Noninvasive Methods for Assessing Liver Fibrosis and Steatosis.

Accurate diagnosis and staging of liver fibrosis is crucial to the individualized management of patients with chronic liver disease. Liver biopsy remains the reference standard for the assessment of steatosis, necroinflammation, and fibrosis. However, over the past decade, there has been an exponential growth in noninvasive tests (NITs) designed to assess liver fibrosis and steatosis. These NITs range from serum biomarkers to imaging assessments of liver tissue stiffness. Current noninvasive methods overcome the limitations of non-specific laboratory markers, conventional imaging, and invasive procedures, and are now starting to be adopted. The Fibrosis-4 index, Enhanced Liver Fibrosis test, and elastography have gained the strongest clinical footholds for the diagnosis of advanced fibrosis. There remains significant interest in demonstrating superiority of any specific test or, alternatively, optimizing a sequential algorithm to provide the most accurate diagnosis of fibrosis staging. This article reviews currently available noninvasive methods for assessing liver fibrosis and steatosis.

Pivoting to telemedicine in a single-day multidisciplinary liver tumor clinic during COVID-19: the Texas Liver Tumor Center experience.

Cancer guidelines recommend that all patients with hepatocellular carcinoma (HCC) have an evaluation by a multidisciplinary team to assess liver health, stage the cancer, and discuss treatment and palliative care options. Coronavirus disease 2019 (COVID-19) had a catastrophic impact on patients with cancer resulting in increased disease burden due to late diagnosis and treatment delays. Late diagnosis has highlighted the need for the early intervention of palliative care for patients with HCC. Conversion to telemedicine has been essential to caring for patients with all stages of cancer without added delays. Texas Liver Tumor Center (TLTC) offers patients with liver cancer at any stage a single-day multidisciplinary evaluation with tumor board review facilitating the early integration of treatment and palliative care services. National Comprehensive Cancer Network (NCCN) guidelines support increasing and improving access to palliative care. TLTC allows for the early integration of palliative care within a 1-day clinic model with an incorporated tumor board. This unique model of patient care decreases the burden of separate patient visits, may expedite the time from diagnosis to first treatment, facilitates the early intervention of palliative care specialists, and allows for optimal screening for clinical trials. In this review, we will provide an overview of the current multidisciplinary models of care for HCC and describe the successful pivot of TLTC from a fully in-person single-day multidisciplinary clinic with a multidisciplinary tumor board (MDTB) to a fully virtual experience, thereby maintaining access to this unique clinical model of patient care during the COVID-19 pandemic. The ability to pivot from in-person clinical visits to completely virtual visits increases patient access to care and enables more physicians to participate. Areas for future study include the impact on patient experience, clinical outcomes, and cost-effectiveness of this high-resource model.

Management of autoimmune and viral hepatitis in immunotherapy: a narrative review.

BACKGROUND AND OBJECTIVE: Cancer immunotherapy has firmly established itself as a pillar of cancer care due to its advantages over traditional anti-tumor therapy but also carries limitations due to potential for severe adverse reactions. This review highlights the current understanding and management of patients with autoimmune and viral hepatitis immune in the setting of immune checkpoint inhibitor (ICI) therapy. METHODS: A literature search was conducted on PubMed, Scopus, Google Scholar SEER*Stat databases (from inception to December 2022) using search terms: "immune checkpoint inhibitor", "autoimmune hepatitis", "viral hepatitis", "HBV pathogenesis", "HCV pathogenesis", "HBV reactivation", "HCV reactivation", "cancer immunotherapy", "immune related adverse events", "immune related hepatitis". KEY CONTENT AND FINDINGS: Pre-existing autoimmune disease (AD), whether active or inactive, can predispose patients receiving ICI therapy to develop autoimmune disease flares or immune-related adverse events (irAEs). Thus, patients with AD have routinely been excluded from clinical trials and data on safety of ICI therapy are limited. Hepatic irAE can be seen in ICI therapy and is a distinct entity from autoimmune hepatitis (AIH). ICI therapy alters the immune environment in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Patients who had prior exposure to HBV are at risk for viral reactivation. However, the prevalence of viral hepatitis in patients receiving immunotherapy is under-recognized and can lead to increases in liver biochemical tests as well as deterioration of liver function ultimately limiting treatment. CONCLUSIONS: The high morbidity and mortality associated with immune-related hepatitis emphasizes the need for screening of underlying diseases, including autoimmune and viral hepatitis, prior to initiation of ICI. Presence of AIH or chronic viral hepatitis is the most important risk factor for hepatic adverse events in ICI therapy. Screening for AIH, HBV and HCV is paramount in patients who will undergo ICI therapy.

High sustained virologic response rates, regardless of race or socioeconomic class, in patients treated with chronic hepatitis C in community practice using a specialized pharmacy team.

Approved direct-acting antiviral (DAA) regimens against hepatitis C virus (HCV) can cure nearly all patients; however, socioeconomic disparities may impact access and outcome. This study assesses socioeconomic factors, differences in insurance coverage and the drug prior authorization process in HCV-infected patients managed in community practices partnered with a dedicated pharmacy team with expertise in liver disease. This Institutional Review Board-approved, ongoing study captures data on a cohort of 2480 patients from community practices. Patients had chronic hepatitis C and were treated with DAA regimens selected by their physician. The HCV Health Outcomes Centers Network provides comprehensive patient management including a dedicated pharmacy support team with expertise in the prior authorization process. In this cohort, 60.1% were male, 49% were Hispanic Whites (HW), 37% were Non-Hispanic Whites (NHW), and 14% were Black/African American (BAA). Eighty-seven percent of patients were treatment-naïve, 74% were infected with genotype 1 virus and 63% had advanced fibrosis/cirrhosis (F3/F4 = 68.2% HW, 65.6% BAA, 55.4% NHW). Forty percent of patients were on disability with the highest percentage in the BAA group and less than one-third were employed full time, regardless of race/ethnicity. Medicare covered 42% of BAA patients versus 32% of HW and NHW. The vast majority of HW (80%) and BAA (75%) had a median income below the median income of Texas residents. Additionally, 75% of HW and 71% of BAA had median income below the poverty level in Texas. Despite the above socioeconomic factors, 92% of all prior authorizations were approved upon first submission and patients received DAAs an average of 17 days from prescription. DAA therapy resulted in cure in 95.3% of patients (sustained virologic response = 94.8% HW, 94.0% BAA, 96.5% NHW). Despite having more advanced diseases and more negative socioeconomic factors, >94% of HW and BAA patients were cured. Continued patient education and communication with the healthcare team can lead to high adherence and > 94% HCV cure rates regardless of race/ethnicity or underlying socioeconomic factors in the community setting.

Hepatitis C Virus Treatment and Solid Organ Transplantation.

Hepatitis C virus (HCV) infection is a common indication for liver transplantation. If the patient's HCV is untreated prior to liver transplant, infection of the allograft is nearly universal and can lead to graft failure. The demand for deceased-donor organ transplantation continues to surpass the available supply of donor organs. Waitlist mortality remains an important concern, and several strategies have been enacted to increase organ supply, such as using high-risk donors, including those who are HCV positive. The development of safe and highly effective HCV therapy with direct-acting antiviral agents has revolutionized the management of liver transplant candidates and transplantrecipients. Moreover, thenewer antiviral therapieshave paved the road for use of HCV-viremic organs, effectively expanding the donor pool and changing the landscape of solid organ transplantation. This article reviews the data on HCV treatment prior to and after organ transplantation.

Review of Current and Potential Treatments for Chronic Hepatitis B Virus Infection.

Chronic hepatitis B virus (HBV) infection remains a major global health burden. Millions of people are at risk for complications of chronic HBV infection, despite the widespread availability of an effective prophylactic vaccine. The current available treatments for HBV infection-interferon and nucleos(t)ide analogues-are effective at suppressing viral replication and decreasing the risk of cirrhosis. However, these treatments have a number of limitations, creating the need for alternative therapeutic agents. Recent advances in drug therapy have heralded a new horizon of novel therapeutic approaches for chronic HBV infection, with several promising antiviral and immunomodulatory agents currently in preclinical or clinical testing. This article reviews the current landscape of HBV treatments and highlights the most recent therapeutic strategies designed to directly target HBV or to improve immune response during chronic infection.

Improving Advance Care Planning in Outpatients With Decompensated Cirrhosis: A Pilot Study.

BACKGROUND: Despite significant morbidity and mortality among patients with decompensated cirrhosis, reported rates of advance directive (AD) completion and goals of care discussions (GCDs) between patients and providers are very low. We aimed to improve these rates by implementing a hepatologist-led advance care planning (ACP) intervention. MEASURES: Rates of AD and GCD completion, as well as self-reported barriers to ACP. INTERVENTION: Provider-led ACP in patients with decompensated cirrhosis without a prior documented AD. OUTCOMES: Sixty-two patients were seen over 115 clinic visits. After the intervention, AD completion rates increased from 8% to 31% and GCD completion rates rose from 0% to 51%. Women (P = 0.048) and nonmarried adults (P = 0.01) had greater changes in AD completion compared to men and married adults, respectively. Needing more time during visits was seen as the major barrier to ACP among providers. CONCLUSIONS/LESSONS LEARNED: Addressing provider and system-specific barriers dramatically improved documentation rates of ACP.

Strongyloides stercoralis Hyperinfection Syndrome as a Cause of Fatal Gastrointestinal Hemorrhage.

Strongyloides stercoralis is a small intestinal nematode that is widespread in regions with poor sanitation. We present a 57-year-old man from Colombia who was undergoing corticosteroid therapy for a meningioma who presented after neurosurgery with abdominal pain and a profound gastrointestinal (GI) bleed. The patient underwent an esophagogastroduodenoscopy (EGD), an attempted embolization, and an exploratory laparotomy to remove the necrosed duodenum. His pathology examination revealed Strongyloides infection of the duodenum, and he died of profound blood loss. This rare diagnosis displays the importance of screening patients at a high risk of Strongyloides infection before starting glucocorticoid therapy.

Liver Disease in Human Immunodeficiency Virus Infection.

Liver disease in human immunodeficiency virus (HIV) remains a main cause of morbidity and mortality. Liver-related morbidity and mortality can be caused by multiple etiologic factors, including opportunistic infections, direct and indirect effects of antiretrovirals, direct and indirect effects of HIV, and viral hepatitides. These factors present with varied liver pathophysiologic mechanisms that lead to abnormalities in liver enzymes and synthetic function test, followed by distinct clinical presentations. This article elucidates the direct effects on HIV in the liver and explores the diagnostic and management challenges in patients with HIV in the era of highly active antiretroviral treatment.

Diagnosis and Evaluation of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis, Including Noninvasive Biomarkers and Transient Elastography.

The incidence and prevalence of nonalcoholic fatty liver disease (NAFLD) are increasing and identification of people at risk of disease progression is extremely important. The current gold standard for diagnosing NAFLD/nonalcoholic steatohepatitis (NASH) is by liver biopsy, but it has several limitations. Noninvasive tests via biomarkers and transient elastography to assess NAFLD/NASH are being used in clinical practice. The most validated diagnostic panels include the NAFLD fibrosis score, FIB-4 (Fibrosis-4), and FibroMeter. Transient elastography is very useful in evaluating advanced fibrosis and cirrhosis.

The proton-coupled folate transporter: impact on pemetrexed transport and on antifolates activities compared with the reduced folate carrier.

The reduced folate carrier (RFC) and the proton-coupled folate transporter (PCFT) are ubiquitously expressed in normal and malignant mammalian tissues and in human solid tumor cell lines. This article addresses the extent to which PCFT contributes to transport of pemetrexed and to the activities of this and other antifolates relative to RFC at physiological pH. Either RFC or PCFT cDNA was stably transfected into a transporter-null HeLa cell variant to achieve activities similar to their endogenous function in wild-type HeLa cells. PCFT and RFC produced comparable increases in pemetrexed activity in growth medium with 5-formyltetrahydrofolate. However, PCFT had little or no effect on the activities of methotrexate, N-(5-[N-(3,4-dihydro-2-methyl-4-oxyquinazolin-6-ylmethyl)-N-methyl-amino]-2-thenoyl)-l-glutamic acid (raltitrexed, Tomudex; ZD1694), or N(alpha)-(4-amino-4-deoxypteroyl)-N(delta)-hemiphthaloyl-l-ornithine (PT523) in comparison with RFC irrespective of the folate growth source. PCFT, expressed at high levels in Xenopus laevis oocytes and in transporter-competent HepG2 cells, exhibited a high affinity for pemetrexed, with an influx K(m) value of 0.2 to 0.8 muM at pH 5.5. PCFT increased the growth inhibitory activity of pemetrexed, but not that of the other antifolates in HepG2 cells grown with 5-formyltetrahydrofolate at physiological pH. These findings illustrate the unique role that PCFT plays in the transport and pharmacological activity of pemetrexed. Because of the ubiquitous expression of PCFT in human tumors, and the ability of PCFT to sustain pemetrexed activity even in the absence of RFC, tumor cells are unlikely to become resistant to pemetrexed as a result of impaired transport because of the redundancy of these genetically distinct routes.

Rodent intestinal folate transporters (SLC46A1): secondary structure, functional properties, and response to dietary folate restriction.

This laboratory recently identified a human gene that encodes a novel folate transporter [Homo sapiens proton-coupled folate transporter (HsPCFT); SLC46A1] required for intestinal folate absorption. This study focused on mouse (Mus musculus) PCFT (MmPCFT) and rat (Rattus norvegicus) PCFT (RnPCFT) and addresses their secondary structure, specificity, tissue expression, and regulation by dietary folates. Both rodent PCFT proteins traffic to the cell membrane with the NH(2)- and COOH-termini accessible to antibodies targeted to these domains only in permeabilized HeLa cells. This, together with computer-based topological analyses, is consistent with a model in which rodent PCFT proteins likely contain 12 transmembrane domains. Transport of [(3)H]folates was optimal at pH 5.5 and decreased with increasing pH due to an increase in K(m) and a decrease in V(max). At pH 7.0, folic acid and methotrexate influx was negligible, but there was residual (6S)5-methyltetrahydrofolate transport. Uptake of folates in PCFT-injected Xenopus oocytes was electrogenic and pH dependent. Folic acid influx K(m) values of MmPCFT and RnPCFT, assessed electrophysiologically, were 0.7 and 0.3 microM at pH 5.5 and 1.1 and 0.8 microM at pH 6.5, respectively. Rodent PCFTs were highly specific for monoglutamyl but not polyglutamyl methotrexate. MmPCFT mRNA was highly expressed in the duodenum, proximal jejunum, liver, and kidney with lesser expression in the brain and other tissues. MmPCFT protein was localized to the apical brush-border membrane of the duodenum and proximal jejunum. MmPCFT mRNA levels increased approximately 13-fold in the proximal small intestine in mice fed a folate-deficient vesus folate-replete diet, consistent with the critical role that PCFT plays in intestinal folate absorption.

Commentary: a case for minimizing folate supplementation in clinical regimens with pemetrexed based on the marked sensitivity of the drug to folate availability.

Pemetrexed is a novel antifolate recently approved for the treatment of pleural mesothelioma and non-small cell lung cancer. In clinical regimens, pemetrexed is administered in conjunction with folic acid to minimize toxicity. However, excessive folate supplementation may also diminish the activity of this agent. The current study demonstrates, in several human solid tumor cell lines, that when extracellular 5-formyltetrahydrofolate levels are increased in vitro, within the range of normal human blood levels, there is a substantial decrease in pemetrexed activity upon continuous exposure to the drug. This was accompanied by a comparable lower level of trimetrexate activity consistent with an expansion of tumor cell folate pools. Likewise, when cells were exposed to pemetrexed with a schedule that simulates in vivo pharmacokinetics, there was markedly less cell killing with higher extracellular folate levels. Data are provided to indicate that 5-formyltetrahydrofolate is an acceptable surrogate for 5-methyltetrahydrofolate, the major blood folate, for this type of in vitro study. These observations and other reports suggest that, in view of the rise in serum folate and fall in serum homocysteine that has accompanied folic acid supplementation of food in the U.S., the addition of folic acid to regimens with pemetrexed should be limited to the lowest recommended level that provides optimal protection from pemetrexed toxicity.

Identification of an intestinal folate transporter and the molecular basis for hereditary folate malabsorption.

Folates are essential nutrients that are required for one-carbon biosynthetic and epigenetic processes. While folates are absorbed in the acidic milieu of the upper small intestine, the underlying absorption mechanism has not been defined. We now report the identification of a human proton-coupled, high-affinity folate transporter that recapitulates properties of folate transport and absorption in intestine and in various cell types at low pH. We demonstrate that a loss-of-function mutation in this gene is the molecular basis for hereditary folate malabsorption in a family with this disease. This transporter was previously reported to be a lower-affinity, pH-independent heme carrier protein, HCP1. However, the current study establishes that a major function of this gene product is proton-coupled folate transport required for folate homeostasis in man, and we have thus amended the name to PCFT/HCP1.

The effect of a novel transition state inhibitor of methylthioadenosine phosphorylase on pemetrexed activity.

Pemetrexed is a new-generation antifolate inhibitor of thymidylate synthase (TS) and a weaker inhibitor of glycinamide ribonucleotide transformylase (GARFT) required for de novo purine synthesis. Methylthioadenosine phosphorylase (MTAP) salvages purines by releasing adenine from methylthioadenosine and is often deleted in mesothelioma. The current study addresses the effect of MTAP on pemetrexed activity using a highly potent transition state inhibitor of MTAP, MT-DADMe-Immucillin A (ImmA; K(i) = 86 pmol/L) in the MTAP(+) NCI-H28 and MTAP(-) NCI-H2052 mesothelioma cell lines. Based on selective nucleoside protection, TS was found to be the primary pemetrexed target in both cell lines with GARFT inhibition requiring 20- to 30-fold higher pemetrexed concentrations. ImmA had no effect on pemetrexed activity but, when thymidine was added, the pemetrexed IC(50) decreased by a factor of approximately 3 in MTAP(+) H28 cells with no effect in MTAP(-) H2052 cells. Conversely, the transfection of MTAP into H2052 cells increased the pemetrexed IC(50) by nearly 3-fold but only in the presence of thymidine; this was reversed by ImmA. An MTAP-specific short interfering RNA produced a 2-fold decrease in pemetrexed IC(50) in MTAP(+) HeLa cells in the presence of thymidine. These data indicate that suppression of constitutive MTAP has no effect on pemetrexed activity when the primary target is TS. There is a modest salutary effect when the pemetrexed target is GARFT alone.