Introduction

Ataxia-telangiectasia (AT) and ataxia-oculomotor apraxia (AOA), which are both autosomal recessive cerebellar ataxia disorders, are characterized by elevated serum alpha-fetoprotein (AFP) levels. However, the source of this increase, its potential clinical consequences, and its relationship with liver diseases remain unknown. This study explored the prevalence of liver diseases and how they contributed to increased AFP in patients with AT and AOA.

Aims & Methods

Eighteen adult patients with AT or AOA followed up between January 1992 and March 2023 were included in the study. Demographic data, clinical findings, liver enzymes, AFP levels, and liver and brain imaging were reviewed retrospectively.

Results

Data of 13 (72%) AT and 5 (28%) AOA patients were analyzed. The mean age of 11 (61%) male and 7 (39%) female patients was 27.3±4.8, and the median age at diagnosis was 7.5 (2-23). The most common clinical findings were ataxia (78%) and dysmetria (56%), and cerebellar atrophy was present in 8 patients who underwent brain imaging. During a mean follow-up period of 15.2±9.1 years, 5 (28%) patients died; 4 (22%) patients had malignancy (1 ALL, 1 pancreatic cancer, 1 gastric cancer and 1 glioblastoma mutliforme) and 1 (6%) patient had sepsis. Liver enzyme elevation was present in half of the patients; ALT/AST in 2 patients, ALP/GGT in 7 patients. Ultrasonography revealed normal findings in the liver in 7 (58%) of 12 patients, hepatomegaly and hepatosteatosis in 4 (33%), and hemangioma in 1 (8%) patient. One of the 2 patients who underwent liver biopsy had chronic active hepatitis and biliary tract injury, and the other patient had granulomatous hepatitis. Serum AFP level was higher than normal in all patients and the median value was 121 (12-913) ng/ml. The AFP level of AT patients [226 (41-913) ng/ml] was significantly higher than that of AOA patients [19 (12-42) ng/ml] (p=0.006). There was no significant relationship between AFP level and age (p=0.437), gender (p=0.568), elevated liver enzymes (p=0.534), hepatosteatosis (p=0.913), or cancer history (p=0.31).

Conclusion

Half of the patients with cerebellar ataxia have elevated liver enzymes and one-third have hepatosteatosis. Although AFP was high in all patients, none developed primary liver cancer during the 15.2±9.1 years follow-up period. The causes of death in these patients are non-hepatic cancers and sepsis.

Disclosure

None

Introduction

The non-invasive identification of liver fibrosis related to metabolic-associated steatotic liver disease is crucial for risk stratification in children [1]. Non-invasive tests, including serum collagen-derived and inflammatory markers, may represent a good surrogate for risk stratification [2].

Aims & Methods

The aim of our study was to investigate the differences in fibrosis and inflammation markers in children with metabolic-associated steatotic liver disease (MASLD) depending on the liver fibrosis presence.
94 patients aged 9 to 17 years (average age 12.15 ± 2.51 years) were included in the study. According to body mass index, transient elastography (Fibroscan®502 touch, Echosens, France) data patients were divided into 4 groups: 1 group consisted of 27 obese patients with MASLD and liver fibrosis ≥F1 (METAVIR), 2 group - 35 obese patients with MASLD without fibrosis, 3 group - 18 obese patients without MASLD, 4 group (control) - 14 patients with normal weight without MASLD. Serum content of hydroxyproline free (HPf) and hydroxyproline protein-bound (HPp/b) according to Osadchuk and glycosaminoglycans (GAG) according to Rimington were evaluated. Serum IL-10 and IL-6 levels were evaluated by an ELISA kit (Wuhan Fine Biotech Co., Ltd, China).

Results

The levels of serum HPp/b were elevated in 100% of 1 group children compared to the control group as well as in 86.9% and 53.8% of 2 and 3 group children respectively (p˂0,05). HPp/b /HPf ratio was increased in children of 1 group by 1.4 times (p<0.05), 2 group - by 1.4 times (p<0.05), 3 group - by 1.3 times (p<0.05) in comparison with the control group. Correlation of HPp/b /HPf ratio with CAP (r=0,307; р<0,05), liver stiffness (r=0,323; р<0,05) was found. Serum GAG content in 1 group of children was 1.3 times (p<0.05) higher as well as IL-6 /IL-10 ratio was 5,4 times higher in comparison with the control group (p<0.05).

Conclusion

Thus, an imbalance between the collagen synthesis and degradation in obese MASLD children was revealed combined with a shift towards pro-inflammatory cytokine production, which might promote fatty liver fibrosis development.

References

1. Armandi A, Michel M, Gjini K, Emrich T, Bugianesi E, Schattenberg JM. Emerging concepts in the detection of liver fibrosis in non-alcoholic fatty liver disease. Expert Rev Mol Diagn. 2023;23(9):771-782. doi:10.1080/14737159.2023.2242779
2. Hammerich L, Tacke F. Hepatic inflammatory responses in liver fibrosis. Nat Rev Gastroenterol Hepatol. 2023;20(10):633-646. doi:10.1038/s41575-023-00807-x

Introduction

Hepatocellular carcinoma (HCC) is an end stage liver disease with increasing morbidity and mortality worldwide. Development of the disease is dependent on various genetic, dietary and environmental factors. While alcohol-related liver disease (ALD/MetALD) remains a major contributor, metabolic dysfunction-associated steatotic liver disease (MASLD) is becoming increasingly relevant in clinical practice. There is increasing evidence for the role of bacteria, for instance, such as Bifidobacterium and Blautia, which were considered protective, while Streptococcus has been associated with disease progression. However, little is known about the alteration of microRNAs (miRNAs) in liver diseases and its interrelationship with microbial environment in view of etiological factors.

Aims & Methods

This study aimed to elucidate gastrointestinal miRNA alterations and explore their relationship with microbiome composition in patients with different stages of liver disease in terms of disease etiology. Multi-omics analyses were performed in a subset of well characterized patients (n=59) with liver disease and healthy controls. Systematic characterization included clinical, laboratory, demographic and imaging characterization and dietary preferences. Patients subclassification included fibrosis stage (no fibrosis, fibrosis, liver cirrhosis(LC)) and etiology (MetALD/ALD vs. MASLD). Fecal miRNAs were extracted using the Qiagen miRNeasy Kit and profiled via Agilent miRNA microarray. Microbiome analyses were performed amplifying the V1-V2 region of the 16S rRNA gene following Illumina sequencing.

Results

For miRNA analysis stringent criteria were applied to identify high quality miRNA targets. From approximately 4,000 candidates filtering resulted in selection of 202 high-quality miRNAs with reliably measurable concentrations. 28 of these miRNAs showed significantly positive alterations in concentration in patients with liver disease and 7 miRNAs significant negative alterations. Specifically, miR-642a-3p, miR-5006, miR-6781, and miR-6849 were elevated in feces in patients with LC. In contrast, miR-6869, miR-4467, and miR-5001 were present in lower concentration in LC patients. Notably, miR-4467 also showed strong negative associations with liver-specific laboratory markers, including gamma-glutamyl transferase (GGT) (r=-0.34; p=0.026) and M65, a marker of apoptosis (r=-0.42; p=0.005). Cross-sectional comparison of miRNA and microbiome data revealed miRNA alterations associated with specific microbial signatures. MiR-6795-5p, which was associated with liver stiffness (r = 0.39, p = 0.01), also correlated positively with the abundance of Streptococcus, a genus linked to disease progression (r=0.29; p=0.047). Conversely, miR-6869, miR-4467, and miR-5001 showed positive correlations with the potentially protective genera Blautia and Bifidobacterium (miR-6869: r_{Bifidobacterium}=0.35; p_{Bifidobacterium}=0.012; r_Blautia=0.37; p_Blautia=0.008; miR-4467: r_Blautia=0.41; p_Blautia=0.002; miR-5001: r_Blautia=0.38; p_Blautia=0.006).

Conclusion

Multi-omics analysis reveals distinct alterations in fecal miRNAs and gut microbiota across different stages of liver disease. Changes in microbial composition were associated with shifts in miRNA profiles, suggesting a functional link in maintaining intestinal homeostasis. These findings highlight the potential of integrated microbiome–miRNA signatures as novel diagnostic and therapeutic targets. Further studies are warranted to validate these associations and explore their clinical applications.