ABCMdb

PMID: 20447715

Pawlikowska L, Strautnieks S, Jankowska I, Czubkowski P, Emerick K, Antoniou A, Wanty C, Fischler B, Jacquemin E, Wali S, Blanchard S, Nielsen IM, Bourke B, McQuaid S, Lacaille F, Byrne JA, van Eerde AM, Kolho KL, Klomp L, Houwen R, Bacchetti P, Lobritto S, Hupertz V, McClean P, Mieli-Vergani G, Shneider B, Nemeth A, Sokal E, Freimer NB, Knisely AS, Rosenthal P, Whitington PF, Pawlowska J, Thompson RJ, Bull LN
Differences in presentation and progression between severe FIC1 and BSEP deficiencies.
J Hepatol. 2010 Jul;53(1):170-8. doi: 10.1016/j.jhep.2010.01.034. Epub 2010 Apr 13., [PubMed]

Sentences

No. Mutations Sentence Comment

15 ABCB11 p.Asp482Gly Among BSEP patients, the course of disease was less rapidly progressive in patients bearing the D482G mutation. Login to comment 64 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly We also performed exploratory analyses to evaluate whether BSEP patients carrying 1 or 2 copies of the common European D482G (c.1445A>G) and/or E297G (c.890A>G) mutations differed from other BSEP patients, and whether FIC1 patients carrying G308V differed from other FIC1 patients. Login to comment 65 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly For clinical findings, we used a three-way categorization of 'FIC1` versus 'D482G BSEP` (BSEP patients carrying D482G on one or both of their ABCB11 alleles) versus 'non-D482G BSEP` (BSEP patients not carrying D482G). Login to comment 66 ABCB11 p.Asp482Gly Since biochemical data were available for relatively few D482G-bearing patients, three-way analyses were not performed, although in some figures the 2 BSEP subgroups are shown separately for qualitative comparison. Login to comment 67 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly The D482G and non-D482G BSEP subgroups do not always sum to the total N for 'all BSEP`, because we could not sub-classify 3 BSEP patients in whom only one mutation was detected and presence of D482G on the 2nd allele was not ruled out; they were excluded from this analysis. Login to comment 77 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly One of two 'common` ABCB11 mutations (D482G or E297G) was identified on one or both alleles in 51 BSEP patients (61%) [2,12]. Login to comment 81 ABCB11 p.Asp482Gly ABCB11 p.Glu297Gly Since functional studies have suggested that the BSEP D482G and E297G mutations may not completely abolish protein function [9,44-47], we performed exploratory analyses stratified by mutation. Login to comment 82 ABCB11 p.Asp482Gly Our results suggested that phenotypic differences exist between BSEP patients with and without D482G (data not shown); those differences that attained statistical significance are discussed below. Login to comment 86 ABCB11 p.Asp482Gly For all patient groups, birth-weights trended below expectation; this only reached statistical significance in non-D482G BSEP patients (p <0.0003, 95% CI 0.88-0.96). Login to comment 88 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly Onset by 3 months was reported in most patients (FIC1: 85%; D482G BSEP: 67%; non-D482G BSEP: 71%). Login to comment 92 ABCB11 p.Asp482Gly Jaundice was less frequent in patients bearing BSEP D482G (48%) than in patients carrying other BSEP mutations (78%; p = 0.013) or in FIC1 patients (78%; p = 0.014) (Table 2). Login to comment 95 ABCB11 p.Asp482Gly Clinically manifest vitamin deficiency was more common in BSEP patients bearing D482G than in FIC1 patients (p = 0.047). Login to comment 97 ABCB11 p.Asp482Gly Seven of the 12 (3 D482G BSEP patients, 3 other BSEP patients, and 1 FIC1 patient) presenting with manifestations of vitamin deficiency were not clinically jaundiced. Login to comment 116 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly Two of six (33%) BSEP patients with D482G and 22/27 (81%) without D482G were reported to have giant cells (p = 0.034). Login to comment 128 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly Feature FIC1 BSEP p* All BSEP D482G Non-D482G FIC1 versus All BSEP Birth-weighta , 0.97 0.93 0.95 0.93 median (0.88-1.09) (0.87-1.02) (0.89-1.05) (0.87-1.00) 0.23 (interquartile range) N = 42 N = 70 N = 19 N = 48 Age (months) at Onset, 2.0 2.0 3.0 1.8 median (0.5-2.0) (1.0-4.5) (1.3-5.0) (0.4-4.0) 0.059 (interquartile range) N = 53 N = 79 N = 18 N = 58 Symptoms initially 25/56 46/81 13/21 30/57 intermittent (45%) (57%) (62%) (53%) 0.17* Jaundice 42/54 57/82 10/21 45/58 (78%) (70%) (48%) (78%) 0.29 Diarrhea 11/54 5/82 2/21 3/58 (20%) (6%) (10%) (5%) 0.017 Manifestations 2/54 10/82 4/21 6/58 of vitamin deficiency (4%) (12%) (19%) (10%) 0.11 Linear and logistic regression, or Fisher Exact test (*), were used. Login to comment 130 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly Bolded entries in the D482G column indicate that results for D482G BSEP patients differ from one or both other groups (as described in the text). Login to comment 138 ABCB11 p.Asp482Gly Four BSEP patients, all without D482G, were diagnosed with hepatocellular carcinoma (HCC). Login to comment 139 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly Overall, 31% of patients were diagnosed with portal hypertension (PH); BSEP patients without D482G developed PH more frequently than those bearing D482G (p = 0.017), and than FIC1 patients (p = 0.022). Login to comment 140 ABCB11 p.Asp482Gly Twenty-four percent of patients were diagnosed with cirrhosis (median age 4.4y, interquartile range 2.3-6.5 y); BSEP patients bearing the D482G mutation survived to an older age without diagnosis of cirrhosis than did other BSEP patients (p = 0.029, hazard ratio = 0.19, 95% CI = 0.04-0.84). Login to comment 170 ABCB11 p.Asp482Gly Of those patients who did not undergo surgical intervention, 7 died (5 FIC1 and 2 BSEP patients without D482G). Login to comment 171 ABCB11 p.Asp482Gly BSEP patients carrying the D482G mutation survived to a greater age without OLT than did other BSEP patients (p = 0.0092, hazard ratio = 0.31, 95% CI = 0.13-0.75) or FIC1 patients (p = 0.045, hazard ratio = 0.41, 95% CI = 0.17-0.98) (Fig. 4A). Login to comment 172 ABCB11 p.Asp482Gly The probability of any form of surgery was less in BSEP patients with D482G than in others, and this bordered on significance (p = 0.050, hazard ratio = 0.56, 95% CI = 0.31-1.00) (Fig. 4B). Login to comment 192 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly Feature FIC1 BSEP p All BSEP D482G Non-D482G FIC1 versus All BSEP Gallstones 0/61 (0%) 27/84 (32%) 8/21 (38%) 17/60 (28%) <0.0001 HCC 0/61 (0%) 4/84 (5%) 0/21 (0%) 4/60 (7%) 0.14 Portal Hypertension 15/61 (25%) 30/84 (36%) 3/21 (14%) 27/60 (45%) 0.20 Diarrhea 37/61 (61%) 17/84 (20%) 4/21 (19%) 13/60 (22%) <0.0001 Pancreatic Disease 7/61 (12%) 1/84 (1%) 1/21 (5%) 0/60 (0%) 0.0099 Rickets 28/61 (46%) 10/84 (12%) 1/21 (5%) 8/60 (13%) <0.0001 Pneumonia 8/61 (13%) 1/84 (1%) 1/21 (5%) 0/60 (0%) 0.0044 Hearing Loss* 19/61 (31%) 0/83 (0%) 0/21 (0%) 0/59 (0%) <0.0001 Failure to thrive 46/51 (90%) 46/78 (59%) 15/21 (71%) 31/55 (56%) 0.0001 Height <3rd percentile 33/39 (85%) 32/65 (49%) 8/19 (42%) 21/43 (49%) 0.0003 Weight <3rd percentile 23/41 (56%) 20/68 (29%) 2/16 (13%) 16/49 (33%) 0.0083 Fisher exact test was used. Login to comment 195 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly Bolded entries in the 'Portal Hypertension` row indicate that results for non-D482G BSEP patients differ from D482G BSEP and FIC1 patients (as described in the text). Login to comment 204 ABCB11 p.Asp482Gly The higher incidence of presentation without jaundice but with vitamin deficiency, and lower frequency of giant cells upon biopsy, in ''D482G BSEP" suggests a more insidious onset; however, the overall clinical picture at presentation does not differ substantially among the BSEP mutation subclasses. Login to comment 205 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly Some features of the disease course in BSEP patients with D482G suggested a more slowly progressing disease, consistent with data suggesting that the D482G BSEP protein retains some function [9,45,46]; when compared to other BSEP patients, those bearing D482G developed portal hypertension less frequently, developed cirrhosis at an A B ALP (IU/l) FIC1 BSEP Age (years) Age (years) Age (years) Age (years) 0 - 1 1 - 2 2 - 4 4 - 6 > 6 0 500 1000 1500 2000 2000 3000 4000 5000 6000 0 - 1 1 - 2 2 - 4 4 - 6 > 6 0 500 1000 1500 2000 2000 3000 4000 5000 6000 FIC1 BSEP sAT 0 - 1 1 - 2 2 - 4 4 - 6 > 6 0 5 10 15 20 25 0 5 10 15 20 25 0 - 1 1 - 2 2 - 4 4 - 6 > 6 Fig. 3. Login to comment 208 ABCB11 p.Asp482Gly For BSEP, filled shapes represent data from patients bearing D482G, and open shapes, all other patients. Login to comment 213 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly D482G BSEP FIC1 Other BSEP D482G BSEP FIC1 Other BSEP Transplant-free Survival (%) 0 25 50 75 100 A B Age (years) 0 5 10 15 20 25 30 Surgery-free Survival (%) 0 25 50 75 100 Age (years) 0 5 10 15 20 25 30 Fig. 4. Login to comment 215 ABCB11 p.Asp482Gly In each case FIC1, D482G BSEP, and other BSEP are plotted. Login to comment 218 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly Among BSEP patients, 5/ 21 (24%) with D482G and 30/60 (50%) without D482G underwent OLT. Login to comment 221 ABCB11 p.Asp482Gly For most disease features, the results of comparison between FIC1 and BSEP patients were similar whether BSEP patients with D482G were included or excluded. Login to comment 222 ABCB11 p.Asp482Gly ABCB11 p.Asp482Gly An exception was portal hypertension, where FIC1 patients had an intermediate phenotype between BSEP D482G and non-D482G patients. Login to comment