Heterozygosity for the alpha1-antitrypsin Z allele may confer genetic risk of cholangiocarcinoma.

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 p(c) = 0.036), reinforced by Armitage trend testing (OR 2.53; p(c) = 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; p(c) = 0.016) and potentially female Z allele carriers (OR 3.37; unadjusted P = 0.022, p(c) = 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.

Combination of bilateral metal stenting and trans-stent photodynamic therapy for palliative treatment of hilar cholangiocarcinoma.

Endoscopic biliary drainage is the mainstay of palliative treatment in patients with unresectable malignant hilar biliary obstruction. While self-expandable metal stents have shown significant advantages in distal tumors, bilateral hilar stenting is technically demanding. Moreover, ingrowth is a significant problem in uncovered stents. We evaluated the feasibility and efficacy of endoscopic bilateral JoStent SelfX deployment in patients with proximal malignant biliary obstruction in combination with photodynamic therapy (PDT) and/or chemotherapy. Twenty-one consecutive patients with malignant hilar biliary strictures were treated with transpapillary bilateral insertion of JoStentSelfX metal stents. Additional PDT was applied in 8 patients (PDT plus chemotherapy n = 4, only PDT n = 4). Solely chemotherapy was performed in 5 patients. Mean (+/- SD) stent patency was 173.9 +/- 201.8 days. The median estimated survival was 12.3 months (95 % CI: 8.5; 15.9). PDT was safely and efficaciously performed after endoscopic stent deployment (1.8 +/- 1.1 sessions/patient). There was a trend towards a longer stent patency in patients receiving additional therapy (202.2 +/- 197.6 vs. 128 vs. 213.2 days; p = 0.38). Furthermore, we observed a significantly longer survival in this cohort (16.5 [12.2; 20.1] vs. 12.3 [1.9; 8.5] months, p < 0.005). Additional therapy had no significant impact on cumulative hospitalization time (16.3 +/- 15.8 vs. 14.4 +/- 22.5 days; p = 0.54). Bilateral insertion of Jostent SelfX in patients with proximal cholangiocarcinoma is feasible and effective and can be safely combined with trans-stent photodynamic therapy.

Association of the c.3972C>T variant of the multidrug resistance-associated protein 2 Gene (MRP2/ABCC2) with susceptibility to bile duct cancer.

BACKGROUND: Multidrug resistance-associated protein 2 (MRP2/ABCC2) is one of the ATP-binding cassette (ABC) transporters expressed on the apical membrane of hepatocytes and cholangiocytes. ABCC2 plays an important role in the biliary clearance of endogenous and exogenous toxic compounds. Recently, the ABCC2 variant c.3972C>T in exon 28 has been shown to be associated with hepatocellular carcinoma risk. Our aim was to assess the role of this ABCC2 variant on cholangiocarcinoma susceptibility. METHODS: Prospectively, we recruited 60 cholangiocarcinoma patients and 73 healthy controls of Caucasian origin. The c.3972C>T polymorphism was genotyped using solution-phase hybridization reactions with 5'-nuclease and fluorescence detection (TaqMan assays). RESULTS: Allele frequencies were in Hardy-Weinberg equilibrium (p > 0.05). The c.3972T allele was significantly more frequent in patients with cholangiocarcinoma (39.2%) compared to healthy controls (26.0%, p = 0.022), resulting in an odds ratio (OR) of 1.83 (95% CI = 1.09-3.08). Armitage's trend test showed a significant association between genotypes and cancer susceptibility (p = 0.026, OR = 1.95). CONCLUSIONS: We describe a novel association between the common ABCC2 variant c.3972C>T and cholangiocarcinoma risk. Further studies are warranted to replicate our findings in different populations and to elucidate the mechanisms of this observation.

Coinheritance of hereditary spherocytosis and reversibility of cirrhosis in a young female patient with hereditary hemochromatosis.

Here we report a 33-years-old woman with hereditary spherocytosis and hemochromatosis due to homozygosity for the C282Y mutation of the HFE gene. The coinheritance of both conditions led to severe iron overload and liver cirrhosis at young age. The patient was treated by repeated phlebotomy, and reversibility of cirrhosis was documented by transient elastography. This report discusses the pathophysiology of iron accumulation in patients with hemolytic anemia combined with HFE C282Y homozygosity. The case indicates that patients with hematological disorders characterized by increased erythropoetic activity should be screened for HFE mutations.

Resolution of refractory ascites after transcoronary septal ablation for hypertrophic obstructive cardiomyopathy in a cirrhotic patient.

This report presents the first case of complete resolution of ascites after transcoronary ablation of septal hypertrophy (TASH) in a cirrhotic patient with concomitant hypertrophic cardiomyopathy (HOCM). A 52-years-old woman with decompensated alcoholic liver cirrhosis was referred to our department for placement of a transjugular intrahepatic portosystemic stent shunt (TIPS) to treat her refractory ascites. The initial treatment with furosemide and spironolactone had to be discontinued because of severe hyponatriemia and an increase of creatinine levels. During further evaluation, HOCM was diagnosed by echocardiography and cardiac catheterization. We performed TASH in order to relieve the dynamic obstruction of the ventricular outflow tract, and the ascites completely resolved without further interventions.