What contribution can genetics make to predict the risk of Alzheimer's disease?

Alzheimer's disease (AD) is the most common neurodegenerative disorder. Although its etiology remains incompletely understood, genetic variants are important contributors. The prediction of AD risk through individual genetic variants is an important topic of research that may have individual and societal consequences when preventive treatments will become available. However, the genetic substratum of AD is heterogeneous. In addition to the extremely rare and fully penetrant pathogenic variants of the PSEN1, PSEN2 or APP genes causing autosomal dominant AD, a large spectrum of risk factors have been identified in complex forms, including the common risk factor APOEɛ4, which is associated with a moderate-to-high risk, common polymorphisms associated with a modest individual risk, and a plethora of rare variants in genes like SORL1, TREM2 or ABCA7 with moderate to high-magnitude effect. Understanding how these genetic factors contribute to AD risk in a given individual, in additional to non-genetic factors, remains a challenge. Over the last 10 years, age-related penetrance curves have progressively incorporated advances in the knowledge of AD genetics, from APOE to common polygenic components and, currently, SORL1 rare variants, which represents an important step towards precision medicine in AD. In this review, we present the complex genetic architecture of AD and we expose the prediction of AD risk according to its underlying genetic component.

Present and future role of endoscopic retrograde cholangiography in primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) is a rare, inflammatory cholestatic liver disease that causes biliary strictures which can lead to secondary complications. About 30-50% of PSC patients develop dominant strictures (DS) in the biliary tree, which are both the cause of jaundice and bacterial cholangitis as well as predilection spots for development of neoplastic development. Cancer is the most common cause of death in PSC. A central concern is to distinguish malignant from benign strictures, which eventually is done by invasive methods to obtain a brush cytology or biopsy sample, in most cases via endoscopic retrograde cholangiography-pancreatography (ERCP). Since medical therapies, like ursodesoxycholic acid or immunosuppressive drugs have no proven effect, therapeutic ERCP has become the primary management strategy to improve symptoms and in some patients may slow down disease progression. This article aims at outlining the current and emerging methods in ERCP in PSC patients.

Prospective comparison of diffusion-weighted MRI and dynamic Gd-EOB-DTPA-enhanced MRI for detection and staging of hepatic fibrosis in primary sclerosing cholangitis.

PURPOSE: To assess the diagnostic value of multiparametric magnetic resonance imaging (MRI) including dynamic Gd-EOB-DTPA-enhanced (DCE) and diffusion-weighted (DW) imaging for diagnosis and staging of hepatic fibrosis in primary sclerosing cholangitis (PSC) using transient elastography as a standard reference. MATERIAL AND METHODS: Multiparametric MRI was prospectively performed on a 3.0-Tesla scanner in 47 patients (age 43.9±14.3 years). Transient elastography derived liver stiffness measurements (LSM), DCE-MRI derived parameters (hepatocellular uptake rate (Ki), arterial (Fa), portal venous (Fv) and total (Ft) blood flow, mean transit time (MTT), and extracellular volume (Ve)) and the apparent diffusion coefficient (ADC) were calculated. Correlation and univariate analysis of variance with post hoc pairwise comparison were applied to test for differences between LSM derived fibrosis stages (F0/F1, F2/3, F4). ROC curve analysis was used as a performance measure. RESULTS: Both ADC and Ki correlated significantly with LSM (r= -0.614; p<0.001 and r= -0.368; p=0.01). The ADC significantly discriminated fibrosis stages F0/1 from F2/3 and F4 (p<0.001). Discrimination of F0/1 from F2/3 and F4 reached a sensitivity/specificity of 0.917/0.821 and 0.8/0.929, respectively. Despite significant inter-subject effect for classification of fibrosis stages, post hoc pairwise comparison was not significant for Ki (p>0.096 for F0/1 from F2/3 and F4). LSM, ADC and Ki were significantly associated with serum-based liver functional tests, disease duration and spleen volume. CONCLUSION: DW-MRI provides a higher diagnostic performance for detection of hepatic fibrosis and cirrhosis in PSC patients in comparison to Gd-EOB-DTPA-enhanced DCE-MRI. KEY POINTS: • Both ADC and hepatocellular uptake rate (Ki) correlate significantly with liver stiffness (r= -0.614; p<0.001 and r= -0.368; p=0.01). • The DCE-imaging derived quantitative parameter hepatocellular uptake rate (Ki) fails to discriminate pairwise intergroup differences of hepatic fibrosis (p>0.09). • DWI is preferable to DCE-imaging for discrimination of fibrosis stages F0/1 to F2/3 (p<0.001) and F4 (p<0.001).

Follow-up magnetic resonance imaging/3D-magnetic resonance cholangiopancreatography in patients with primary sclerosing cholangitis: challenging for experts to interpret.

BACKGROUND: In patients with primary sclerosing cholangitis follow-up magnetic resonance imaging (MRI) with magnetic resonance cholangiopancreatography (MRCP) is performed by many centres, particularly for the early detection of biliary malignancies and strictures. Clinically meaningful MRI-based definitions of primary sclerosing cholangitis related complications are, however, lacking. AIM: To investigate how primary sclerosing cholangitis experts interpret follow-up MRI/MRCP with a focus on conclusions that may impact clinical decision-making in primary sclerosing cholangitis. METHODS: Within the International Primary Sclerosing Cholangitis Study Group, an online survey on 16 real-life primary sclerosing cholangitis cases including clinical and biochemical information as well as a T2-weighted liver MRI/3D-MRCP was conducted. The interpretation of images and subsequent recommendations were assessed using a multiple-choice questionnaire. An inter-rater reliability calculation (Fleiss' kappa) was performed and factors potentially affecting the interpretation of magnetic resonance images were analysed using generalised linear mixed-effect models. RESULTS: Forty-four members/associates of the International Primary Sclerosing Cholangitis Study Group (median experience in the care of primary sclerosing cholangitis patients: 14 years) completed the survey. The MRI interpretation significantly varied among the participants. The lowest agreement was found with respect to the indication to perform subsequent endoscopic retrograde cholangiopancreatography (ERCP; Κ = 0.12, 95%CI 0.11-0.14). Elevated total bilirubin was the variable with the strongest effect on the rate of suspected dominant strictures, cholangiocarcinoma or ERCP recommendations. Liver cirrhosis did not prevent participants from recommending ERCP. Overall, the survey participants' recommendations contrasted the real-life management and outcome. CONCLUSIONS: In primary sclerosing cholangitis, the interpretation of follow-up MRI/3D-MRCP significantly varies even among experts and seems to be primarily affected by bilirubin levels. Generally accepted MRI-based definitions of primary sclerosing cholangitis-related complications are urgently needed.

[Primary sclerosing cholangitis : Current diagnostics and treatment]. / Primär sklerosierende Cholangitis : Aktuelle Diagnostik und Therapie.

Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology. Characteristic features are multifocal strictures and dilatations of the bile ducts. In 60-80 % of cases the PSC is strongly associated with chronic inflammatory bowel disease, mostly in the form of pancolitis. The diagnosis is established based on detection of typical cholangiographic lesions of the bile ducts and exclusion of secondary causes of sclerosing cholangitis. There is no approved medical treatment, but in Germany ursodeoxycholic acid is frequently used. Clinically relevant stenoses can be successfully treated by interventional endoscopy. Patients with PSC suffer from a greatly increased risk of hepatobiliary malignancies, especially with respect to cholangiocarcinoma and colorectal cancer and therefore require regular surveillance and screening. Liver transplantation is currently the only curative treatment option.

Gadolinium-based relative contrast enhancement in primary sclerosing cholangitis: additional benefit for clinicians?

AIM: To evaluate the benefit of extracellular gadolinium-based contrast agent (GBCA) enhanced magnetic resonance imaging (MRI) in addition to conventional non-enhanced T2-weighted imaging (WI) for quantification of inflammatory or fibrotic alterations in the liver parenchyma of patients with primary sclerosing cholangitis (PSC). MATERIAL AND METHODS: MRI (3 T) examinations were reviewed retrospectively by two radiologists in 27 PSC patients (age 42.9±15.6 years), and 19 controls. Regions of interest (ROIs) were drawn onto T2 hyperintense and T2 isointense areas and copied to section position matched non-enhanced and delayed-phase contrast-enhanced T1WI. Signal intensities (SI) obtained from ROIs of the multiphase T1WI were used to calculate relative liver enhancement (RLE). The interobserver agreement of RLE and quantified T2 signal was calculated using Bland-Altman analysis. RLE assessed for both T2 hyperintense (RLEhyper) and T2 isointense (RLEiso) areas were compared in patients and controls (RLEhealthy). RESULTS: The interobserver agreement of RLE in affected hyperintense areas (bias -0.77, limits of agreement -51.7 to 50.1) was superior to the quantification of T2 signal only in these areas (bias -3.35, limits of agreement -162.4 to 155.7). The RLEhyper (86.2±9.7%) was higher than the RLEiso (59.8±6.2%, p=0.03) and the RLEhealthy (53.2±2.7%, p=0.002). The mean RLEiso was not significantly different from the RLEhealthy (p=0.3). CONCLUSION: The extracellular gadolinium-based RLE of T2 hyperintense areas could be a useful add-on for routine follow up MRI in the detection of early inflammatory changes, possibly preceding formation of fibrotic scarring in PSC patients, if validated in larger cohorts.

A prospective multicentre study of the epidemiology and outcomes of bloodstream infection in cirrhotic patients.

OBJECTIVES: To describe the current epidemiology of bloodstream infection (BSI) in patients with cirrhosis; and to analyse predictors of 30-day mortality and risk factors for antibiotic resistance. METHODS: Cirrhotic patients developing a BSI episode were prospectively included at 19 centres in five countries from September 2014 to December 2015. The discrimination of mortality risk scores for 30-day mortality were compared by area under the receiver operator risk and Cox regression models. Risk factors for multidrug-resistant organisms (MDRO) were assessed with a logistic regression model. RESULTS: We enrolled 312 patients. Gram-negative bacteria, Gram-positive bacteria and Candida spp. were the cause of BSI episodes in 53%, 47% and 7% of cases, respectively. The 30-day mortality rate was 25% and was best predicted by the Sequential Organ Failure Assessment (SOFA) and Chronic Liver Failure-SOFA (CLIF-SOFA) score. In a Cox regression model, delayed (>24 hours) antibiotic treatment (hazard ratio (HR) 7.58; 95% confidence interval (CI) 3.29-18.67; p < 0.001), inadequate empirical therapy (HR 3.14; 95% CI 1.93-5.12; p < 0.001) and CLIF-SOFA score (HR 1.35; 95% CI 1.28-1.43; p < 0.001) were independently associated with 30-day mortality. Independent risk factors for MDRO (31% of BSIs) were previous antimicrobial exposure (odds ratio (OR) 2.91; 95% CI 1.73-4.88; p < 0.001) and previous invasive procedures (OR 2.51; 95% CI 1.48-4.24; p 0.001), whereas spontaneous bacterial peritonitis as BSI source was associated with a lower odds of MDRO (OR 0.30; 95% CI 0.12-0.73; p 0.008). CONCLUSIONS: MDRO account for nearly one-third of BSI in cirrhotic patients, often resulting in delayed or inadequate empirical antimicrobial therapy and increased mortality rates. Our data suggest that improved prevention and treatment strategies for MDRO are urgently needed in the liver cirrhosis patients.

Predicting ADR from PDR and individual adenoma-to-polyp-detection-rate ratio for screening and surveillance colonoscopies: A new approach to quality assessment.

BACKGROUND AND AIMS: Adenoma detection rate (ADR) has been established as a quality indicator for screening colonoscopy. Because ADR is cumbersome to obtain in routine practice, polyp detection rate (PDR), polypectomy rate (PR) and adenoma-to-polyp-detection-rate-ratio (APDRR) have been proposed to estimate ADR. This study aimed to evaluate APDRR in order to estimate ADR (ADRest) in different settings. METHODS: Average risk screening and surveillance colonoscopies from a community-based private practice and a tertiary academic hospital setting were retrospectively evaluated. APDRR was calculated as averaged group APDRR for all study procedures (APDRR) and for the first half of study procedures of each gastroenterologist (APDRRag) or individually for each gastroenterologist on the basis of his or her first 25, 50 and 100 colonoscopies (APDRRind). ADRest was determined from PDR by using APDRR, APDRRag, and APDRRind, respectively. RESULTS: A total of 2717 individuals were analyzed. Using APDRR, significant correlations between ADR and ADRest were observed for the entire (0.944, p < 0.001), proximal (0.854, p < 0.001), and distal (0.977, p < 0.001) colon. These correlations were lost when APDRRag was used to estimate each gastroenterologist's ADR for the second half of his or her included colonoscopies. However, ADR and ADRest correlated significantly with a root-mean-square-error of 6.8% and 5.8% when APDRRind on the basis of each gastroenterologist's first 50 and 100 colonoscopies was used for subsequent colonoscopies. CONCLUSIONS: ADR for subsequent colonoscopies of an individual endoscopist can be reliably estimated from PDR by using an individually calculated APDRR. Prospective studies are needed to verify this promising approach in different practice settings.

IL-15-deficient mice develop enhanced allergic responses to airway allergen exposure.

BACKGROUND: Interleukin-15 is a pleiotropic cytokine that is critical for the development and survival of multiple haematopoietic lineages. Mice lacking IL-15 have selective defects in populations of several pro-allergic immune cells including natural killer (NK) cells, NKT cells, and memory CD8+ T cells. We therefore hypothesized that IL-15-/- mice will have reduced inflammatory responses during the development of allergic airway disease (AAD). OBJECTIVE: To determine whether IL-15-/- mice have attenuated allergic responses in a mouse model of AAD. METHODS: C57BL/6 wild-type (WT) and IL-15-/- mice were sensitized and challenged with ovalbumin (OVA), and the development of AAD was ascertained by examining changes in airway inflammatory responses, Th2 responses, and lung histopathology. RESULTS: Here, we report that IL-15-/- mice developed enhanced allergic responses in an OVA-induced model of AAD. In the absence of IL-15, OVA-challenged mice exhibited enhanced bronchial eosinophilic inflammation, elevated IL-13 production, and severe lung histopathology in comparison with WT mice. In addition, increased numbers of CD4+ T and B cells in the spleens and bronchoalveolar lavage (BAL) were also observed. Examination of OVA-challenged IL-15Rα-/- animals revealed a similar phenotype resulting in enhanced airway eosinophilia compared to WT mice. Adoptive transfer of splenic CD8+ T cells from OVA-sensitized WT mice suppressed the enhancement of eosinophilia in IL-15-/- animals to levels observed in WT mice, but had no further effects. CONCLUSION AND CLINICAL RELEVANCE: These data demonstrate that mice with an endogenous IL-15 deficiency are susceptible to the development of severe, enhanced Th2-mediated AAD, which can be regulated by CD8+ T cells. Furthermore, the development of disease as well as allergen-specific Th2 responses occurs despite deficiencies in several IL-15-dependent cell types including NK, NKT, and γδ T cells, suggesting that these cells or their subsets are dispensable for the induction of AAD in IL-15-deficient mice.

[Thickening or hypoplasia of the fovea]. / Verdickung oder Hypoplasie der Fovea.

A 64-year-old female patient complained of a bilateral reduction in vision. The foveal reflex was remarkable bilaterally and optical coherence tomography (OCT) demonstrated the absence of a foveal depression. After exclusion of possible diseases foveal hypoplasia was diagnosed. This rare alteration of the fovea should not be mistaken for foveal edema. A volume scan with a narrow grid is advisable to avoid a misinterpretation.

Clinical management of chronic hepatitis B infection: results from a registry at a German tertiary referral center.

PURPOSE: We studied a cohort of adult patients with chronic hepatitis B (CHB) infection, followed at a tertiary referral liver center in Germany over 12.5 years to analyze the clinical features and impact of management on disease progression and survival of CHB patients in general and of those with CHB and HCC in particular. METHODS: We retrospectively evaluated the medical records of 242 adult (age ≥ 18 years) patients. CHB was defined as positive hepatitis B surface antigen (HBsAg) and/or HBV-DNA levels >10 IU/mL for at least 6 months. Patient demographics, HBV markers, antiviral treatment, laboratory parameters, liver imaging and histology were recorded for each visit. HCC patients were divided into two groups and separately analyzed (group 1: n = 24, HCC at first visit and group 2: n = 11, HCC during surveillance). RESULTS: The mean age was 44 years in CHB patients without HCC (63% male) and about 59 years in patients with HCC (77% male). Antiviral therapy was given to 59% of patients without HCC compared to only 25% in group 1 and 18% in group 2 with comparable median HBV DNA levels of approximately 36,000 IU/mL. There was no statistically significant difference concerning the HCC stages (Milan, UCSF, BCLC) at first diagnosis. Five-year survival was 19% in group 1 vs. 64% in group 2 (p = 0.019), with LTx performed in 12 vs. 45%, respectively. CONCLUSION: Surveillance of CHB patients did not result in early stage detection of HCC but in a higher likelihood to receive potentially curative treatments.

[Inflammatory diseases with liver and joint involvement. A differential diagnostic challenge]. / Inflammatorische Erkrankungen mit Leber- und Gelenkbeteiligung. Eine differenzialdiagnostische Herausforderung.

Elevated levels of liver enzymes in patients with rheumatic symptoms require a comprehensive differential diagnostic thought process. On the one hand there can be hepatic involvement of primarily rheumatological diseases but this is quite rare. Drug-induced liver injury by antirheumatic medication is more frequent. On the other hand arthralgia can be a sign of primary hepatopathy whereby hemochromatosis and autoimmune hepatitis (AIH) are typical examples. Furthermore, some liver diseases are associated with rheumatological diseases, such as primary biliary cirrhosis (PBC) and chronic hepatitis C infection (HCV). Only an exact diagnosis will lead to specific treatment which will improve the symptoms and course of disease.

Acute liver failure following minocycline treatment - a case report and review of the literature.

We present the case of a 23-year-old female patient with acute liver failure following intake of minocycline. This patient had severe hypereosinophilia and massively increased IgE levels. Experimental studies in this case revealed elevated IFN-γ-, as well as TNF-α-producing CD4+ and CD8+ T-cells after in vitro stimulation with minocycline, indicating a type I/IgE-mediated as well as type II/cytotoxic reaction in the pathogenesis of minocycline-induced liver failure. Although mild forms of liver involvement are well known side effects of minocycline, only 8 cases with acute liver failure have been reported, and we present a review of all cases.

[Autoimmune liver diseases]. / Autoimmunerkrankungen der Leber.

Autoimmune liver diseases are divided into autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC). They play an important role in the differential diagnosis of acute and chronic liver diseases. Diagnostic criteria consist of biochemical parameters (liver function tests, immunoglobulins, autoantibodies), imaging (ultrasound, MRCP, ERCP) and histopathologic characteristics. The treatment of choice in AIH is a combined immunosuppressive therapy of prednisolone and azathioprine. Ursodeoxycholic acid is the treatment of choice for PBC and improves liver biochemistry and prolongs transplant-free survival by slowing histological progression in the majority of patients. To date, there is no effective medical treatment option for patients with PSC.

Regulatory B cells from hilar lymph nodes of tolerant mice in a murine model of allergic airway disease are CD5+, express TGF-ß, and co-localize with CD4+Foxp3+ T cells.

In a biphasic, ovalbumin (OVA)-induced murine asthma model where allergic airway disease is followed by resolution and the development of local inhalational tolerance (LIT), transforming growth factor (TGF)-ß-expressing CD5(+) B cells were selectively expanded locally in hilar lymph nodes (HLN) of LIT mice. LIT HLN CD5(+) B cells, but not LIT HLN CD5(-) B cells, induced expression of Foxp3 in CD4(+)CD25(-) T cells in vitro. These CD5(+) regulatory B cells (Breg) and CD4(+)Foxp3(+) T cells demonstrated similar increases in expression of chemokine receptors (CXCR4 and CXCR5) and co-localized in HLN B cell zones of LIT mice. The adoptive transfer of LIT HLN CD5(+) B cells, but not LIT HLN CD5(-) B cells, increased the number of CD4(+)Foxp3(+) T cells in the lung and inhibited airway eosinophilia in this OVA model. Thus, Breg in HLNs of LIT mice reside in a CD5(+) TGF-ß-producing subpopulation and co-localize with CD4(+)Foxp3(+) T cells.

De novo partial trisomy 18p and partial monosomy 18q in a patient with anorectal malformation.

Anorectal malformations (ARM) encompass a broad clinical spectrum which ranges from mild anal stenosis to severe anorectal anomalies such as complex cloacal malformations. The overall incidence of ARM is around 1 in every 2,500 live births. Although causative genes for a few syndromic forms have been identified, the molecular genetic background of most ARM remains unknown. The present report describes a patient with a de novo 13.2-Mb deletion of chromosome 18q22.3-qter and a 2.2-Mb de novo duplication of chromosomal region 18pter-p11.32 located at the telomeric end of chromosome 18q. The patient presented with ARM and the typical features of 18q- syndrome (De-Grouchy syndrome). The combination of a partial duplication of the short arm and a partial deletion of the long arm of chromosome 18 has been described in 16 previous cases. However, this is the first report of an association between this complex chromosomal rearrangement and ARM.

[A rare cause of variceal bleeding]. / Seltene Ursache einer Fundusvarizenblutung.

BACKGROUND: Agnogenic myeloid metaplasia (AMM) is a clonal stem cell disease, which is characterized by myelofibrosis, osteosclerosis and pancytopenia. Affected patients frequently develop portal hypertension secondary to extramedullary hematopoiesis, which rarely becomes clinically relevant. CASE REPORT: We here report on a 63-year-old patient with a first presentation of variceal bleeding. The patient was diagnosed with portal hypertension and due to marked splenomegaly, liver cirrhosis was suspected. Subsequently, an extramedullary hematopoiesis and AMM could be diagnosed. The variceal bleeding was initially treated endoscopically. The patient has received cytoreductive therapy and a splenorenal shunt, which has led to remission and long-term survival. CONCLUSION: Agnogenic myeloid metaplasia is a rare cause of portal hypertension and may present with variceal bleeding. Clinicians should be aware of this rare cause of portal hypertension, as treatment of the underlying disease with cytoreductive therapy and appropriate management of portal hypertension may lead to long-term survival.