AKR1D1 and CYP7B1 mutations in patients with inborn errors of bile acid metabolism: Possibly underdiagnosed diseases.

BACKGROUND: Inborn errors of bile acid metabolism (IEBAM) cause rare but treatable genetic disorders that can present as neonatal cholestasis or neurological diseases. Without timely primary bile acid treatment, patients may develop liver failure early in life. This study aimed to analyze the types and treatment outcomes of IEBAM in Taiwanese infants and document the allele frequency of CYP7B1 hot spot mutations in the population. METHODS: Urine samples from patients with infantile intrahepatic cholestasis and suspected IEBAM were subjected to urinary bile acid analysis by gas chromatography-mass spectrometry (GC/MS). Genetic diagnoses were made using direct sequencing or next-generation sequencing. We also tested healthy control subjects for a probable hot spot point mutation of CYP7B1. RESULTS: Among the 75 patients with infantile intrahepatic cholestasis tested during 2000 -2016, three had ∆4-3-oxosteroid 5ß-reductase deficiency with AKR1D1 mutations, and three had oxysterol-7α-hydroxylase deficiency with CYP7B1 mutation. Two patients with ∆4-3-oxosteroid 5ß-reductase deficiency were successfully treated with cholic acid. The three unrelated infants with oxysterol 7α-hydroxylase deficiencies had the same p.R112X homozygous CYP7B1 mutation. Two had mild renal or neurological involvement. Among 608 healthy control subjects, the allele frequency of the heterozygous mutation for p.R112X was 2/1216 (0.16%). The only surviving patient with oxysterol 7α-hydroxylase deficiency recovered from liver failure after chenodeoxycholic acid (CDCA) treatment beginning at 3 months of age. CONCLUSION: Distinct types of IEBAM disease were found in the Taiwanese population. Patients with early diagnosis and early treatment had a favorable outcome. IEBAM prevalence rates may be higher than expected due to the presence of heterozygous mutations in the general population.

Endometrial cancer incidence in breast cancer patients correlating with age and duration of tamoxifen use: a population based study.

BACKGROUND: Our study aimed to assess the endometrial cancer risk after tamoxifen adjuvant treatment for female breast cancer patients in Taiwan. MATERIALS AND METHODS: A total of 74,280 breast cancer patients between January 1997 and December 2004 were included in the study; 39,411 received tamoxifen treatment and 34,869 did not. Tamoxifen-associated endometrial cancer was defined as endometrial cancer that occurred in patients at least 6-month after the diagnosis of breast cancer, who underwent tamoxifen treatment. RESULTS: A total of 222 patients developed endometrial cancer, and of these,153 (69 %) were seen in patients with tamoxifen treatment, and 69 (31%) were seen in patients without the use of tamoxifen. The incidence of endometrial cancer was 0.388% (153/39,411) in patients with tamoxifen treatment, while was 0.198% (69/34,869) in patients without tamoxifen treatment. Logistic regression analysis demonstrated that tamoxifen use and age over 35 years were significantly correlated with development of endometrial cancer (p<0.001 and p=0.002, respectively). The odds ratio was 2.94 (95%CI, 2.13-4.06) for 3 years or longer tamoxifen use. The odds ratio was 4.08 (95%CI, 1.67-9.93) for women older than 35 years compared to those 35 or younger than 35 years. There were no significant differences in prior hormone exposure, hypertension and diabetes. CONCLUSIONS: To the best of our knowledge, this is the largest population based study that shows in patients with breast cancer, tamoxifen use for more than three years or patients older than 35 years was associated with a significantly increased risk for developing endometrial cancer.