Safety and efficacy of in vitro fertilisation in patients with chronic liver disease and liver transplantation recipients.

BACKGROUND & AIMS: Chronic liver disease and liver transplantation (LT) can delay both timing and ability of women to conceive. With increased awareness and availability of in vitro fertilisation (IVF), the need for accurate counselling is paramount. To date, minimal data exist on outcomes of IVF in patients with chronic liver disease, cirrhosis, or post-LT. We report the largest experience of IVF in women with liver-related subfertility (LRSF). METHODS: A retrospective analysis was performed on 42 women with LRSF who had undergone 57 IVF cycles between 1990 and 2019. RESULTS: Forty-two women with LRSF received IVF; 9 cycles in 6 women with cirrhosis, 14 cycles in 11 women post-LT, and 34 cycles in 25 women without cirrhosis. The main aetiologies of liver disease included HBV, HCV, and autoimmune hepatitis (AIH). Of 57 IVF cycles evaluated, 43 (75%) resulted in successful implantation. Eight (2 post-LT, 3 with cirrhosis, 4 without cirrhosis) resulted in miscarriage. The live birth rate (LBR) was 74% (32/43). Two of 9 (22%) patients with cirrhosis, 4/14 (29%) patients who were post-LT, and 6/34 (18%) patients without cirrhosis had unsuccessful IVF attempts. Nine of 57 (16%) IVF cycles resulted in new liver enzyme derangement during therapy, which improved after treatment completion. Six pregnancies (2 in patients who were post-LT, 4 without cirrhosis) were complicated by obstetric cholestasis (OC). Ovarian hyperstimulation syndrome (OHSS) was rare (n = 3, 7%). One patient with AIH-related cirrhosis decompensated after initiating IVF, warranting discontinuation of therapy. There were no maternal deaths. Three women developed a hypertensive disorder of pregnancy. Half the pregnancies resulted in premature deliveries (range 27-36 weeks). CONCLUSIONS: In selected cases, IVF in women with LRSF can be successful. However, patients should be counselled on the potential increased risks of OHSS, OC, and prematurity. LAY SUMMARY: Women with liver disease or those who have had a liver transplant can experience difficulties getting pregnant. In this study, we look at whether alternative approaches to achieve pregnancy are harmful in these women. Overall, there were no significant issues with the use of in vitro fertilisation in women with liver disease, but they need to be aware of potential risks, such as early delivery of the baby.

Bacterial Infection in Patients with Cirrhosis: Don't Get Bugged to Death.

Bacterial infection remains a leading cause of mortality and morbidity for patients with cirrhosis, with hospitalization, alterations in the intestinal microbiota, and therapeutic drugs all implicated in its development. Bacterial infections also remain the most common precipitant of acute-on-chronic liver failure, with infection occurring as a direct consequence of the progression of this syndrome. Furthermore, recent epidemiological analyses have demonstrated that infections due to multidrug-resistant bacteria are occurring with increasing frequency in patients with cirrhosis. Despite significant advances in the understanding of the pathophysiological processes triggered by an infection in patients with cirrhosis, a demonstrable survival benefit for the sickest patients who require ICU admission has not yet occurred. Early diagnosis of infection and appropriate antimicrobial treatment is essential to ensuring optimal outcomes for these patients. This review provides an evidence-based analysis of both the current strategies for prevention and the recommended management of common bacterial infections in patients with cirrhosis.

Non-Invasive Markers (ALBI and APRI) Predict Pregnancy Outcomes in Women With Chronic Liver Disease.

OBJECTIVES: Rates of pregnancy in women with cirrhosis are increasing. Risk of hepatic decompensation during pregnancy, therefore, merits tailored obstetric and hepatology care. Prognostic markers that determine pregnancy outcomes are lacking. METHODS: Medical records of women who attended hepatology clinic at King's College Hospital with chronic liver disease (CLD) who became pregnant from 1983 to 2017 were reviewed. Information on demographics, clinical history, serology, and outcome of pregnancy was collected. RESULTS: In all, 165 pregnancies occurred in 100 women with CLD including 80 pregnancies in 48 women with cirrhosis. Median age of conception in cirrhotic and non-cirrhotic women were 26 years (16-44) and 28 years (16-51) respectively (p = 0.015). Whilst women with cirrhosis had similar live birth rate to non-cirrhotic women (75 vs. 85% p = 0.119), they were significantly less likely to proceed beyond 37 weeks gestation (45 vs. 58% p = 0.033). Women who received preconception counseling were more likely to have stable liver disease at conception (100 vs 86% p = 0.02). Compared with preconception MELD (model for end stage liver disease), preconception Albumin-Bilirubin score (ALBI) more accurately predicted live birth with an area under the receiver-operator curve (AUROC) of 0.741 (p < 0.001), and preconception AST to platelet ratio index (APRI) more accurately predicted ability to proceed beyond 37 weeks gestation with an AUROC of 0.700 (p < 0.001). CONCLUSIONS: Most women with cirrhosis who conceived achieved a successful pregnancy outcome. ALBI and APRI scores can prognosticate pregnancy outcomes in women with CLD. Preconception counseling by a hepatologist or specialist obstetrician improved patient care in this group.

Successful pregnancy outcomes following liver transplantation is predicted by renal function.

Liver transplantation (LT) is a successful treatment for both acute liver failure and end-stage liver disease. The number of women of reproductive age undergoing LT is increasing. Pregnancy outcomes are favorable, but there is still a lack of prognostic markers. We aimed to identify factors predictive of adverse pregnancy outcomes in LT recipients. An analysis of all pregnancies occurring in LT recipients from 1989 to 2016 at King's College Hospital was performed. Clinical data of 162 conceptions in 93 women were reviewed. Descriptive and regression analyses were done to examine associations between laboratory markers and hepatological scores with pregnancy outcomes of live birth and preterm birth. Median age at LT was 23 years (range, 1-41 years), with a median age at conception of 30 years (range, 18-47 years). The live birth rate was 75% (n = 121). Of live births, 35% (n = 39/110 available) were delivered preterm. Preconception creatinine levels were higher in patients who had a preterm birth (85 versus 74 µmol/L; P = 0.008), with a preconception estimated glomerular filtration rate (eGFR) <90 mL/minute significantly associated with preterm delivery (P = 0.04). Progressive decline in eGFR predicted outcome, with gestational length declining with increasing chronic kidney disease (CKD) stage: CKD 0-1 = 39 weeks (median), CKD 2 = 37 weeks, and CKD 3 = 35 weeks. The risk of preterm birth was greatest in women with an eGFR <60 mL/minute (P = 0.004). Moreover, hypertension-related complications during pregnancy, such as gestational hypertension, preeclampsia, or eclampsia, were also associated with prematurity (P = 0.01). Women taking steroid-based immunosuppression had an increased risk of infection during pregnancy or postpartum (15% versus 4%; P = 0.02). In conclusion, although the majority of women have a successful pregnancy outcome after LT, preconception renal function predicts pregnancy outcome and steroids increase risk of infection during pregnancy or postpartum. Liver Transplantation 24 606-615 2018 AASLD.

Palliative care in end-stage liver disease: Time to do better?

Optimal involvement of palliative care (PC) services in the management of patients with decompensated cirrhosis and end-stage liver disease (ESLD) is limited. This may result from both ignorance and the failure to recognize the spectrum and unpredictability of the underlying liver condition. Palliative care is a branch of medicine that focuses on quality of life (QoL) by optimizing symptom management and providing psychosocial, spiritual, and practical support for both patients and their caregivers. Historically, palliative care has been underutilized for patients with decompensated liver disease. This review provides an evidence-based analysis of the benefits of the integration of palliative care into the management of patients with ESLD. Liver Transplantation 24 961-968 2018 AASLD.

Co-prescription of gastro-protectants in hospitalized patients: an analysis of what we do and what we think we do.

BACKGROUND: Proton pump inhibitors (PPIs) reduce the risk of upper gastrointestinal hemorrhage (UGIH) associated with the use of many medications. GOALS: To examine how clinicians perceive such risk and whether PPI co-prescribing is based on an accurate assessment. STUDY METHODS: Clinicians in a single teaching hospital were asked to estimate risk of UGIH and comment on PPI co-prescription in hypothetical patients. Records of 160 hospital in-patients (median age; 74 y) were then reviewed to examine PPI prescribing and risk factors for UGIH. RESULTS: In general, clinicians estimated UGIH risk accurately and reported low thresholds for PPI co-prescription. Prescribing records showed regular PPI use increased between admission and discharge of patients from 61/160 (38%) to 93/160 (58%). Ten percent had a prior history of peptic ulcer disease. Proton pump inhibitor prescription was significantly associated with the use of aspirin and clopidogrel. Half of the patients with multiple risk factors for UGIH on admission and almost a third at discharge were not co-prescribed a PPI. CONCLUSIONS: Clinicians generally estimate correctly the risk of UGIH and report a low threshold for prescribing gastro-protection. Despite this, prescribing practice does not consistently take account of relative risk of UGIH. Targeted PPI co-prescribing on the basis of risk factors would lead to more rational PPI use.

Bid and calpains cooperate to trigger oxaliplatin-induced apoptosis of cervical carcinoma HeLa cells.

The Bcl-2 homology 3-only protein Bid is an important mediator of death receptor-induced apoptosis. Recent reports and this study suggest that Bid may also mediate genotoxic drug-induced apoptosis of various human cancer cells. Here, we characterized the role of Bid and the mechanism of Bid activation during oxaliplatin-induced apoptosis of HeLa cervical cancer cells. Small hairpin RNA-mediated silencing of Bid protected HeLa cells against both death receptor- and oxaliplatin-induced apoptosis. Expression of a Bid mutant in which caspase-8 cleavage site was mutated (D59A) reactivated oxaliplatin-induced apoptosis in Bid-deficient cells but failed to reactivate death receptor-induced apoptosis, suggesting that caspase-8-mediated Bid cleavage did not contribute to oxaliplatin-induced apoptosis. Overexpression of bcl-2 or treatment with the pan-caspase inhibitor N-benzyloxycarbonyl-Val-Ala-dl-Asp-fluoromethylketone abolished caspase-2, -8, -9, and -3 activation as well as Bid cleavage in response to oxaliplatin, suggesting that Bid cleavage occurred downstream of mitochondrial permeabilization and was predominantly mediated by caspases. We also detected an early activation of calpains in response to oxaliplatin. Calpain inhibition reduced Bid cleavage, mitochondrial depolarization, and activation of caspase-9, -3, -2, and -8 in response to oxaliplatin. Further experiments, however, suggested that Bid cleavage by calpains was not a prerequisite for oxaliplatin-induced apoptosis: single-cell imaging experiments using a yellow fluorescent protein-Bid-cyan fluorescent protein probe demonstrated translocation of full-length Bid to mitochondria that was insensitive to calpain or caspase inhibition. Moreover, calpain inhibition showed a potent protective effect in Bid-silenced cells. In conclusion, our data suggest that calpains and Bid act in a cooperative, but mutually independent, manner to mediate oxaliplatin-induced apoptosis of HeLa cells.

Efficacy and Tolerability of Direct-Acting Antivirals for Hepatitis C in Older Adults.

OBJECTIVES: To evaluate the efficacy and tolerability of direct-acting antiviral (DAA) therapy in individuals aged 65 and older. DESIGN: Retrospective review between June 2014 and January 2017. SETTING: Viral hepatitis outpatient clinic. PARTICIPANTS: Individuals aged 65 and older treated with DAA therapy for hepatitis C virus (HCV) during the study period (N=113) divided into 2 cohorts: aged 65 to 74 (n=88) and aged 75 and older (n=25). MEASUREMENTS: Drug-drug interactions (DDIs), adverse events (AEs), and rates of sustained virologic response with DAA therapy were assessed. RESULTS: Sustained virologic response rate was 97.7% in individuals aged 65 to 74 and 95.8% in those aged 75 and older. Individuals aged 75 and older were more likely to be taking more than 2 medications per day for chronic conditions (84% vs 62%, p=.02) and more likely to have clinically significant DDIs necessitating cessation or adjustment of medications before commencement of DAA therapy (80% vs 36%, p=.001). Moreover, individuals aged 75 and older were more likely to experience an AE during therapy (50% vs 26%, p=.03) and were more susceptible to developing anemia secondary to ribavirin (60% vs 20%, p=.02). CONCLUSION: DAA therapy is highly efficacious for the treatment of HCV in older adults, but those aged 75 and older are more likely to have clinically significant pretreatment DDIs and experience AEs, including ribavirin-induced anemia, during therapy.

Severe Symptomatic Primary CMV Infection in Inflammatory Bowel Disease Patients with Low Population Seroprevalence.

BACKGROUND: Cytomegalovirus disease in patients with inflammatory bowel disease is frequently the result of viral reactivation. Conversely, primary CMV infection is believed to be uncommon in immunocompetent adults due to high population seroprevalence. OBJECTIVES: The aim of this study was to examine the frequency and severity of primary cytomegalovirus infection in an adult cohort of IBD patients. STUDY DESIGN: A retrospective review of a prospectively maintained database of 3200 IBD patients attending a single academic centre was performed. Patients with primary CMV infection 2010-13 were identified; clinical, serologic, and virologic parameters were studied in detail. The seroprevalence of CMV in the patient population was also evaluated. RESULTS: Eight patients with IBD (UC = 3, IBD-U = 1, CD = 4) presented with primary CMV infection. Patients presented with both gastrointestinal and extraintestinal symptoms. Mean age was 33 years, and median duration of disease was 72 months. All eight patients were receiving a thiopurine immunomodulator. Median duration of IM use was 144 weeks (range 7-720 weeks). All 8 patients required hospitalisation, with 1 ICU admission; the median length of hospital stay was 11 days (range 6-27). Infection resolved in all cases with withdrawal of immunomodulator and/or antiviral therapy. Seroprevalence of IgG to CMV, indicating prior exposure, in a subgroup of IBD patients (n = 80) was 30.5% and increased with age. CONCLUSION: Primary cytomegalovirus infection can cause a severe illness in IBD patients, particularly those receiving immunosuppression. In areas where adult CMV seroprevalence is low, evidence of CMV should be sought in IBD patients presenting with any febrile systemic illness.

Systems analysis of BCL2 protein family interactions establishes a model to predict responses to chemotherapy.

Apoptotic desensitization is a hallmark of cancer cells, but present knowledge of molecular systems controlling apoptosis has yet to provide significant prognostic insights. Here, we report findings from a systems study of the intrinsic pathway of apoptosis by BCL2 family proteins and clinical translation of its findings into a model with applications in colorectal cancer (CRC). By determining absolute protein quantifications in CRC cells and patient tumor samples, we found that BAK and BAX were expressed more highly than their antiapoptotic inhibitors. This counterintuitive finding suggested that sole inhibition of effector BAX and BAK could not be sufficient for systems stability in nonstressed cells. Assuming a model of direct effector activation by BH3-only proteins, we calculated that the amount of stress-induced BH3-only proteins required to activate mitochondrial apoptosis could predict individual death responses of CRC cells to 5-fluorouracil/oxaliplatin. Applying this model predictor to protein profiles in tumor and matched normal tissue samples from 26 patients with CRCs, we found that differences in protein quantities were sufficient to model the increased tumor sensitivity to chemotherapy compared with normal tissue. In addition, these differences were sufficient to differentiate clinical responders from nonresponders with high confidence. Applications of our model, termed DR_MOMP, were used to assess the impact of apoptosis-sensitizing drugs in lowering the necessary dose of state-of-the-art chemotherapy in individual patients. Together, our findings offer a ready clinical tool with the potential to tailor chemotherapy to individual patients.