Sleeping Beauty and Hepatitis B: An Evidence-Based Guide for Dermatologists.

The association between immunosuppressive therapy for dermatologic conditions and the subsequent reactivation of hepatitis B is of major medical concern. It remains a point of interest across multiple disciplines, including hepatology, dermatology, rheumatology, and infectious disease. Accordingly, we present an evidence-based practice algorithm on how best to approach a patient with presumptively cleared hepatitis B infection when anticipating the initiation of immunosuppressive therapy. This guide delineates the risk of reactivation by taking into account the immunosuppressive agent of choice and presents recommendations for antiviral prophylaxis and laboratory monitoring. Booster vaccination as a potential to decrease the risk of hepatitis B reactivation is likewise discussed. (SKINmed. 2021;19:-0).

External Validation of Four Point-of-Care Noninvasive Scores for Predicting Advanced Hepatic Fibrosis in a Predominantly Hispanic NAFLD Population.

BACKGROUND: The development of point-of-care biomarkers of disease has become a major focus of interest in nonalcoholic fatty liver disease (NAFLD). The NAFLD fibrosis score (NFS), BARD, FIB-4, and aspartate aminotransferase-to-platelet ratio index (APRI) are commonly used for advanced NAFLD fibrosis prediction. However, the performance of these scores among in a predominantly Hispanic patient population, a population with the highest prevalence of NAFLD, has not been examined. METHODS: We performed a retrospective study among patients with histologically confirmed and staged NAFLD at the Ben Taub General Hospital, Houston, Texas, to externally validate four noninvasive advanced fibrosis prediction scores. Their discriminatory ability was assessed using the area under the receiver operating characteristic curve (AUROC). Sensitivity, specificity, positive, and negative predictive values were calculated. RESULTS: We included 99 NAFLD patients, of whom 37 (37.4%) had advanced fibrosis. The cohort was predominantly Hispanic (73.7%). The AUROC for detecting advanced fibrosis were: NFS 0.79 (95% confidence interval, 0.69-0.88), BARD 0.76 (0.67-0.86), FIB-4 0.77 (0.68-0.87), and APRI 0.70 (0.59-0.81). Using the low cutoff for the NFS (- 1.455) had the highest sensitivity (81.1%) and the highest negative predictive value (85.4%) among the overall study population. CONCLUSIONS: Noninvasive scores for advanced NAFLD fibrosis have moderate discriminatory ability in Hispanic patients with NFS having a small advantage. The AUROCs of these scores were similar to those reported in Caucasian populations. However, they had uniformly lower negative predictive values among our predominantly Hispanic study population, suggesting that they are not reliable for ruling out advanced fibrosis among this high-risk population.

Stauffer Syndrome: A Comprehensive Review of the Icteric Variant of the Syndrome.

Stauffer syndrome is a rare paraneoplastic syndrome classically associated with renal cell carcinoma (RCC). This association gave it the historical name of nonmetastatic nephrogenic hepatic dysfunction syndrome without jaundice. It is a syndrome of unclear pathophysiology characterized by a reversible anicteric elevation of liver enzymes, alkaline phosphatase, erythrocyte sedimentation rate (ESR), thrombocytosis, prolongation of prothrombin time, and hepatosplenomegaly in the absence of direct hepatobiliary obstruction or jaundice. A rare atypical variant of this syndrome with jaundice has been recently described in the literature. Thus, it is important to consider both these variants of Stauffer syndrome in the differential diagnosis of unexplained cholestasis in the absence of hepatic metastasis. This may allow early recognition and treatment of an occult malignancy. Herein, we present a comprehensive review of the literature available on the icteric variant of the Stauffer syndrome, outlining its association with various malignancies and the diagnostic challenges it poses. The objective of this review is to help clinicians in its early diagnosis and management.

Macro-aspartate Aminotransferase: Misleading Finding in a Patient with Non-alcoholic Fatty Liver Disease.

Persistent elevation of aspartate aminotransferase (AST) activity in serum due to the presence of a macro-enzyme form of AST (macro-AST) may lead to diagnostic confusion in many clinical conditions, particularly in those associated with chronic liver disease. We present a case of macro-AST in a patient with non-alcoholic fatty liver disease in which polyethylene glycol precipitation confirmed the cause of disproportionately elevated AST as macro-AST.

Autoimmune Hepatitis Refractory to Treatment Due to Underlying Grave's Disease.

A 24-year-old Hispanic woman presented to our facility with a two-week history of abdominal pain, nausea, vomiting, diarrhea, jaundice, and scleral icterus. Initial laboratory workup revealed elevated transaminases, direct hyperbilirubinemia, and positive anti-smooth muscle antibody. Liver biopsy confirmed the diagnosis of autoimmune hepatitis and our patient was started on oral prednisone therapy. Her liver enzymes initially began to normalize but then spontaneously started up-trending. She was subsequently readmitted to the hospital for further management, at which time she also complained of palpitations, heat intolerance, and sweating. Laboratory workup revealed hyperthyroidism secondary to Grave's disease. Our patient was not a candidate for methimazole or propylthiouracil treatment due to her hepatic dysfunction, so she was started on hydrocortisone due to its secondary effect of decreased conversion of thyroxine to triiodothyronine. She achieved biochemical remission of her autoimmune hepatitis on this regimen and was transitioned back to oral prednisone therapy. Her liver enzymes normalized once she underwent radioactive iodine ablation of her thyroid. This clinical course suggests that autoimmune hepatitis with concurrent Grave's disease may be refractory to treatment until the underlying hyperthyroid state is corrected.

Pathogenesis of Alcoholic Liver Disease: An Update.

Apart from the classic knowledge that ethanol mediates its hepatotoxicity through its metabolism to acetaldehyde, a well-known hepatotoxic molecule, recent research has elucidated several key mechanisms that potentiate ethanol's damage to the liver parenchyma, such as generation of free radicals, activation of Kupffer cells, and alterations to the human bacterial and fungal microbiome. Genetic studies have suggested the role of PNPLA3 and TM6SF2 gene mutations in the progression of alcoholic liver disease.

Unique metabolomic signature associated with hepatorenal dysfunction and mortality in cirrhosis.

The application of nontargeted metabolomic profiling has recently become a powerful noninvasive tool to discover new clinical biomarkers. This study aimed to identify metabolic pathways that could be exploited for prognostic and therapeutic purposes in hepatorenal dysfunction in cirrhosis. One hundred three subjects with cirrhosis had glomerular filtration rate (GFR) measured using iothalamate plasma clearance, and were followed until death, transplantation, or the last encounter. Concomitantly, plasma metabolomic profiling was performed using ultrahigh performance liquid chromatography-tandem mass spectrometry to identify preliminary metabolomic biomarker candidates. Among the 1028 metabolites identified, 34 were significantly increased in subjects with high liver and kidney disease severity compared with those with low liver and kidney disease severity. The highest average fold-change (2.39) was for 4-acetamidobutanoate. Metabolite-based enriched pathways were significantly associated with the identified metabolomic signature (P values ranged from 2.07E-06 to 0.02919). Ascorbate and aldarate metabolism, methylation, and glucuronidation were among the most significant protein-based enriched pathways associated with this metabolomic signature (P values ranged from 1.09E-18 to 7.61E-05). Erythronate had the highest association with measured GFR (R-square = 0.571, P <0.0001). Erythronate (R = 0.594, P <0.0001) and N6-carbamoylthreonyladenosine (R = 0.591, P <0.0001) showed stronger associations with measured GFR compared with creatinine (R = 0.588, P <0.0001) even after controlling for age, gender, and race. The 5 most significant metabolites that predicted mortality independent of kidney disease and demographics were S-adenosylhomocysteine (P = 0.0003), glucuronate (P = 0.0006), trans-aconitate (P = 0.0018), 3-ureidopropionate (P = 0.0021), and 3-(4-hydroxyphenyl)lactate (P = 0.0047). A unique metabolomic signature associated with hepatorenal dysfunction in cirrhosis was identified for further investigations that provide potentially important mechanistic insights into cirrhosis-altered metabolism.

Liver transplant length of stay (LOS) index: A novel predictive score for hospital length of stay following liver transplantation.

An index to predict hospital length of stay after liver transplantation could address unmet clinical needs. Length of stay is an important surrogate for hospital costs and efforts to limit stays can preserve our healthcare resources. Here, we devised a scoring system that predicts hospital length of stay following liver transplantation. We used univariate and multivariate analyses on 73 635 adult liver transplant recipient data and identified independent recipient and donor risk factors for prolonged hospital stay (>30 days). Multiple imputation was used to account for missing variables. We identified 22 factors as significant predictors of prolonged hospital stay, including the most significant risk factors: intensive care unit (ICU) admission (OR 1.75, CI 1.58-1.95) and previous transplant (OR 1.60, CI 1.47-1.75). The length of stay (LOS) index assigns weighted risk points to each significant factor in a scoring system to predict prolonged hospital stay after liver transplantation with a c-statistic of 0.75. The LOS index demonstrated good discrimination across the entire population, dividing the cohort into tertiles, which had odds ratios of 2.25 (CI 2.06-2.46) and 7.90 (7.29-8.56) for prolonged hospital stay (>30 days). The LOS index utilizes 22 significant donor and recipient factors to accurately predict hospital length of stay following liver transplantation. The index further demonstrates the basis for a clear clinical recommendation to mitigate risk of long hospitalization by minimizing cold ischemia time.

Non-alcoholic fatty liver disease and cardiovascular risk.

Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease associated with insulin resistance and metabolic syndrome. The spectrum of disease ranges from simple steatosis to steatohepatitis and progression to cirrhosis. Compelling evidence over the past several years has substantiated a significant link between NAFLD and cardiovascular disease ranging from coronary artery disease to subclinical carotid atherosclerosis. Close follow up, treatment of risk factors for NAFLD, and cardiovascular risk stratification are necessary to predict morbidity and mortality in this subset of patients.

Everolimus with early withdrawal or reduced-dose calcineurin inhibitors improves renal function in liver transplant recipients: A systematic review and meta-analysis.

Calcineurin inhibitors (CNI) are the mainstay of immunosuppression after liver transplantation (LT), but CNIs are associated with significant nephrotoxicity. Recently, mTOR inhibitors such as sirolimus and everolimus (EVR) have been used with or without CNIs in LT recipients for their renal-sparing effect. We conducted a systematic review and meta-analysis of randomized controlled trials (RCT) that examined the effect of EVR with CNI minimization or withdrawal on renal function in LT recipients. RCT of primary adult LT recipients with baseline GFR >30 mL/min who received EVR with CNI minimization or withdrawal were included. Four RCTs (EVR n=465, control n=428) were included. In three RCTs, EVR was initiated 4 weeks following LT; these studies were used to assess the primary outcome. All four studies were used to assess the secondary outcomes. Based on this study, EVR use with CNI minimization in LT recipients is associated with improved renal function at 12 months by GFR of 10.2 mL/min (95% CI: 2.75-17.8). EVR use was not associated with an increased risk of biopsy-proven acute rejection (RR 0.68, 95% CI: 0.31-1.46), graft loss (RR 1.60, 95% CI: 0.51-5.00), or mortality (RR 1.34, 95% CI 0.62-2.90). However, it was associated with an increased risk of overall infections (RR 1.45, 95% CI: 1.10-1.91).

Plasmapheresis for Refractory Pruritus due to Drug-Induced Cholestasis.

Pruritus can be a distressing symptom seen in various cholestatic disorders. It is treated with medications like bile acid sequestrants. Drug-induced cholestasis usually resolves with withdrawal of the causative medication. We describe a case of refractory pruritus due to drug-induced cholestasis, not improved with withdrawal of the drug, managed effectively with multiple sessions of plasmapheresis.

Hepatitis C Associated B-cell Non-Hodgkin Lymphoma: Clinical Features and the Role of Antiviral Therapy.

The link between chronic hepatitis C virus (HCV) infection and a subset of B-cell non-Hodgkin lymphomas (B-NHL) is strongly supported by epidemiological studies. Evidence demonstrating complete regression of lymphoma after antiviral treatments suggests possible chronic antigenic stimulation for the origin of B-NHL and provides evidence for a virus-mediated lymphomagenesis. B-NHL is a heterogeneous group of lymphomas with varied clinical presentation and may be indolent or aggressive. The optimal management of HCV related B-NHL is not clear. Antiviral treatment may be sufficient for low-grade lymphomas, but chemotherapy is necessary in patients with high grade lymphomas. Interferon (IFN)-based antiviral treatment regimens for HCV infection are limited by poor tolerance and suboptimal antiviral response. Recently approved novel direct acting antiviral (DAA) drugs are highly effective and safe. This has opened a new era for the treatment of HCV related B-NHL alone or in conjunction with chemotherapy. Treatment of HCV associated B-NHL should be performed in an interdisciplinary approach in close consultation with hematologist and hepatologist. In this review, we summarize data regarding clinical features and epidemiology of B-NHL and discuss novel therapeutic approaches, including DAAs, that may prove to be effective in the treatment of HCV associated lymphomas.

Hepatocellular carcinoma review: current treatment, and evidence-based medicine.

Hepatocellular carcinoma (HCC) is the fifth most common tumor worldwide. Multiple treatment options are available for HCC including curative resection, liver transplantation, radiofrequency ablation, trans-arterial chemoembolization, radioembolization and systemic targeted agent like sorafenib. The treatment of HCC depends on the tumor stage, patient performance status and liver function reserve and requires a multidisciplinary approach. In the past few years with significant advances in surgical treatments and locoregional therapies, the short-term survival of HCC has improved but the recurrent disease remains a big problem. The pathogenesis of HCC is a multistep and complex process, wherein angiogenesis plays an important role. For patients with advanced disease, sorafenib is the only approved therapy, but novel systemic molecular targeted agents and their combinations are emerging. This article provides an overview of treatment of early and advanced stage HCC based on our extensive review of relevant literature.

Time course of collagen peak in bile duct-ligated rats.

BACKGROUND: One of the most useful experimental fibrogenesis models is the "bile duct-ligated rats". Our aim was to investigate the quantitative hepatic collagen content by two different methods during the different stages of hepatic fibrosis in bile duct-ligated rats on a weekly basis. We questioned whether the 1-wk or 4-wk bile duct-ligated model is suitable in animal fibrogenesis trials. METHODS: Of the 53 male Wistar rats, 8 (Group 0) were used as a healthy control group. Bile duct ligation (BDL) had been performed in the rest. Bile duct-ligated rates were sacrificed 7 days later in group 1 (10 rats), 14 days later in group 2 (9 rats), 21 days later in group 3(9 rats) and 28 days later in group 4 (9 rats). Eight rats underwent sham-operation (Sham). Hepatic collagen measurements as well as serum levels of liver enzymes and function tests were all analysed. RESULTS: The peak level of collagen was observed biochemically and histomorphometricly at the end of third week (P < 0.001 and P < 0.05). Suprisingly, collagen levels had decreased with the course of time such as at the end of fourth week (P < 0.01 and P < 0.05). CONCLUSION: We have shown that fibrosis in bile duct-ligated rats is transient, i.e. reverses spontaneously after 3 weeks. This contrasts any situation in patients where hepatic fibrosis is progressive and irreversible as countless studies performed by many investigators in the same animal model.

CYP1A2*1F and GSTM1 alleles are associated with susceptibility to porphyria cutanea tarda.

Porphyria cutanea tarda (PCT) is a cutaneous porphyria with sporadic (type 1) and familial (type 2) subtypes, both resulting from decreased hepatic uroporphyrinogen decarboxylase (UROD) activity. Environmental and genetic factors are involved in the development of PCT, and genetic variants in the cytochrome P450 (CYP ) genes, CYP1A1 and CYP1A2, have been implicated. We investigated the association between PCT and variants in CYP1A1, CYP1A2 and CYP2E1, and the glutathione-S-transferase (GST ) genes, GSTM1 and GSTT1. PCT diagnosis was based on urinary or plasma porphyrin profiles. Patients were classified as type 1 or 2 PCT based on UROD mutation analysis. The CYP1A2*1F promoter A allele frequency was significantly higher (P < 0.022) and the A/A genotype frequency marginally higher in PCT patients overall (P < 0.057), with the A/A genotype significantly more common in type 1 PCT (P < 0.043). The presence of the wild-type GSTM1 allele also was associated significantly with PCT (P < 0.019). Neither hemochromatosis (HFE) mutations, tobacco smoking, hepatitis C and HIV infection, ethanol consumption, nor estrogen use were associated with these allelic variants. Age at onset was significantly lower in type 2 PCT patients (P < 0.001), as observed previously. Thus, positive associations between PCT and the CYP1A2*1F promoter A allele and A/A genotype and the wild-type GSTM1 allele indicates that these functional hepatic biotransformation enzymes are risk factors for the development of this disease.

Hepatotoxicity fears contribute to underutilization of statin medications by primary care physicians.

INTRODUCTION: The safety and efficacy of hydroxymethylglutaryl CoA reductase inhibitors (statins) have been extensively demonstrated, but in clinical practice, there remains significant underutilization of these medications. The authors hypothesized that this underutilization could stem in part from fear of liver damage caused by statins. The purpose was to determine whether concern about hepatotoxicity acts as a barrier among primary care physicians to prescribing statins for patients with elevated liver transaminase values and/or underlying liver disease. METHOD: The survey included 937 primary care physicians from 138 academic centers in the United States, and the following were measured: (1) comparison of statin prescribing for patients with clinical indications and (a) no mention of liver transaminase values, (b) elevated liver transaminase values and (c) underlying liver disease; (2) correlation between perception of statin hepatotoxicity and statin prescribing. RESULTS: Seventy-one percent of respondents would prescribe statins in scenario 1, (45-year-old woman with low-density lipoprotein 240 mg/dL), whereas only 50% would prescribe statins if the baseline liver transaminase values were elevated to 1.5 times upper limit of normal (P < 0.001). This prescribing rate dropped even further to 40% in scenario 3 (55-year-old man with known coronary disease, low-density lipoprotein 250 mg/dL and hepatitis C). Thirty-seven percent of respondents had falsely elevated perceptions of statin hepatotoxicity risk, and these perceptions correlated inversely with statin prescribing. The method of survey administration prevented calculation of response rate, possibility of response bias exists. CONCLUSION: Despite extensive data documenting safety of statins, primary care physicians harbor significant hepatotoxicity concerns, and these concerns act as a barrier to statin utilization.

Terlipressin therapy for reversal of type 1 hepatorenal syndrome: a meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: Hepatorenal syndrome (HRS) is a serious complication of advanced liver disease and carries a poor prognosis. Recent trials have indicated that terlipressin may be effective in reversing HRS. Our aim was to evaluate the efficacy of terlipressin therapy in reversing type 1 HRS defined as a serum creatinine <1.5 mg/dL during treatment. METHODS: Randomized controlled trials in which patients with type 1 HRS received at least 3 days of terlipressin therapy and albumin in the intervention arm were included after a systematic search of the published English reports. Studies with other vasoconstrictor therapies in the control group were excluded. RESULTS: A total of 223 patients with HRS type 1 in four different trials, were included in the final analysis. Alcohol-related cirrhosis was the most common underlying etiology. The risk ratio for reversal in type 1 HRS with terlipressin therapy was 3.66 (95% confidence interval 2.15-6.23). Recurrence of HRS was low (8%). Serious side-effects requiring discontinuation of therapy were seen only in 6.8% of patients on terlipressin therapy. There was a trend towards improved transplant-free survival at 90 days in the terlipressin group (relative risk 1.86 95% confidence interval 1.0-3.4, P = 0.05). CONCLUSIONS: Terlipressin is effective in reversing HRS type 1. Recurrence of HRS is rare with at least 14 days of therapy. Serious side-effects requiring discontinuation of therapy are less common. There appears to be a survival benefit in patients with HRS treated with terlipressin.

Antiviral therapy reduces risk of hepatocellular carcinoma in patients with hepatitis C virus-related cirrhosis.

BACKGROUND & AIMS: The effects of antiviral therapy on prevention of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV)-related cirrhosis are unclear. We performed a systematic review and meta-analysis to assess HCC risk reduction in patients with HCV-related cirrhosis who have received antiviral therapy. METHODS: Twenty studies (4700 patients) were analyzed that compared untreated patients with those given interferon (IFN) alone or ribavirin. Risk ratios (RRs) determined effect size using a random effects model. RESULTS: Pooled data showed reduced HCC risk in the treatment group (RR, 0.43; 95% confidence interval [CI], 0.33-0.56), although the data were heterogenous (chi(2) = 59.10). Meta-regression analysis showed that studies with follow-up durations of more than 5 years contributed to heterogeneity. Analysis of 14 studies (n = 3310) reporting sustained virologic response (SVR) rates with antiviral treatment showed reduced HCC risk in patients with an SVR, compared with nonresponders (RR, 0.35; 95% CI, 0.26-0.46); the maximum benefits were observed in patients treated with ribavirin-based regimens (RR, 0.25; 95% CI, 0.14-0.46). Meta-analysis of 4 studies assessing the role of maintenance IFN in nonresponders did not show HCC risk reduction (RR, 0.58; 95% CI, 0.33-1.03). No publication bias was detected by the Egger test analysis (P > 0.1). CONCLUSIONS: The risk of HCC is reduced among patients with HCV who achieve an SVR with antiviral therapy. Maintenance therapy with IFN does not reduce HCC risk among patients who do not respond to initial therapy. View this article's video abstract atwww.cghjournal.org.

Severe radiation therapy-related soft tissue toxicity in a patient with porphyria cutanea tarda: a literature review.

BACKGROUND: Some porphyrias are associated with cutaneous phototoxicity due to photoactivation of porphyrins, but whether ionizing radiation can have an additive effect is not clear. We report a case of severe radiation therapy-related toxicity in a patient with porphyria cutanea tarda and review the literature. METHODS: A 50-year-old man with porphyria cutanea was treated for lower lip squamous cell carcinoma with definitive radiation therapy. During radiation therapy, acute toxicity was of an expected onset and severity. Six months after treatment completion, he developed skin hypopigmentation, soft tissue fibrosis, and areas of painful denuded skin and crusting within the previous treatment field. RESULTS: Reports of 7 patients with porphyria receiving radiation therapy to at least 9 separate sites were reviewed, with only 1 previous report suggestive of increased radiation therapy-related toxicity. CONCLUSION: Based on this and 1 other report, caution is warranted when considering radiation therapy in patients with active porphyria.