Nonbiliary Cirrhosis Research Articles

Outcome of patients treated with molecular adsorbent recirculating system albumin dialysis: A national multicenter study.

Background and AimThe molecular adsorbent recirculating system (MARS) is the most widely used device to treat liver failure. Nevertheless, data from widespread real‐life use are lacking.MethodsThis was a retrospective multicenter study conducted in all French adult care centers that used MARS between 2004 and 2009. The primary objective was to evaluate patient survival according to the liver disease and listing status. Factors associated with mortality were the secondary objectives.ResultsA total of 383 patients underwent 393 MARS treatments. The main indications were acute liver failure (ALF, 32.6%), and severe cholestasis (total bilirubin >340 μmol/L) (37.2%), hepatic encephalopathy (23.7%), and/or acute kidney injury–hepatorenal syndrome (22.9%) most often among patients with chronic liver disease. At the time of treatment, 34.4% of the patients were listed. Overall, the hospital survival rate was 49% (95% CI: 44–54%) and ranged from 25% to 81% depending on the diagnosis of the liver disease. In listed patients versus those not listed, the 1‐year survival rate was markedly better in the setting of nonbiliary cirrhosis (59% vs 15%), early graft nonfunction (80% vs 0%), and late graft dysfunction (72% vs 0%) (all P < 0.001). Among nonbiliary cirrhotic patients, hospital mortality was associated with the severity of liver disease (HE and severe cholestasis) and not being listed for transplant. In ALF, paracetamol etiology and ≥3 MARS sessions were associated with better transplant‐free survival.ConclusionOur study suggests that MARS should be mainly used as a bridge to liver transplantation. Survival was correlated with being listed for most etiologies and with the intensity of treatment in ALF.

Biliary Intraepithelial Neoplasia in Non-biliary Cirrhosis-Report From 100 Explanted Livers: A Single Center Experience.

Background:Intrahepatic cholangiocarcinoma is a highly malignant tumor with a very short 5-year survival. Multistep carcinogenesis has been suggested as the main pathway for the development of this tumor. Main suggested precursors have been (1) biliary intraepithelial neoplasia (BilIN) and (2) intraductal papillary neoplasm of bile duct (IPNB). The former is flat and does not produce grossly and radiologically detectable mass lesion, but the latter produces grossly identifiable lesion.Objectives:The development of bile duct dysplasia (BilIN) in chronic biliary diseases has been investigated and proved, but the incidence of BilIN in non-biliary causes of cirrhosis such as hepatitis B and non-alcoholic steatohepatitis has very rarely been investigated. In this study, we have tried to find out the prevalence of BilIN in non-biliary cirrhosis.Patients and Methods:During the study period (2017-2018) in 100 explanted livers with the diagnosis of non-biliary cirrhosis, thorough sampling (at least 20 sections) was performed, and pathologic sections were studied for the presence of BilIN.Results:In the 100 studied livers with different diagnoses of non-biliary causes of cirrhosis, 31% of cases showed BilIN-1 and 2% of cases showed BiliIN-2. No case of BilIN-3 has been identified.Discussion and Conclusions:Non-biliary causes of cirrhosis should be considered as precursors of cholangiocarcinoma (BilIN); however, the incidence of this occurrence is low.

Liver transplantation in Spain.

Liver transplantation (LT) activity started in Spain in 1984 and has exceeded 23,700 interventions, with more than 1000 transplants performed yearly. Every hospital needs official authorization to perform a LT, which implies the obligation to register all patients on the national waiting list. The Spanish National Transplant Organization (ONT) provides essential support for organ procurement, allocation, and management of the waiting list at a national level. Liver allocation is center-oriented as all available organs are referred to the ONT for the whole country. The allocation rules for LT are made according to disease severity after consensus among professionals from every transplant center and ratified by representatives of the regional health authorities. Authorization and location/distribution of transplant centers are regulated by the country (Spain) and by the different regions according to the Real Decreto 1723/2012. For a total population of 47,850,795 inhabitants, there are 24 centers for LT for adults (1 team/2 million people) and 5 for LT for children (1 team/9.5 million people). Nonbiliary cirrhosis, particularly alcohol- and hepatitis C virus-related cirrhosis (60%), and tumors, mainly hepatocellular carcinoma (19%), are the most common indications for LT in Spain. Unusual causes of LT include metabolic diseases like Wilson's disease, familial amyloid polyneuropathy and hyperoxaluria type I, polycystic kidney and liver disease, and some tumors (epithelioid hemangioendothelioma and neuroendocrine tumors). Important efforts are now being undertaken to improve the quality and transplantability of extended criteria livers, in particular those arising from DCD, which represent the greatest opportunity to expand the donor pool. These efforts have to be addressed to adapt the organ preservation procedures, be it through the application of regional perfusion in situ or the use of machine perfusion preservation ex situ. Liver Transplantation 22 1259-1264 2016 AASLD.

Endothelin-1 Activation of the Endothelin B Receptor Modulates Pulmonary Endothelial CX3CL1 and Contributes to Pulmonary Angiogenesis in Experimental Hepatopulmonary Syndrome

Hepatic production and release of endothelin-1 (ET-1) binding to endothelin B (ETB) receptors, overexpressed in the lung microvasculature, is associated with accumulation of pro-angiogenic monocytes and vascular remodeling in experimental hepatopulmonary syndrome (HPS) after common bile duct ligation (CBDL). We have recently found that lung vascular monocyte adhesion and angiogenesis in HPS involve interaction of endothelial C-X3-C motif ligand 1 (CX3CL1) with monocyte CX3C chemokine receptor 1 (CX3CR1), although whether ET-1/ETB receptor activation influences these events is unknown. Our aim was to define if ET-1/ETB receptor activation modulates CX3CL1/CX3CR1 signaling and lung angiogenesis in experimental HPS. A selective ETB receptor antagonist, BQ788, was given for 2 weeks to 1-week CBDL rats. ET-1 (±BQ788) was given to cultured rat pulmonary microvascular endothelial cells overexpressing ETB receptors. BQ788 treatment significantly decreased lung angiogenesis, monocyte accumulation, and CX3CL1 levels after CBDL. ET-1 treatment significantly induced CX3CL1 production in lung microvascular endothelial cells, which was blocked by inhibitors of Ca(2+) and mitogen-activated protein kinase (MEK)/ERK pathways. ET-1-induced ERK activation was Ca(2+) independent. ET-1 administration also increased endothelial tube formation in vitro, which was inhibited by BQ788 or by blocking Ca(2+) and MEK/ERK activation. CX3CR1 neutralizing antibody partially inhibited ET-1 effects on tube formation. These findings identify a novel mechanistic interaction between the ET-1/ETB receptor axis and CX3CL1/CX3CR1 in mediating pulmonary angiogenesis and vascular monocyte accumulation in experimental HPS.

Extensive biliary intraepithelial neoplasia (BilIN) and multifocal early intrahepatic cholangiocarcinoma in non-biliary cirrhosis

Biliary intraepithelial neoplasia (BilIN), a preneoplastic condition that may precede invasive intrahepatic cholangiocarcinoma (ICC), has been compared to pancreatic intraepithelial neoplasia (PanIN), a precursor lesion of pancreatic carcinoma. Biliary tract carcinoma development and progression is associated with several gene alterations, but BilIN lesions have yet to be studied in detail by molecular techniques. We describe a case of extensive intrahepatic biliary dysplasia, with lesions ranging from BilIN-1 to BilIN-3 lesions, and multifocal microscopic ICC in hepatitis C virus (HCV)- and alcohol-related cirrhosis. The small ICC foci had remained undetected prior to transplantation. Fluorescence in situ hybridization (FISH) analysis was performed on three foci of BilIN-3 lesions and on three microinvasive ICC foci with a combination of three FISH probes directed against genes frequently altered in pancreatic and biliary tract carcinomas. FISH analysis revealed a CDKNA2 heterozygous deletion in one BilIN-3 focus, and in one non-contiguous ICC focus, although the deletion was just above the chosen threshold. No deletions were detected in the genomic regions encoding TP53 and SMAD4. This report documents for the first time the development of multifocal ICC in the setting of extensive biliary dysplasia in a patient with three risk factors, HCV infection, alcohol abuse, and cirrhosis, and suggests heterogeneous carcinogenesis in ICC and possible involvement of the CDKNA2 gene.

Pulmonary Angiogenesis in a Rat Model of Hepatopulmonary Syndrome

Hepatopulmonary syndrome (HPS), defined as intrapulmonary vasodilation, occurs in 10%-30% of cirrhotics and increases mortality. In a rat model of HPS induced by common bile duct ligation (CBDL), but not thioacetamide (TAA)-induced nonbiliary cirrhosis, lung capillary density increases, monocytes accumulate in the microvasculature, and signaling factors in the angiogenesis pathway (Akt and endothelial nitric oxide synthase [eNOS]) are activated. Pentoxifylline (PTX) directly decreases lung endothelial Akt and eNOS activation, blocks intravascular monocyte accumulation, and improves experimental HPS; we evaluated whether pulmonary angiogenesis develops in this model. TAA- and PTX-treated animals were evaluated following CBDL. Lung angiogenesis was assessed by quantifying factor VIII-positive microvessels and levels of von Willebrand factor (vWf), vascular endothelial cadherin (VE-cadherin), and proliferating cell nuclear antigen (PCNA). Angiogenic factors including phospho-Akt, phospho-eNOS, vascular endothelial growth factor (VEGF)-A, and phospho-VEGF receptor-2 (p-VEGFR-2) were compared and monocyte accumulation was assessed. Following CBDL, but not TAA exposure, rats developed HPS that was temporally correlated with increased numbers of lung microvessel; increased levels of vWf, VE-cadherin and PCNA; and activation of Akt and eNOS. Angiogenesis was accompanied by increased pulmonary VEGF-A and p-VEGFR-2 levels, with VEGF-A staining in accumulated intravascular monocytes and alveolar endothelial cells. Following CBDL, PTX-treated rats had reduced numbers of microvessels, reduced lung monocyte accumulation, downregulation of pulmonary angiogenic factors, and reduced symptoms of HPS. A specific increase in pulmonary angiogenesis occurs as experimental HPS develops, accompanied by activation of VEGF-A-associated angiogenic pathways. PTX decreases the angiogenesis, reduces the symptoms of HPS, and downregulates VEGF-A mediated pathways.

Cholangiocyte Endothelin 1 and Transforming Growth Factor β1 Production in Rat Experimental Hepatopulmonary Syndrome

Cholangiocyte Endothelin 1 and Transforming Growth Factor β1 Production in Rat Experimental Hepatopulmonary Syndrome

Cholangiocyte Endothelin 1 and Transforming Growth Factor β1 Production in Rat Experimental Hepatopulmonary Syndrome

Hepatic production and release of endothelin 1 plays a central role in experimental hepatopulmonary syndrome after common bile duct ligation by stimulating pulmonary endothelial nitric oxide production. In thioacetamide-induced nonbiliary cirrhosis, hepatic endothelin 1 production and release do not occur, and hepatopulmonary syndrome does not develop. However, the source and regulation of hepatic endothelin 1 after common bile duct ligation are not fully characterized. We evaluated the sources of hepatic endothelin 1 production after common bile duct ligation in relation to thioacetamide cirrhosis and assessed whether transforming growth factor beta1 regulates endothelin 1 production. Hepatopulmonary syndrome and hepatic and plasma endothelin 1 levels were evaluated after common bile duct ligation or thioacetamide administration. Cellular sources of endothelin 1 were assessed by immunohistochemistry and laser capture microdissection of cholangiocytes. Transforming growth factor beta1 expression and signaling were assessed by using immunohistochemistry and Western blotting and by evaluating normal rat cholangiocytes. Hepatic and plasma endothelin 1 levels increased and hepatopulmonary syndrome developed only after common bile duct ligation. Hepatic endothelin 1 and transforming growth factor beta1 levels increased over a similar time frame, and cholangiocytes were a major source of each peptide. Transforming growth factor beta1 signaling in cholangiocytes in vivo was evident by increased phosphorylation and nuclear localization of Smad2, and hepatic endothelin 1 levels correlated directly with liver transforming growth factor beta1 and phosphorylated Smad2 levels. Transforming growth factor beta1 also stimulated endothelin 1 promoter activity, expression, and production in normal rat cholangiocytes. Cholangiocytes are a major source of hepatic endothelin 1 production during the development of hepatopulmonary syndrome after common bile duct ligation, but not in thioacetamide-induced cirrhosis. Transforming growth factor beta1 stimulates cholangiocyte endothelin 1 expression and production. Cholangiocyte-derived endothelin 1 may be an important endocrine mediator of experimental hepatopulmonary syndrome.

Ectonucleotidase NTPDase2 is Selectively Down-Regulated in Biliary Cirrhosis

Background Portal fibroblasts are newly identified, potentially fibrogenic liver cells that are distinct from hepatic stellate cells. The ectonucleotidase* nucleoside triphosphate diphosphohydrolase 2 (NTPDase2) is restricted to portal fibroblasts in the normal liver. However, the fate of NTPDase2 after bile duct ligation (BDL) is unknown. Aims The aim of this study was to assess the effect of experimental rat and disease-mediated human biliary cirrhosis on NTP-Dase2 expression in the liver. Methods Cirrhosis was induced in experimental rats via BDL and carbon tetrachloride (CCI4) administration. Archived human liver biopsy specimens from normal liver, primary biliary cirrhosis, or hepatitis C cirrhosis were examined. Changes in expression of NTPDase2 were determined using confocal immunofluorescence, immunoblot, and real-time polymerase chain reaction. Results Confocal immunofluorescence demonstrated a decrease in NTPDase2 expression after BDL. Immunoblot and real-time polymerase chain reaction demonstrated a decrease in NTPDase2 expression by portal fibroblasts after BDL. No decrease in NTP-Dase2 protein was noted after CCI4 administration, and NTPDase2 messenger ribonucleic acid was markedly up-regulated after CCI4 administration. Confocal immunofluorescence demonstrated a shift of NTPDase2 expression from portal areas to central areas that colocalized with α-smooth muscle actin after CCI4 administration. In human biopsy specimens, NTPDase2 expression was lost in cirrhosis owing to primary biliary cirrhosis, whereas NTPDase2 expression was shifted to bridging fibrous bands in cirrhosis owing to hepatitis C. Conclusions Loss of NTPDase2 is a common pathway in both rat and human manifestations of biliary cirrhosis. Conversely, in nonbiliary cirrhosis, NTPDase2 is shifted from the portal area to bridging fibrous bands. Elucidations of the mechanisms regulating NTP–Dase2 expression may lead to new therapeutic approaches to fibrotic liver disease.

Ectonucleotidase NTPDase2 Is Selectively Down-Regulated in Biliary Cirrhosis

BackgroundPortal fibroblasts are newly identified, potentially fibrogenic liver cells that are distinct from hepatic stellate cells. The ectonucleotidase* nucleoside triphosphate diphosphohydrolase 2 (NTPDase2) is restricted to portal fibroblasts in the...

ET-1 and TNF-alpha in HPS: analysis in prehepatic portal hypertension and biliary and nonbiliary cirrhosis in rats.

Common bile duct ligation (CBDL) triggers a molecular cascade resulting in the hepatopulmonary syndrome (HPS). Both increased hepatic endothelin-1 (ET-1) production and pulmonary vascular ET(B) receptor expression with stimulation of endothelial nitric oxide synthase and TNF-alpha mediated inducible nitric oxide synthase and heme oxygenase-1 expression in pulmonary intravascular macrophages occur. Whether biliary cirrhosis is unique in triggering ET-1 and TNF-alpha alterations and HPS is unknown. We evaluated for HPS in rat prehepatic portal hypertension [partial portal vein ligation (PVL)], biliary (CBDL) and nonbiliary [thioacetamide treatment (TAA)] cirrhosis, and assessed ET-1 infusion in normal and PVL animals. Control, PVL, CBDL, TAA-treated, and ET-1-infused PVL animals had ET-1 and TNF-alpha levels measured and underwent molecular and physiological evaluation for HPS. HPS developed only in biliary cirrhosis in association with increased plasma ET-1 and TNF-alpha levels and the development of established molecular changes in the pulmonary microvasculature. In contrast, PVL did not increase ET-1 or TNF-alpha levels and TAA treatment increased TNF-alpha levels alone, and neither resulted in the full development of molecular or physiological changes of HPS despite portal pressure increases similar to those after CBDL. Exogenous ET-1 increased TNF-alpha levels and triggered HPS after PVL. Combination of ET-1 and TNF-alpha overproduction is unique to biliary cirrhosis and associated with experimental HPS. ET-1 infusion increases TNF-alpha levels and triggers HPS in prehepatic portal hypertension. ET-1 and TNF-alpha interact to trigger pulmonary microvascular changes in experimental HPS.

Intrahepatic cholangiocarcinoma in cirrhosis presents granulocyte and granulocyte-macrophage colony-stimulating factor

Intrahepatic cholangiocarcinoma (ICC) and combined hepatocellular and cholangiocarcinoma (HC-CC) are known to arise occasionally in hepatitis-related cirrhosis, although their clinicopathological features remain unclarified. In this study, we characterized the ICC (9 cases) and ICC elements of HC-CC (11 cases) arising in nonbiliary cirrhosis. Thirty-three hepatocellular carcinomas (HCC) associated with nonbiliary cirrhosis and 24 ICC without cirrhosis were used as controls. Prominent neutrophilic infiltration was frequent in ICC with cirrhosis (78%) and ICC elements of combined HC-CC (72%). Neutrophilic infiltration-related cytokines (interleukin 8, granulocyte colony-stimulating factor [G-CSF], and granulocyte macrophage colony-stimulating factor [GM-CSF]) were expressed frequently and intensely in carcinoma cells of ICC with cirrhosis (40%, 80%, and 60%, respectively) and in ICC elements of the combined one (13%, 38%, and 63%, respectively). Interleukin 8 was expressed in 18% of ICC without cirrhosis, irrespective of neutrophilic infiltration. Neutrophilic infiltration and expression of G-CSF and GM-CSF were in parallel ( P < 0.05). G-CSF and GM-CSF mRNA were detected by RT-PCR in tissue specimens expressing G-CSF and GM-CSF at the protein level. Such neutrophilic infiltration and expression of G-CSF and GM-CSF were not evident in controls. The expressions of c-kit and c-Met, as a hematopoietic and hepatic stem cell marker, were seen frequently in ICC with cirrhosis (80% and 80%, respectively) and ICC elements of the combined one (63% and 50%, respectively). The present study revealed that the frequent expression of G-CSF and GM-CSF is a characteristic of ICC with cirrhosis and ICC in combined carcinoma, probably representing a phenotype of fetal hepatic parenchymal cell. The expression of these cytokines may be causally related to prominent neutrophilic infiltration.

Predictive models of short- and long-term survival in patients with nonbiliary cirrhosis

The limited number of donor organs has placed a burden on the medical community to improve patient selection and timing of liver transplantation (LT). We aim to evaluate short- and long-term survival of 124 consecutive patients with a diagnosis of nonbiliary cirrhosis. Seventeen clinical, biochemical, functional, and hemodynamic parameters were computed. Patient survival was evaluated in the short term (3 months) by logistic regression, and the predictive power of the model was evaluated using receiver operating characteristic curves and the log likelihood ratio. For the long-term (up to 5 years) prognosis, the Cox proportional model was used. During follow-up, 54 patients died and 20 patients underwent LT. In the short-term study, the Model for End-Stage Liver Disease score (including bilirubin level, international normalized ratio [INR], and creatinine level) was as predictive as our score, which contained only two independent indicators (bilirubin and creatinine levels). In the long-term study, three independent variables (albumin level, INR, and creatinine level) emerged from the Cox model, and patients were classified into three survival-risk groups according to a prognostic index (PI): −1.039 × albumin (grams per deciliter) + 1.909 × loge INR + 1.207 × loge serum creatinine (milligrams per deciliter). Survival probabilities at 1 and 5 years were 89% and 80%, 63% and 52%, and 23% and 10% with a low, medium, and high PI, respectively. The validation study using the split-sample technique and data from independent patients confirmed that a high PI (>−2.5) identifies patients with a poor prognosis within 5 years. We thus have shown and validated that risk for death at the short and long term of patients with nonbiliary cirrhosis can be predicted with great accuracy using models containing a few simple and easily obtained objective variables, and these survival models are useful tools in clinical decision making, especially in deciding to list patients for LT and prioritization on the liver waiting list. (Liver Transpl 2003;9:260-267.)

90 Endothelin-1 in experimental hepatopulmonary syndrome: evaluation in prehepatic portal hypertension, billiary and nonbiliary cirrhosis

90 Endothelin-1 in experimental hepatopulmonary syndrome: evaluation in prehepatic portal hypertension, billiary and nonbiliary cirrhosis

Cholangiocarcinoma Occurring in a Liver With Multiple Bile Duct Hamartomas (von Meyenburg Complexes)

A 59-year-old woman presented with epigastric pain and weight loss. Ultrasound, computed tomography, and magnetic resonance imaging scans of the abdomen showed a tumor in segments 6 and 7 of the right liver lobe, measuring 8 cm in greatest diameter. The tumor was subsequently resected, and histopathology showed a poorly differentiated adenocarcinoma immunoreactive for CA 19-9 and cytokeratin 19. In the absence of any other clinically detectable primary tumor, the lesion was diagnosed as a peripheral intrahepatic cholangiocarcinoma. In addition, multiple bile duct hamartomas were found in the surrounding parenchyma. The tumor was unrelated to Caroli disease, primary sclerosing cholangitis, ulcerative colitis, or nonbiliary cirrhosis, as demonstrated by further clinical and histopathologic investigations, but probably was associated with the presence of multiple bile duct hamartomas. To our knowledge, this is the eighth reported case of a cholangiocarcinoma associated with multiple bile duct hamartomas.

Cholangiocarcinoma occurring in a liver with multiple bile duct hamartomas (von Meyenburg complexes).

A 59-year-old woman presented with epigastric pain and weight loss. Ultrasound, computed tomography, and magnetic resonance imaging scans of the abdomen showed a tumor in segments 6 and 7 of the right liver lobe, measuring 8 cm in greatest diameter. The tumor was subsequently resected, and histopathology showed a poorly differentiated adenocarcinoma immunoreactive for CA 19-9 and cytokeratin 19. In the absence of any other clinically detectable primary tumor, the lesion was diagnosed as a peripheral intrahepatic cholangiocarcinoma. In addition, multiple bile duct hamartomas were found in the surrounding parenchyma. The tumor was unrelated to Caroli disease, primary sclerosing cholangitis, ulcerative colitis, or nonbiliary cirrhosis, as demonstrated by further clinical and histopathologic investigations, but probably was associated with the presence of multiple bile duct hamartomas. To our knowledge, this is the eighth reported case of a cholangiocarcinoma associated with multiple bile duct hamartomas.

Liver transplantation in patients with non-biliary cirrhosis

Liver transplantation in patients with non-biliary cirrhosis

Liver transplantation in patients with non-biliary cirrhosis: prognostic value of preoperative factors

Background/Aim: The type of disease indicating liver tranplantation is one of the most powerful predictors of postoperative survival. This may be an important problem in evaluating the prognostic significance of other factors when patients with liver diseases of very different nature are jointly studied. To minimize this bias, the present study aimed to investigate preoperative prognostic factors in liver transplantation only in patients with non-biliary cirrhosis. Methods: Twenty-three preoperative standard clinical and laboratory variables were analyzed as possible prognostic factors in 162 patients receiving liver transplantation for non-biliary cirrhosis. Data for seven splanchnic and systemic hemodynamic variables were also analyzed in 55 patients. Results: Using univariate analyses followed by a multivariate analysis, only preoperative blood urea nitrogen (BUN) reached statistical significance as an independent predictor of hospital survival; the survival rate at the end of hospitalization being 90% in patients with BUN≤25 mg/dl and 65% in patients with BUN > 25 mg/dl ( p=0.0008). Similarly, preoperative BUN was the only variable independently predicting cumulative long-term survival, with an 87% survival probability at 1 year and 73% at 4 years in patients with BUN≤25 mg/dl, and 61% an 49%, respectively, in patients with BUN > 25 mg/dl ( p=0.0014). Conclusions: Renal function parameters are the most powerful preoperative predictors of survival after liver transplantation in patients with non-biliary cirrhosis. It is suggested that liver transplantation is indicated in these patients before marked renal dysfunction develops.

Hemosiderosis in cirrhosis: A study of 447 native livers

BACKGROUND & AIMS: Hemosiderosis may have a detrimental effect on some chronic liver diseases. The aim of this study was to determine the prevalence and diagnostic implications of hemosiderosis in cirrhosis.METHODS: Tissue iron in 447 cirrhotic livers was studied histologically and chemically.RESULTS: Positive iron staining was found in 145 cases (32.4%), and increased chemical hepatic iron concentration was found in 91 cases (20.3%), including 38 cases (8.5%) with hepatic iron overload in the hemochromatosis range, defined by an iron index of > or = 1.9 (iron index equals hepatic iron concentration in micromoles per gram divided by age). However, homozygous hemochromatosis seemed to have caused the cirrhosis in only 5 instances. Stainable iron was found in 22%-67% of the cases with nonbiliary cirrhosis but in only 7%-20% of cases with biliary cirrhosis. Most available pretransplant biopsy specimens failed to show evidence of homozygous hemochromatosis.CONCLUSIONS: Iron overload is very common in many types of nonbiliary cirrhosis but rare in biliary cirrhosis. The hemosiderosis of affected livers seems to be acquired and to occur rapidly once cirrhosis has developed; cirrhosis alone may cause iron accumulation. In the presence of cirrhosis, hepatic iron indices of >1.9 should not be interpreted as proof of homozygous hemochromatosis.(Gastroenterology 1997 Mar;112(3):882-8)

Intrahepatic Cholangiocarcinomas Associated with Nonbiliary Cirrhosis

To determine the prevalence and clinicopathologic features of cholangiocarcinoma (CC) associated with nonbiliary cirrhosis, we performed a clinicopathologic study. Among the 5,563 autopsies in our laboratories during the past 14 years, 85 (1.5%) were CCs. Four (4.7%) were associated with cirrhosis, due to hepatitis B virus in one case and cryptogenic (probably non-A non-B hepatitis virus) in the remaining three. Clinically, patients with CC and cirrhosis were characterized by male preponderance, lower age, past history of liver injury, and elevated values of zinc sulfate and thymol turbidity tests. Pathologically, all CCs with cirrhosis were basically adenocarcinoma; other histologic features included adenocarcinoma resembling bile ductules without mucin (one case), adenocarcinoma with broad areas of signet ring cell carcinoma (one case), adenocarcinoma with extensive sarcomatoid transformation (one case), and adenocarcinoma associated with hepatoliths (one case). Immunohistochemically, immunophenotypes of carcinoma cells of CC with cirrhosis were not different from those of CC without cirrhosis. Carcinoembryonic antigens, CA19-9, DU-PAN-2, and biliary-type cytokeratins were positive and alpha-fetoprotein was negative, suggesting that our CCs are not hepatocellular neoplasms but true CCs. It must be stressed that there are actual CCs arising in nonbiliary cirrhotic livers.