Background and Aims: Hepatitis C Virus (HCV) is uniformly recurrent after liver transplant (LT) and recurrence is associated with an increased risk of mortality. Immunosuppressive medications increase the risk of chronic kidney disease, and the presence of chronic kidney disease presents a challenge for HCV treatment in LT recipients. The aim of this study was to assess changes in glomerular filtration rates (GFRs) of LT recipients receiving HCV treatment.

Methods: This is a retrospective study of LT patients who received HCV treatment between 2015 and 2016 (n = 60). The outcomes of interest were differences in serum creatinine levels and in GFR, measured at treatment initiation and at 24 weeks after treatment. The average age of the patients was 59 years-old, and 17% were cirrhotic and 67% were treatment-experienced. All patients received sofosbuvir/ledipasvir without ribavirin.

Results: All patients achieved sustained virologic response at 12 weeks after treatment (SVR12). At baseline, 55% of patients had GFR <60 mL/min per 1.73 m2. Among those patients, GFR did not change in 18%, 33% had improved GFR, and 48% had worsened GFR. Up to 45% of the patients had a GFR >60 mL/min per 1.73 m2. Among those patients, GFR did not change in 81%, and 19% had worsened GFR. In the entire cohort, 65% of patients had improved or stable GFR and 35% had worsened GFR. The average change in serum creatinine between baseline and 24 weeks was 0.10 (p = 0.18).

Conclusions: This study showed improved or unchanged GFR in 65% and worsened GFR in 35% of LT recipients who achieved SVR12. Worsening of GFR was more frequently encountered in those with impaired renal function at baseline. Caution should be used when treating HCV in LT recipients, especially those with baseline status of renal impairment.

Hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection is a complex clinical entity that has an estimated worldwide prevalence of 1–15%. Most clinical studies have shown that progression of disease is faster in HBV-HCV coinfected patients compared to those with monoinfection. Hepatocellular carcinoma development appears to have higher rate in coinfections. Viral replication in coinfected cells is characterized by a dominance of HCV over HBV replication. There are no established guidelines for treatment of HBV-HCV coinfection. Studies on interferon-based therapies and direct-acting antivirals have shown varying levels of efficacy. Clinical reports have indicated that treatment of HCV without suppression of HBV increases the risk for HBV reactivation. In this review, we appraise studies on both direct-acting antivirals and interferon-based therapies to evaluate the efficacy and rates of reactivation with each regimen. Screening for and prevention of coinfection are important to prevent serious HBV reactivations.

Repair of sustained liver injury results in fibrosis (i.e. the accumulation of extracellular matrix proteins), and ultimately the complete distortion of parenchymal architecture of the liver, which we call cirrhosis. Detecting and staging of fibrosis is thus a mainstay in the management of chronic liver diseases, since many clinically relevant decisions, such as starting treatment and/or monitoring for complications including hepatocellular carcinoma, may depend on it. The gold standard for fibrosis staging is liver biopsy, the role of which, however, is questioned nowadays because of cost, hazards and poor acceptance by patients. On the other hand, imaging techniques and/or measurement of direct and indirect serum markers have not proved to be completely satisfactory under all circumstances as alternatives to liver biopsy. Making progress in this field is now more crucial than ever, since treatments for established fibrosis appear on the horizon. Fine dissection of the pathways involved in the pathophysiology of liver diseases has put forward several novel candidate biomarkers of liver fibrosis, such as growth arrest-specific6, Mac-2-binding protein, osteopontin, placental growth factor, growth/differentiation factor 15 and hepatocyte growth factor. All molecules have been suggested to have potential to complement or substitute methods currently used to stage liver diseases. Here, we review the pros and cons for their use in this setting.

Background and Aims: To evaluate the prevalence and significance of elevated cancer antigen-125 (CA-125) levels in patients with cirrhosis being treated in a tertiary care liver center and its correlation with objective markers of disease severity.

Methods: We retrospectively reviewed medical records of 172 adult patients with cirrhosis (due to any etiology) after obtaining CA-125 serum analysis. Demographics, etiology of cirrhosis, model of end-stage liver disease (MELD) score, Child’s Turcotte-Pugh classification, albumin bilirubin (ALBI) score, degree of ascites, presence of esophageal varices, serum CA-125 level and various other parameters were collected. Statistical analysis was performed using SPSS software and descriptive statistics.

Results: Elevated CA-125 levels were noted in 147 patients (85%) of the study population. Higher MELD score was associated with higher CA-125 levels (p = 0.001). Statistically significant correlation was observed between elevated CA-125 levels and degree of ascites (p < 0.001), ALBI score (p < 0.001) and Child’s Turcotte-Pugh class (p < 0.001). No correlation was observed with presence or absence of esophageal varices. Near-normal CA-125 levels were noted in patients with cirrhosis but undetectable ascites on ultrasound imaging. No differences were observed in mean values between male and female patients (p = 0.207). Regression analysis confirmed that CA-125 levels had a better correlation with degree of ascites than MELD score or ALBI score.

Conclusions: Elevated CA-125 levels were noted in 85% of patients with cirrhosis at our center. Our study establishes that the more advanced the degree of decompensation based on MELD score, Child’s Turcotte-Pugh classification and ALBI score, the higher the elevation in CA-125. Absence of ascites was associated with normal CA-125 level, with a direct correlation between high levels and worsening ascites, but there was no statistically significant correlation with esophageal varices, indicating that elevated CA-125 levels could be related to mechanical stretch of the peritoneum rather than portal hypertension itself. Further multi-centered studies are required to confirm and validate these findings.

Hepatitis E virus (HEV) is one of the leading causes of acute viral hepatitis. It also causes acute liver failure and acute-on-chronic liver failure in many patients, such as those suffering from other infections/liver injuries or organ transplant/chemotherapy recipients. Despite widespread sporadic and epidemic incidents, there is no specific treatment against HEV, justifying an urgent need for developing a potent antiviral against it. This review summarizes the known antiviral candidates and provides an overview of the potential targets for the development of specific antivirals against HEV.

The composite tumors of the liver are very rare, including the coexistence of HCC (hepatocellular carcinoma) with NEC (neuroendocrine carcinoma). The rare occurrence of these tumors necessitates more reported cases in order to fully understand their clinical characteristics, behaviors and treatments. Herein is described an incidental collision tumor of HCC-NEC, along with a review of the literature focusing on their clinicopathological findings and prognosis. The tumor presented here was found incidentally in the hepatectomy specimen of a 56-year-old man who had undergone liver transplantation for rapidly progressive liver failure because of alcoholic hepatitis and cirrhosis. Imaging and laboratory examinations did not demonstrate tumor-related findings. During macroscopic examination, two sharply defined and distinctive areas (1.7 cm and 0.6 cm dimension respectively) were detected among the cirrhotic nodules. The characteristic histopathological features and immunohistochemical findings allowed a diagnosis of HCC-NEC to be made. There was no evidence of recurrence and metastasis after 10 months following surgery. The present case and review revealed that these tumors are frequently found in older ages and males. Although serum markers are valuable in the discrimination of malignant tumors, their absence cannot completely rule out composite HCC-NEC. Diagnosis requires a comprehensive histopathological evaluation together with immunohistochemistry. The NEC component might influence the treatment strategy and eventually the outcome of the patient. In conclusion, the rare occurrence of HCC-NEC and the lack of diagnostic clinical signs and symptoms do not exclude their consideration in the differential diagnosis of liver tumors, especially in patients with the chronic liver disease.

Non-alcoholic steatohepatitis (NASH) results from inflammation and hepatocyte injury in the setting of hepatic steatosis. Non-alcoholic steatohepatitis increases the risk of progression to liver fibrosis and cirrhosis, and is the most rapidly growing etiology for liver failure and indication for liver transplantation in the USA. Weight loss and lifestyle modification remain the standard first-line treatment, as no USA Food and Drug Administration-approved pharmacotherapy currently exists. The past decade has seen an explosion of interest in drug development targeting pathologic pathways in non-alcoholic steatohepatitis, with numerous phase 2 and 3 trials currently in progress. Here, we concisely review the major targets and mechanisms of action by class, summarize results from completed pivotal phase 2 studies, and provide a detailed outline of key active studies with trial data for drugs in development, including obeticholic acid, elafibranor, cenicriviroc and selonsertib.

When cells are subject to endoplasmic reticulum (ER) stress due to inflammation, inadequate nutrition or infection, a characteristic environment of glucose starvation, acidosis and hypoxia is created. All the conditions cited contribute to ER stress as well as the unfolded protein response (UPR). The UPR is active in a variety of human tumor types. Depending on the severity of ER stress, the UPR can exert a cytoprotective function by resolving the misfolded or unfolded protein, further reducing the ER protein load in mild stress, or by sending signal to cells to undergo cell death by apoptosis in the severe condition. Recent studies suggest that the glucose-regulated protein (GRP)78, or immunoglobulin heavy chain binding protein (BiP), not only confers an advantage to cell survival through an anti-apoptotic function but also may improve cell proliferation and angiogenesis. Understanding how the UPR can induce adaptation to chronic stress instead of apoptosis in cells will be of invaluable significance toward finding a cure for ER stress-associated diseases. This review covers what is known about the adaptive responses of cells when facing ER stress and how these information may lead to discoveries of novel treatments for various related disorders. Studies have suggested that ER stress promotes tissue remodeling under a variety of conditions and through several mechanisms, including activation of apoptosis, epithelial-mesenchymal transition, and enhanced inflammatory response. This review also focuses on the major cell components in the gut, primarily epithelial cells and mesenchymal cells, for which a myriad of evidence suggests that sustained ER stress causes epithelial cell damage along with resultant mucosal barrier dysfunction, stimulates mesenchymal cell differentiation, and induces myofibroblasts activation and their secretion of excess extracellular protein leading to matrix collagen-rich tissue formation. Several key questions are still not answered by the fibrosis research and are discussed in this review: for example, the mechanisms of ER stress induction and the specific signaling pathway(s) activated by which UPR leads to development of organ fibrosis, or how to maintain ER stress at a basal level instead of exacerbating its physiological role that is otherwise necessary to maintain intracellular homeostasis. Ultimately, further investigations are needed to bridge the gap between our current understanding of ER stress mechanisms and to identify efficient anti-fibrotic therapeutic regimens.

Nonalcoholic fatty liver disease (NAFLD) ranges from simple steatosis to NAFLD-related liver cirrhosis and is a main cause of chronic liver diseases. Patients with nonalcoholic steatohepatitis and fibrosis are at a great risk of the progression to cirrhosis or hepatocellular carcinoma, both of which are tightly associated with liver-related mortality. Liver biopsy is still the gold standard for the diagnosis of NAFLD, but some defects, such as serious complications, sampling error and variability in histologic evaluation among pathologists, remain problematic. Therefore, noninvasive, repeatable and accurate diagnostic methods are urgently needed. Ultrasonography is a well-established and lower-cost imaging technique for the diagnosis of hepatic steatosis, especially suitable for population census, but limited by its low sensitivity to diagnose mild steatosis and being highly operator-dependent. Computed tomography also lacks the sensitivity to detect mild steatosis and small changes in fat content, and presents a potential radiation hazard. Controlled attenuation parameter based on the FibroScan® technology is a promising tool for noninvasive semiquantitative assessment of liver fat content, but the accuracy rate depends on the operator’s expertise and is affected by age, width of the intercostal space, skin capsular distance and body mass index. Magnetic resonance imaging and magnetic resonance spectroscopy are regarded as the most accurate quantitative methods for measuring liver fat content in clinical practice, especially for longitudinal follow up of NAFLD patients. In this review, we mainly introduce the current imaging methods that are in use for evaluation of liver fat content and we discuss the advantages and disadvantages of each method.

Adoption of the model for end-stage liver disease score by Organ Procurement and Transplant Network (OPTN) deceased donor liver allocation policy in 2002 has led to an increase in the number of simultaneous liver kidney (SLK) transplantation. Since kidney function recovery following liver transplantation is difficult to predict, allocation of the kidney for SLK transplantation thus far has not been based on much rationale and evidence. Lack of OPTN policy towards SLK organ allocation has resulted in great variations among transplant centers regarding SLK transplantation. Increasing use of kidneys towards SLK transplantation diverts deceased donor kidneys away from candidates awaiting kidney-alone transplantation. Recently OPTN/United Network of Organ Sharing has implemented medical eligibility criteria for adult SLK transplantation which also includes a concept of safety net. Implementation of the new policy is a move in a positive direction, providing consistency in our practice and evidence-based guidelines in selecting candidates for SLK transplantation. This policy needs to be monitored prospectively and modified based on new data that will emerge over time. This review outlines the literature on SLK transplantation and efforts towards developing rational policy on SLK organ allocation.

Background and Aims: Recurrent hepatitis C (HCV) disease in liver transplant (LT) recipients is associated with significant morbidity and mortality. With the availability of noninterferon-based therapy, eliminating HCV may be achievable in LT recipients.

Methods: We studied all consecutive recipients who underwent LT at the University of California Los Angeles between January 2005 and June 2017. We collected data on date of transplant and last follow-up, as well as laboratory values. We also recorded type and timing of antiviral therapy relative to LT. Analyses were performed to assess the proportion of LT recipients who are viremic after transplant.

Results: Six hundred thirty-four patients underwent LT with a diagnosis of HCV. There was a statistically significant trend for patients to be cured before (p < 0.001) and after liver transplantation (p < 0.001) for the study period of 2014 to 2016 relative to 2005 and 2013, respectively. Of the 634 recipients eligible for therapy, 8% and 74% were treated within 12 months of transplant for the study periods 2005 to 2013 and 2014 to 2016, respectively. There was a significant decrease between the two study periods in the proportion of patients undergoing re-LT 1 year after the original LT: 5.5% (n = 28/510) and 1.5% (n = 2/124) respectively for study periods 2005 to 2013 and 2014 to 2016 respectively (p = 0.011).

Conclusions: The proportion of LT recipients who are viremic has decreased over time. Eliminating HCV in LT recipients is feasible after the introduction of direct-acting agents. Curing HCV should translate to improved clinical outcomes in LT recipients who were transplanted for HCV infection with longer follow-up. Preliminary results suggest the decreased need for transplant in the direct-acting agents era.

Asymptomatic bacteriuria (ASB) poses a serious health problem to pregnant women and fetuses. However, in most developing countries, routine screening for ASB and antimicrobial sensitivity test are rarely performed. This study, therefore, aimed to determine the best diagnostic method for routine screening of ASB and antimicrobial susceptibility pattern among pregnant women attending an antenatal clinic in the Ashanti Region of Ghana.

Urine samples from 412 pregnant women between the ages of 16 and 45 years-old attending antenatal clinic at Anglogold Ashanti Health Foundation Hospital and Ellolab Diagnostic Centre were screened for ASB by microscopy, dipstick urinalysis and bacteria culture. Susceptibility of the positive isolates were assessed against commonly used antimicrobial agents, adopting the disc diffusion test method.

Of the 412 pregnant women screened, 72 tested positive for ASB by the urine culture method, which translates into an overall prevalence of 17.5%. There was no association between age, marital status, occupation, parity, educational background nor duration of pregnancy with ASB (p > 0.05). Additionally, dipstick urinalysis was found to be a better diagnostic method than microscopy. The most isolated bacteria were Escherichia coli (62.5%) and Klebsiella pneumoniae (30.6%), and nitrofurantoin and nalidixic acid were the most effective antimicrobial agents.

Routine urine culture and antimicrobial susceptibility test should be carried out on all pregnant women attending antenatal clinic to detect possible ASB and prescribe appropriate drugs, such as nitrofurantoin and nalidixic acid, to prevent any related complications. However, in health centers that lack bacterial culture facilities, dipstick urinalysis should be the preferred screening option.

Regional anesthesia is the preferred modality for obstetric patients undergoing cesarean section due to the risks associated with general anesthesia in pregnant women. Single-shot spinal anesthesia is usually administered, which may be associated with post-block maternal hypotension, despite adequate intravenous fluid therapy. This is deleterious for the uteroplacental circulation, leading to poor outcomes in both the mother and fetus. There are several vasopressors which are used for treatment of these hypotensive episodes. Mephentermine is a sympathomimetic, having both direct and indirect actions. It has many side effects, however, including increased risks of arrhythmias, hypertension, central nervous system stimulation and abuse potential. Yet, it is still used in many developing countries, due to low cost and easy availability. We hereby report a case of rhythm disturbance with missed beats following use of mephentermine to counter hypotension after spinal anesthesia for cesarean section. The rhythm disturbance had a spontaneous resolution, with the patient maintaining hemodynamic stability during and after the episode.

Electromagnetic fields have been evaluated in multiple environments as a source of incidental exposure as well as a therapeutic treatment modality. At low levels and in specific therapies, electromagnetic fields have been found to be safe and may have positive effects on human physiology that improve disease course or alter the severity of some ailments. We conducted a study to investigate whether a commercial Federal Drug Administration-approved electromagnetic field generator device used for stress reduction and relaxation has the capability to impart a measurable impact on the cardiac autonomic nervous system.

This study was designed as a randomized double-blind, sham-stimulation controlled study in healthy subjects. The stimulation or treatment was the application of parasympathetic-targeted electromagnetic fields through the Federal Drug Administration-approved Resonator® device for 60 m. The primary measurements of treatment effect were heart rate variability (measured at baseline and every 15 m) and salivary cortisol (pre- and postapplication). The active treatment consisted of two sessions, 60 m in duration. The electromagnetic field algorithm applied was A160 (3.1 × 10−8 to 3.2 × 10−8 Gauss, frequency range of 0.857–0.859 Hz). All participants received both a sham and an active treatment session, the order of which was randomized.

A total of 28 patients completed both sessions. The measured difference in cortisol between the groups was not statistically significant (p = 0.66). There was a trend towards decreased cortisol levels over time in both groups (p = 0.09 for time trend). Measured heart rate variability showed a nonsignificant reduction in low frequency to high frequency ratio (low frequency/high frequency) at 60 m.

While the results were nonsignificant, the trend towards a reduction in low frequency/high frequency is suggestive of a delayed electromagnetic field effect. This study is hypothesis-generating since additional research is needed to either adjust the electromagnetic field treatment dose/duration during sessions or delay the final data collection of heart rate variability and salivary cortisol until hours after the active treatment.

Malaria and tuberculosis remain endemic in tropical regions and most often coexist, increasing the burden of malaria mortality due to unintended interactions of the co-administered drugs employed in the management of the infections. Rifampicin (RIF) and amodiaquine (ADQ) are likely to be administered concurrently in the treatment of patients with tuberculosis and malaria. The metabolism of ADQ is mediated principally by CYP2C8, while RIF is a known inducer of this enzyme. This study, therefore, investigated the effect of RIF on the disposition of ADQ, a major partner drug in the first-line treatment against uncomplicated malaria in line with the World Health Organization recommendations.

Sixteen healthy volunteers received oral 150 mg dose of RIF daily for 5 days with or without oral 600 mg single dose of ADQ on the fifth day (5th dose) with a 4-week wash out period, in a crossover fashion. Blood samples were collected at predetermined time intervals of 0, 1, 2, 4, 6, 8, 12, 24, 36 and 48 h. Plasma samples were analyzed for ADQ and its major metabolite desethylamodiaquine using a validated RP-high-performance liquid chromatography. Pharmacokinetic parameters were obtained using appropriate software and subjected to appropriate statistical analysis.

Coadministration of ADQ and RIF resulted in significant decreases in the critical pharmacokinetic parameters of ADQ, such as area under the curve (AUC0–∞) of about 66%, time to peak plasma concentration (Tmax) of about 10%, maximum plasma concentration of about 44%, and elimination half-life of about 55%, while the AUC0–∞ and Tmax of the main metabolite desethylamodiaquine increased about 2-fold and 3-fold respectively during the coadministration of RIF with ADQ. The metabolic ratio increased significantly, from 1.55 to 2.68. The AUC0–∞ and Tmax of the drug ADQ, as well as the maximum concentration of both the drug and its metabolite fell outside the point of estimates of the test/reference ratio of the geometric means of 80–125% of bioequivalence range.

An interaction was established during coadministration of RIF and ADQ, confirming RIF as a strong inducer of CYP2C8 in vivo, which may lead to malaria therapeutic failure or adverse drug reactions with ADQ and contribute to the rate at which resistance to ADQ develops.