We detected anomalies of the parenchyma of the kidney and liver in a substantial proportion of our BBS cohort by using high-resolution US together with emerging technical devices (ATI, SWE, and SWD) enabling the quantitative and qualitative assessment of liver tissue in particular. The percentage of patients with parenchymal alterations was significantly higher than reported from other studies, and those were detected at an early stage - in part even before the elevation of liver enzymes - indicating a high sensitivity of the applied methods.
Study cohort
The distribution of pathogenic variants in our BBS cohort was similar to other recent studies from Europe and the USA with a predominance of pathogenic variations in BBS1 and BBS10 (9, 10, 11), but differed from a study in China, where the majority of patients were affected by mutations in BBS2 and BBS7 (40). Moreover, we noted an accumulation of the hot spot mutations c.271dupT (p.Cys91Leufs*5) in BBS10 and c.1169T > G (p.Met390Arg) in BBS1. The proportion of two truncating mutations was higher than the subgroup of two missense mutations and thus different to other recent studies (9, 10). Overall, BMI SDS was increased in our patients (with a wide range) and significantly higher in patients with mutations in BBS10 compared to those with BBS1 mutations which is consistent with published data (13). Body length was within the normal range without any differences regarding sex and age. However, the subgroup of BBS1 patients were significantly taller than patients affected by a pathogenic variation in BBS10 which could be due to the overall milder clinical course, particularly in the case of the BBS1 hot spot mutation (11, 13).
Renal involvement
In children, the average total kidney volume fell within the normal range, albeit with considerable variation. The higher volumes observed in adults could be attributed to the correlation between renal size and BMI (41, 42) and the fact that normal values were adjusted for weight up to a limit of 60 kg, a threshold significantly exceeded by the adult patients. Kidney abnormalities were detected in 75% of patients, which is a substantially higher proportion than in other studies (1, 2, 9, 11). Persistent fetal lobulation was present in 44% and therefore more than 10 times as frequent compared to the estimated prevalence (4%) in the normal population. This may indicate an impaired embryonic renal development as result of the underlying ciliopathy in BBS (43). In the literature, patients with variants in the BBS genes 2, 5, 8, 9, 10, 12, 16, and 17 were demonstrated to develop a more severe kidney phenotype than patients with mutations in BBS1, BBS4, or BBS7. This was comparable to our study. However, in our study, the latter subgroups also showed a multitude of structural anomalies with a higher frequency than in other studies (40), indicating the high sensitivity of the applied US methods (44). Consistent with recent studies (9, 10, 11), our results support the milder renal involvement in patients with BBS1 mutations.
Urinary tract disorders were rarely detected in our cohort, however, a high bladder volume, measured incidentally, was seen in 20% of cases. This finding should be considered during clinical evaluations and when assessing possible post renal complications (12, 38).
Twenty-seven percent of patients presented with an impaired kidney function (CKD 2–5), 23% of these (6% of the total study population) progressed to ESKD. These numbers are comparable to other studies or even lower, especially considering the substantial proportion of adult patients in our cohort given. Impairment of renal function was a particular finding in patients with a pathogenic variant in BBS10 (and, to a lesser extent, in those with variants in BBS genes 2, 4, 16, and 17). Conversely, patients with variants in BBS1, 5, 7, 9, and 12 presented with stable kidney parameters. The three patients who developed ESKD were affected by mutations in BBS2, 10, and 16 and started renal replacement therapy at ages 6, 10, and 46 years. Recent data indicate that the risk for the development of ESKD is not only increased in the first year of life and at preschool age (9), but also later in adulthood and with higher prevalence in females than in males (10). The inherited structural abnormalities of the kidneys in BBS, when combined with the metabolic risks associated with obesity, and secondary conditions such as type 2 diabetes or NAFLD, may serve as an additional factor exacerbating the decline in kidney function later in life (45).
Hepatic Involvement
More than half of the cohort demonstrated ATI and SWE levels above the 97th percentile, indicative of hepatic parenchymal changes such as steatosis and fibrosis. This exceeds even the high figures reported in the literature, which indicates a prevalence of steatosis in 27% of adult BBS patients (19) due to increased echogenicity of the liver parenchyma and the reported prevalence of hepatic fibrosis (1, 2). Accordingly, ATI and/or SWE were altered in a substantial proportion of our patients although standard US examination (size, echogenicity and liver margin) as well as serum liver enzymes were within the normal range, indicating a high sensitivity of the applied US techniques and their ability to reveal even subtle parenchymal lesions (23). ATI showed a weak association with the size of the liver, spleen, and kidney as well as liver echogenicity and enzymes, all of which are indicators of hepatic steatosis. ATI and SWE were associated with BMI SDS and abdominal wall thickness, obesity-related parameters and well-known drivers of hepatic steatosis and fibrosis. Again, patients with BBS10 mutations were more severely affected (and showed higher ATI levels) than the BBS1 subgroup.
SWD was significantly increased (above 97th percentile) in 23% of our cohort, displaying a higher occurrence among males. Elevated SWD levels are an indicator of inflammation and increased liver viscosity (23). The correlation with male sex might point to a potential higher inflammation risk within this subgroup. However, the lower incidence of pathological kidney findings indicates that liver viscosity could also be influenced by other variables, underscoring the need for further research (46).
The pathophysiology of liver involvement in BBS still remains elusive, with factors such as ciliary dysfunction (47), severe early-onset obesity, and recent findings pointing to the hepatic BBSome as possible contributors (48). The hepatic phenotype in BBS widely varies from NAFLD, including steatosis and nonalcoholic steatohepatitis (NASH), to liver cirrhosis and an increased risk of hepatocellular carcinoma (49, 50, 51). Emerging treatment modalities may prove to be a crucial tool for the treatment and/or prophylaxis of these serious organ manifestations. This specifically applies to Melanocortin 4 Receptor (MC4R) agonists (setmelanotide), which are already approved by the European Medicines Agency for the treatment of children aged six and above (52). MC4R–deficient animals have been established as successful models of NAFLD (53, 54, 55) and the hepatic expression of the MC4 receptor has been demonstrated (56, 57). Thus, high-definition US could play an important role in assessing the benefit of new therapeutic options by monitoring therapeutic success.
Limitations
In a small number of patients, complete diagnostic data could not be obtained due to technical availability (SWD) or technical challenges associated with obesity (liver perfusion). As BBS is a rare disease, the number of participants was limited. However, the present cohort included a larger number of patients compared to previous clinical studies. In addition, the large number of different BBS genes and pathogenic variants within these genes complicates analyses. Unfortunately, histopathological data from liver biopsy were available for only one patient. Therefore, the results from the US examinations, especially concerning the new, high-end technologies, had to be interpreted by comparison with published data from healthy children and adults as well as patients with other underlying diseases (27, 30).