Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Meinel, K.
Role of ‘Atypical’ Bile Acids in Itch
Doktoratsstudium der Medizinischen Wissenschaft; Humanmedizin; [ Dissertation ] Medizinische Universität Graz; 2022. pp. 121
[OPEN ACCESS]
FullText
- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Jahnel Jörg
- Schlagenhauf Axel
- Wagner Martin
- Altmetrics:
- Abstract:
- Background: Pruritus is a common symptom in pediatric and adult patients with chronic cholestatic liver disease (CCLD) like autoimmune sclerosing cholangitis (ASC) and progressive familial intrahepatic cholestasis (PFIC), and the key clinical finding in intrahepatic cholestasis of pregnancy (ICP). Increased bile acid (BA) levels and enhanced autotaxin (ATX) activity are assumed to play a role in the pathophysiology of cholestatic pruritus amongst others, however, the exact etiology remains unknown. Besides the typical human BA, the appearance of ‘atypical’ muricholic acids (MCA) in pediatric and adult CCLD patients has been observed. This study aimed to determine total BA (tBA), total MCA (tMCA) levels and profiles of BA/MCA isoforms in serum of pediatric ASC and PFIC patients with and without pruritus and of pregnant women with and without ICP. ATX antigen levels were studied in serum of all study groups. We hypothesized that a rise of specific BA/MCA correlates with a surge in plasmatic ATX levels. Methods: We investigated fasting serum human BA, MCA, and ATX antigen levels in 27 pediatric CCLD patients aged 1-18 years (ASC n=20 [with pruritus n=6, without pruritus n=14]; PFIC n=7 [with pruritus n=5, without pruritus n=2]) and 23 healthy age-matched controls as well as in 19 ICP patients and 20 healthy pregnant controls. BA profiling was done using high-performance liquid chromatography-tandem mass spectrometry. ATX antigen levels were determined using a commercial ELISA. Pruritus was assessed by a visual analogue scale of pruritus (PVAS) in pediatric patients ≥ 5 years of age. Results: ASC- and PFIC patients exhibited significantly higher tBA (ASC: median: 42.4 µmol/L, interquartile range [IQR]: 18.5-100.1; PFIC median: 262.6 µmol/L, IQR: 32.3-451.7) and tMCA levels, (ASC: median: 0.59 µmol/L, IQR: 0.16-1.00; PFIC: median: 7.39 µmol/L, IQR: 1.31-37.13) than healthy controls (tBA: median: 1.7 µmol/L, IQR: 0.9-3.6; ASC p<0.0001; PFIC p<0.0001; tMCA: (median: 0.05 µmol/L, IQR: 0.001-0.16, ASC p=0.0006; PFIC p<0.0001). In pediatric patients, only PFIC patients showed elevated ATX antigen levels (median: 1650 ng/ml, IQR: 776.9-3742) compared to controls (median: 315.9 ng/ml, IQR: 251.1-417.2; PFIC p=0.0003). ASC patients with pruritus showed only a minor increase in tBA levels (median: 76.5 µmol/L, IQR: 54.7-205), but strikingly higher taurine (T) -conjugated BA (median: 16.4 µmol/L, IQR: 8.9-41.4) and tMCA (median: 1.15 µmol/L, IQR: 0.77-2.44) levels compared to ASC patients without pruritus (tBA median: 24.3 µmol/L, IQR: 16.2-80.8; p<0.0408; T-conjugated BA median: 1.3 µmol/L, IQR: 0.8-4.9; p=0.0023; tMCA median: 0.30 µmol/L, IQR: 0.13-0.64, p=0.0033). BA/MCA profiles distinctly differed depending on presence/absence of pruritus. In contrast to PFIC patients, ATX antigen levels were not significantly elevated in ASC patients with (median: 665.8 ng/ml, IQR: 357.8-1203) and without pruritus (median: 391.0 ng/ml, IQR: 283.2-485.6). In ICP patients, tBA levels were significantly increased compared to healthy pregnant controls (tBA-median: 3.7 µmol/L, IQR: 1.8-7.8 vs. 1.7 µmol/L, IQR: 1.2-3.1; p=0.0063). However, tBA levels in ICP patients were significantly lower than in pediatric ASC and PFIC patients with and without pruritus (ICP vs. ASC: p=0.0033; ICP vs. PFIC: p=0096). TMCA levels were comparable in ICP patients and in pregnant controls but more scattered in the latter group (tMCA-median: 0.1 µmol/L, IQR: 0.05-0.4 vs. 0.07 µmol/L, IQR: 0.03-0.11). In ICP patients and pregnant controls, ATX antigen levels were also increased, however, without a statistically significant difference between the groups (p=0.1771). Compared to all pediatric study groups, ATX antigen levels were significantly increased in ICP patients as well as in pregnant controls. Moreover, ATX antigen levels did not correlate with tBA or tMCA levels in ICP patients. Conclusion: Despite the same underlying disease, pediatric ASC patients with prur