Clinical utility of genomic analysis in adults with idiopathic liver disease.

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 18 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 (∼25%) 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.

High prevalence of antibiotic-resistant bacterial infections among patients with cirrhosis at a US liver center.

BACKGROUND & AIMS: There are limited data on the prevalence or predictors of antibiotic-resistant bacterial infections (AR-BI) in hospitalized patients with cirrhosis in North America. Exposure to systemic antibiotics is a risk factor for AR-BI; however, little is known about the effects of the increasingly used oral nonabsorbed antibiotics. METHODS: We analyzed data from patients with cirrhosis and bacterial infections hospitalized in a liver unit at a US hospital between July 2009 and November 2010. Multivariate logistic regression was used to determine predictors of AR-BI. Data were analyzed on the first bacterial infection of each patient (n = 115), and a sensitivity analysis was performed on all infectious episodes per patient (n = 169). RESULTS: Thirty percent of infections were nosocomial. Urinary tract infections (32%) and spontaneous bacterial peritonitis (24%) were most common. Of the 70 culture-positive infections, 33 (47%) were found to be antibiotic resistant (12 were vancomycin-resistant Enterococci, 9 were extended-spectrum ß-lactamase-producing Enterobacteriaceae, 7 were quinolone-resistant gram-negative rods, and 5 were methicillin-resistant Staphylococcus aureus). Exposure to systemic antibiotics within 30 days before infection was associated independently with AR-BI, with an odds ratio (OR) of 13.5 (95% confidence interval [CI], 2.6-71.6). Exposure to only nonabsorbed antibiotics (rifaximin) was not associated with AR-BI (OR, 0.4; 95% CI, 0.04-2.8). In a sensitivity analysis, exposure to systemic antibiotics within 30 days before infection and nosocomial infection was associated with AR-BI (OR, 5.2; 95% CI, 1.5-17.7; and OR, 4.2; 95% CI, 1.4-12.5, respectively). CONCLUSIONS: The prevalence of AR-BI is high in a US tertiary care transplant center. Exposure to systemic antibiotics within 30 days before infection (including those used for prophylaxis of spontaneous bacterial peritonitis), but not oral nonabsorbed antibiotics, is associated with development of an AR-BI.

Advance Care Planning for Patients with Cirrhosis in a Structured Inpatient/Outpatient Hepatology Program.

Background: Patients with end-stage liver disease (ESLD) have high mortality, but low utilization of palliative care. A transitional care liver clinic (TCLC), bridging inpatient hepatology care to outpatient clinics, should offer the ideal setting for advance care planning (ACP). Objective: To examine ACP and related outcomes for TCLC patients who died within one year of the initial TCLC visit. Design: Retrospective chart review. Setting: Nontransplant eligible ESLD patients, seen in TCLC postdischarge from an inpatient liver unit. Measurements: Charts were reviewed for demographics, clinical data, ACP discussions, code status, location of death, and palliative care consultations. Results: Of the 58 patients who showed for the initial TCLC visit, 18 (31%) died within one year. Most patients were men (67%) with alcoholic cirrhosis (72%), Child-Pugh class C (55.5%) and median age of 56 years (37-72 years). There were no ACP discussions in any TCLC visits even after subsequent hospitalizations. Until their terminal hospitalization, 17 patients (94%) remained full code. Palliative care was consulted for 10 patients (56%). Despite late initiation, within two weeks of death for 6 of those 10 patients, palliative care consultation facilitated arrangements for out-of-hospital death: at home or inpatient hospice (70% vs. 12%, p = 0.01). Conclusions: Despite a structured program for ESLD patients, there were no ACP discussions until the terminal hospitalization. These findings support the need to integrate palliative care interventions in the management of ESLD patients, especially taking advantage of postdischarge visits.

Being accompanied to liver discharge clinic: An easy measure to identify potential liver transplant candidates among those previously considered ineligible.

BACKGROUND: Patients with cirrhosis deemed ineligible for liver transplantation are usually followed in general hepatology or gastroenterology clinics, with the hope of re-evaluation once they meet the appropriate criteria. Specific strategies to achieve liver transplant eligibility for these patients have not been studied. AIM: To assess clinical and sociodemographic factors associated with future liver transplant eligibility among patients initially considered ineligible. METHODS: This is a retrospective study of patients with cirrhosis considered non-transplant eligible, but without absolute contraindications, who were scheduled in our transitional care liver clinic (TCLC) after discharge from an inpatient liver service. Transplant candidacy was assessed 1 year after the first scheduled TCLC visit. Data on clinical and sociodemographic factors were collected. RESULTS: Sixty-nine patients were identified and the vast majority were Caucasian men with alcoholic cirrhosis. 46 patients (67%) presented to the first TCLC visit. Seven of 46 patients that showed to the first TCLC visit became transplant candidates, while 0 of 23 patients that no-showed did (15.2% vs 0%, P = 0.08). Six of 7 patients who showed and became transplant eligible were accompanied by family or friends at the first TCLC appointment, compared to 13 of 39 patients who showed and did not become transplant eligible (85.7% vs 33.3%, P = 0.01). CONCLUSION: Patients who attended the first post-discharge TCLC appointment had a trend for higher liver transplant eligibility at 1 year. Being accompanied by family or friends during the first TCLC visit correlated with higher liver transplant eligibility at 1 year (attendance by family or friends was not requested). Patient and family engagement in the immediate post-hospitalization period may predict future liver transplant eligibility for patients previously declined.