Artificial-intelligence-based decision support tools for the differential diagnosis of colitis.

BACKGROUND: Whereas Artificial Intelligence (AI) based tools have recently been introduced in the field of gastroenterology, application in inflammatory bowel disease (IBD) is in its infancies. We established AI-based algorithms to distinguish IBD from infectious and ischemic colitis using endoscopic images and clinical data. METHODS: First, we trained and tested a Convolutional Neural Network (CNN) using 1796 real-world images from 494 patients, presenting with three diseases (IBD [n = 212], ischemic colitis [n = 157], and infectious colitis [n = 125]). Moreover, we evaluated a Gradient Boosted Decision Trees (GBDT) algorithm using five clinical parameters as well as a hybrid approach (CNN + GBDT). Patients and images were randomly split into two completely independent datasets. The proposed approaches were benchmarked against each other and three expert endoscopists on the test set. RESULTS: For the image-based CNN, the GBDT algorithm and the hybrid approach global accuracies were .709, .792, and .766, respectively. Positive predictive values were .602, .702, and .657. Global areas under the receiver operating characteristics (ROC) and precision recall (PR) curves were .727/.585, .888/.823, and .838/.733, respectively. Global accuracy did not differ between CNN and endoscopists (.721), but the clinical parameter-based GBDT algorithm outperformed CNN and expert image classification. CONCLUSIONS: Decision support systems exclusively based on endoscopic image analysis for the differential diagnosis of colitis, representing a complex clinical challenge, seem not yet to be ready for primetime and more diverse image datasets may be necessary to improve performance in future development. The clinical value of the proposed clinical parameters algorithm should be evaluated in prospective cohorts.

Isolated bacterial infection without decompensation has no impact on survival of compensated patients with cirrhosis.

BACKGROUND & AIMS: Bacterial infections (BI) affect the natural course of cirrhosis and were suggested to be a landmark event marking the transition to the decompensated stage. Our specific aim was to evaluate the impact of BI on the natural history of compensated cirrhosis. METHODS: We analyzed 858 patients with cirrhosis, evaluated for the INCA trial (EudraCT 2013-001626-26) in 2 academic medical centers between February 2014 and May 2019. Only patients with previously compensated disease were included. They were divided into 4 groups: compensated without BI, compensated with BI, 1st decompensation without BI, and 1st decompensation with BI. RESULTS: About 425 patients (median 61 [53-69] years) were included in the final prospective analysis. At baseline, 257 patients were compensated (12 [4.7%] with BI), whereas 168 patients presented with their 1st decompensation (42 [25.0%] with BI). In patients who remained compensated MELD scores were similar in those with and without BI. Patients with their first decompensation and BI had higher MELD scores than those without BI. Amongst patients who remained compensated, BI had no influence on transplant-free survival, whereas patients with their 1st decompensation and concurrent BI had significantly reduced transplant-free survival as compared with those without BI. The development of BI or decompensation during follow-up had a greater impact on survival than each of these complications at baseline. CONCLUSIONS: In compensated patients with cirrhosis, the 1st decompensation associated to BI has worse survival than decompensation without BI. By contrast, BI without decompensation does not negatively impact survival of patients with compensated cirrhosis.

Could inherited predisposition drive non-obese fatty liver disease? Results from German tertiary referral centers.

Non-alcoholic fatty liver disease (NAFLD) is frequent among obese individuals with metabolic syndrome. Variants PNPLA3 p.I148M, TM6SF2 p.E167K and MBOAT7 rs641738 are associated with higher liver fat contents. Here we analyzed 63 biopsied non-obese, non-diabetic patients with NAFLD (39 men, age: 20-72 years) recruited within the German NAFLD CSG program. The frequencies of the PNPLA3, TM6SF2 and MBOAT7 polymorphisms were compared with the remaining patients in the NAFLD CSG cohort and with a control population (n = 174). Serum CK18-M30 was measured by ELISA. In non-obese NAFLD patients, the frequency of the PNPLA3 p.I148M allele (74.6%), but not of the TM6SF2 or MBOAT7 polymorphisms, was significantly (P < 0.05) higher as compared to the other patients in the NAFLD CSG cohort (54.9%) or controls (40.2%). The presence of the minor PNPLA3 p.I148M risk allele increased the risk of developing NAFLD (OR = 3.29, P < 0.001) and was associated with higher steatosis, fibrosis, and serum CK18-M30 levels (all P < 0.05). According to the population attributable fraction (PAF), 49.8% of NAFLD cases could be eliminated if the PNPLA3 mutation was absent. The MBOAT7 polymorphism was more frequent (P = 0.019) in patients with severe hepatic steatosis. In conclusion, PNPLA3, and to a lesser extent, MBOAT7 variants are associated with NAFLD risk and modulate liver injury in non-obese patients without diabetes.

A Variant of COL3A1 (rs3134646) Is Associated With Risk of Developing Diverticulosis in White Men.

BACKGROUND: Colonic diverticulosis is one of the most common gastroenterological disorders. Although diverticulosis is typically benign, many individuals develop diverticulitis or other aspects of diverticular disease. Diverticulosis is thought to stem from a complex interaction of environmental, dietary, and genetic factors; however, the contributing genetic factors remain unknown. OBJECTIVE: The aim of our present study was to determine the role of genetic variants within genes encoding for collagens of the connective tissue in diverticulosis. DESIGN: This was a transsectional genetic association study. SETTINGS: This study was conducted at three tertiary referral centers in Germany and Lithuania. PATIENTS: Single-nucleotide polymorphisms in COL3A1 (rs3134646, rs1800255) and COL1A1 (rs1800012) were genotyped in 422 patients with diverticulosis and 285 controls of white descent by using TaqMan assays. MAIN OUTCOME MEASURES: The association of colonoscopy-proven diverticulosis with genetic polymorphisms with herniations was assessed in multivariate models. RESULTS: The rs3134646, rs1800255, and rs1800012 variants were significantly associated with the risk of developing diverticulosis in the univariate model; however, these associations were not significant in the multivariate logistic regression analysis including additional nongenetic variables. When selectively analyzing sexes, the genotype AA (AA) in rs3134646 remained significantly associated with diverticulosis in men (OR, 1.82; 95% CI, 1.04-3.20; p = 0.04). LIMITATIONS: Because a candidate approach was used, additional relevant variants could be missed. Within our cohort of patients with diverticulosis, only a small proportion had diverticular disease and thus, we could not examine the variants in these subgroups. Functional studies, including the analysis of the involved collagens, are also warranted. CONCLUSIONS: Our study shows that a variant of COL3A1 (rs3134646) is associated with the risk of developing colonic diverticulosis in white men, whereas rs1800255 (COL3A1) and rs1800012 (COL1A1) were not associated with this condition after adjusting for confounding factors. Our data provide novel valuable insights in the genetic susceptibility to diverticulosis. See Video Abstract at http://links.lww.com/DCR/A504.

Selective association of nonaspirin NSAIDs with risk of diverticulitis.

PURPOSE: The purpose of this study is to investigate the association of intake of nonsteroidal anti-inflammatory drugs (NSAIDs) and in particular nonaspirin NSAIDs and compare it with other risk factors for the progression of diverticulosis to diverticulitis in patients who underwent colonoscopy. METHODS: A total of 194 patients who underwent complete colonoscopy in our center between 2012 and 2016 were recruited: 144 with diverticulosis without prior diverticulitis (median age 71 years, 59.7% men) and 50 with diverticulitis (median age 64 years, 54.0% men). Data concerning current and previous medication as well as concomitant diseases were collected using a structured questionnaire and by revision of patients medical charts. RESULTS: Patients with diverticulitis were significantly (p < 0.001) younger as compared to individuals with plain diverticulosis (median age 64 versus 71 years, respectively). The intake of NSAIDs significantly (p = 0.002) increased the risk of prior diverticulitis (OR 3.2, 95% CI 1.5-6.9). In the multivariate model, both age (p < 0.001) and NSAIDs (p = 0.03) proved to be independent determinants of diverticulitis. When analyzing aspirin intake, it was not associated with diverticulitis. CONCLUSIONS: Our study demonstrates, in line with previous reports, that intake of NSAIDs is associated with diverticulitis. We show in particular that nonaspirin NSAIDs might be selectively associated with diverticulitis. These results point to divergent role of aspirin and nonaspirin NSAIDs in the development of diverticulitis.

Effects of Gene Variants Controlling Vitamin D Metabolism and Serum Levels on Hepatic Steatosis.

BACKGROUND/AIMS: Common genetic variations in vitamin D metabolism are associated with liver stiffness. Whether these genes are implicated in hepatic steatosis remains unclear. Here we aimed to analyse the association of common vitamin D pathway gene variants with liver steatosis. METHODS: Liver steatosis was assessed non-invasively in 241 patients with chronic liver conditions by controlled attenuation parameter (CAP). The following polymorphisms were genotyped using TaqMan assays: group-specific component (GC) rs7041, 7-dehydrocholesterol reductase (DHCR7) rs12785878, cytochrome P450 2R1 (CYP2R1) rs10741657, -vitamin D receptor (VDR) rs7974353. Chemiluminescence immunoassay determined serum 25-hydroxyvitamin D (25(OH) D) concentrations. RESULTS: Vitamin D deficiency (defined by 25(OH)D concentrations <20 ng/mL) occurred in 66% of patients. Median CAP was 296 (100-400) dB/m. Patients with advanced steatosis (CAP ≥280 dB/m) had significantly (p = 0.033) lower 25(OH)D levels as compared to patients with CAP <280 dB/m. Moreover, the rare allele [T] in GC rs7041 was significantly (p = 0.018) associated with higher 25(OH)D levels in patients with CAP <280 dB/m. However, GC, DHCR7, CYP2R1, and VDR polymorphisms were not related to liver steatosis and obesity traits. CONCLUSIONS: Higher CAP values are associated with low serum 25(OH)D concentrations but not with common vitamin D pathway gene variants.

The common PNPLA3 variant p.I148M is associated with liver fat contents as quantified by controlled attenuation parameter (CAP).

BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is becoming the most prevalent liver disorder. The PNPLA3 (adiponutrin) variant p.I148M has been identified as common genetic modifier of NAFLD. Our aim was to assess the relationships between genetic risk and non-invasively measured liver fat content. METHODS: Hepatic steatosis was quantified by transient elastography, using the controlled attenuation parameter (CAP) in 174 patients with chronic liver diseases (50% women, age 18-77 years). In addition, a cohort of 174 gender-matched healthy controls (50% women, age 32-77 years) was recruited. The PNPLA3 mutation as well as the novel NAFLD-predisposing genetic variant (TM6SF2 p.E167K) were genotyped with allele-specific probes. RESULTS: The PNPLA3 genotype correlated significantly (P = 0.001) with hepatic CAP measurements. The p.148M risk allele increased the odds of developing liver steatosis (OR = 2.39, P = 0.023). In multivariate models, BMI and PNPLA3 mutation were both independently associated with CAP values (P < 0.001 and P = 0.007, respectively). Carriers of the TM6SF2 risk allele presented with increased aminotransferase activities (ALT: P = 0.007, AST: P = 0.004), but the presence of this variant did not affect CAP values. CONCLUSIONS: The PNPLA3 p.I148M variant represents the most important prosteatotic genetic risk factor. NAFLD carriers of this variant should be followed up carefully, with elastography and CAP being ideally suited for this purpose.

Vitamin D deficiency is associated with mortality in patients with advanced liver cirrhosis.

BACKGROUND: Chronic liver disease is the fifth most common cause of mortality in Europe. Recently, vitamin D deficiency has been associated with an increased risk of mortality in the general population. As patients with advanced liver disease frequently exhibit vitamin D deficiency, we assessed for a possible association of vitamin D deficiency with survival in a cohort of patients with advanced liver disease. METHODS: Sixty-five patients with liver cirrhosis (median age, 58 years; range, 19-76 years; 66% male; Child-Pugh stage C, 46%) were included in our prospective single-centre survival study. Serum 25-hydroxyvitamin D concentrations were measured by chemiluminescence immunoassay. The optimal cut-off was determined using receiver operating characteristic (ROC) and Kaplan-Meier analysis. Chi-square statistics and multivariate binary logistic regression analysis were also conducted. RESULTS: Median serum vitamin D levels were 8·2 ng/mL (range <4·0-95·8 ng/mL). Overall, 48% of patients (31/65) died during a 24-month follow-up period. ROC analysis determined a vitamin D level of 6·0 ng/mL as optimal cut-off for discriminating survivors from nonsurvivors. Kaplan-Meier analysis of survival confirmed low vitamin D levels as significant predictor of death (P = 0·012). Finally, multivariate analysis identified low vitamin D levels (OR = 6·3; 95% CI, 1·2-31·2; P = 0·012) and MELD scores (OR = 1·4; 95% CI, 1·2-1·7; P < 0·001) as independent predictors of survival. CONCLUSION: Low vitamin D levels are associated with increased mortality in patients with advanced liver disease. Thus, serum levels of vitamin D might represent a critical marker of survival in advanced liver cirrhosis.

Common genetic variation in vitamin D metabolism is associated with liver stiffness.

UNLABELLED: Recently, genome-wide studies identified genetic variants that affect serum 25-hydroxyvitamin D levels in healthy populations (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, at CYP2R1; and rs7041, at vitamin D binding protein, GC). Because vitamin D deficiency is associated with advanced liver disease, we hypothesized that these variants are associated with 25(OH)-vitamin D levels and liver fibrosis. Overall, 712 Caucasian patients with chronic liver diseases were included. Liver fibrosis was assessed by transient elastography (TE) and/or histology. Serum levels of 25(OH)-vitamin D were correlated with TE and fibrosis stages. Genotypes were determined using TaqMan assays and tested for association with vitamin D and liver stiffness. Serum 25(OH)-vitamin D levels were inversely correlated with liver stiffness and histology (P < 0.001). Homozygous carriers of the rare DHCR7 allele or the common CYP2R1 allele presented with reduced 25(OH)-vitamin D levels (P < 0.05). The variant rs12785878 in the DHCR7 locus was associated with liver stiffness in both patients with TE <7.0 kPa and TE between 7.0 and 9.5 kPa. 25(OH)-vitamin D levels correlated with sunshine hours at the time of inclusion (P < 0.001). CONCLUSION: Common variation in 25(OH)-vitamin D metabolism is associated with liver stiffness in patients presenting with low to moderately increased elasticity. Although the susceptible DHCR7 genotype confers small risk, we speculate that the observed stiffness differences indicate a stronger influence of 25(OH)-vitamin D on initiation rather than progression of hepatic fibrosis.

Vitamin D in chronic liver disease.

UNLABELLED: Chronic liver disease (CLD) and several related extrahepatic manifestations such as hepatic osteodystrophy are associated with deficiency of vitamin D, which has therefore been suggested as therapeutic target. Vitamin D undergoes hepatic 25-hydroxylation, rendering the liver critical to the metabolic activation of this vitamin. Vitamin D deficiency is highly prevalent in CLD patients, and vitamin D levels are inversely related to the severity of CLD. Declining levels of carrier proteins such as albumin and vitamin D-binding protein might also be critical in CLD. Intervention studies report improvements of CLD following supplementation, and benefits to health outcomes in particular with respect to hepatitis C virus infection have recently been documented. CONTENT: We discuss vitamin D sources, functions and metabolism with a focus on the inherent complications of analytical measurements, such as the interference of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D C-3 epimers. Global discrepancies in the definition of optimal serum 25-hydroxyvitamin D levels are covered, and the prevalence of vitamin D deficiency in CLD is reviewed. We also address the functional mechanisms underlying this deficiency, and refer to associations between genetic variation in vitamin D metabolism and CLD. Lastly, we consider the health implications of a vitamin D deficiency in CLD and consider therapeutic options. SUMMARY: Herein, we focus on the epidemiological and functional relationships between vitamin D deficiency and CLD, followed by a discussion of the potential implications for therapeutic interventions.

Gallstone disease in Swedish twins is associated with the Gilbert variant of UGT1A1.

BACKGROUND & AIMS: The Gilbert syndrome-associated functional TATA box variant UGT1A1*28 (A(TA)7TAA) was found to increase susceptibility to pigment gallstone formation in patients with haemolytic anaemia. Further studies in extensive cohorts demonstrated an increased risk of this variant for cholesterol gallstone disease (GD). We now investigated this polymorphism as a determinant of symptomatic GD in Swedish twins. METHODS: The Swedish Twin Registry was merged with the Hospital Discharge and Causes of Death Registries and searched for GD-related diagnoses among monozygotic (MZ) twins living in the Stockholm area. In addition, we screened the TwinGene database for GD. In total, we found 44 MZ twin pairs with and eight MZ twins without GD to be evaluable. GD-free twins from TwinGene (109 concordantly MZ and 126 independent DZ) served as controls. UGT1A1*28 genotyping was performed using TaqMan assays. RESULTS: Overall, 58 and 8 of 106 twins with GD were hetero- and homozygous UGT1A1 risk allele carriers respectively. The case-control association tests showed a significantly (P < 0.05) increased risk of developing GD (OR = 1.62, 95% CI 1.00-2.63) in heterozygotes carriers and in addition, a trend (P = 0.075) for an increased risk among carriers (OR = 1.52, 95% CI 0.97-2.44) of the risk allele. CONCLUSION: These data from Swedish twins confirm the Gilbert variant as risk factor for GD. Our observation is in line with nucleation in bilirubin supersaturated bile representing an initial step in cholelithogenesis.

Liver fibrosis: how many samples in transjugular liver biopsy are sufficient? Histological vs. clinical value.

PURPOSE: Liver biopsy (LB) is a diagnostic procedure to obtain histological diagnosis, grading and staging in individuals with liver diseases. Most commonly LB is performed percutaneously. However, transjugular liver biopsy (TJLB) is considered as an alternative. The aim of this prospective study was to evaluate the diagnostic accuracy of TJLB. METHODS: TJLB with a semi-automatic Tru-Cut System (18G) was performed in 39 patients with various liver diseases (21 females and 18 males; age range 11-77 years). The number of complete portal tracts (CPTs), lengths and numbers of acquired cores, number of performed cutting steps (passes), and the possibility to obtain histological diagnosis were analyzed. RESULTS: There were no procedure-related complications, and in total 45 procedures were performed. Diagnosis could be established in 88.8 % of all samples, in five cases histology yielded no diagnosis due to an inadequate number of CPTs or sample fragmentation. In average, 4 passes were performed and 4 (range 1-7) cores were obtained. Median core length was 1.1 cm (range 0.4-1.9 cm), median number of CPTs was 7 (range 0-20). Liver fibrosis in general led to a decreased number of CPTs (p < 0.05). CONCLUSIONS: TJLB is a safe procedure allowing histological diagnosis of liver diseases. In our cohort, performing 4 cutting procedures during TJLB resulted in a sufficiently high specimen quality, particularly in individuals with liver cirrhosis.

Identification of combined genetic determinants of liver stiffness within the SREBP1c-PNPLA3 pathway.

The common PNPLA3 (adiponutrin) variant, p.I148M, was identified as a genetic determinant of liver fibrosis. Since the expression of PNPLA3 is induced by sterol regulatory element binding protein 1c (SREBP1c), we investigate two common SREBP1c variants (rs2297508 and rs11868035) for their association with liver stiffness. In 899 individuals (aged 17-83 years, 547 males) with chronic liver diseases, hepatic fibrosis was non-invasively phenotyped by transient elastography (TE). The SREBP1c single nucleotide polymorphisms (SNPs) were genotyped using PCR-based assays with 5'-nuclease and fluorescence detection. The SREBP1c rs11868035 variant affected liver fibrosis significantly (p = 0.029): median TE levels were 7.2, 6.6 and 6.0 kPa in carriers of (TT) (n = 421), (CT) (n = 384) and (CC) (n = 87) genotypes, respectively. Overall, the SREBP1c SNP was associated with low TE levels (5.0-8.0 kPa). Carriers of both PNPLA3 and SREBP1c risk genotypes displayed significantly (p = 0.005) higher median liver stiffness, as compared to patients carrying none of these variants. The common SREBP1c variant may affect early stages of liver fibrosis. Our study supports a role of the SREBP1c-PNPLA3 pathway as a "disease module" that promotes hepatic fibrogenesis.

The toll-like receptor 2 (TLR2) -196 to -174 del/ins polymorphism affects viral loads and susceptibility to hepatocellular carcinoma in chronic hepatitis C.

Chronic hepatitis C virus (HCV) infection is a major risk factor for hepatocellular carcinoma (HCC). HCV proteins core and NS3 can bind to toll-like receptor 2 (TLR2) and trigger inflammatory responses. Polymorphisms in the TLR2 gene predispose to various forms of malignancy but have not been studied in HCV-associated HCC. Here, we investigated whether single nucleotide polymorphisms (SNPs), rs4696480, rs5743708, rs5743704 and the -196 to -174 del/ins polymorphism of the TLR2 gene affect the risk for HCC in chronic hepatitis C. The study involved 189 and 192 HCV genotype 1 infected patients with and without HCC, respectively, as well as 347 healthy controls. TLR2 alleles were determined by hybridization probe assays and allele-specific short fragment polymerase chain reaction on a LightCycler system. All TLR2 polymorphisms matched the Hardy-Weinberg equilibrium in each study group. Although TLR2 SNPs showed no effect, the frequency of the TLR2 -196 to -174 del allele was significantly higher in patients with HCV-associated HCC (22.5%) than in HCV-infected patients without HCC (15.6%, p = 0.016) and healthy controls (15.3%, p = 0.003). HCV-infected carriers of a TLR2 -196 to -174 del allele had significantly higher HCV viral loads than TLR2 -196 to -174 ins/ins homozygous patients (p = 0.031). Finally, in carriers of the TLR2 -196 to -174 del allele, stimulation of monocytes resulted in significantly lower TLR2 expression levels and interleukin-8 (IL-8) induction than in individuals with the TLR2 -196 to -174 ins/ins genotype (p < 0.05). Our data suggest the TLR2 -196 to -174 del allele to affect HCV viral loads and to increase the risk for HCC in HCV genotype1-infected patients.

The CXCL1 rs4074 A allele is associated with enhanced CXCL1 responses to TLR2 ligands and predisposes to cirrhosis in HCV genotype 1-infected Caucasian patients.

BACKGROUND & AIMS: CXCL1 is a ligand for CXC chemokine-receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. Here, we investigated whether the CXCL1 rs4074 polymorphism affects CXCL1 expression and progression of chronic hepatitis C virus (HCV) infection towards cirrhosis. METHODS: The study involved 237 patients with chronic HCV genotype 1 infection (75 with cirrhosis) and 342 healthy controls. The CXCL1 rs4074 polymorphism was determined by a LightSNiP assay on the LightCycler system. CXCL1 serum levels and induction in response to HCV proteins were studied by ELISA. RESULTS: Distributions of CXCL1 genotypes (GG/GA/AA) matched the Hardy-Weinberg equilibrium in all subgroups (HCV-associated cirrhosis: 29.3%/54.7%/16.0%; non-cirrhotic HCV infection: 45.1%/44.4%/10.5%, healthy controls: 46.2%/40.9%/12.9%). HCV-infected cirrhotic patients had a significantly greater CXCL1 rs4074 A allele frequency (43.3%) than patients without cirrhosis (32.7%, OR=1.573, p=0.03) and healthy controls (33.3%, OR=1.529, p=0.02). In vitro carriers of the A allele produced greater amounts of CXCL1 in response to TLR2-ligands including HCV core and NS3, and HCV-infected carriers of the CXCL1 rs4074 A allele had higher CXCL1 serum levels than those with the G/G genotype. Moreover, multivariate Cox-regression analysis confirmed age and the presence of a CXCL1 rs4074 A allele as risk factors for cirrhosis. CONCLUSIONS: Enhanced production of CXCL1 in response to HCV antigens in carriers of the rs4074 A allele together with its increased frequency in cirrhotic patients with hepatitis C suggest the CXCL1 rs4074 A allele as a genetic risk factor for cirrhosis progression in hepatitis C.

Etiologies and outcomes of acute liver failure in Germany.

BACKGROUND & AIMS: Acute liver failure (ALF) is a severe form of acute liver injury that can progress to multiple organ failure. We investigated causes and outcomes of ALF. METHODS: Eleven university medical centers in Germany were asked to report patients with (primary) severe acute liver injury (sALI) (international normalized ratio [INR] >1.5 but no hepatic encephalopathy) and primary ALF (INR >1.5 with overt hepatic encephalopathy) treated from 2008 to 2009. Data were analyzed from 46 patients with sALI and 109 patients with ALF. RESULTS: The most frequent etiologies of primary ALF were non-acetaminophen drug-induced (32%), indeterminate (24%), and viral (21%); acetaminophen ingestion was the cause of ALF in only 9% of patients. The support of a ventilator was required by 44% of patients with ALF, vasopressors by 38%, and renal replacement by 36%. Seventy-nine patients with ALF (72%) survived until hospital discharge, 38 (35%) survived without emergency liver transplantation (ELT), and 51 received ELT (47%); 80% of patients who received ELT survived until discharge from the hospital. CONCLUSIONS: In Germany, drug toxicity, indeterminate etiology, and viral hepatitis appear to be the major causes of primary ALF, which has high mortality. Patients with ALF are at great risk of progressing to multiple organ failure, but 80% of patients who receive ELT survive until discharge from the hospital.

Cancer risk in chronic hepatitis B: Do genome-wide association studies hit the mark?

To identify susceptibility variants for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), we conducted a genome-wide association study by genotyping 440,794 SNPs in 355 chronic HBV carriers with HCC and 360 chronic HBV carriers without HCC, all of Chinese ancestry. We identified one intronic SNP (rs17401966) in KIF1B on chromosome 1p36.22 that was highly associated with HBV-related HCC and confirmed this association in five additional independent samples, consisting of 1,962 individuals with HCC, 1,430 control subjects and 159 family trios. Across the six studies, the association with rs17401966 was highly statistically significant (joint odds ratio = 0.61, P = 1.7 × 10(-18) ). In addition to KIF1B, the association region tagged two other plausible causative genes, UBE4B and PGD. Our findings provide evidence that the 1p36.22 locus confers susceptibility to HBV-related HCC, and suggest that KIF1B-, UBE4B- or PGD-related pathways might be involved in the pathogenesis of this malignancy.

A frequent variant in the human bile salt export pump gene ABCB11 is associated with hepatitis C virus infection, but not liver stiffness in a German population.

BACKGROUND: The human ATP-binding cassette, subfamily B, member 11 (ABCB11) gene encodes the bile salt export pump, which is exclusively expressed at the canalicular membrane of hepatocytes. A frequent variant in the coding region, c.1331 T>C, leading to the amino acid exchange p.V444A, has been associated with altered serum bile salt levels in healthy individuals and predisposes homozygous carriers of the [C] allele for obstetric cholestasis. Recently, elevated bile salt levels were shown to be significantly associated with rates and risk of cirrhosis in patients with chronic hepatitis C virus (HCV) infection treated with pegylated interferon-α2 and ribavirin, suggesting a potential role for bile salt levels in HCV treatment outcomes and in the fibrogenic evolution of HCV-related liver disease. The aim of this study was to investigate a possible association of ABCB11 c.1331 T>C with hepatitis C virus (HCV) infection and fibrosis stages as assessed by non-invasive transient elastography in a German cohort of patients. METHODS: ABCB11 c.1331 T>C genotype was determined by allelic discrimination assay in 649 HCV infected cases and 413 controls. Overall, 444 cases were staged for fibrotic progression by measurement of liver stiffness. RESULTS: Homo- or heterozygous presence of the frequent [C] allele was associated with HCV positivity (OR = 1.41, CI = 1.02 - 1.95, p = 0.037). No association was detectable between the ABCB11 c.1331 T>C genotype and increased liver stiffness. CONCLUSIONS: Our data confirm that homozygous presence of the major [C] allele of ABCB11 c.1331 T>C is a genetic susceptibility factor for HCV infection, but not for liver fibrosis.

Parenchyma-preserving hepatic resection for colorectal liver metastases.

BACKGROUND: Hepatic resection of colorectal liver metastases is the only curative treatment option. As clinical and experimental data indicate that the extent of liver resection correlates with growth of residual metastases, the present study analyzes the potential benefit of a parenchyma-preserving liver surgery approach. METHODS: Data from a prospectively maintained database of patients undergoing liver resection for colorectal metastases were reviewed. Evaluation of outcome was performed using the Kaplan-Meier method. Correlations were calculated between clinical-pathological variables. RESULTS: One hundred sixty-three patients underwent 198 liver resections for colorectal metastases: 26 major hepatectomies, 65 minor anatomical resections, 78 non-anatomical resections, as well as 29 combinations of minor anatomical and non-anatomical procedures. Overall 1-, 3-, and 5-year survival was 93%, 62%, and 40%, respectively. Patients with repeated liver resections had a 5-year survival of 27%. Interestingly, large dissection areas were associated with a significant reduction of the 5-year survival rate (33%). Five-year survival after major hepatectomy was not significantly reduced. CONCLUSION: For colorectal liver metastases, minor resections offer a prolonged survival compared to major hepatectomies. As patients with stage IV colorectal disease are candidates for repeat resections, preservation of hepatic parenchyma is of increasing importance in the setting of multi-modal and repeated therapy approaches.