Gluten’s silent strike: Unmasking its impact on liver health

Abstract

Once considered a concern solely for the gut, gluten is now recognized as an important factor in the pathogenesis of metabolic dysfunction-associated steatotic liver disease. Studies estimate that 18%-40% of individuals with gluten-related diseases have elevated liver enzyme levels, with 9% of patients with unexplained hypertransaminasemia ultimately diagnosed with gluten sensitivity. Hepatic manifestations of gluten sensitivity range from mild transaminase elevations to autoimmune liver diseases, metabolic dysfunction-associated steatotic liver disease, and even cirrhosis. Up to 50% of untreated cases of gluten-induced liver dysfunction show significant hepatic injury, which can lead to liver failure in severe cases. The pathophysiology is multifaceted and involves increased intestinal permeability, immune dysregulation, and shared genetic risk factors. A gluten-free diet leads to normalized liver enzymes in 75%-90% of cases within 1 year. Long-term gluten-free diet adherence has been paradoxically linked to higher body mass index, insulin resistance and increased hepatic steatosis risk, which raise concerns about its metabolic impact. Our review dissects the gluten-liver axis, emphasizing a need for early recognition, targeted screening, and personalized dietary interventions. Ultimately, given the increasing global burden of metabolic and autoimmune liver diseases, understanding gluten’s role is essential for optimizing liver health and preventing progressive hepatic injury.

Key Words: Gluten; Liver dysfunction; Gut-liver axis; Gluten-free diet; Metabolic liver disease; Autoimmune hepatitis; Transaminase elevation; Hepatic steatosis; Celiac hepatitis; Non-celiac gluten sensitivity

Core Tip: Gluten, once viewed solely as a gastrointestinal concern, is now implicated in a wide spectrum of hepatic disorders ranging from mild hypertransaminasemia to cirrhosis. Up to 40% of patients with celiac disease and 9% of those with unexplained elevated liver enzymes may have underlying gluten sensitivity. A gluten-free diet normalizes transaminase levels in most cases, yet long-term adherence may paradoxically exacerbate metabolic liver disease. This article elucidates the complex interplay between gluten, gut permeability, immune activation, and liver pathology. Recognizing gluten’s hepatic implications is crucial for early screening, tailored dietary management, and prevention of progressive liver injury in at-risk individuals.

INTRODUCTION

Diet plays an important role in the pathogenesis of multiple gastrointestinal (GI) and hepatic disorders[1,2]. In recent years, consumption of gluten-containing cereals, such as wheat, rye and barley, has been implicated in a spectrum of disorders, collectively termed gluten-related disorders (GRDs). GRDs encompass a broad range of conditions, including: (1) Autoimmune diseases: Celiac disease (CeD), dermatitis herpetiformis, and gluten ataxia; (2) Non-autoimmune, non-allergic disorders: Non-celiac gluten sensitivity (NCGS); and (3) IgE mediated allergic reactions: Classic wheat allergy, wheat-dependent exercise-induced anaphylaxis, and occupational asthma. These GRDs exhibit distinct pathophysiological mechanisms and clinical manifestations[3]. GRDs have historically been studied in the context of intestinal damage or malabsorption, as well as systemic inflammation[4]. However, emerging evidence suggests that gluten’s influence extends beyond the gut, playing a significant role in liver dysfunction. Despite its growing recognition, the impact of gluten on liver health is still underappreciated in both clinical and research settings[5,6].

Recent studies have indicated that about 10%-50% of individuals with GRDs exhibit elevated liver enzymes, with a notable proportion of patients with unexplained hypertransaminasemia ultimately diagnosed with gluten sensitivity. These hepatic manifestations range from mild transaminase elevations to more severe conditions like autoimmune liver diseases, metabolic dysfunction-associated steatotic liver disease (MASLD) or even cirrhosis[7]. The underlying pathophysiology is complex and multifactorial because it involves intestinal permeability (“leaky gut”) and immune-mediated mechanisms, as well as genetic predisposition. A gluten-free (GF) diet (GFD) can reverse liver enzyme abnormalities in most affected individuals, but long-term GFD adherence has been associated with metabolic disturbances, such as increased body mass index (BMI) and insulin resistance[8].

Our review will dissect the complex interactions between gluten and liver disease while analyzing epidemiological patterns, clinical presentations, underlying mechanisms, and therapeutic ramifications. As metabolic and autoimmune liver disease increasingly threatens global disease burden, insights into the gluten-liver connection can help in early diagnosis, focused screenings, and efficient management. This underappreciated aspect of gluten-associated disorders requires a multidisciplinary approach to maximize liver health in at-risk patients.

EPIDEMIOLOGY AND PREVALENCE OF GLUTEN-INDUCED LIVER DYSFUNCTION

GRDs like CeD and NCGS are increasingly recognized as contributors to liver dysfunction. Approximately 18%-40% of patients with newly diagnosed CeD have elevated liver enzymes. Hypertransaminasemia is frequently reported in these patients, with transient enzyme elevations often resolving upon the adoption of a strict GFD. Liver enzyme abnormalities, like elevated alanine aminotransferase and aspartate aminotransferase, are more prevalent in gluten-related conditions. NCGS also exhibits measurable hepatic effects, and this elevation often occurs independently of overt liver disease, serving as an early marker of gluten-induced hepatopathy[9,10].

Some populations are more susceptible to gluten-related liver dysfunction (GRLD) based on genetic and immunological causes. Human leukocyte agent (HLA)-DQ2/DQ8 haplotypes are considered a main risk factor for CeD. Autoimmune hepatitis (AIH), type 1 diabetes, primary biliary cholangitis (PBC) and metabolic syndrome often accompany gluten disorders. Infants and children with undiagnosed CeD frequently present with asymptomatic liver dysfunction, highlighting the importance of early screening.

Hepatic presentations of GRDs vary from incidental elevations in transaminases to more severe illness like AIH, MASLD, and cirrhosis[11]. Susceptible individuals exposed to gluten over time can develop chronic liver inflammation and fibrosis, warranting early diagnosis and dietary therapy. Hence, understanding the epidemiology of GRLD is important for early diagnosis, risk stratification, and management to avoid long-term hepatic consequences[12,13].

GRLD PATHOPHYSIOLOGY

The gut-liver axis plays a central role in maintaining liver health, which facilitates communication between the GI tract and the liver through portal circulation, immune signaling and microbial metabolites[14]. GRLD is driven by complex interactions between the gut and immune system in genetically predisposed individuals. The gut-liver axis is disrupted in patients with gluten sensitivity, which could lead to hepatic inflammation, metabolic disturbances, and in severe cases, progression to chronic liver disease[7].

A primary mechanism linking gluten ingestion to liver dysfunction is gut dysbiosis, where an imbalance in the gut microbiome alters immune responses and increases systemic inflammation. Individuals with GRDs, such as CeD and gluten sensitivity, exhibit significant gut microbiota dysbiosis characterized by a reduction in beneficial bacteria including Lactobacillus and Bifidobacterium, and an increased abundance of pro-inflammatory taxa such as Proteobacteria and Enterobacteriaceae, which may contribute to extraintestinal manifestations, including liver dysfunction. This dysbiotic state promotes excessive intestinal immune activation and leads to increased bacterial translocation and endotoxin exposure. As the primary site for processing gut-derived antigens, the liver responds with heightened immune activity and triggers inflammatory cascades that contribute to hepatocyte injury and liver enzyme release. Kupffer cells are liver resident macrophages that become overactivated in response to these signals by producing high levels of pro-inflammatory cytokines, such as tumor necrosis factor α, interleukin (IL)-6, and IL-1β. Hence, this inflammatory response leads to hepatocellular stress, mitochondrial dysfunction, and lipid accumulation, which can progress to fibrosis or cirrhosis if untreated[5].

A primary factor in this pathological process is increased intestinal permeability, which is also known as leaky gut. In genetically predisposed individuals with GRDs, ingestion of gluten triggers the release of zonulin - a physiological regulator of tight junctions - via gliadin binding to the C-X-C chemokine receptor type 3 receptor on intestinal epithelial cells. Increased zonulin levels loosen tight junctions, allowing luminal contents, such as undigested gluten peptides, bacterial endotoxins, and inflammatory mediators, pass into systemic circulation[15]. Entry of these molecules stimulates widespread immune activation, including within the liver where antigen-presenting cells, such as dendritic cells and macrophages, react by initiating inflammatory signaling pathways. This process adds to hepatocyte apoptosis and oxidative stress, each of which is involved in liver dysfunction pathogenesis. Patients with gluten-associated liver disease tend to have very high levels of circulating endotoxins and inflammatory markers, which further supports the association of gut permeability with hepatic inflammation[16].

Immune systems also play a central role in GRLD, with both innate and adaptive immune responses contributing to hepatocellular damage. Gluten-derived gliadin peptides are recognized as foreign antigens by the immune system, leading to CD4+ T-cell activation in the gut-associated lymphoid tissue. These T-cells then trigger pro-inflammatory cytokine release and stimulate antigen-presenting cells, which migrate to the liver and amplify the inflammatory response (Figure 1)[7]. The immune-mediated process is exacerbated by molecular mimicry, where similarities between gluten peptides and self-antigens lead to cross-reactivity, leading the immune system to mistakenly attack hepatocytes. This mechanism has been observed in cases of gluten sensitivity-associated AIH, where the presence of autoantibodies such as anti-tissue transglutaminase (anti-tTG) and anti-nuclear antibodies suggests the breakdown of immunological self-tolerance.

Figure 1 Pathophysiological cascade of gluten and liver. This figure illustrates the proposed pathophysiological cascade through which gluten exposure may lead to liver dysfunction in genetically predisposed individuals. The process begins with gut dysbiosis, characterized by a decrease in beneficial bacteria such as Lactobacillus and an increase in pro-inflammatory taxa like Proteobacteria. This microbial imbalance contributes to the release of zonulin, increasing intestinal permeability - a phenomenon termed “leaky gut”. The compromised intestinal barrier allows antigen and endotoxin translocation into circulation, which triggers immune activation and cytokine-mediated inflammation. Subsequent liver inflammation results from immune cell migration and cytokine signaling within hepatic tissue. Persistent inflammation and immune-mediated damage can culminate in chronic liver disease, including metabolic dysfunction-associated steatotic liver disease, autoimmune hepatitis, and cirrhosis. Genetic and metabolic influences, such as human leukocyte antigen-DQ2/DQ8 haplotypes and insulin resistance, further modulate the severity and progression of hepatic injury in gluten-sensitive individuals.

Beyond immune dysregulation, genetic predisposition is critical in determining susceptibility to GRLD[17]. The strongest genetic associations are found in individuals carrying the HLA-DQ2 or HLA-DQ8 alleles, which are linked to CeD and other autoimmune conditions. These HLA molecules present gluten-derived peptides to immune cells and initiate a prolonged and exaggerated immune response. In addition to HLA genes, other genetic factors influence disease progression, including variations in IL-10 and tumor necrosis factor α, which regulate inflammatory responses, as well as mutations in genes involved in gut barrier integrity, such as those encoding zonulin and claudins. Polymorphisms in genes related to hepatic metabolism and detoxification within the cytochrome P450 family further modulate an individual’s risk of developing liver dysfunction in response to gluten exposure[15].

The interplay between gut permeability, immune activation, and genetic susceptibility creates a self-perpetuating inflammation and tissue damage cycle, highlighting how the complexity of GRLD and severity of hepatic involvement widely vary, with some individuals exhibiting only mild transaminase elevations while others progress to steatosis, fibrosis, or cirrhosis[5].

CLINICAL MANIFESTATIONS OF GRLD

Beyond its classical GI manifestations, CeD is increasingly recognized as a multisystem disorder with a broad spectrum of hepatic involvement (Table 1). Gluten-related hepatic injury in adult CeD patients includes asymptomatic elevation of liver enzymes, cirrhosis, MASLD, autoimmune liver diseases (AIH, PBC, primary sclerosing cholangitis), non-cirrhotic portal fibrosis (NCPF), hepatic vascular complications [hepatic vein outflow tract obstruction (HVOTO), extrahepatic portal vein obstruction (EHPVO)], and hepatic malignancies. Understanding the pathophysiology, clinical presentation, and management of these hepatic manifestations is essential for hepatologists, as early recognition and intervention, particularly with a GFD, can significantly alter disease course and prognosis.

Table 1 Hepatic manifestations of gluten-related disorders and expected response to a gluten-free diet.

Hepatic manifestation	Typical pattern	Proposed mechanisms	Suggested workup	Expected response to strict GFD	Additional management	Evidence base
Isolated transaminase elevation (“celiac hepatitis”)	Mild-moderate hepatocellular ALT/AST rise; normal bilirubin/ALP	Increased intestinal permeability; immune activation; micronutrient deficiencies	Rule out viral hepatitis, MASLD, alcohol, DILI, AIH/PBC; celiac serology (tTGIgA with total IgA ± DGPIgG)	Frequent normalization within 6-12 months; reassess if persistent > 12 months	Dietitianled GFD education; monitor ALT/AST at 3 months, 6 months, 12 months	Moderate (cohort and caseseries data)
MASLD/NAFLD overlap	Steatosis on imaging; ± insulin resistance, dyslipidemia	PostGFD weight gain; highgluten induced GF products; microbiome shifts; insulin resistance	Metabolic profile (BMI/waist, lipids, glucose); elastography or MRPDFF for risk stratification	Mixed; improves with weight loss and Mediterraneanstyle GFD	Lifestyle therapy; Mediterraneanstyle GFD; manage cardiometabolic risk per guidelines	Low-moderate (observational; small trials in NAFLD)
AIH overlap	Marked transaminase elevation; autoantibodies; interface hepatitis on biopsy	Shared HLA/immunogenetic susceptibility; loss of tolerance	Autoantibodies (ANA/SMA/LKM); IgG; liver biopsy when indicated	GFD may aid control, but immunosuppression usually required	Standard AIH therapy (steroids ± azathioprine) with GFD adherence	Low (case series/case reports)
PBC association	Cholestatic ALP/GGT elevation; AMA positivity	Autoimmune clustering; shared susceptibility	AMA, PBCspecific antibodies; cholestatic evaluation	Unclear; liver biochemistry typically responds to ursodeoxycholic acid (UDCA) rather than GFD alone	Treat per PBC guidelines (UDCA ± secondline therapy)	Low (observational association)
PSC association	Cholestatic labs; cholangiographic beading/strictures	Immune dysregulation; gut–liver axis perturbation	MRCP/ERCP; IBD screening; cholestatic panel	No established effect of GFD on PSC course	Manage per PSC guidance; surveillance for cholangiocarcinoma and IBD	Very low (limited reports)
Hypoalbuminemia, coagulopathy; steatosis secondary to malnutrition	Low albumin; elevated INR (vitamin K deficiency); fatty liver on imaging	Protein–calorie and fatsoluble vitamin deficiencies; smallbowel injury	Nutritional panel (iron, folate, B12, vitamins A/D/E/K); celiac activity assessment	Improves with mucosal healing and targeted supplementation	Vitamin repletion; dietitian followup; repeat labs to document correction	Low (case series, pediatric prominence)

ALT: Alanine transaminase; AST: Aspartate transaminase; ALP: Akaline phosphatase; MASLD: Metabolic dysfunctionassociated steatotic liver disease; DILI: Druginduced liver injury; AIH: Autoimmune hepatitis; PBC: Primary biliary cholangitis; tTG: Tissue transglutaminase; DGP: Deamidated gliadin peptide; GFD: Glutenfree diet; GF: Gluten free; BMI: Body mass index; MR: Magnetic resonance; PDFF: Platelet discriminant fraction; NAFLD: Nonalcoholic fatty liver disease; HLA: Human leukocyte agent; ANA: Anti-nuclear antibody; SMA: Smooth muscle antibody; LKM: Liver kidney muscle; GGT: Gamma glutamyl transferases; UDCA: Ursodeoxycholic acid; MRCP: Magnetic resonance cholangiopancreatography; PSC: Primary sclerosing cholangitis; ERCP: Endoscopic retrograde cholangio-pancreaticography; IBD: Inflammatory bowel disease; INR: International normalised ratio.

Hepatic manifestations in patients with NCGS

With urbanization and increasing dietary awareness, more people are adopting GFDs, causing an increase in NCGS[18]. NCGS is defined by the presence of gluten-related symptoms in the absence of celiac-specific antibodies and with normal duodenal histology. The most commonly reported symptoms involve the GI tract (bloating, abdominal pain, altered bowel habits) but are also extraintestinal (headache, fatigue, musculoskeletal pain, neuropsychiatric complaints)[19]. While CeD is well known for its association with hepatic manifestations, including hypertransaminasemia, MASLD and AIH, hepatic manifestations have not been reported in patients with NCGS[20].

Proposed mechanisms for hepatic injury in NCGS, such as innate immune activation, cytokine-mediated injury, and dysbiosis, remain theoretical[18]. No studies have established a direct causal link between NCGS and primary hepatic abnormalities in adults. A study by Remes-Troche et al[21] of 22 patients with NCGS showed that obesity increased by 5% 6 months after starting a GFD, and 20% of those patients presented with de novo hepatic steatosis. However, these findings are not sufficient to establish hepatic involvement as a characteristic of NCGS. Confounding factors must also be considered, including dietary changes and obesity.

Asymptomatic liver enzyme elevation

The most common hepatic manifestation of CeD in adults is the asymptomatic elevation of aminotransferases, often referred to as “celiac hepatitis”. This manifests in roughly 18%-21% of adults at the time of diagnosis[17,22,23]. The pathophysiology involves increased intestinal permeability due to gluten-induced mucosal injury, allowing translocation of antigens and inflammatory mediators into the portal circulation, resulting in mild, reversible hepatocellular injury[5,7]. Clinically, individuals are generally asymptomatic, and the abnormality is incidentally identified during routine laboratory testing. Most cases are mild, with transaminase elevations less than five times the upper limit of normal[24]. The American College of Gastroenterology recommends that all adults with unexplained liver enzyme elevation be screened for CeD, given the high likelihood of reversibility with a GFD[25]. Initiation of a strict GFD leads to normalization of liver enzymes in 78%-86% of cases within 6-12 months[26]. Persistent abnormalities beyond this period should be promptly evaluated for alternative or coexisting liver diseases.

MASLD

MASLD, formerly known as NAFLD, is increasingly recognized in patients with CeD[27,28]. Its pathophysiology is complex, involving chronic inflammation, alterations in the gut-liver axis, and potential weight gain and dietary shifts after GFD initiation[29,30]. While some patients with malnutrition-related steatosis at diagnosis may show improvement following nutritional rehabilitation and a GFD, others may develop or experience worsening of MASLD during follow-up, likely due to increased caloric and fat intake associated with adherence to a GFD[27]. More than 40% of adults with CeD may develop hepatic steatosis during long-term follow-up, even in the absence of fibrosis progression[26]. Management is individualized and multidisciplinary, focusing on dietary counseling, weight management, and optimization of metabolic risk factors. Hence, the American College of Gastroenterology emphasizes the need for regular metabolic and nutritional monitoring in adults with CeD, particularly after GFD initiation[12,25].

Cirrhosis and advanced liver disease

Cirrhosis is an uncommon but clinically significant hepatic outcome in adults with CeD[31,32]. Its pathogenesis is multifactorial, involving chronic immune activation, persistent inflammation, and, in some cases, malabsorption-related metabolic disturbances[33]. Recent studies indicate that CeD is overrepresented among patients with cryptogenic cirrhosis, with a prevalence of approximately 4.7%[33]. Importantly, adults with cryptogenic cirrhosis and previously unrecognized CeD may experience biochemical improvement after initiation of a GFD, including reductions in MELD and Child-Turcotte-Pugh scores[34]. The extent of reversibility is closely associated with liver disease stage at diagnosis. Advanced fibrosis or established cirrhosis may not be entirely reversible; however, stabilization and improved outcomes are achievable by strict dietary compliance. Hence, screening for CeD in adults with cryptogenic cirrhosis is recommended, as early identification and dietary intervention can prevent progression to hepatic failure[35].

Autoimmune liver diseases

Autoimmune liver diseases (AIH, PBC, primary sclerosing cholangitis) are significantly more common in CeD, with adjusted odds ratios of 7.1 for AIH and 4.2 for PBC; anti-tTG positivity further increases this risk[36]. The pathophysiological link is likely related to shared genetic susceptibility (notably HLA-DR3 and HLA-DQ2), increased intestinal permeability, and dysregulated mucosal immunity[37]. The prevalence of CeD in patients with AIH and PBC is higher than in the general population, and vice versa. These manifest with cholestatic or hepatocellular injury liver enzyme pattern, pruritus, jaundice, and signs of portal hypertension in advanced disease[38]. In contrast to celiac hepatitis, autoimmune liver diseases typically do not remit solely with a GFD.

NCPF and hepatic vascular complications

NCPF and hepatic vascular complications, including HVOTO such as Budd-Chiari syndrome and EHPVO, are rare but clinically significant manifestations in adults with CeD[39]. Its pathophysiology is thought to involve shared autoimmune mechanisms and a prothrombotic state, which may be driven by chronic inflammation, malabsorption-related deficiencies, and the presence of antiphospholipid or other autoantibodies[40]. NCPF presents with features of portal hypertension (splenomegaly, variceal bleeding) but preserved hepatic synthetic function, while HVOTO and EHPVO manifest as hepatomegaly, ascites, and recurrent variceal bleeding[41]. A GFD does not reverse established vascular complications, but strict dietary adherence may reduce the risk of further thrombotic events.

Hepatic malignancies

Hepatic malignancies are rare but serious complications of long-standing, untreated CeD. These primarily include T-cell lymphoma, and, less commonly, hepatocellular carcinoma[9]. Etiology involves translocation of pro-oncogenic factors to the liver through increased intestinal permeability. A GFD does not reverse established malignancy but may reduce the risk of developing hepatic lymphoma by preventing chronic inflammation[42].

GFD AND LIVER HEALTH

A GFD is the cornerstone therapy in managing GRLD. In patients with CeD and concomitant liver involvement, most commonly presenting as hypertransaminasemia or celiac hepatitis, adherence to a GFD leads to normalization of transaminase levels in approximately 78%-86% of cases within 6-12 months. The reduction in liver inflammation after gluten withdrawal is linked to improved intestinal barrier integrity, reduced immune response, and improved gut bacteria balance. In immune-mediated liver diseases such as gluten sensitivity-associated AIH, gluten withdrawal is associated with reductions in autoantibody titers (e.g., anti-tTG, ANA) and attenuation of hepatic inflammation, which may slow disease progression. Furthermore, patients with MASLD on a GFD show improvements in hepatic steatosis, lipid metabolism, and insulin sensitivity, highlighting the benefits of a GFD[29,43].

Paradoxically, strict adherence to GFD in patients with CeD or NCGS is associated with increased BMI, insulin resistance, and risk of obesity and metabolic syndrome, all of which are established etiologic factors for hepatic steatosis and fibrosis. This phenomenon is largely attributable to the high glycemic index, increased sugar and saturated fat content, and low fiber of many commercially available GF processed foods, which often replace whole grains with refined starches and added sugars. Such dietary patterns promote an obesogenic environment, increase hepatic de novo lipogenesis, and contribute to the development and progression of MASLD and fibrosis. A GFD, particularly when based on processed GF products, is frequently deficient in vitamin D, B vitamins (notably folate, B6, and B12), iron, calcium, magnesium, and dietary fiber. These deficiencies are compounded by the lack of mandatory fortification in GF flours and the exclusion of nutrient-rich whole grains. Micronutrient deficiencies exacerbate oxidative stress and contribute to liver disease progression. For example, vitamin D deficiency is associated with increased hepatic inflammation and fibrosis, while iron and B vitamin deficiencies may worsen anemia and hepatic metabolic dysfunction[29,43].

Commercial GF products often substitute wheat with refined starches (rice, corn, potato, tapioca) and are typically lower in protein and fiber and higher in carbohydrate/sodium - features that raise glycemic index and may promote post-prandial hyperinsulinemia, weight gain, and insulin resistance relevant to MASLD risk. Comparative nutrient analyses consistently demonstrate that GF products contain less fiber and protein and, in several categories, more saturated fat and salt than their gluten-containing counterparts. Many GF breads also exhibit a higher glycemic index[44]. In CeD cohorts, BMI frequently increases after initiation of a GFD as nutrient absorption normalizes. Observational studies further link treated CeD to higher rates of metabolic syndrome and fatty liver, underscoring the need for diet-quality counseling[27,45].

Mechanistically, a GFD can alter gut microbiota composition, such as by reducing beneficial Bifidobacterium species, particularly when fiber intake decreases. Reduced fiber intake, in turn, lowers short-chain fatty acid production, which is critical for maintaining epithelial barrier integrity and metabolic regulation along the gut-liver axis[46].

A practical, hepatoprotective strategy is a Mediterranean-style GFD, emphasizing minimally processed, naturally GF foods, such as vegetables, fruits, legumes, nuts, and seeds, along with extra-virgin olive oil, fish, and certified GF whole grains or pseudocereals (e.g., oats, quinoa, buckwheat). Ultra-processed GF snacks and sweets should be limited. Mediterranean-pattern diets improve hepatic steatosis and insulin sensitivity in NAFLD, supporting their adoption when gluten avoidance is required[47]. To address common micronutrient gaps in GF products (iron, folate, thiamine, niacin, riboflavin, and others), clinicians should prefer fortified staples and monitor status with dietitian-led follow-up.

CLINICAL APPROACH TO THE DIAGNOSIS AND MANAGEMENT OF GRLD

The clinical approach to diagnosing and managing GRLD requires early recognition and a multidisciplinary management approach that integrates dietary intervention and patient education. Given the substantial proportion of individuals with GRDs who exhibit elevated liver enzymes - ranging from mild transaminase elevations to progressive hepatic disease - screening for liver dysfunction should be an integral part of evaluating patients with CeD and NCGS. Screening for liver dysfunction should be incorporated into the routine evaluation of patients with CeD, particularly those with persistently elevated liver enzymes of unknown etiology, coexisting autoimmune disorders such as type 1 diabetes mellitus or autoimmune thyroiditis, or unexplained hepatic dysfunction accompanied by GI symptoms suggestive of gluten sensitivity[28].

Accurate diagnosis relies on a combination of serological, histological, and imaging-based assessments. Serological markers, including anti-tTG and endomysial antibodies, have an established role in identifying gluten sensitivity. However, their sensitivity and specificity vary, particularly in cases of seronegative CeD or NCGS. In individuals with persistent liver enzyme abnormalities despite negative celiac serology, further evaluation with duodenal biopsy may be warranted to confirm gluten-induced enteropathy. Liver biopsy is reserved for cases where autoimmune liver disease, MASLD, or advanced fibrosis is suspected. Non-invasive markers such as transient elastography (FibroScan) and serum biomarkers like the aspartate aminotransferase-to-platelet ratio index can aid in assessing hepatic fibrosis and steatosis, minimizing the need for invasive procedures. Additionally, genetic testing for HLA-DQ2 and HLA-DQ8 alleles may aid in diagnosis in ambiguous cases, given their strong association with GRDs.

Management of GRLD requires a personalized, multidisciplinary approach. While adherence to a GFD remains the cornerstone of treatment, individual variability in gluten sensitivity and hepatic response requires tailored interventions. Some patients experience rapid improvement in liver enzymes upon gluten withdrawal, while others require additional interventions to manage concurrent metabolic or autoimmune conditions. Collaboration between gastroenterologists, hepatologists, and dietitians is essential for optimizing patient outcomes, particularly in those with overlapping conditions such as AIH, MASLD, or advanced fibrosis. Nutritional counseling plays a critical role in ensuring that patients maintain a balanced diet that supports liver health while avoiding gluten-related hepatic injury.

To optimize liver outcomes and minimize negative metabolic sequelae, dietary management should focus on an individualized, nutrient-dense GFD that emphasizes whole, minimally processed foods. Incorporation of alternative GF grains such as quinoa, buckwheat, amaranth, millet, and sorghum - rich in fiber, protein, unsaturated fats, and micronutrients - should be encouraged over refined GF products. The Mediterranean diet, characterized by high intake of vegetables, fruits, legumes, nuts, whole grains, and healthy fats (e.g., olive oil), is associated with reduced hepatic steatosis, improved insulin sensitivity, and favorable cardiometabolic outcomes, and is recommended by the American Association for the Study of Liver Diseases and the American Heart Association for patients with MASLD. Coffee consumption (≥ 3 cups/day) may also confer hepatic benefit in the absence of contraindications[48].

Maintaining long-term adherence to a GFD is highly challenging, particularly given the social and economic barriers to sustaining strict dietary compliance. Patient education is central to empowering individuals to make informed dietary choices and to recognize hidden sources of gluten in processed or prepared foods. Support groups and online tools can increase compliance by teaching functional skills in meal planning and dining out. Management of possible adverse metabolic implications, such as elevated BMI and insulin resistance, necessitates active nutritional management. Patients should be closely monitored by a primary care physician, with regular measurement of BMI, waist circumference, and laboratory indices such as fasting glucose, lipid profile, and homeostatic model assessment of insulin resistance. Liver function tests should be performed at diagnosis and periodically thereafter, as abnormal transaminases are common and may precede GI symptoms. In patients at higher risk or with abnormal findings, periodic hepatic ultrasound and further metabolic evaluation are warranted for early detection of steatosis and MASLD. Finally, active and individualized strategies tailored to patient-specific risk factors are associated with improved hepatic outcomes[49,50].

CONCLUSION

The recognition of gluten’s impact on liver health represents a crucial advance in our understanding of GRDs. Once thought to be confined to the gut, gluten’s influence extends to the liver through mechanisms involving intestinal permeability, immune dysregulation, and gut-liver axis interactions. The association between GRDs and hepatic dysfunction is emphasized by the high prevalence of elevated liver enzymes in individuals with CeD or NCGS, ranging from mild transaminase elevations to severe autoimmune and metabolic liver diseases. A GFD can often reverse liver enzyme abnormalities, suggesting it could be effective. However, the metabolic consequences of long-term GFD adherence, such as increased BMI and hepatic steatosis risk, warrant careful dietary management.

Despite growing evidence, GRLD remains underdiagnosed and underappreciated. Given the increasing global burden of metabolic and autoimmune liver diseases, incorporating gluten-related screening in patients with unexplained liver enzyme elevations or cryptogenic liver disease is imperative. Further research is needed to elucidate the precise mechanisms linking gluten to hepatic injury and to optimize dietary recommendations for individuals with gluten sensitivity. A multidisciplinary approach integrating active nutritional intervention, regular metabolic and hepatic monitoring, and individualized care plans, is central to optimizing long-term outcomes in patients with GRLD.

Prospective, well-phenotyped cohort studies across the spectrum of GRDs should quantify the incidence, natural history, and modifiers of GRLD, using standardized case definitions and adjudicated hepatic endpoints (biochemical normalization, elastography/magnetic resonance platelet discriminant fraction-based fibrosis/steatosis trajectories, decompensation, and transplant-free survival). To establish causality, adequately powered randomized trials are needed that compare structured dietary strategies - e.g., standard vs Mediterranean GFDs and dietitian-led adherence programs - against pharmacologic or adjunctive therapies, with prespecified liver outcomes and metabolic safety readouts. Parallel mechanistic work should develop and validate biomarkers that distinguish GRLD from other hepatopathies, integrating serology (tTG/endomysial antibody, deamidated gliadin peptides), permeability and inflammatory markers (e.g., zonulin panels), genetics (HLA haplotypes), microbiome/metabolomic signatures, and imaging-based phenotypes into predictive models.

For effective clinical translation, future. research should develop and test stage-specific nutritional algorithms, addressing isolated transaminasemia, MASLD, autoimmune overlap, and cirrhosis, and evaluate scalable, objective methods for monitoring adherence by integrating serologic indices with digital dietary tools and periodic assessments of diet quality. Pragmatic, multicenter designs with long-term follow-up, cost-effectiveness analyses, and patient-reported outcomes will be essential to inform guidelines and personalize care.