Graft‐versus‐host disease (GvHD) and toxic epidermal necrolysis (TEN) are rare and severe complications after liver transplantation. While mild acute GvHD is quite different from TEN and easy to ...distinguish, severe acute GvHD and TEN can be hard to differentiate because of similar clinical symptoms. We herein report a case with rapid progression of critical illness, after liver transplantation, caused by GvHD or TEN, although between those, diagnosis was not possible during the clinical course. Although, based on the timing/progression of the symptoms and the chimerism of >40%, the case seemed much more clinically consistent with GVHD, the combination of clinical symptoms together with skin rashes and the histologic appearance of skin lesions indicated diagnosis of a Stevens‐Johnson syndrome/TEN overlap. The true diagnostic dilemma in such cases is discussed in detail, as these cases emphasize the need for more advanced diagnostic techniques.
Abnormalities in dopaminergic neurotransmission are now accepted as factors in predisposing to ADHD. Evidence of associations between dopamine transporter gene polymorphism and ADHD was first ...reported by Cook et al. We confirmed the DAT1 association and also identified two additional susceptibility loci at the DRD5 and DBH. Notably, none of the associated variants at these three genes are known to be expressed. Other variants within or closely mapped to the associated alleles are likely to be relevant. In this investigation, we analyse additional markers creating a high-density map across and flanking these genes, and measure intermarker linkage disequilibrium (LD). None of the newly examined markers were more strongly associated with ADHD. At DAT1, the pattern of intermarker LD and haplotype association with the phenotype between exon 9 and the 3' of the gene suggests that the functional variant at DAT1 may be located to this region. For DRD5, three markers, covering a region of approximately 68 kb including the single DRD5 exon are all associated with disease, and thus do not provide localizing information. However, the data for DBH point to a region close to the centre of the gene. Correlation between D' and physical distance was observed between markers at DAT1 and DRD5 for distances less than 50 kb. This was not the case for DBH, where LD breakdown was observed between the intron 5 and intron 9 polymorphisms although they are only 9 kb apart. Further genetic analysis is unlikely to refine the location of susceptibility variants and functional assessment of variants within associated regions is required.
Recently the common adiponutrin (PNPLA3) polymorphism p.I148M has been identified as a genetic determinant of severe forms of non-alcoholic fatty liver disease and alcoholic liver disease. ...Additionally, insulin resistance - linked to the development of non-alcoholic steatohepatitis - increases the risk of developing gallstones. Here we assessed whether the PNPLA3 p.I148M (c.444 C-G) polymorphism affects glucose and lipid levels and increases gallstone risk. We analysed 229 individuals with gallstones from 108 families (age 24-80 years, BMI 17-55 kg/m(2)) and 258 gallstone-free controls (age 20-70 years, BMI 14-43 kg/m(2)). Fasting glucose, triglyceride and cholesterol serum levels were determined. The p.I148M polymorphism was genotyped using a PCR-based assay with 5'-nuclease and fluorescence detection. Case-control association tests and nonparametric linkage (NPL) analysis in sib-pairs were performed. Individuals carrying the GG genotype had significantly (P<0.0001) higher median fasting glucose levels as compared to GC and CC carriers. After adjustment for multiple testing, we detected a trend for an association between triglyceride levels and variant adiponutrin in gallstone patients (P=0.032), and gallstone cases carrying the genotype CC presented with significantly higher triglyceride levels than the corresponding controls (P<0.003). No significant effects on cholesterol metabolism were detected. Neither genotype distributions nor NPL scores provided evidence for association or linkage between the PNPLA3 variant and gallstones. In conclusion, homozygous carriers of the PNPLA3 risk allele display higher fasting glucose. Although this adiponutrin variant may affect triglyceride homeostasis, it does not increase the risk of cholelithiasis.
Aliment Pharmacol Ther 2011; 33: 389–394
Summary
Background Alpha1‐antitrypsin (α1AT) deficiency caused by Z allele homozygosity represents a well‐established risk factor for hepatocellular ...carcinoma. Previous studies have also implicated α1AT Z heterozygosity in cholangiocarcinogenesis.
Aim To assess the ‘common’ Z and S alleles as well as the promoter variant rs8004738 for association with cholangiocarcinoma.
Methods We genotyped 182 Caucasian patients and 350 controls for rs28929474 (Z), rs17580 (S) and the variant rs8004738. Exploratory analyses were performed in relation to gender and cholangiocarcinoma localisation.
Results rs28929474 was significantly enriched in the cholangiocarcinoma group (4.1 vs. 1.7%; OR 2.46, 95% CI 1.14–5.32; Bonferroni corrected pc = 0.036), reinforced by Armitage trend testing (OR 2.53; pc = 0.032). The rs8004738 (promoter) minor allele tended to be overrepresented in Z heterozygotes (30.0 vs. 16.7%: P = 0.13). Exploratory data analyses suggested a high genetic risk for extrahepatic tumour localisation (OR 3.0; pc = 0.016) and potentially female Z allele carriers (OR 3.37; unadjusted P = 0.022, pc = 0.088).
Conclusions These data point to a novel role of α1AT Z heterozygosity as a potential genetic susceptibility factor for cholangiocarcinoma formation and suggest a contribution of aberrant α1AT function in biliary carcinogenesis. However, given the overall low rs28929474 minor allele frequency, larger studies are warranted to confirm and extend our findings.
Patients with inherited bleeding disorders frequently suffer from chronic hepatitis C virus (HCV) mono‐ or human immunodeficiency virus (HIV)/HCV coinfection. Non‐invasive markers for liver fibrosis ...are warranted for these patients. We tested a large cohort of haemophilic patients with HCV mono‐ or HIV/HCV coinfection for correlation of transient elastography (TE) with two simple surrogate markers of liver fibrosis and for differences in fibrosis stages according to these markers. We prospectively enrolled HCV‐positive patients with congenital bleeding disorders with or without HIV coinfection. Liver function tests and platelet counts were determined and TE was performed. Aspartate aminotransferase‐to‐platelet ratio index (APRI) and a simple index called FIB‐4 were calculated and results were correlated with TE. A total number of 174 patients were included (23% HCV, 36% HIV/HCV coinfected, 33% with cleared HCV and 8% with ongoing HIV but cleared HCV). TE correlated significantly with APRI and FIB‐4 (r = 0.60; P < 0.001 and r = 0.54; P < 0.001 respectively). This correlation was pronounced in patients with ongoing HCV infection (r = 0.67; P < 0.001 and r = 0.60; P < 0.001). Prediction of advanced fibrosis resulted in concordance rates >80% with combinations of TE plus APRI and APRI plus FIB‐4. HIV/HCV coinfected patients did not present with advanced fibrosis stages when compared with HCV‐monoinfected patients. Combinations of two non‐invasive markers may significantly reduce the number of liver biopsies in patients with bleeding disorders and advanced liver fibrosis. Furthermore, our data support previous studies that observed a favourable outcome in patients with HIV/HCV and a preserved immune function in times of highly active antiretroviral therapy.
PDF
