ABSTRACT
BACKGROUND & AIMS: Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. The use of whole-exome sequencing (WES) for the assessment of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in the diagnosis and management of adults with unexplained liver disease despite comprehensive evaluation by a hepatologist and with no history of alcohol overuse. METHODS: We performed WES and deep phenotyping of 19 unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center in the US. RESULTS: Analysis of the exome in 19 cases identified 4 monogenic disorders in 5 unrelated adults. Patient 1 suffered for 18â¯years from devastating complications of undiagnosed type 3 familial partial lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver aminotransferases, amelioration of dyslipidemia, and decreases in daily insulin requirements. Patients 2 and 3 were diagnosed with MDR3 deficiency due to recessive mutations in ABCB4. Patient 4 with a prior diagnosis of non-alcoholic steatohepatitis was found to harbor a mitochondrial disorder due to a homozygous pathogenic variant in NDUFB3; this finding enabled initiation of disease preventive measures including supplementation with antioxidants. Patient 5 is a lean patient with hepatic steatosis of unknown etiology who was found to have a damaging heterozygous variant in APOB. CONCLUSIONS: Genomic analysis yielded an actionable diagnosis in a substantial number (â¼25%) of selected adult patients with chronic liver disease of unknown etiology. This study supports the use of WES in the evaluation and management of adults with idiopathic liver disease in clinical practice. LAY SUMMARY: We performed whole-exome sequencing in 19 adult patients with unexplained liver disease after an unrevealing conventional work-up performed by a hepatologist. In 5 cases, genomic analysis led to a diagnosis and informed treatment and management of the disease. Therefore, we suggest using whole-exome sequencing in the evaluation and management of adults with unexplained liver disease.
Subject(s)
Exome Sequencing , Liver Diseases/genetics , ATP Binding Cassette Transporter, Subfamily B/deficiency , ATP Binding Cassette Transporter, Subfamily B/genetics , Adult , Aged , Cholestasis, Intrahepatic/genetics , Female , Genomics , Humans , Lipodystrophy, Familial Partial/genetics , Male , Middle Aged , PPAR gamma/geneticsABSTRACT
BACKGROUND: Teduglutide is a glucagon-like peptide 2 (GLP-2) analog that has been approved for the treatment of adult short bowel syndrome (SBS)-associated intestinal failure (IF; SBS-IF). Teduglutide increases villus height and crypt depth in the small bowel mucosa, promoting nutrition absorption and enteral independence from parenteral nutrition (PN). We aim to report our single-center experience with teduglutide in adult patients with SBS to provide real-world context to its use. METHOD: We conducted a retrospective analysis on patients managed within our tertiary-level intestinal rehabilitation program to identify patients with SBS-IF treated with teduglutide from 2009-2015. The current report includes all patients at our center who had any exposure to teduglutide, including those who received commercial drug after approval by the Food and Drug Administration (FDA) and outside the scope of clinical trials. RESULTS: A total of 18 patients were treated with teduglutide. Eleven patients (61%) achieved complete enteral independence from PN and/or intravenous fluids (IV) at a median time of 10 months (range: 3-36 months). PN/IV volume requirement was reduced in all patients except two. Ten of the 11 patients (91%) who achieved enteral autonomy had colon. All patients off PN/IV required additional oral vitamins and electrolyte supplementations. CONCLUSION: Our preliminary experience is consistent with prior reports of successful partial or complete weaning from PN/IV with teduglutide treatment in adult patients with SBS. The presence of colon appears to be favorable in obtaining enteral independence from PN/IV, regardless of residual small bowel length. Patients on teduglutide may remain at high risk of micronutrient deficiencies.
