Δ4-3-oxosteroid-5β-reductase deficiency: Responses to oral bile acid therapy and long-term outcomes

Table 1 Clinical and laboratory¹ features of the 12 patients diagnosed with Δ4-3-oxosteroid 5β-reductase deficiency at first presentation

Patient No.	Sex	Age at first symptom	Age at first visit (mo)	TB (μmol/L)	DB (μmol/L)	ALT (U/L)	AST (U/L)	GGT (U/L)	TBA (μmol/L)	Organomegaly	INR2	Molecular defect3
1	F	14 d	2.5	292	214	169	309	46	4.6	Hepatomegaly	1.23	c.933delG/c.1023+5A>C
2	M	1 mo	11	146	108	101	405	40	1.6	Hepatosplenomegaly	1.17	c.158A>G/ c.158A>G
3	M	3 d	2	96	64	176	183	33	3	Hepatomegaly	1.03	c.396C>A/c.722A>T
4	M	3 d	1	310	218	76	213	51	5.5	Hepatomegaly	1.52	c.919G>T/c.919G>T
5	M	10 d	10	146	113	210	207	65	6.1	Hepatosplenomegaly	1.14	c.797G>A/-
6	F	1 mo	8	324	252	267	584	108	1.4	Hepatomegaly	2.17	c.148C>T/-
7	M	1 mo	8	211	126	234	734	66	7.9	Hepatomegaly	1.1	c.797G>A/C.797G>A
8	M	3 d	1	320	158	523	703	51	2.5	Hepatomegaly	1.36	c.797G>A/C.797G>A
9	F	10 d	1	378	232	1317	1416	62	8.5	Hepatomegaly	1.9	c.614delT/C.797G>A
10	M	3 d	2	160	126	531	896	64	5.9	Hepatosplenomegaly	1.28	c.593C>T/c.797G>A
11	M	3 d	3	125	76	79	161	38	1.4	Hepatomegaly	1.02	c.278delA/-
12	M	1 mo	2.5	204	112	339	619	50	1.8	Hepatomegaly	2.11	c.919C>T/C.919C>T
Normal range				5-21	0-3.4	0-40	0-40	7-50	0-10		0.8-1.2

¹At least 5 d after cessation of bile acid administration;

²After vitamin K1 parenteral administration;

³NM_005989 was used as reference. TB: Total bilirubin; DB: Direct bilirubin; ALT: Alanine aminotransferase; AST: Aspartate transferase; GLT: Gamma-glutanyl transferase; ALB: Albumin.

Table 2 Evolution of liver function tests and international normalized ratio during oral ursodeoxycholic acid therapy in nine children¹ with ∆4-3-oxosteroid 5β-reductase deficiency

Patient No.	Starting age	Dosage (d.kg)/duration of therapy	Before UDCA administration				At the end of UDCA therapy
			TB / DB (μmol/L)	ALT/AST (U/L)	ALB (g/L)	INR	TB/DB (μmol/L)	ALT/AST (U/L)	ALB (g/L)	INR
1	2.5 mo	20 mg/3 mo	241/177	73/172	38	1.23	292/214	169/309	33	1.46
3	2 mo	30 mg/4 mo	96/64	176/183	43	1.03	8.7/5.9	51/29	44	n.a.
4	1 mo	20 mg/1.5 mo; 40 mg/1 wk	150/58	76/159	35	1.43	310/218	76/273	36	1.52
5	10 mo	18 mg/1 mo; 40 mg/4 mo	126/66	340/262	49	n.a.	6.7/2.9	8/16	42	n.a.
6	8 mo	20 mg/6 mo	221/142	235/204	32	1.24	324/252	267/584	33	2.17
7	8 mo	10 mg/2 mo	268/121	532/897	38	1.16	19/15	100/124	52	0.9
8	1 mo	16 mg/6 mo	308/131	150/187	41	1.13	273/148	448/410	28	1.36
9	1 mo	18 mg/3 mo	316/243	1240/1565	37	1.71	358/258	195/283	32	n.a.
11	3 mo	18 mg/2 mo	122/87	106/155	n.a.	1.02	85/68	83/167	39	n.a.
		Normal range	5-21/0-3.4	0-40	35-52	0.8-1.2	5-21/0-3.4	0-40	35-52	0.8-1.2

¹Patients 2, 10, and 12 did not receive ursodeoxycholic acid therapy. n.a.: Not available; UDCA: Ursodeoxycholic acid; ALT: Alanine aminotransferase; AST: Aspartic transaminase; TB: Total bilirubin; DB: Direct bilirubin; INR: International normalized ratio; ALB: Albumin.

Table 3 Evolution of clinical feature or liver function tests during oral chenodeoxycholic acid therapy in 11 children with ∆4-3-oxosteroid 5β-reductase deficiency

Patient No.	Starting age (mo)	Starting dosage (mg/kg per day)	Dosage adjustment (mg/kg per day × duration)	Age (mo) at LFTs normalization	Dosage maintaining normal LFTs and suppressing atypical bile acids (mg/kg per day)	Status/age at last follow-up
1	5.5	8	8 mo × 7 mo; 10 × -	9	10	Normal/4 yr 11 mo
2	11	12	12 mo × 1 mo; 8 mo × 0.75 mo; 4.5 mo × 5 mo; 5.5 × -	31	5.5	Normal/4 yr
3	6	10	10 mo × 24 mo; 9 mo × 12 mo, 8 × -	13	8	Normal/4 yr 9 mo
4	3	5	5 mo × 1mo; 3 mo × 2 mo; 7 mo × 4.5 mo; 8 mo × 2.5 mo; 11 mo × 13 mo; 8 × -	26	8	Normal/6 yr 7 mo
6	14	8	8 wk × 3 wk; 6 wk × 1 wk; 5 mo × 2.5 mo; 6 mo × 3 mo; 7 × -	18	7	Normal/2 yr 11 mo
7	10	10	10 wk × 1 wk; 8 mo × 1 mo; 0 wk × 1 wk; 5 × -	14	5	Normal/2 yr 4 mo
8	7	10	10 wk × 1 wk; 4 mo × 2 mo; 5 mo × 6 mo; 6 mo × 2 mo	N.A.	N.A.	Transplanted/1 yr 6 mo
9	4	8	8 mo × 2 mo; 9 mo × 2 mo; 10 × -	10	10	Normal/1 yr 5 mo
10	3.5	10	10 × -	6.5	10	Normal/11 mo
11	5	10	10 mo × 13 mo; 7 × -	8	7	Normal/2 yr
12	2.5	10	10 × -	5	10	Normal/8 mo

The dosage of chenodeoxycholic acid was reduced if serum alanine aminotransferase and aspartic transaminase obviously elevated with obviously elevated total bile acid level; increased if not sufficient suppression of atypical bile acid demonstrated by fast atom bombardment ionization mass spectrometry after the resolution of jaundice. N.A.: Not applicable; LFT: Liver function test.