In this prospective-observational study of 125 newly-diagnosed celiac patients, 31 (24.8%) had elevated ALT at diagnosis. However, only two patients had significant elevations of over 3xULN, one of whom was later co-diagnosed with auto-immune hepatitis. Patients with elevated ALT at diagnosis were younger, had associated elevated AST levels (but not cholestatic enzymes), and tended to present more commonly with diarrhea, compared to the remaining of the cohort. Their natural history was similar to that of normal-ALT patients, including clinical improvement rates on GFD, growth, aTTG decrease rate, and basic laboratory results' changes, over one year of follow-up.
Elevated liver enzymes, most notably ALT, were previously described as one of the extra-intestinal manifestations of celiac disease, ranging between 4–40% of newly diagnosed patients (Table 4; 8–15). Studies in children demonstrate a downward trend in the incidence of elevated ALT at celiac diagnosis over time. Recent reports demonstrated relatively low prevalence of 5–15% (13–15), compared to older studies in pediatrics with prevalence of up to ~ 40%; similar to the prevalence in adult CD patients (8–12, 21). In our study, using a relatively low threshold, we found 25% of patients with some degree of ALT elevation. However, considering the commonly used 40 IU threshold, only 5% of patients had ALT elevations; in line with the results of recent studies in children. These temporary changes, we presume, reflect the net effects of increased awareness of celiac disease in the public and among treating physicians, with resultant quicker diagnosis for some, and an overall increase in celiac diagnosis in general, specifically of patients with a less severe phenotype of disease.
Table 4
Elevated liver enzymes in newly diagnosed celiac disease patients- literature review
| Authors | Study design | Cohort | Age mean, range (Y) | ALT (IU) ULN | Patients with elevated ALT (%) | significant correlations | associated primary liver diseases |
| Bonamico et al, 1986(8) | Retrospective | 65 | 3.5, 0.6–18 | 45 | 18 (27.7) | | |
| Demir et al, 2000(9) | Retrospective | 81 | 5.9, 0.8–16 | n/a | 16 (19.8) | | Cirrhosis (2) |
| Farre et al, 2002(10) | Prospective | 114 | 4.5, 0.9–17 | n/a | 37 (32.0) | Younger age at diagnosis | |
| Arslan et al, 2005(11) | Prospective | 27 | 6, 1–11 | 45 | 7 (25.9) | | |
| Di Biase et al, 2010(12) | Prospective | 350 | 9, 1–16 | 41 | 140 (40.0) | | AIH (7) |
| Äärelä el al, 2016(13) | Retrospective | 150 | median- 7.3 IQR- 4.3–11.8 | 30 | 22 (14.7) | Higher Marsh score; elevated TSH | |
| Lee et al, 2016(14) | Prospective | 185 | 10, 6.7–14.5 | 40 | 28 (15.1) | Younger age at diagnosis | fatty liver disease (1) |
| Benelli et al, 2019(15) | Retrospective/ Prospective | 700 | Median- 7.4 IQR- 0.8–17.9 | 40 | 27 (3.9) | Younger age at diagnosis; low Hb; low ferritin | PSC (1) |
| Y- years, IU- international unit; ALT- alanine aminotransferase; ULN- upper limit of normal; AIH- autoimmune hepatitis;IQR- inter-quartile range; TSH- thyroid stimulating hormone; Hb- hemoglobin; PSC- primary sclerosing cholangitis. |
Our finding of association between elevated ALT at presentation and young age at diagnosis was previously described by others: Farre et al., Lee et al., and Benelli et al. (10, 14–15). Other associations however, were less consistent: Benelli et al., described the association of elevated ALT with a complex of symptoms and laboratory findings, designated as "malabsorption", including diarrhea, failure to thrive, low hemoglobin and ferritin levels at presentation (15). Furthermore, other associations described by others, such as higher Marsh scores, lower hemoglobin, ferritin and thyroid-stimulating-hormone levels at diagnosis, were not significant in our present study (13, 15). Considering these findings together, we postulate that those patients who are diagnosed younger, on the background of overall global trend of increasing age at celiac diagnosis (22, 23), have a more aggressive phenotype of disease resulting in earlier diagnosis, a more "classical" symptomatic gastrointestinal presentation (i.e. diarrhea) and extra intestinal manifestations.
Nevertheless, despite the high number of patients with elevated ALT, the clinical significance of this finding is limited. The vast majority of patients (80%) normalized their ALT once started on GFD within three months, and all by one year of follow-up. Furthermore, the natural history of patients with elevated ALT, including clinical improvement, weight gain, linear growth, and basic laboratory studies, did not differ from the remaining of the cohort (Fig. 2).
A key element affecting the primary endpoint of our study- the prevalence of elevated liver enzymes among newly diagnosed celiac patients, is the threshold beyond which a result is considered abnormal. Most of past studies set the upper limit of norm at ALT values of 30–45 U/l (Table 4). We chose to rely on the cutoff of 24 U/l, an average value for males and females, as was found in the national health and nutritional survey (NHANES, 17,18). This threshold is now widely accepted as the "true" upper limit of normal in lean and healthy children. Setting the bar at a low threshold, increased the sensitivity of our study and therefore increased the prevalence we found; however, most of these abnormal findings were not clinically significant, and ultimately only two patients had substantial elevations. Analyzing AST levels yielded similar results to ALT analysis (data is partially shown); however, the usage of AST in children is hampered by lack of specificity to the liver, especially in the face of the commonly encountered increased AST levels caused by technical problems in blood drawing resulting in hemolysis. Cholestatic enzymes' elevations were not noted in previous reports, and apart from a single patient with a one-time-only GGT elevation, neither did we find such patients. Finally, our ability to assess alkaline-phosphatase in the cohort was hindered by lack of specificity of the enzyme to the liver, and the fact that children have a high bone turn-over rate as part of their natural growth, causing elevated alkaline-phosphatase levels of bone origin.
Overtime, celiac disease is associated with other autoimmune disorders, most notably diabetes mellitus type 1 with a co-prevalence of ~ 10% (24). In our cohort, we found only 7 (6%) patients with other autoimmune diseases, lower than expected. This may reflect the relatively short follow-up that failed to fully appreciate the auto-immune burden in this cohort. On the contrary, 38 (30%) patients had a positive auto-immune and/or inflammatory family history, underscoring the strong genetic background of this disease.
One patient, presenting with significantly elevated ALT, was co-diagnosed with autoimmune hepatitis. It is likely that the hepatitis evident as highly-ELE was driven mainly by specific auto-antibodies targeting hepatic epitopes, rather than the non-specific auto-antibodies milieu produced by the CD pathogenesis. Nevertheless, it is difficult to assess the true separate contribution of each of the autoimmune processes. Celiac disease prevalence in children with AIH is 3.5%-6.4%, and AIH prevalence in patients with celiac disease 1.4% (25–37); further data describing the temporary relationships and interplay of the co-diagnoses is lacking.
The observational-prospective nature of our study enabled us to collect detailed demographic, anthropometric and clinical data during the diagnostic process of the participants and up to one year of follow up. The majority of patients normalized their ALT levels quickly once the gluten free diet was introduced, and all, within the one-year follow-up timeframe. Therefore, prolonging the follow-up duration was not likely to produce further prognostication results regarding the patients with ELE. The main limitation of our study is the moderate size of the cohort and consequently small number of participants with significant ALT elevations, preventing further sub-group analysis. Patients with significant ALT elevations may very well present a specific disease phenotype; however, our study was not large enough to detect it.
In conclusion, setting a low threshold, ALT abnormalities were common (~ 25%) among newly diagnosed celiac patients and were typically associated with young age at diagnosis; however, significant ALT elevations are uncommon (1.6%). The natural history of celiac patients with elevated ALT is similar to that of patients with normal liver enzymes. While for most newly diagnosed celiac patients the existence of elevated liver enzymes is clinically insignificant, significant elevations (> 3xULN) failing to normalize on gluten free diet, should raise concern of a co-existing primary liver disease, and warrant further investigations.