Cryptogenic Hypertransaminasaemia Research Articles

Celiac Disease: A Forty-Year Analysis in an Italian Referral Center.

Celiac disease (CD) is an autoimmune disorder triggered by gluten ingestion. Herein, we assessed clinical, serological and histopathological findings of a single-center, large cohort of CD patients diagnosed and followed-up over forty years. From January 1980 to December 2020, 1547 CD patients (1170 females; age range: 8-81 years; F:M ratio = 3.1:1) were diagnosed in an Italian tertiary referral center. Comorbidities and complications were recorded at diagnosis and during follow-up. CD diagnoses quadrupled after 2000. The most frequent phenotype was the non-classical CD (63.3%), and the most prevalent histotype was Marsh 3C (44.7%). Gastrointestinal manifestations, detectable in 51% of patients, were diarrhea (24.3%), bloating (28%) and aphthous stomatitis (19.7%). The most common CD-associated disorder was osteopenia (59.9%), predominant in females (64.3%); extraintestinal manifestations included anemia (35.8% iron-deficiency; 87% folic acid malabsorption), cryptogenic hypertransaminasemia (27.9%), and recurrent miscarriages (11.5%). Thyroiditis (26.9%), type 1 diabetes mellitus (2.9%), and dermatitis herpetiformis (1.4%) were the most common CD-related autoimmune disorders. Six patients had inflammatory bowel disease. Complications and mortality rate occurred in 1.8% and 1.9%, respectively. This single-center, large cohort analysis confirmed that CD presentation changed over the years, with an increase of non-classical and subclinical clinical phenotypes.

Prevalence of Celiac Disease in Patients With Liver Diseases: A Systematic Review and Meta-Analyses.

A subset of patients with celiac disease (CeD) has liver involvement in the form of hypertransaminasemia, liver cirrhosis, and autoimmune hepatitis. We conducted a systematic review with meta-analyses to determine the pooled prevalence of CeD in patients with cryptogenic cirrhosis, all-cause cirrhosis, cryptogenic hypertransaminasemia, and all-cause hypertransaminasemia. We searched PubMed and EMBASE up to January 2022. Cross-sectional, case-control, and prospective cohort studies performing serological tests and/or intestinal biopsy for CeD on patients with cryptogenic cirrhosis, all-cause cirrhosis, cryptogenic hypertransaminasemia, and all-cause hypertransaminasemia were included to calculate pooled estimates of seroprevalence and the prevalence of biopsy-confirmed CeD in these 4 groups. Of 6,871 articles screened, 20 articles were included finally in 3 meta-analyses for cryptogenic cirrhosis, all-cause cirrhosis, and cryptogenic hypertransaminasemia. For the all-cause hypertransaminasemia group, a qualitative review of 4 studies was conducted instead of a meta-analysis due to significant differences in studies. The pooled prevalence (95% confidence interval) of biopsy-confirmed CeD in cryptogenic cirrhosis was 4.6% (2.2%-7.5%) while the pooled prevalence of biopsy-confirmed CeD in all-cause cirrhosis was 0.8% (0%-3.4%). The pooled prevalence of biopsy-confirmed CeD in cryptogenic hypertransaminasemia was 5.7% (3.2%-8.8%). Nearly 1 in 20 patients each with cryptogenic cirrhosis and cryptogenic hypertransaminasemia have CeD; hence, they should both be considered high-risk groups for CeD. While the prevalence of CeD in those with all-cause cirrhosis is similar to that in general population, it may be worth screening them for CeD because liver pathology has the potential for reversal in them.

Celiac Disease and Liver Abnormalities: What Relationships?

Celiac disease (CD) may be associated with liver abnormalities (LA) and these abnormalities are often liver blood tests abnormalities corresponding to cryptogenic hypertransaminasemia or celiac hepatitis (CH) which is reversible after strict gluten free diet (GFD). CH may be the only manifestation of unrecognized CD. Other LA may be associated, especially those of dysimmune origin or overload. The mechanisms of these associations are unclear and the role of the GFD is uncertain.

Serologic testing for celiac disease in young people with elevated transaminases.

A cryptogenic elevation of transaminases is the most common hepatic manifestation in celiac disease (CD). In adult patients and pediatric patients with cryptogenic hypertransaminasemia, the prevalence of CD was 4% and 12%, respectively. However, there are no related data from China in this regard. We aimed to investigate the status of CD in young Chinese patients with elevated transaminases. A total of 125 patients with elevated transaminases and 125 healthy individuals as controls with matched age and sex were involved in the study. Serum markers of hepatitis B were determined in patients with elevated transaminases. All subjects were screened for CD by testing serum IgA antitissue transglutaminase antibodies (anti-tTG IgA), and total serum IgA was determined in order to rule out IgA deficiency. None of the subjects were seropositive to IgA anti-tTG antibodies. No association between CD and elevated transaminases was found. Hepatitis B viral infections were one of the main causes of raised transaminases. Before the exclusion of every known cause of raised transaminase levels, routine serological screening for CD should not be recommended for patients who only present elevated transaminases.

The changing clinical profile of celiac disease: a 15-year experience (1998-2012) in an Italian referral center

BackgroundCeliac disease is a multiform, challenging condition characterized by extremely variable features. Our goal was to define clinical, serological and histopathological findings in a large cohort of celiacs diagnosed in a single referral center.MethodsFrom January 1998 to December 2012, 770 patients (599 females, median age 36 years, range 18-78 years) were diagnosed as celiacs at St.Orsola-Malpighi Hospital (Bologna, Italy). The clinical phenotypes were classified as: 1) classical (malabsorption syndrome); 2) non-classical (extraintestinal and/or gastrointestinal symptoms other than diarrhea); 3) subclinical. Serology, duodenal histology, comorbidities, response to gluten-free diet and complications were evaluated.ResultsDisease onset was symptomatic in 610 patients (79%), while 160 celiacs showed a subclinical phenotype. In the symptomatic group the non-classical prevailed over the classical phenotype (66% vs 34%). Diarrhea was found in 27%, while other gastrointestinal manifestations were bloating (20%), aphthous stomatitis (18%), alternating bowel habit (15%), constipation (13%) and gastroesophageal reflux disease (12%). Extraintestinal manifestations included osteopenia/osteoporosis (52%), anemia (34%), cryptogenic hypertransaminasemia (29%) and recurrent miscarriages (12%). Positivity for IgA tissue transglutaminase antibodies was detected in 97%. Villous atrophy was found in 87%, while 13% had minor lesions consistent with potential celiac disease. A large proportion of patients showed autoimmune disorders, i.e. autoimmune thyroiditis (26.3%), dermatitis herpetiformis (4%) and diabetes mellitus type 1 (3%). Complicated celiac disease was very rare.ConclusionsOur study demonstrates that the clinical profile of celiac disease changed over time with an increasing rate of non-classical and subclinical phenotypes.

Celiac disease hidden by cryptogenic hypertransaminasemia mistaken for fatty liver

A variety of signs and symptoms have been reported in regards to the typical and atypical presentations of CD. It is now well recognised that its onset may occur at any age and that atypical forms of CD are much more prevalent than its classic form (1).In this case, where the patient presented with high BMI and evidence of grade I of fatty liver disease, CD was suspected due to mildly abnormal bloating, cryptogenic hypertransaminasemia, abnormal LFT and poor response to fatty liver treatment. This presentation type is not uncommon; diagnosis was confirmed by the presence of subtotal villous atrophy in the biopsy specimen, positive specific antibody screening (AGA, tTG and EMA antibodies), negative antibody screening and normalization of liver enzymes on a gluten-free diet (Tab. 2, Ref. 13).

Meta-analysis: coeliac disease and hypertransaminasaemia

There may be a positive association between coeliac disease and serum hypertransaminasaemia but evidence is conflicting. To conduct a systematic review and meta-analysis to determine the prevalence of coeliac disease in adults presenting with cryptogenic serum hypertransaminasaemia and the prevalence of hypertransaminasaemia in patients with newly diagnosed coeliac disease. MEDLINE and EMBASE were searched up to August 2010. Case series and case-control studies recruiting adults with either cryptogenic hypertransaminasaemia that applied serological tests for coeliac disease and/or distal duodenal biopsy to participants or newly diagnosed biopsy-proven coeliac disease that assessed serum transaminases were eligible. The pooled prevalence of coeliac disease in individuals presenting with abnormal serum transaminases and the pooled prevalence of hypertransaminasaemia in newly diagnosed coeliac disease were calculated with 95% confidence intervals (CI). Eleven eligible studies were identified. Pooled prevalences of positive coeliac serology and biopsy-proven coeliac disease in cryptogenic hypertransaminasaemia were 6% (95% CI 3% to 10%) and 4% (95% CI 1% to 7%) respectively. Pooled prevalence of abnormal serum transaminases in newly diagnosed coeliac disease was 27% (95% CI 13% to 44%). Exclusion of gluten led to normalisation of serum transaminase levels in 63% to 90% of patients within 1 year. Undetected coeliac disease is a potential cause for cryptogenic hypertransaminasaemia in 3% to 4% of cases. More than 20% of individuals with newly diagnosed coeliac disease may have abnormal serum transaminases and these normalise on a gluten-free diet in the majority of cases.

Coeliac disease and hypertransaminasaemia: a systematic review and meta-analysis

<h3>Introduction</h3> Several studies have suggested a positive association between coeliac disease (CD) and hypertransaminasaemia, but no single study has systematically synthesised all available evidence examining this issue. We conducted a systematic review and meta-analysis to determine the prevalence of CD in adults presenting with cryptogenic hypertransaminasaemia, as well as the prevalence of hypertransaminasaemia in patients with newly-diagnosed CD. <h3>Methods</h3> MEDLINE and EMBASE were searched (up to September 2010) to identify case series and case-control studies (sample size &gt;90) that applied serological tests and/or distal duodenal biopsy to unselected adult patients (&gt;90% aged 16 years or over) with cryptogenic hypertransaminasaemia. The proportion of individuals with abnormal serum transaminases who had either positive coeliac serology, or biopsy-proven CD, were combined to give a pooled prevalence, with 95% confidence intervals (CI). Studies of patients with newly-diagnosed biopsy-proven CD that applied tests of liver function were also eligible. The pooled prevalence of hypertransaminasaemia among newly-diagnosed CD patients was calculated with 95% CIs. <h3>Results</h3> The search identified 2705 citations. Of these, 31 appeared relevant and were retrieved for evaluation. Twelve studies were eligible for inclusion, with excellent agreement between investigators (Kappa = 0.86). Six studies, involving 919 patients, reported the prevalence of positive coeliac serology or biopsy-proven CD in patients with cryptogenic hypertransaminasaemia, with a pooled prevalence of 5.9% (95% CI 2.7% to 10.3%). Five studies excluded other causes of abnormal serum transaminases prior to screening for CD. When only these five studies were analysed, the pooled prevalence increased to 6.4% (95% CI 2.6% to 11.7%). The pooled prevalence of biopsy-proven CD in cryptogenic hypertransaminasaemia in the 6 studies was 3.6% (95% CI 1.4% to 7.0%) and 4.1% (95% CI 1.4% to 8.2%) in the five studies that first excluded other causes of abnormal transaminases. A further six studies, involving 1830 patients, reported the frequency of abnormal serum transaminases in newly-diagnosed CD, with a pooled prevalence of 22% (95% CI 8% to 39%). <h3>Conclusion</h3> More than 20% of individuals with newly-diagnosed CD may have abnormal serum transaminases. The prevalence of CD in individuals with hypertransaminasaemia is between 3% and 4%, suggesting that routine screening for CD in this group of patients may be worthwhile. However, yield may be lower in individuals in whom other potential causes of hypertransaminasaemia have not already been excluded.

Reliability of the bright liver echo pattern in diagnosing steatosis in patients with cryptogenic and HCV-related hypertransaminasaemia

To evaluate the reliability of the bright liver (BL) echo pattern on ultrasound to detect histological steatosis in chronic cryptogenic hypertransaminasaemia (CCH) and hepatitis C virus (HCV)-related forms of hypertransaminasaemia. One hundred and fifty patients, 54 with CCH and 96 with HCV hypertransaminasaemia (76 genotype 1/2 and 20 genotype 3), were enrolled. Histological steatosis was measured as the percentage of hepatocytes involved. The reliability of the BL sign was estimated using the sensitivity, specificity, positive and negative predictive values. Histological steatosis was present in 102/150 patients (68%) divided into 59/96 (62%) in the HCV group and 43/54 (79.6%) in the CCH group (chi(2)=4.4; p=0.035). In a multivariate analysis, the variable associated with the BL echo pattern was steatosis percentage (p=0.0018). Steatosis percentage was higher in CCH group than in the HCV genotype 1/2 and 3 groups (p=0.02). The sensitivity of the BL echo pattern was 88% in the CCH group [confidence interval (CI) 95% 74-95] versus 61% (CI 95% 44-73) in the HCV genotype 1/2 group. The CI indicates that ultrasound can provide evidence for steatosis in a statistically significant way in the CCH versus HCV genotype 1/2 patients. In the genotype 3 group, the sensitivity was high (90%), but the limited number of cases limited the statistical significance due to the high CI. In CCH the BL echo pattern has excellent reliability in diagnosing steatosis, better than in HCV hypertransaminasaemia because of the higher prevalence and extent of steatosis.

Pathogenesis and Clinical Significance of Liver Injury in Celiac Disease

Abnormalities of liver function are one of the manifold extraintestinal manifestations of celiac disease. Although the spectrum of liver manifestations associated with celiac disease is particularly wide, two main forms of liver damage namely, cryptogenic and autoimmune, appear to be strictly related to gluten-sensitive enteropathy. The most frequent finding is represented by a cryptogenic hypertransaminasemia, observed in about a half of untreated celiac patients, as an expression of a mild liver dysfunction with a histological picture of nonspecific reactive hepatitis (celiac hepatitis) reverting to normal after 6-12 months of a strict gluten-free diet. In a few cases, when celiac disease is diagnosed, a more severe liver injury, characterized by a cryptogenic chronic hepatitis or liver cirrhosis, is present. In these patients, liver damage can still improve after a gluten-free diet institution. Moreover, a close association between celiac disease and autoimmune liver disorders has been widely demonstrated. Indeed, celiac disease has been found in 3-7% of patients with primary biliary cirrhosis, in 3-6% with autoimmune hepatitis, and in 2-3% with primary sclerosing cholangitis. Differently from cryptogenic liver injury, autoimmune liver dysfunction, found in celiac disease, does not usually improve after a gluten-free diet. Presently, it is difficult to establish if the two main kinds of liver injury found in celiac disease (cryptogenic and autoimmune) are discrete entities with a different pathogenesis or if they are an expression of the same disorder where genetic factors and the duration of gluten exposure may determine the severity and the pattern of liver injury.

Cryptogenic Liver Disease in Four Children: A Novel Congenital Disorder of Glycosylation

We investigated the metabolic defect(s) of four children who presented with isolated cryptogenic chronic liver disease, coagulopathy, and abnormalities of several unrelated serum glycoproteins. Analysis of the patients' serum glycoproteins and fibroblasts suggest they have a novel congenital disorder of glycosylation (CDG). All had abnormal transferrin (Tf) isoelectric focusing (IEF) profiles. More detailed analysis of Tf by electrospray ionization mass spectrometry (ESI-MS) showed a plethora of abnormal glycosylations that included loss of 1-2 sialic acids and 1-2 galactose units, typical of Group II defects. Tf from two patients also lacked 1-2 entire oligosaccharide chains, typical of Group One disorders. Total serum N-glycans were analyzed by HPLC and matrix-assisted laser desorption/ionization mass spectrometry and also showed increased proportion of neutral glycan chains lacking sialic acids and galactose units. Analysis of patient fibroblasts eliminated CDG-Ia, through CDG-Ih, -IL and CDG-IId. Our results suggest that a subset of children with clinically asymptomatic, cryptogenic hypertransaminasemia and/or liver steato-fibrosis may represent a novel type of CDG-X with an unknown defect(s). Clinicians are encouraged to test such patients for abnormal Tf glycosylation by ESI-MS.

Screening for Autoantibodies to Tissue Transglutaminase Reveals a Low Prevalence of Celiac Disease in Blood Donors with Cryptogenic Hypertransaminasemia

Patients with chronic cryptogenic hypertransaminasemia are at high risk of developing celiac disease (CD). In fact, among the various serological disorders, CD patients at onset frequently present hypertransaminasemia. In this study, we evaluated usefulness and reliability of the new test for antitissue transglutaminase (tTG) in screening for CD as well as in estimating the prevalence of CD in a population of blood donors presenting unexplained hypertransaminasemia at donation. Controls were 180 consecutive healthy donors without hypertransaminasemia and 20 CD patients with known antiendomysial antibody (EmA) positivity. Out of 22,204 blood donors over a period of 2 years, we found 258 subjects (1.2%) with cryptogenic hypertransaminasemia. Four of these subjects (1.5%) were positive for anti-tTG, but only 3 of them were positive for EmA. EmA were negative in all the remaining hypertransaminasemia subjects. In the control groups, anti-tTG antibodies were negative in all the 180 healthy donors without hypertransaminasemia, but positive in all the CD patients known to be EmA positive. 3 of the 4 subjects positive for anti-tTG, including 2 who were also EmA positive, underwent biopsy of the distal duodenal mucosa which showed a picture compatible with CD only in the 2 patients with concomitant EmA positivity. After 3 months of gluten-free diet, the serum transaminase values normalized in these 2 patients. In conclusion, the prevalence of CD in our blood bank population was lower than that reported in other similar studies, but the new test for anti-tTG showed a good sensitivity and reliability, and, therefore, it can be proposed as a first-level test in screening for CD in selected populations such as subjects with hypertransaminasemia.

Coeliac disease hidden by cryptogenic hypertransaminasaemia

Hypertransaminasaemia of unknown, cryptogenic, origin occasionally has been found to be the only sign of coeliac disease. Raised concentrations of transaminases, or aminotransferases, have been retrospectively observed in about a half of patients with coeliac disease who are on a gluten-containing diet. We aimed to establish the overall prevalence of coeliac disease among patients with cryptogenic hypertransaminasaemia. Of the 600 consecutive patients referred to our outpatient clinic for liver disease due to raised serum transaminases from September, 1995, to June, 1997, 55 were classified as having cryptogenic hypertransaminasaemia after the exclusion of every known cause of liver disease. These patients were tested by indirect immunofluorescence for IgA to endomysium and for IgA and IgG to gliadin. Five patients were positive for both IgA to endomysium and IgG to gliadin, whereas IgA to gliadin was only found in four patients. IgG to gliadin was also present in another patient who was not positive for antibodies to endomysium. The six antibody-positive patients had duodenal biopsy that showed a subtotal villous atrophy consistent with coeliac disease in the five patients with antibodies to endomysium. The patient with only IgG to gliadin had a normal small-intestine mucosa. None of the five patients with coeliac disease had gastrointestinal symptoms. Liver biopsy samples were taken from three of the five patients with flat mucosa and showed a histological picture of nonspecific reactive hepatitis. Transaminase concentrations reverted to normal within 6 months in four patients with coeliac disease who followed a strict gluten-free diet. Our results show that about 9% of patients with cryptogenic hypertransaminasaemia are affected by symptom-free coeliac disease. Gluten-sensitive enteropathy and antibody screening for coeliac disease by means of antibodies to endomysium and gliadin should be considered in these patients.