Progressive liver, kidney, and heart degeneration in children and adults affected by TULP3 mutations.

Organ fibrosis is a shared endpoint of many diseases, yet underlying mechanisms are not well understood. Several pathways governed by the primary cilium, a sensory antenna present on most vertebrate cells, have been linked with fibrosis. Ciliopathies usually start early in life and represent a considerable disease burden. We performed massively parallel sequencing by using cohorts of genetically unsolved individuals with unexplained liver and kidney failure and correlated this with clinical, imaging, and histopathological analyses. Mechanistic studies were conducted with a vertebrate model and primary cells. We detected bi-allelic deleterious variants in TULP3, encoding a critical adaptor protein for ciliary trafficking, in a total of 15 mostly adult individuals, originating from eight unrelated families, with progressive degenerative liver fibrosis, fibrocystic kidney disease, and hypertrophic cardiomyopathy with atypical fibrotic patterns on histopathology. We recapitulated the human phenotype in adult zebrafish and confirmed disruption of critical ciliary cargo composition in several primary cell lines derived from affected individuals. Further, we show interaction between TULP3 and the nuclear deacetylase SIRT1, with roles in DNA damage repair and fibrosis, and report increased DNA damage ex vivo. Transcriptomic studies demonstrated upregulation of profibrotic pathways with gene clusters for hypertrophic cardiomyopathy and WNT and TGF-ß signaling. These findings identify variants in TULP3 as a monogenic cause for progressive degenerative disease of major organs in which affected individuals benefit from early detection and improved clinical management. Elucidation of mechanisms crucial for DNA damage repair and tissue maintenance will guide novel therapeutic avenues for this and similar genetic and non-genomic diseases.

Sex, Genotype, and Liver Volume Progression as Risk of Hospitalization Determinants in Autosomal Dominant Polycystic Liver Disease.

BACKGROUND & AIMS: Autosomal dominant polycystic liver disease is a rare condition with a female preponderance, based mainly on pathogenic variants in 2 genes, PRKCSH and SEC63. Clinically, autosomal dominant polycystic liver disease is characterized by vast heterogeneity, ranging from asymptomatic to highly symptomatic hepatomegaly. To date, little is known about the prediction of disease progression at early stages, hindering clinical management, genetic counseling, and the design of randomized controlled trials. To improve disease prognostication, we built a consortium of European and US centers to recruit the largest cohort of patients with PRKCSH and SEC63 liver disease. METHODS: We analyzed an international multicenter cohort of 265 patients with autosomal dominant polycystic liver disease harboring pathogenic variants in PRKCSH or SEC63 for genotype-phenotype correlations, including normalized age-adjusted total liver volumes and polycystic liver disease-related hospitalization (liver event) as primary clinical end points. RESULTS: Classifying individual total liver volumes into predefined progression groups yielded predictive risk discrimination for future liver events independent of sex and underlying genetic defects. In addition, disease severity, defined by age at first liver event, was considerably more pronounced in female patients and patients with PRKCSH variants than in those with SEC63 variants. A newly developed sex-gene score was effective in distinguishing mild, moderate, and severe disease, in addition to imaging-based prognostication. CONCLUSIONS: Both imaging and clinical genetic scoring have the potential to inform patients about the risk of developing symptomatic disease throughout their lives. The combination of female sex, germline PRKCSH alteration, and rapid total liver volume progression is associated with the greatest odds of polycystic liver disease-related hospitalization.

Safety and efficacy of off-label bulevirtide monotherapy in patients with HDV with decompensated Child-B cirrhosis-A real-world case series.

BACKGROUND AND AIMS: Chronic hepatitis D is the most debilitating form of viral hepatitis frequently progressing to cirrhosis and subsequent decompensation. However, the HDV entry inhibitor bulevirtide is only approved for antiviral treatment of patients with compensated disease. We aimed for the analysis of real-world data on the off-label use of bulevirtide in the setting of decompensated liver cirrhosis. APPROACH AND RESULTS: We conducted a retrospective study in patients with HDV with decompensated liver disease at German, Austrian, and Italian centers. We included 19 patients (47% male, mean age: 51 years) with liver cirrhosis Child-Pugh B. The median MELD score was 12 (range 9-17) at treatment initiation. The median observation period was 41 weeks. Virologic response was achieved in 74% and normal alanine aminotransferase was observed in 74%. The combined response was achieved by 42%. The most relevant adverse events included self-limited alanine aminotransferase flares, an asymptomatic increase in bile acids, and the need for liver transplantation. Despite bile acid increases, adverse events were considered unrelated. Clinical and laboratory improvement from Child-Pugh B to A occurred in 47% (n = 9/19). Improvements in the amount of ascites were observed in 58% of the patients initially presenting with ascites (n = 7/12). CONCLUSIONS: This report on off-label bulevirtide treatment in patients with decompensated HDV cirrhosis shows similar virologic and biochemical response rates as observed in compensated liver disease. Significant improvements were observed in surrogates of hepatic function and portal hypertension. However, this improvement was not seen in all patients. Controlled trials are needed to confirm the safety and efficacy of bulevirtide in decompensated HDV cirrhosis.

Secondary Sclerosing Cholangitis Following Coronavirus Disease 2019 (COVID-19): A Multicenter Retrospective Study.

BACKGROUND: Secondary sclerosing cholangitis (SSC) is a rare disease with poor prognosis. Cases of SSC have been reported following coronavirus disease 2019 (COVID-SSC). The aim of this study was to compare COVID-SSC to SSC in critically ill patients (SSC-CIP) and to assess factors influencing transplant-free survival. METHODS: In this retrospective, multicenter study involving 127 patients with SSC from 9 tertiary care centers in Germany, COVID-SSC was compared to SSC-CIP and logistic regression analyses were performed investigating factors impacting transplant-free survival. RESULTS: Twenty-four patients had COVID-SSC, 77 patients SSC-CIP, and 26 patients other forms of SSC. COVID-SSC developed after a median of 91 days following COVID-19 diagnosis. All patients had received extensive intensive care treatment (median days of mechanical ventilation, 48). Patients with COVID-SSC and SSC-CIP were comparable in most of the clinical parameters and transplant-free survival was not different from other forms of SSC (P = .443, log-rank test). In the overall cohort, the use of ursodeoxycholic acid (UDCA) (odds ratio [OR], 0.36 [95% confidence interval {CI}, .16-.80], P = .013; log-rank P < .001) and high serum albumin levels (OR, 0.40 [95% CI, .17-.96], P = .040) were independently associated with an increased transplant-free survival, while the presence of liver cirrhosis (OR, 2.52 [95% CI, 1.01-6.25], P = .047) was associated with worse outcome. Multidrug-resistant organism (MDRO) colonization or infection did not impact patients' survival. CONCLUSIONS: COVID-SSC and CIP-SSC share the same clinical phenotype, course of the disease, and risk factors for its development. UDCA may be a promising therapeutic option in SSC, though future prospective trials are needed to confirm our findings.

A SEC61A1 variant is associated with autosomal dominant polycystic liver disease.

BACKGROUND AND AIMS: Autosomal dominant polycystic liver and kidney disease is a spectrum of hereditary diseases, which display disturbed function of primary cilia leading to cyst formation. In autosomal dominant polycystic kidney disease a genetic cause can be determined in almost all cases. However, in isolated polycystic liver disease (PLD) about half of all cases remain genetically unsolved, suggesting more, so far unidentified genes to be implicated in this disease. METHODS: Customized next-generation sequencing was used to identify the underlying pathogenesis in two related patients with PLD. A variant identified in SEC61A1 was further analysed in immortalized patients' urine sediment cells and in an epithelial cell model. RESULTS: In both patients, a heterozygous missense change (c.706C>T/p.Arg236Cys) was found in SEC61A1, which encodes for a subunit of the translocation machinery of protein biosynthesis at the endoplasmic reticulum (ER). While kidney disease is absent in the proposita, her mother displays an atypical polycystic kidney phenotype with severe renal failure. In immortalized urine sediment cells, mutant SEC61A1 is expressed at reduced levels, resulting in decreased levels of polycystin-2 (PC2). In an epithelial cell culture model, we found the proteasomal degradation of mutant SEC61A1 to be increased, whereas its localization to the ER is not affected. CONCLUSIONS: Our data expand the allelic and clinical spectrum for SEC61A1, adding PLD as a new and the major phenotypic trait in the family described. We further demonstrate that mutant SEC61A1 results in enhanced proteasomal degradation and impaired biosynthesis of PC2.

Liver Injury after Selective Androgen Receptor Modulator Intake: A Case Report and Review of the Literature.

Liver injury associated with selective androgen receptor modulators (SARMs) is an issue that has not been reported often. We report a case of a previously healthy 24-year-old male, who was referred to our hospital for severe jaundice with intense pruritus. He had previously taken the SARM Enobosarm (also known as Ostarine) for muscle-building purposes. Blood serum levels of total bilirubin exceeded 30 mg/dL with only a slight elevation of liver enzymes. Liver biopsy revealed isolated hepatocellular cholestasis (bland cholestasis) with limited inflammation or necrosis. Supportive treatment was begun in our hospital with molecular adsorbent recirculation system (MARS) albumin dialysis, as well as cholestyramine for pruritus relief. During therapy, bilirubin levels and symptoms regressed, and after five sessions of dialysis, the patient could be released from our clinic in a markedly improved clinical and laboratory condition. However, bilirubin parameters regressed slowly after this, reaching normal levels as late as six months after first intake of the compound. Exome-based genetic testing brought about no pathogenic variants for cholestatic liver disease in our patient. Nevertheless, three common heterozygous polymorphisms associated with an increased risk for intrahepatic cholestasis could be identified. Our case demonstrates that SARMs can cause severe liver injuries not prominently mentioned in safety data sheets. Therefore, these compounds constitute a potential danger to the user's health. This holds especially true when taking SARMs without supervision by a medical professional, which should consist of a thorough monitoring of liver enzyme and bilirubin levels.

Real-world effect of ribavirin on quality of life in HCV-infected patients receiving interferon-free treatment.

BACKGROUND & AIMS: Ribavirin (RBV) is commonly used for the treatment of hepatitis C virus (HCV) infection. However, RBV is associated with a reduced quality of life (QOL). We aim to assess the impact of RBV on QOL in a real-world setting. METHODS: In a prospective study, QOL was measured by a SF-36 questionnaire in 174 patients. In all, 85 patients were treated with RBV and 89 patients without RBV. QOL was assessed at baseline, week 12 of treatment and 24 weeks after treatment. RESULTS: Patients treated with RBV were more likely to have HCV genotype 2 and 3 infection and cirrhosis (all P < .05). RBV-treated patients reported lower scores for several domains of QOL already at baseline. During HCV treatment, RBV-free treatment led to an increase in all measured dimensions of quality of life, whereas RBV treatment led to a decrease in the emotional and physical functioning. After treatment, all dimensions for QOL showed improvement across the study cohort, regardless whether RBV was part of the treatment regimen. However, 28.8%-45.2% of treated patients perceive a sustained reduction in their physical or mental capacity after treatment, not related to RBV usage or SVR, but related to older age (P = .03) and cirrhosis (P = .02). CONCLUSIONS: During treatment, RBV leads to a reduced QOL, whereas RBV-free treatment leads to an increased QOL. After treatment, QOL strongly increases in both, RBV and RBV-free treated patients. Some patients perceive a sustained reduction in QOL, which seems unrelated to treatment.

Origin, prevalence and response to therapy of hepatitis C virus genotype 2k/1b chimeras.

BACKGROUND & AIMS: Little is known about the epidemiology and frequency of recombinant HCV genotype 2/1 strains, which may represent a challenge for direct antiviral therapy (DAA). This study aims to identify the epidemiology and phylogeny of HCV genotype 2/1 strains and encourages genotype screening, to select the DAA-regimen that achieves the optimal sustained virologic response. METHODS: Consecutive samples from HCV genotype 2 infected patients, according to commercial genotyping, from Germany, Italy and Israel were re-genotyped by Sanger-based sequencing. Virologic, epidemiological, and phylogenetic analyses including other published chimeras were performed. RESULTS: Sequence analysis of 442 supposed HCV genotype 2 isolates revealed 61 (genotype 2k/1b (n=59), 2a/1b (n=1) or 2b/1a (n=1)) chimeras. No chimeras were observed in Italy, but the frequency was 14% and 25% in Germany and Israel. Treatment of viral chimera with sofosbuvir/ribavirin led to virologic relapse in 25/27 patients (93%). Nearly all patients treated with genotype 1-based DAA-regimens initially (n=8/9), or after relapse (n=13/13), achieved a sustained virologic response. Most patients with 2k/1b chimeras (88%) were originally from eight different areas of the former Soviet Union. All known 2k/1b chimeras harbour the same recombination breakpoint and build one phylogenetic cluster, while all other chimeras have different phylogenies. CONCLUSIONS: The HCV genotype 2k/1b variant derives from one single recombination event most likely in the former Soviet Union, while other chimeras are unique and develop independently. A relatively high frequency has been observed along the migration flows, in Germany and Israel. In countries with little migration from the former Soviet Union the prevalence of 2k/1b chimeras is expected to be low. Treatment with sofosbuvir plus ribavirin is insufficient, but genotype 1-based regimens seem to be effective. Lay summary: The frequency of recombinant HCV is higher than expected. A novel recombinant variant (HCV genotype 2a/1b) was identified. Screening for recombinant viruses would contribute to increased response rates to direct antiviral therapy.

Interferon-free cure of chronic Hepatitis C is associated with weight gain during long-term follow-up.

Background and aim The advent of direct-acting antivirals has revolutionized treatment of chronic hepatitis C with very high cure rates and excellent tolerability compared to interferon-based hepatitis C virus (HCV) treatment. However, long-term effects of interferon-free cure of HCV infection on the metabolic condition of patients have not been investigated so far. Methods We investigated weight development during and after antiviral treatment of hepatitis C. In a prospective single-center cohort study, interferon-free antiviral treatment was initiated in 284 patients. Each patient's weight was monitored 1 year before the start of treatment, at baseline (BL), end of treatment (EOT), follow-up week 24 (FU24), and follow-up week 48 (FU48). Results Weight gain after HCV cure was observed in 20 %, 33 %, and 44 % of patients at EOT, FU24, and FU48, respectively. The mean overall weight change at FU48 compared to baseline was 1.45 kg (95 % CI 0.44; 2.46, p = 0.02, compared to the pretreatment period). Multivariate regression revealed age as the only factor predicting weight change at FU48 (B - 0.107, 95 % CI, - 0.202 to - 0.011, p = 0.03), while gender, cirrhosis, diabetes mellitus, ribavirin, and body mass index had no influence. In the subgroup of patients younger than 60 years, mean weight gain at FU48 compared to baseline was 2.8 kg (95 % CI, 1.23 - 4.4). In contrast, patients 60 years and older had a mean weight change of - 0.04 kg (95 % CI, - 1.12 to 1.03, p = 0.005). Conclusions Cure of HCV by interferon-free antiviral treatment was associated with weight gain in up to 44 % of patients during long-term follow-up. Weight gain occurred predominantly in patients younger than 60 years. The precise mechanism of weight gain remains to be elucidated.

Comparative analysis of SEC61A1 mutant R236C in two patient-derived cellular platforms.

SEC61A1 encodes a central protein of the mammalian translocon and dysfunction results in severe disease. Recently, mutation R236C was identified in patients having autosomal dominant polycystic liver disease (ADPLD). The molecular phenotype of R236C was assessed in two cellular platforms. Cells were immortalized by retroviral transduction of an oncogene (UCi) or reprogrammed to induced pluripotent stem cells (iPSC) that were differentiated to cholangiocyte progenitor-like cells (CPLC). UCi and CPLC were subjected to analyses of molecular pathways that were associated with development of disease. UCi displayed markers of epithelial cells, while CPLCs expressed typical markers of both cholangiocytes and hepatocytes. Cells encoding R236C showed a stable, continuous proliferation in both platforms, however growth rates were reduced as compared to wildtype control. Autophagy, cAMP synthesis, and secretion of important marker proteins were reduced in R236C-expressing cells. In addition, R236C induced increased calcium leakiness from the ER to the cytoplasm. Upon oxidative stress, R236C led to a high induction of apoptosis and necrosis. Although the grade of aberrant cellular functions differed between the two platforms, the molecular phenotype of R236C was shared suggesting that the mutation, regardless of the cell type, has a dominant impact on disease-associated pathways.

A Novel Insertion in the Hepatitis B Virus Surface Protein Leading to Hyperglycosylation Causes Diagnostic and Immune Escape.

Chronic hepatitis B virus (HBV) infection is a global health threat. Mutations in the surface antigen of HBV (HBsAg) may alter its antigenicity, infectivity, and transmissibility. A patient positive for HBV DNA and detectable but low-level HBsAg in parallel with anti-HBs suggested the presence of immune and/or diagnostic escape variants. To support this hypothesis, serum-derived HBs gene sequences were amplified and cloned for sequencing, which revealed infection with exclusively non-wildtype HBV subgenotype (sgt) D3. Three distinct mutations in the antigenic loop of HBsAg that caused additional N-glycosylation were found in the variant sequences, including a previously undescribed six-nucleotide insertion. Cellular and secreted HBsAg was analyzed for N-glycosylation in Western blot after expression in human hepatoma cells. Secreted HBsAg was also subjected to four widely used, state-of-the-art diagnostic assays, which all failed to detect the hyperglycosylated insertion variant. Additionally, the recognition of mutant HBsAg by vaccine- and natural infection-induced anti-HBs antibodies was severely impaired. Taken together, these data suggest that the novel six-nucleotide insertion as well as two other previously described mutations causing hyperglycosylation in combination with immune escape mutations have a critical impact on in vitro diagnostics and likely increase the risk of breakthrough infection by evasion of vaccine-induced immunity.

Enhanced monitoring and detection of recent genotype 3 hepatitis E virus infection through urine antigen testing.

Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis. Numerous studies have investigated the dynamics of HEV infection markers, but the most suitable marker for diagnosing ongoing or recent HEV infection remains to be determined. Recent evidence suggests that serum antigen testing is superior to serum IgM and RNA quantification. Moreover, it has been found that infected individuals excrete HEV antigen in significant quantities through urine. To address this question, we conducted a longitudinal analysis involving 16 patients with acute or chronic HEV infection in an area where genotype 3 HEV is prevalent. Our findings indicate that the diagnostic and monitoring capabilities of antigen testing for HEV infection can be further enhanced by measuring it in urine. Additionally, we were able to demonstrate that this enhancement is likely due to the presence of HEV-reactive IgG in blood plasma, which hampers efficient detection of HEV antigen through sandwich ELISA. In conclusion, urine-based antigen testing appears to be superior to measuring anti-HEV antibodies or viral RNA for diagnosing suspected HEV infection and monitoring ongoing infections.

Treating hepatitis D with bulevirtide - Real-world experience from 114 patients.

Background & Aims: Bulevirtide is a first-in-class entry inhibitor of hepatitis B surface antigen. In July 2020, bulevirtide was conditionally approved for the treatment of hepatitis D, the most severe form of viral hepatitis, which frequently causes end-stage liver disease and hepatocellular carcinoma. Herein, we report the first data from a large multicenter real-world cohort of patients with hepatitis D treated with bulevirtide at a daily dose of 2 mg without additional interferon. Methods: In a joint effort with 16 hepatological centers, we collected anonymized retrospective data from patients treated with bulevirtide for chronic hepatitis D. Results: Our analysis is based on data from 114 patients, including 59 (52%) with cirrhosis, receiving a total of 4,289 weeks of bulevirtide treatment. A virologic response defined as an HDV RNA decline of at least 2 log or undetectable HDV RNA was observed in 87/114 (76%) cases with a mean time to virologic response of 23 weeks. In 11 cases, a virologic breakthrough (>1 log-increase in HDV RNA after virologic response) was observed. After 24 weeks of treatment, 19/33 patients (58%) had a virologic response, while three patients (9%) did not achieve a 1 log HDV RNA decline. No patient lost hepatitis B surface antigen. Alanine aminotransferase levels improved even in patients not achieving a virologic response, including five patients who had decompensated cirrhosis at the start of treatment. Treatment was well tolerated and there were no reports of drug-related serious adverse events. Conclusions: In conclusion, we confirm the safety and efficacy of bulevirtide monotherapy in a large real-world cohort of patients with hepatitis D treated in Germany. Future studies need to explore the long-term benefits and optimal duration of bulevirtide treatment. Impact and implications: Clinical trials proved the efficacy of bulevirtide for chronic hepatitis D and led to conditional approval by the European Medical Agency. Now it is of great interest to investigate the effects of bulevirtide treatment in a real-world setting. In this work, we included data from 114 patients with chronic hepatitis D who were treated with bulevirtide at 16 German centers. A virologic response was seen in 87/114 cases. After 24 weeks of treatment, only a small proportion of patients did not respond to treatment. At the same time, signs of liver inflammation improved. This observation was independent from changes in hepatitis D viral load. The treatment was generally well tolerated. In the future, it will be of interest to investigate the long-term effects of this new treatment.

Distinct and non-redundant roles of microglia and myeloid subsets in mouse models of Alzheimer's disease.

Mononuclear phagocytes are important modulators of Alzheimer's disease (AD), but the specific functions of resident microglia, bone marrow-derived mononuclear cells, and perivascular macrophages have not been resolved. To elucidate the spatiotemporal roles of mononuclear phagocytes during disease, we targeted myeloid cell subsets from different compartments and examined disease pathogenesis in three different mouse models of AD (APP(swe/PS1), APP(swe), and APP23 mice). We identified chemokine receptor 2 (CCR2)-expressing myeloid cells as the population that was preferentially recruited to ß-amyloid (Aß) deposits. Unexpectedly, AD brains with dysfunctional microglia and devoid of parenchymal bone marrow-derived phagocytes did not show overt changes in plaque pathology and Aß load. In contrast, restriction of CCR2 deficiency to perivascular myeloid cells drastically impaired ß-amyloid clearance and amplified vascular Aß deposition, while parenchymal plaque deposition remained unaffected. Together, our data advocate selective functions of CCR2-expressing myeloid subsets, which could be targeted specifically to modify disease burden in AD.

Management of Hepatic Sarcoidosis.

BACKGROUND AND AIMS: Liver involvement in sarcoidosis may occur in up to 60% of all patients. As many patients experience only minor symptoms, a high number of undiagnosed cases must be assumed. In order to successfully identify patients with hepatic sarcoidosis, a throughout characterization of these patients and their course of disease is necessary. METHODS: We collected 40 patients from four German centers to evaluate current treatment standards and course of disease. All of our patients underwent liver biopsy with histologically proven granulomatous hepatitis. RESULTS: Detailed characterization of our patients showed an overall benign course of disease. Treatment was very diverse with glucocorticoids for 1 year in 55% (22/40), 5-10 years in 18% (7/40), and permanently in 18% (7/40). Other treatments included disease-modifying anti-rheumatic drugs (DMARDs), the conventional non-biological type in 53% of all patients (of these 81% received azathioprine, 46% metotrexate, 10% hydroxychloroquine, 10% mycophenolate mofetil and 10% cyclophosphamide and biologicals in 8%. Despite these very diverse treatments, patients generally showed slow progression of the disease. Two patients died. None of our patients received a liver transplantation. CONCLUSIONS: Patients received diverse treatments and generally showed slow progression of the disease. Based on our experience, we proposed a diagnostic work up and surveillance strategy as a basis for future, prospective register studies.

Weight Gain after Interferon-Free Treatment of Chronic Hepatitis C-Results from the German Hepatitis C-Registry (DHC-R).

Chronic hepatitis C can be treated very effectively with direct-acting antivirals (DAA) with only minor side effects compared to an interferon-containing treatment regimen. The significance of metabolic comorbidities after HCV cure is not well defined. This study aims to investigate short- and long-term weight change of patients receiving interferon-free antiviral treatment for chronic hepatitis C. The German Hepatitis C-registry (DHC-R) is a national multicenter real-world cohort. A total of 5111 patients were followed prospectively after DAA treatment for up to 3 years. Weight change compared to baseline was analyzed at end of treatment and at years 1, 2, and 3 after completion of antiviral therapy. Regression analysis was performed to identify baseline predictors for weight change. While there was no relevant mean weight change (-0.2 kg, SD 4.3 kg) at the end of antiviral treatment, weight started to increase during long-term follow-up reaching +1.7 kg (SD 8.0 kg, p < 0.001) compared to baseline at 3 years (follow-up year 3, FU3) after completion of antiviral therapy. 48%, 31%, and 22% of patients had a weight gain greater than 1, 3, and 5 kg at FU3, respectively. During follow-up, a body mass index (BMI) <30 proved to be the only consistent predictor for weight gain. DAA treatment is followed by a substantial weight gain (+3 kg or more) in one-third of the patients during long-term follow-up. Non-obese patients seemed to be most vulnerable to weight gain. The body compartment involved in weight gain as well as the mechanism of weight gain remain to be elucidated.

Chronic Hepatitis E Virus Infection during Lymphoplasmacytic Lymphoma and Ibrutinib Treatment.

Hepatitis E virus (HEV) is an increasingly recognised pathogen, affecting several hundred thousand individuals in western countries each year. Importantly, the majority of immunocompromised individuals are not able to clear HEV but develop a chronic course of infection. In the case of lymphoma, which is an inherent immunosuppressive disease per se, chemotherapy can even further exacerbate the immunosuppressive status. As the mechanism of HEV chronification is barely understood, it is important to gain knowledge about the influence of chemotherapeutic drugs on the HEV replication cycle to guide rational clinical management of HEV infection in such patients. In this case report, a 70 year old man was diagnosed with lymphoplasmacytic lymphoma. As we observed the occurrence of chronic HEV after treatment with the Bruton's tyrosine kinase (BTK) inhibitor ibrutinib in vivo, we investigated the influence of BTK signaling and ibrutinib treatment in the HEV replication cycle in vitro. First, we detected an HEV-induced mobilisation of BTK in human liver cells during HEV replication. A moderate antiviral effect against HEV replicating isolates including genotypes 1 and 3 was observed, suggesting that ibrutinib did not support HEV replication in a direct manner. Combinatory treatments of ibrutinib with ribavirin indicated that ibrutinib did not influence the antiviral effect of ribavirin. Taken together, chemotherapy targeting cellular factors for the treatment of lymphomas may be a neglected risk factor for the chronification of HEV. For ibrutinib, despite the upregulation of its target BTK during HEV replication, we observed neither a proviral effect on HEV replication nor an influence on the antiviral effect of ribavirin, suggesting that the chronification of HEV may be favoured by its immunosuppressive effect.