背景:进行性家族性肝内胆汁淤积3型(PFIC3)是由ABCB4基因的致病变异引起的常染色体隐性遗传疾病。本研究旨在探讨PFIC3患者ABCB4基因型及临床表型特征。
方法:收集并分析了PubMed和CNKI数据库中13例新发PFIC3患儿以及82例报道患儿的临床和分子遗传学数据。
结果:13例新的PFIC3患者包括6名女性和7名男性,主要表现是肝肿大,脾肿大,黄疸,瘙痒,以及增加水平的γ-谷氨酰转肽酶(GGT)。检测到14个新的ABCB4变体,包括八个被诊断为可能致病的和六个,致病性。在所有95例PFIC3病例中,在85.3%(81/95)观察到肝肿大,瘙痒占67.4%(64/95),脾肿大52.6%(50/95),黄疸占48.4%(46/95),门静脉高压症患者占34.7%(33/95),GGT升高患者占100%(88/88)。66.1%(39/59)的患者对口服熊去氧胆酸(UDCA)治疗有不同程度的阳性反应,其中38.5%(15/39)在实验室变化方面完全恢复。尽管53例患者的病情保持稳定(58.9%,53/90),其余37例患者的临床结局不乐观(41.1%,37/90),包括7人死亡,27人经历了另3人等待肝移植。在95例患者中共检测到96种ABCB4变异。具有双等位基因无效变异的PFIC3患者表现出更早的发病年龄[10.5(2,18)与19(8,60)个月,p=0.007],较低的UDCA反应率[18.2%(2/11)与77.1%(37/48),p=0.001],和更多没有希望的临床结果[80%(12/15)与33.3%(25/75),p=0.001],与非双等位基因无效变异体相比。
结论:PFIC3表现为肝肿大,瘙痒,以血清GGT水平升高为生化标志的脾肿大和黄疸。尽管观察到对UDCA治疗的反应有不同程度的改善,41.1%的PFIC3患者预后不良。双等位基因无效变异的ABCB4基因型与严重的PFIC3表型相关。此外,这项研究中的14个新变体扩展了ABCB4突变谱,并为PFIC3患者的诊断提供了新的分子生物标志物。
Progressive familial intrahepatic cholestasis type 3 (PFIC3) is an autosomal recessive disease caused by pathogenic variants of the gene ABCB4. This study aimed to investigate the ABCB4 genotypic and the clinical phenotypic features of PFIC3 patients.
The clinical and molecular genetic data of 13 new pediatric patients with PFIC3 as well as 82 reported ones in the PubMed and CNKI databases were collected and analyzed.
The 13 new PFIC3 patients included six females and seven males, and the main presentations were hepatomegaly, splenomegaly, jaundice, and pruritus, as well as increased levels of gamma-glutamyl transpeptidase (GGT). Fourteen new ABCB4 variants were detected, including eight diagnosed to be likely-pathogenic and six, pathogenic. Among all the 95 PFIC3 cases, hepatomegaly was observed in 85.3% (81/95), pruritus in 67.4% (64/95), splenomegaly in 52.6% (50/95), jaundice in 48.4% (46/95), portal hypertension in 34.7% (33/95) and GGT elevation in 100% (88/88) of the patients. Positive responses at varied degrees to oral ursodeoxycholic acid (UDCA) treatment were observed in 66.1% (39/59) of the patients, among whom 38.5% (15/39) fully recovered in terms of the laboratory changes. Although the condition remained stable in 53 patients (58.9%, 53/90), the clinical outcomes were not promising in the rest 37 cases (41.1%, 37/90), including 7 died, 27 having undergone while another 3 waiting for liver transplantation. A total of 96 ABCB4 variants were detected in the 95 patients. PFIC3 patients with biallelic null variants exhibited earlier onset ages [10.5 (2, 18) vs. 19 (8, 60) months, p = 0.007], lower UDCA response rate [18.2% (2/11) vs. 77.1% (37/48), p = 0.001], and more unpromising clinical outcomes [80% (12/15) vs. 33.3% (25/75), p = 0.001], compared with those with non-biallelic null variants.
PFIC3 presented with hepatomegaly, pruritus, splenomegaly and jaundice with increased serum GGT level as a biochemistry hallmark. Although varying degrees of improvement in response to UDCA therapy were observed, 41.1% of PFIC3 patients exhibited unfavorable prognosis. ABCB4 genotypes of biallelic null variants were associated with severer PFIC3 phenotypes. Moreover, the 14 novel variants in this study expanded the ABCB4 mutation spectrum, and provided novel molecular biomarkers for diagnosis of PFIC3 patients.