper initiation and monitoring of a GFD are crucial [16].

Celiac serology and standardized questionnaires are the cornerstone tools, but each has its limitations. While antibody titration is commonly used to monitor the response to a GFD, the accuracy of serological tests has been debated for years without reaching a clear consensus. New non-invasive technologies, such as kits for gluten excretion in urine and feces, are emerging as potential complementary tools for monitoring adherence [101]. Recently, specific non-coding microRNAs circulating in the bloodstream [102] or excreted in stools [59] have been identified in both untreated and treated CD individuals. These microRNAs are emerging as promising low-invasive biomarkers for GFD adherence, as they are not over- or under-expressed in healthy individuals or those with other gastrointestinal diseases. MicroRNAs, which are small non-coding RNAs (18–22 nucleotides), regulate gene expression at the post-transcriptional level and play key roles in biological processes such as inflammation, apoptosis, autoimmunity, and carcinogenesis [103]. Increasing evidence suggests a link between specific nutrient intake and microRNA expression. Fecal microRNA profiles can vary based on anthropometric traits and lifestyle habits, and they may even distinguish subjects with different dietary patterns [59]. In this context, diet influences the gut microbiome, driving the selection of specific microbial taxa. Evidence suggests mutual regulation between fecal microRNAs and the gut microbiota, mediated by diet-induced microbial metabolites [59].

Professional nutritional counseling from the beginning of a GFD is critical. Continuous, personalized follow-up that includes assessing the patient’s nutritional status and providing timely supplementation when necessary is recommended. Furthermore, evaluating the various life factors that influence patient’s dietary choices is desirable [16].

A lifelong GFD requires strict dietary adherence, which can significantly affect the patient’s life [104]. Social factors are particularly important in maintaining compliance with a GFD [104]. Celiac patients are often challenged when eating outside, at school, work, or social gatherings, as they must discreetly identify hidden sources of gluten without feeling judged by others [104].

Enhancing patients’ knowledge of both the disease and the GFD is crucial for improving adherence and achieving a balanced diet [105]. Nationally developed and regularly updated comprehensive food composition databases should be easily accessible to the general public [72].

A GFD should be as varied as possible and include plant-based foods like fruits, vegetables, legumes, nuts, and naturally gluten-free whole grain cereals and pseudo-cereals. These foods are rich in complex carbohydrates, fiber, vitamins, and minerals. Reducing the consumption of processed gluten-free products, poor-quality fats, and simple sugar is recommended [45]. Special attention should be given to iron, calcium, vitamin D, and B vitamins, due to their clinical relevance in CD. The adequate intake of these nutrients through food sources, and supplementation, if necessary, is recommended.

4. Nutritional Consequences of Physical Activity as a Complement to a GFD

Physical activity is defined as the use of skeletal muscles with energy expenditure and is known to promote an anti-inflammatory response in various tissues, including muscles, adipose tissue, and the heart. It is widely recognized as a modifiable risk factor for numerous chronic diseases, such as rheumatoid arthritis. The World Health Organization underscores the multidimensional benefits of regular physical activity, which range from metabolic and cardioprotective effects to improvements in psychological well-being [106].

Similar to other chronic gastrointestinal disorders [107,108], individuals with CD often struggle to maintain regular physical activity [26,109], despite its value as a complementary intervention alongside proper nutrition. A study by Passananti et al. found that people with CD frequently experience fatigue and may reduce their social activities, further decreasing their physical activity levels [26]. Likewise, Dowd et al. reported low physical activity levels in female CD patients on a GFD, as measured by the International Physical Activity Questionnaire [109].

While the role of physical activity has been more extensively researched in IBD—such as in the BE-FIT-IBD study in Italy [107,108]—it remains relatively underexplored in CD. In IBD, it is well established that low-intensity physical activity can positively affect the quality of life in patients with mild or remissive Crohn’s disease without exacerbating the disease or increasing the risk of flare-ups. Higher levels of physical activity are associated with improved quality of life, though intense, sweat-inducing exercises are generally avoided. Despite these insights, precise recommendations and guidelines for physical activity in IBD are still lacking, and patients often express a desire for more in-depth discussions on the subject during their clinical visits.

Several observational studies on quality of life in CD patients have noted that initiating and adhering to a GFD has a positive impact on both physical activity levels and overall well-being [15,104]. One notable but small interventional study from Spain [14] randomized perimenopausal and postmenopausal female CD patients into three groups: one receiving twelve weeks of aerobic physical activity sessions combined with a dietitian-supervised GFD, another group with only the supervised GFD, and a control group without any specific intervention. This study showed that the group participating in physical activity experienced improvements in menopausal symptoms, mood, and bone stiffness, as measured by ultrasound [14]. Similarly, an observational study on children with CD found that those engaging in more vigorous physical activity had greater lean mass and BMD, regardless of the duration of their GFD adherence [58].

5. Discussion

CD should be considered in clinical scenarios involving nutritional deficiencies, as well as immune or inflammatory conditions linked to untreated CD. In such cases, serological testing is recommended, and if positive, a confirmatory intestinal biopsy is mandatory for adults. In this review, we have discussed the frequency, mechanisms, and possible diagnostic and therapeutic interventions for the main clinical features associated with CD malabsorption (see Figure 1). These include global malnourishment with failure-to-thrive, specific deficiencies such as iron deficiency, anemia, vitamin B group deficiency, bone health impairment, reproductive health issue, skin and mucosal pathologies, neuropathies, and the association with T1DM (Figure 1). Although we have covered a wide range of topics, we do not claim to be exhaustive, given the complexity of CD’s various clinical manifestations, both nutritional and non-nutritional, and the intricate connections with other conditions, lifestyle factors, and diseases.

We have also explored the correction or persistence of nutritional deficiencies on a GFD, as well as the potential for new imbalances to develop (Figure 1). While a GFD may lead to the insufficient intake of certain nutrients, particularly fiber, calcium, iron, folate, and other vitamins, clear strategies to prevent these deficiencies have yet to be firmly established. Possible interventions include dietary modifications, micronutrient supplementation, and promoting physical activity. Conversely, there is evidence of the excessive intake of total calories, simple sugars, fats, and sodium in individuals following a GFD, although this has not been conclusively linked to an increased risk of cardiovascular disease or obesity.

It is also important to recognize the growing number of people adopting a GFD, driven not only by the rise in CD and gluten-sensitivity diagnoses but also by personal choice. Today, the typical individual starting a GFD is no longer the traditionally malnourished CD patient, and as such, the effects of a GFD will continue to evolve, necessitating ongoing monitoring. Furthermore, emerging research is increasingly focusing on the epigenetic effects and the influence of a GFD on the gut microbiome, highlighting the need for future investigations in these areas.

6. Practical Conclusions

• Screening for CD in high-risk groups, such as individuals with autoimmune diseases, infertile women, and selectively malnourished patients, is recommended.
• A GFD is a nutritionally safe intervention that leads to CD remission in most cases.
• The involvement of an expert dietitian at diagnosis is encouraged to promote dietary adherence and establish a balanced GFD.
• During follow-up, a dietitian can help detect and correct nutritional imbalances.
• Hematological profiles, including iron and folate status, as well as calcium–vitamin D3 balance, should be assessed at diagnosis, monitored during a GFD, and corrected if symptomatic or persistent.
• Persistence of iron deficiency is common, often due to low iron intake, increased requirements, or ongoing mucosal damage. Oral iron therapy is recommended in such cases.
• For persistent anemia, a thorough exclusion of non-CD-related causes should be conducted.
• Bone density should be assessed in adults, particularly women, but also in younger patients with additional osteoporosis risk factors.
• In cases of persistent mucosal damage and unresolved nutritional imbalances after one to two years of a GFD, further investigation is necessary.

7. Future Clinical and Research Directions

• The mechanisms behind symptoms and nutritional deficiencies in CD patients without villous atrophy remain unclear and require further study.
• The usefulness of screening for CD in asymptomatic T1DM patients needs further prospective studies. The complexity of managing these patients goes beyond treating each condition independently and is affected by extra-biological factors.
• More evidence is needed to support bone densitometry at diagnosis for all CD patients. The development of alternative, low-cost methods for assessing bone mass and resistance could be beneficial.
• The clinical relevance of micronutrient deficiencies is not always well defined, and micronutrient supplementation policies for CD vary significantly between Europe and the United States.
• The mechanisms behind neurological, dermatological, psychological, hepatic, and reproductive health issues associated with CD are often not solely related to nutrition and remain unclear.
• The impact of the global trend toward overweight and obesity on patients following a GFD, whether for CD, non-celiac gluten sensitivity, or other conditions, should be monitored. This emerging patient profile introduces new challenges, such as the potential use of bariatric surgery for obesity in CD patients.
• The synergy between a GFD and regular physical activity PA is not well understood. Physical activity plays a critical role in managing CD, influencing overall health, symptom control, quality of life, social interactions, GFD adherence, and compliance with medical advice. Further research is needed.
• Epigenetic mechanisms underlying CD pathogenesis and their relationship to a GFD are key areas for future research.