Differences in presentation and progression between severe FIC1 and BSEP deficiencies

Abstract

Background & aims: Progressive familial intrahepatic cholestasis (PFIC) with normal serum levels of gamma-glutamyltranspeptidase can result from mutations in ATP8B1 (encoding familial intrahepatic cholestasis 1 [FIC1]) or ABCB11 (encoding bile salt export pump [BSEP]). We evaluated clinical and laboratory features of disease in patients diagnosed with PFIC, who carried mutations in ATP8B1 (FIC1 deficiency) or ABCB11 (BSEP deficiency). Our goal was to identify features that distinguish presentation and course of these two disorders, thus facilitating diagnosis and elucidating the differing consequences of ATP8B1 and ABCB11 mutations.

Methods: A retrospective multi-center study was conducted, using questionnaires and chart review. Available clinical and biochemical data from 145 PFIC patients with mutations in either ATP8B1 (61 "FIC1 patients") or ABCB11 (84 "BSEP patients") were evaluated.

Results: At presentation, serum aminotransferase and bile salt levels were higher in BSEP patients; serum alkaline phosphatase values were higher, and serum albumin values were lower, in FIC1 patients. Elevated white blood cell counts, and giant or multinucleate cells at liver biopsy, were more common in BSEP patients. BSEP patients more often had gallstones and portal hypertension. Diarrhea, pancreatic disease, rickets, pneumonia, abnormal sweat tests, hearing impairment, and poor growth were more common in FIC1 patients. Among BSEP patients, the course of disease was less rapidly progressive in patients bearing the D482G mutation.

Conclusions: Severe forms of FIC1 and BSEP deficiency differed. BSEP patients manifested more severe hepatobiliary disease, while FIC1 patients showed greater evidence of extrahepatic disease.

Figure 1. The distribution of biochemical data at presentation. Medians and interquartile ranges are shown

A: Serum transaminase values shown as sAT: defined as FULN of ALT if available, otherwise FULN of AST (FULN, fold of the upper limit of the normal range). For FIC1 deficiency, N = 31; for BSEP deficiency, N = 40. B: Serum albumin values (FLLN, fold lower limit of normal range). For FIC1 deficiency, N = 27; for BSEP deficiency, N = 28. The horizontal dashed line marks the upper (A) or lower (B) limit of normal.

Figure 2. Discriminating FIC1 and BSEP deficiencies

A: ROC curve for prediction of FIC1 versus BSEP deficiency. The curves for sAT (serum aminotransferase activity, expressed as FULN) versus chance are shown. B: Probability of FIC1 versus BSEP deficiency. The predicted probability of FIC1 versus BSEP deficiency is obtained from ^{1/(1+e[1.88×log₂SAT−2.11])}. All values of sAT <2 collectively confer a sensitivity of 81% (95% CI of 63–93%) and specificity of 88% (95% CI of 73–96%) for FIC1 deficiency. Similarly, all values of sAT >2 collectively have sensitivity of 88% (95% CI of 73–96%) and specificity of 81% (95% CI of 63–93%) for BSEP deficiency.

Figure 3. Serum transaminase and ALP values over time

Medians and interquartile ranges for the indicated age bins are shown. For BSEP, filled shapes represent data from patients bearing D482G, and open shapes, all other patients. (A) Serum transaminase values, expressed as sAT. P-values (t-test) from comparison of log-transformed data from BSEP and FIC1 disease: age 0–1: <0.0001; age 1–2: = 0.0001; age 2–4: = 0.0015; age 4–6: = 0.95; age >6: = 0.30. (B) ALP values. P-values (t-test) from comparison of log-transformed data from BSEP and FIC1 disease: age 0–1: = 0.0017; age 1–2: = 0.0013; age 2–4: = 0001; age 4–6: = 0.20; age >6: = 0.53.

Figure 4. Kaplan-Meier analysis for survival is shown

In each case FIC1, D482G-BSEP and other BSEP are plotted. Fig.4A shows survival without OLT. 26/61 (43%) FIC1 patients, and 38/84 (45%) BSEP patients underwent OLT. Among BSEP patients, 5/21 (24%) with D482G and 30/60 (50%) without D482G underwent OLT. Fig. 4B shows survival without OLT, PEBD or IE.