Non-cirrhotic Liver Disease Research Articles

Coexisting liver disease is associated with increased mortality after surgery for diverticular disease.

Coexistence of liver disease in patients undergoing surgery for diverticular disease (DD) may increase the risk of postoperative complications, but the evidence is limited. To investigate the impact of liver disease on mortality and reoperation rates following surgery for DD. We performed a cohort study based on medical databases of all patients undergoing surgery for DD in Denmark during 1977-2011, categorizing them into three cohorts according to history of liver disease: patients with non-cirrhotic liver disease, those with liver cirrhosis, and those without liver disease (comparison cohort). Using the Kaplan-Meier method, we computed mortality in each cohort for 0-30, 31-60, and 61-90 days following surgery for DD. We used a Cox regression model to compute hazard ratios as measures of the relative risk (RR) of death, controlling for potential confounders, including other comorbidities. In addition, we assessed the reoperation rate within 30 days of initial surgery. Of 14,408 patients undergoing surgery for DD, 233 (1.6 %) had non-cirrhotic liver disease and 91 (0.6 %) had liver cirrhosis. Thirty-day mortality was 9.9 % in patients without liver disease and 14.6 % in patients with non-cirrhotic liver disease [adjusted RR = 1.64 (95 % confidence interval [CI] 1.16-2.31)]. Among patients with liver cirrhosis, mortality was 24.2 % [adjusted RR = 2.70 (95 % CI 1.73-4.22)]. Liver cirrhosis had an impact on mortality up to 60 days after surgery for DD. The reoperation rate was approximately 10 % in each cohort. Preexisting liver disease has a major impact on postoperative mortality following surgery for DD.

Pathogenesis of hepatocarcinogenesis in non-cirrhotic nonalcoholic fatty liver disease: Potential mechanistic pathways.

Although hepatocellular carcinoma (HCC) primarily arises in the background of liver cirrhosis, the development of HCC in nonalcoholic fatty liver disease (NAFLD) without cirrhosis is increasingly recognized. The pathogenesis of NAFLD associated non-cirrhotic HCC is distinct from that of cirrhotic HCC because the metabolic syndrome (MS) along with obesity and insulin resistance (IR) underlie several unique mechanisms that promote tumorigenesis. IR associated with MS, NAFLD, and type 2 diabetes mellitus lead to the release of multiple pro-inflammatory cytokines, including tumor necrosis factor alpha, interleukin-6, leptin and resistin, as well as decreased amounts of adiponectin. These processes favor the development of hepatic steatosis and inflammation within the liver, which precede HCC development. Nevertheless, further investigation is necessary to elucidate the determinants for development of HCC in patients with NAFLD in the absence of cirrhosis.

Hepatic Perfusion Parameters of Contrast-Enhanced Ultrasonography Correlate With the Severity of Chronic Liver Disease

In the study described here, we introduced a new ratio acquired with contrast-enhanced ultrasonography (CEUS): a liver parenchyma blood supply ratio that differentiates arterial and portal phases. Our purpose was to determine whether this ratio and other liver parenchyma perfusion parameters acquired with CEUS can be correlated with the severity of chronic liver disease. Twelve patients with non-cirrhotic chronic liver disease, 35 patients with cirrhosis (child class A: n = 10; child class B: n = 13; child class C: n = 12) and 21 healthy volunteers were examined by CEUS. Time–intensity curves were drawn for regions of interest located in liver parenchyma and right kidney cortex using QLAB quantification software. The arterial and portal phases were differentiated by the time to the maximum enhancement of right kidney and liver parenchyma perfusion data acquired from the time–intensity curves: the intensity of liver parenchyma perfused by hepatic arterial flow (Iap), the intensity of total perfusion of liver parenchyma (Ipeak), the intensity of liver parenchyma perfused by portal venous flow (Ipp) and the ratio of portal perfusion to total perfusion of liver parenchyma expressed by the parameters Ipp/Ipeak, Ipeak, Ipp and Ipp/Ipeak significantly decreased in patients with cirrhosis and in patients with non-cirrhotic chronic liver disease, whereas Iap increased. The parameters Ipp, Ipeak, Ipp/Ipeak and Iap correlated with the severity of chronic liver disease (r = −0.938, p < 0.001; r = −0.790, p < 0.001; r = −0.931 p < 0.001; r = 0.31, p < 0.05). The diagnostic accuracy rates for cirrhosis expressed as areas under receiver operating characteristic curves were 0.93 for Ipeak, 0.98 for Ipp, 0.98 for Ipp/Ipeak, and 0.69 for Iap. Liver parenchyma perfusion parameters obtained by CEUS were correlated with the severity of chronic liver disease and have the potential to assess cirrhosis non-invasively.

Systematic review of congenital and acquired portal-systemic shunts in otherwise normal livers.

Portal-systemic shunts (PSSs) are rarely seen in healthy individuals or patients with non-cirrhotic liver disease. They may play an important role in hepatic metabolism as well as in the spread of gastrointestinal metastatic tumours to specific organs. Small spontaneous PSSs may be more common than generally thought. However, epidemiological data are scarce and inconclusive. This systematic review examined the prevalence of reported PSSs and the associated detection methods. Literature up to 2011 was reviewed for adult patients with proven congenital or acquired PSSs. Only PSSs in normal livers were analysed for the methods of diagnosis. Eligible studies were identified by searching relevant databases, including PubMed, Embase, MEDLINE and the Cochrane Library. The selection of eligible articles was carried out using predefined inclusion criteria (adult, non-surgical PSS) and a set of search terms that were established before the articles were identified. Eighty studies were included describing 112 patients with congenital or acquired PSSs. The majority were diagnosed incidentally using Doppler ultrasound imaging and CT. Congenital and acquired PSSs are rare. They are usually clinically asymptomatic and discovered incidentally by radiological techniques. They may be clinically relevant owing to drug, tumour cell, metabolic and pathogen shunting.

Discovery and validation of urinary metabotypes for the diagnosis of hepatocellular carcinoma in West Africans.

There is no clinically applicable biomarker for surveillance of hepatocellular carcinoma (HCC), because the sensitivity of serum alpha-fetoprotein (AFP) is too low for this purpose. Here, we determined the diagnostic performance of a panel of urinary metabolites of HCC patients from West Africa. Urine samples were collected from Nigerian and Gambian patients recruited on the case-control platform of the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) program. Urinary proton nuclear magnetic resonance ((1) H-NMR) spectroscopy was used to metabolically phenotype 290 subjects: 63 with HCC; 32 with cirrhosis (Cir); 107 with noncirrhotic liver disease (DC); and 88 normal control (NC) healthy volunteers. Urine samples from a further cohort of 463 subjects (141 HCC, 56 Cir, 178 DC, and 88 NC) were analyzed, the results of which validated the initial cohort. The urinary metabotype of patients with HCC was distinct from those with Cir, DC, and NC with areas under the receiver operating characteristic (AUROC) curves of 0.86 (0.78-0.94), 0.93 (0.89-0.97), and 0.89 (0.80-0.98) in the training set and 0.81 (0.73-0.89), 0.96 (0.94-0.99), and 0.90 (0.85-0.96), respectively, in the validation cohort. A urinary metabolite panel, comprising inosine, indole-3-acetate, galactose, and an N-acetylated amino acid (NAA), showed a high sensitivity (86.9% [75.8-94.2]) and specificity (90.3% [74.2-98.0]) in the discrimination of HCC from cirrhosis, a finding that was corroborated in a validation cohort (AUROC: urinary panel = 0.72; AFP = 0.58). Metabolites that were significantly increased in urine of HCC patients, and which correlated with clinical stage of HCC, were NAA, dimethylglycine, 1-methylnicotinamide, methionine, acetylcarnitine, 2-oxoglutarate, choline, and creatine. The urinary metabotyping of this West African cohort identified and validated a metabolite panel that diagnostically outperforms serum AFP.

Mo1001 Nodular Regenerative Hyperplasia: Many Ways to Get There

Introduction: Nodular Regenerative Hyperplasia (NRH) is a rare noncirrhotic portal hypertensive liver disease characterized by the diffuse transformation of hepatic parenchyma into regenerative nodules without fibrosis. Although the specific etiology has yet to be elucidated, NRH has been associated with various diseases, conditions and medications. Thus, whether NRH occurs from a single unifying pathophysiologic process or multiple different processes is still uncertain. Aims: To characterize biochemical, radiological, and histologic markers of liver disease in patients (pts) with and without NRH in multiple disease cohorts. Methods: Pts with chronic granulomatous disease (CGD), sickle cell disease (SCD), systemic mast cell disease (SMCD), common variable immunodeficiency disease (CVID) and sporadic cases of NRH underwent hepatologic evaluation and liver biopsy for clinical care purposes were evaluated with biomarkers of liver disease, radiologic imaging and histopathologic analysis. Results: 137 pts were evaluated and 56 (41%) were diagnosed with NRH histologically. Of those with NRH, 11 (20%) had CGD, 22 (39%) SCD, 7 (13%) SMCD, 12 (21%) CVID and 4 (7%) sporadic disease. Age at biopsy across all NRH cohorts was significantly older compared to the non-NRH population (mean 40 vs. 33 years, p=0.0128). Patients with NRH had significantly higher alkaline phosphatase (197 vs. 190 U/L, p=0.01), increased liver volumes (2152 vs. 1166 cm3, p=0.01) and increased spleen volumes (after excluding SCD) (1071 vs. 410 cm3, p=0.01), which negatively correlated with platelets ( ρ -0.58, p= 0.002). In the SCD cohort, pts with NRH had increased gamma-glutamyltransferase (128 vs. 67 U/L, p=0.03) and increased lactate dehydrogenase (432 vs. 322 U/L, p=0.01). On histologic evaluation, SCD-NRH pts had increased lobular inflammation (p=0.04). SMCDNRH pts had increased portal and peri-portal inflammation (p=0.005 and p=0.01, respectively), veno-occlusive changes (p=0.04), portal venopathy (p=0.001) and sinusoidal dilation (p=0.03). Conclusions: Despite parallels in clinical disease presentation, histopathologic examination of NRH in separate disease cohorts suggests different mechanistic pathways. Given the potential for multiple etiologies, NRH may be more common than previously thought. Further investigation should focus on the underlying disease process as it may provide a window into biology.

Mo1002 MELD Score Is a Risk for First Episode of Spontaneous Bacterial Peritonitis in Patients With Cirrhosis

Introduction: Nodular Regenerative Hyperplasia (NRH) is a rare noncirrhotic portal hypertensive liver disease characterized by the diffuse transformation of hepatic parenchyma into regenerative nodules without fibrosis. Although the specific etiology has yet to be elucidated, NRH has been associated with various diseases, conditions and medications. Thus, whether NRH occurs from a single unifying pathophysiologic process or multiple different processes is still uncertain. Aims: To characterize biochemical, radiological, and histologic markers of liver disease in patients (pts) with and without NRH in multiple disease cohorts. Methods: Pts with chronic granulomatous disease (CGD), sickle cell disease (SCD), systemic mast cell disease (SMCD), common variable immunodeficiency disease (CVID) and sporadic cases of NRH underwent hepatologic evaluation and liver biopsy for clinical care purposes were evaluated with biomarkers of liver disease, radiologic imaging and histopathologic analysis. Results: 137 pts were evaluated and 56 (41%) were diagnosed with NRH histologically. Of those with NRH, 11 (20%) had CGD, 22 (39%) SCD, 7 (13%) SMCD, 12 (21%) CVID and 4 (7%) sporadic disease. Age at biopsy across all NRH cohorts was significantly older compared to the non-NRH population (mean 40 vs. 33 years, p=0.0128). Patients with NRH had significantly higher alkaline phosphatase (197 vs. 190 U/L, p=0.01), increased liver volumes (2152 vs. 1166 cm3, p=0.01) and increased spleen volumes (after excluding SCD) (1071 vs. 410 cm3, p=0.01), which negatively correlated with platelets ( ρ -0.58, p= 0.002). In the SCD cohort, pts with NRH had increased gamma-glutamyltransferase (128 vs. 67 U/L, p=0.03) and increased lactate dehydrogenase (432 vs. 322 U/L, p=0.01). On histologic evaluation, SCD-NRH pts had increased lobular inflammation (p=0.04). SMCDNRH pts had increased portal and peri-portal inflammation (p=0.005 and p=0.01, respectively), veno-occlusive changes (p=0.04), portal venopathy (p=0.001) and sinusoidal dilation (p=0.03). Conclusions: Despite parallels in clinical disease presentation, histopathologic examination of NRH in separate disease cohorts suggests different mechanistic pathways. Given the potential for multiple etiologies, NRH may be more common than previously thought. Further investigation should focus on the underlying disease process as it may provide a window into biology.

The risk of perioperative adverse events in patients with chronic liver disease

Chronic liver disease is a common comorbidity in surgery. To assess post-operative morbidity and mortality in relation to progression of chronic liver disease and to identify the risk factors. Six hundred and nine consecutive patients with chronic liver disease who underwent surgery were classified into two groups: non-cirrhotic (n = 363) and cirrhotic (n = 246). Randomly selected patients without underlying liver disease who underwent surgery were used as control group (n = 148). The occurrence of major post-operative complications was higher in the non-cirrhotic group than in the control group (11.8% vs. 6.1%, P = 0.051); age, type of surgery and serum albumin level were independent predictors for post-operative morbidity. The frequency of significant post-operative liver damage (14.9% vs. 12.2%, P = 0.920) and mortality (0.6% vs. 0.7%, P = 0.871) did not differ between the two groups. The cirrhotic group had markedly higher incidences of post-operative mortality (10.2%), major complications (32.5%) and significant liver damage (43.1%) than the control and non-cirrhotic groups (all P < 0.001). Type of surgery, Child-Pugh score and model for end-stage liver disease score were independently associated with post-operative morbidity and mortality in patients with cirrhosis. Specific data regarding post-operative morbidity and mortality were presented according to progression of liver disease and type of surgery. Non-cirrhotic chronic liver diseases were associated with higher risk of post-operative morbidity, particularly in cases of major surgery, older age and hypoalbuminaemia. Cirrhosis further increased the risk, even death, depending on degree of hepatic decompensation and type of surgery.

Nondiseased Liver Stiffness Measured by Shear Wave Elastography

The purpose of this study was to investigate the value of liver stiffness in patients without liver disease using shear wave elastography and to determine the liver stiffness threshold value for identifying patients with chronic liver diseases. A total of 150 patients who underwent liver sonography coupled with shear wave elastography were enrolled. On the basis of clinical and pathologic criteria, they were assigned to 1 of 2 groups: nondiseased liver (n = 97) and noncirrhotic chronic liver disease (n = 53). Liver stiffness was measured in the right liver, and the median value of 10 measurements was calculated. Both mean and median values in the nondiseased liver group were compared with those in the noncirrhotic chronic liver disease group. To validate this comparison, liver stiffness of the patients who underwent liver biopsy revealing either no fibrosis (fibrosis score F0; n = 5) or substantial fibrosis (F2; n = 14) was also investigated and compared. To determine the optimal threshold value for determining chronic liver disease, a receiver operating characteristic curve analysis was performed. The mean liver stiffness value in the nondiseased liver group was 5.4 kPa. In the noncirrhotic chronic liver disease group, the mean value was 8.1 kPa. Differences between the nondiseased liver and both noncirrhotic chronic liver disease groups were statistically significant (P < .001). The optimal liver stiffness threshold value for discriminating nondiseased liver from noncirrhotic chronic liver disease was 6.9 kPa. The sensitivity using this threshold was 94%. In the biopsy-proven patients, the mean liver stiffness values were 6.0 kPa in the F0 group and 9.9 kPa in the F2 group. The range of liver stiffness in patients with nondiseased liver and the optimal threshold value for discriminating these patients from those with chronic liver disease were identified.

Histomorphological features of pancreas and liver in chronic alcoholics--an analytical study in 390 autopsy cases.

Chronic pancreatitis and liver disease are two conditions that commonly co-exist in chronic alcoholics with variable incidences. To evaluate frequency pancreatitis in patients with a history of chronic alcohol abuse. A total of 390 autopsies over 11 year's period were included in the study. Gross and microscopic assessment of liver and pancreas were performed. Available clinical and laboratory parameters were recorded. Age ranged from 22 to 65 years with a mean age of 45.32 years. All 390 consecutive patients included in the study were males. Majority of the patients had primarily presented with alcohol related liver diseases whereas few had presented with features of pancreatitis. Micronodular cirrhosis was present in 292 cases. Features of chronic pancreatitis were observed in 42 cases and 8 of these cases had associated changes of acute hemorrhagic pancreatitis. Prevalence of pancreatitis was more in cirrhotics as compared to non-cirrhotics, and acute pancreatitis was mostly seen in non-cirrhotics. Dominant pattern of fibrosis was perilobular followed by periductal, intralobular and diffuse. Chronic pancreatitis as evidence by the presence of parenchymal fibrosis was more frequently observed in alcoholic cirrhosis cases than that in non-cirrhotic alcoholic liver disease, thereby suggesting common underlying pathobiology in the development of fibrosis in liver as well as in pancreas.

Do you need to provide VTE prophylaxis for patients with end-stage liver disease and an elevated INR?

ratio [RR] 1.7; 95% CI, 1.5–2.0) and in those with noncirrhotic liver disease (RR 1.9; 95% CI, 1.7–2.0). In a subgroup analysis of unprovoked VTE, which excluded patients with a diagnosis of cancer, fractures, trauma, surgery, or pregnancy within 90 days of hospitalization, the risk of unprovoked VTE was increased compared with controls in patients with cirrhosis (RR 2.1; 95% CI, 1.8–2.4) and in patients with noncirrhotic liver disease (RR 2.1; 95% CI, 1.9–2.3). 1

Non‐alcoholic fatty liver disease contributes to hepatocarcinogenesis in non‐cirrhotic liver: A clinical and pathological study

Hepatocellular carcinoma (HCC) is a major complication of cirrhosis and has been increasing in incidence in recent years. Fatty liver disease is an increasingly common cause of chronic liver disease, and there have been several case reports of HCC in patients with non-cirrhotic fatty liver disease. However, there is limited data from systematic studies with histological confirmation of the presence of both the HCC and the non-cirrhotic fatty liver disease. We studied the occurrence of fatty liver disease and the associated demographic, clinical, and pathological characteristics of a large cohort of patients with HCC in non-cirrhotic livers. Patients with intrahepatic cholangiocarcinoma (CC) occurring in non-cirrhotic livers and diagnosed during the same time period were used as the comparison group. Significant steatosis in the nontumor liver had a statistically significant association with HCC, being present in 54% (85/157) of HCC compared with 27% (32/120) of CC (P < 0.0001). Steatohepatitis was present in 15% (24/157) of HCC and 1% (2/120) of CC (P = 0.0014). Furthermore, HCC was more prevalent in cases with higher grades of steatosis. In addition, the recently described intratumoral steatohepatitic morphology of HCC (SH-HCC) was also associated with significant steatosis in nontumor liver, with significant steatosis being present in 89% with SH-HCC compared with 50% without SH-HCC (P = 0.0162). Finally, SH-HCC was increasingly more prevalent in patients with higher grades of nontumor steatosis. Taken together, these findings suggest a strong association between fatty liver disease and HCC in non-cirrhotic livers.

Does the cost of care differ for patients with fee-for-service vs. capitation of payment? A case–control study in gastroenterology

There is growing evidence to demonstrate overuse of medical resources in fee for service (FFS) payment models (in which physicians are reimbursed according to volume of care provided) compared to capitation payment models (in which physicians receive a fixed salary regardless of level of care provided). In this medical centre, patients with and without insurance are admitted through the same access point (emergency room) and cared for by the same physicians. Therefore, apart from insurance status, all other variables influencing delivery of care are similar for both patient groups. However, physician reimbursement differs for both groups: FFS for patients with private insurance (i.e. the admitting physician's reimbursement escalates progressively with each day that the patient spends in hospital) and base salary irrespective of care provided for patients with universal insurance (capitation payment model). All admitting physicians are aware of the patient's insurance status and the duration of hospitalization is at the discretion of the admitting physician. This study aimed to compare cost of care of patients with and without insurance admitted to a teaching hospital with a primary gastroenterology or hepatology (GIH) diagnosis. All hospital inpatients admitted between January 2008 and December 2009 with a primary GI-related diagnosis related group (DRG) were identified. Patients were classified as uninsured (state-funded) or privately insured. Only DRGs with at least five patients in both the insured and uninsured patient groups were analyzed to ensure a precise estimate of inpatient costs. Patient level costing (PLC) was used to express the total cost of hospital care for each patient; PLC comprised a weighted daily bed cost plus cost of all medical services provided (e.g. radiology, pathology tests) calculated according to an activity-based costing approach, cost of medications were excluded. An overall mean cost of care per patient was calculated for both groups. All costs were discounted to 2009 values. In total, 630 patients were admitted with one of 11 GIH DRGs, 181 (29 %) with private insurance. Pooled mean cost of care was higher for uninsured (6,781 euros/patient) compared to insured patients (6,128 euros/patient). Apart from patients with 'non-cirrhotic non-alcoholic liver disease (non-complex)' in whom mean cost was higher for insured patients, there were no significant differences in mean cost of care nor mean patient age for insured and uninsured groups for any other diagnoses. Inpatient hospital costs were equivalent for patients with and without private health insurance when care was provided in a single hospital. Provision of care for all patients in a common hospital setting regardless of health insurance status may reduce disparities in healthcare utilization.

Liver disease and 30-day mortality after colorectal cancer surgery: a Danish population-based cohort study

BackgroundColorectal cancer (CRC) is common, with surgery as the main curative treatment. The prevalence of chronic liver disease has increased, but knowledge is limited on postoperative mortality in patients with liver disease who undergo CRC surgery. Hence, we examined 30-day mortality after CRC surgery in patients with liver disease compared to those without liver disease.MethodsWe used medical databases to conduct a nationwide cohort study of all patients undergoing CRC surgery in Denmark from 1996 through 2009. We further identified patients diagnosed with any liver disease before CRC surgery and categorized them into two cohorts: patients with non-cirrhotic liver disease and patients with liver cirrhosis. Patients without liver disease were defined as the comparison cohort. Using the Kaplan-Meier method, we computed 30-day mortality after CRC surgery in each cohort. We used a Cox regression model to compute hazard ratios as measures of the relative risk (RR) of death, controlling for potential confounders including comorbidities. In order to examine the impact of liver disease in different subgroups, we stratified patients by gender, age, cancer stage, cancer site, timing of admission, type of surgery, comorbidity level, and non-hepatic alcohol-related disease.ResultsOverall, 39,840 patients underwent CRC surgery: 369 (0.9%) had non-cirrhotic liver disease and 158 (0.4%) had liver cirrhosis. Thirty-day mortality after CRC surgery was 8.7% in patients without liver disease and 13.3% in patients with non-cirrhotic liver disease (adjusted RR of 1.49 95% confidence interval (CI): 1.12-1.98). Among patients with liver cirrhosis, mortality was 24.1%, corresponding to an adjusted RR of 2.59 (95% CI: 1.86-3.61). The negative impact of liver disease on postoperative mortality was found in all subgroups.ConclusionsPre-existing liver disease was associated with a markedly increased 30-day mortality following CRC surgery.

A case of hepatopulmonary syndrome solved by mycophenolate mofetil (an inhibitor of angiogenesis and nitric oxide production)

The autoimmune lymphoproliferative syndrome (ALPS) is a rare, multisystemic disease, caused by an inherited defect in the Fas apoptotic pathway, characterized by a chronic non-malignant lymphoid accumulation and autoimmune manifestations. Lung, kidney, liver, and gut infiltration is described in severe, multisystemic cases; so far there has been no description of hepatopulmonary syndrome (HPS), for which orthotopic liver transplantation (OLT) is currently the only known effective treatment. A teenage boy, diagnosed with ALPS at 4years of age (lymph nodes enlargement, splenomegaly, immune cytopenias), was stable until 13years of age, when he developed insidious hypoxemia (PaO 2 =46.7mmHg). He was diagnosed with HPS on the basis of hypoxemia, non-cirrhotic liver disease with portal hypertension, and pulmonary vascular dilatation (intrapulmonary shunt=45%). He was treated with oxygen (maximum 6L/min), prednisolone and sirolimus. There was significant regression of all manifestations of ALPS, except for the pulmonary symptoms, therefore, after evaluation in referral centers in England, OLT was proposed. Since he was to undergo major surgery, sirolimus, which has wound-healing problems, was switched to mycophenolate mofetil (MMF). Following this change, we observed a huge improvement in pulmonary symptoms and reduction of oxygen needs. The intrapulmonary shunt decreased from 45% to 0% in less than a year, and it has not changed since (18months after complete normalization), on continued treatment with MMF. Indication for OLT was suspended. In the last year, lymphoid proliferation increased again, with huge splenomegaly, but no recurrence of HPS. The addition of sirolimus to MMF produced again a rapid resolution of lymphoid proliferation. The dramatic and unexpected regression of HPS may have been due to inhibition of angiogenesis and nitric oxide (NO) production by MMF (both important pathways/mediators in HPS pathogenesis). Therefore, we propose to perform clinical trials with MMF, and/or other angiogenesis and NO inhibitors, on a long-term treatment basis, to confirm their potential as a valid alternative to medical treatment of HPS.

Impact of disease severity on healthcare costs in patients with chronic hepatitis C (CHC) virus infection

Hepatitis C virus (HCV) infection increases total healthcare costs but the effect of the severity of liver disease associated with chronic hepatitis C (CHC) on healthcare costs has not been well studied. We analyzed the demographics, healthcare utilization, and healthcare costs of CHC patients in a large U.S. private insurance database (January, 2002 to August, 2010), with at least 1 year of baseline enrollment and 30 days of continuous follow-up. Patients were stratified by liver disease severity: noncirrhotic liver disease (NCD), compensated cirrhosis (CC), and endstage liver disease (ESLD), as defined by the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9) codes. Mean all-cause and HCV-related healthcare costs per-patient-per-month (PPPM) during follow-up (mean 634 days) are reported in 2010 U.S.$ from the payer's perspective. A total of 53,796 patients with CHC were included (NCD: 41,858 [78%]; CC: 3,718 [7%]; and ESLD: 8,220 [15%]). Mean all-cause PPPM healthcare costs were 32% and 247% higher for patients with CC and ESLD compared to those with NCD ($1,870 and $4,931 versus $1,420; P < 0.001) and were independent of age or comorbid conditions. Pharmacy, ambulatory, and inpatient care collectively accounted for 90% of NCD costs and 93% of CC and ESLD costs. The largest cost components were inpatient costs for those with ESLD (56%) and ambulatory costs for those with CC and NCD (37% and 36%, respectively). Overall, 56% of costs were HCV-related and this proportion increased with severity (46%, 57%, and 71% for patients with NCD, CC, and ESLD, respectively). The direct healthcare costs associated with CHC are high, increase in association with the progression of liver disease, and are highest in those with ESLD.

296 Role of Sphingosine Kinase-2 in Acetaminophen-Induced Liver Injury

suppressor gene (TSG) promoters and 3 MINT loci using quantitative assays. Fractional allelic loss (FAL), which is representative for CIN, was calculated using 400 microsatellite markers in a subset of 110 tumors. The association between hypomethylation of repetitive DNA elements and FAL was compared with that between hypermethylation of TSGs and FAL. Prominent hypomethylation at repetitive DNA elements was detected in well-differentiated tumors with progressive decrease in methylation levels with the de-differentiation of tumors. Hierarchical clustering analysis using methylation levels of repetitive DNA sequences as well as TSGs/MINT loci was performed to classify HCCs carrying progressive global hypomethylation or extensive regional hypermethylation. HCCs with progressive hypomethylation showed significantly higher FAL scores than HCCs with mild hypomethylataion in both the well-differentiated HCCs as well as moderately or poorly-differentiated tumors (p = 0.0015 for well-differentiated tumors and p = 0.0270 in poorly-differentiated tumors). Multivariate analysis, using several clinicopathological factors as covariables, revealed that the category of progressive hypomethylation and non-cirrhotic background livers were independent factors that associated with high FAL score (p = 0.0265 for progressed hypomethylation and p = 0.0021 for non-cirrhotic liver). On the other hand, no relationship was observed between extensive hypermethylation on TSGs/MINT loci and FAL. The significant association between progressive hypomethylation on repetitive DNA sequences and CIN suggests that global hypomethylation might trigger development of CIN during HCC formation, particularly for the cancers that occur in the background of non-cirrhotic liver disease.

Comparison of Circulating Endothelial Cell/Platelet Count Ratio to Aspartate Transaminase/Platelet Ratio Index for Identifying Patients with Cirrhosis

Circulating endothelial cells (CECs) are indicative of vascular injury and correlate with severity of vascular diseases. A pilot study showed that the ratio of CEC to platelet count (CEC/PC) was effective in predicting cirrhosis. Therefore, we evaluated CEC/PC in a larger cohort of patients, correlated it with cirrhosis, and compared its operating characteristics with previously described biomarker for cirrhosis, the AST/platelet ratio index (APRI). Fifty-three patients with cirrhosis, 20 matched healthy controls, and 9 patients with noncirrhotic liver disease were recruited. Peripheral blood sample was collected and analyzed to enumerate nucleated CEC CD146+, CD105+, CD45- using a commercial assay. Median CEC counts were significantly higher in patients with cirrhosis (62 cells/4 mL, interquartile range [IQR]: 43.5-121) as compared with controls (31 cells/4 mL, IQR: 22.2-40). The CEC/PC was also significantly elevated in cirrhotics (0.69, IQR: 0.39-1.48) compared with controls (0.12, IQR: 0.09-0.20) and noncirrhotics (0.21, IQR: 0.08-0.43). Receiver operator characteristic (ROC) analysis revealed that CEC cutoff value of ≥37 cells/4 mL showed sensitivity of 81% and specificity of 75% for differentiating cirrhosis from controls (area under the curve [AUC]: 0.80; 95% confidence interval [CI] 0.67-0.91). The CEC/PC ratio cutoff value of ≥0.23 showed sensitivity of 91% and specificity of 82% (AUC: 0.92; 95% CI 0.83-0.99). The APRI cutoff value of ≥0.4 showed sensitivity of 94% and specificity of 85% for differentiating cirrhosis from control patients (AUC: 0.96; 95% CI 0.90-1.0). A product of CEC and APRI, termed CAPRI (CEC-APRI), effectively distinguished patients with cirrhosis from controls; with cutoff value of ≥12.7, showing higher sensitivity of 98% and specificity of 85% (AUC: 0.98; 95% CI 0.96-1.0). The CEC/PC ratio is significantly elevated in patients with cirrhosis and demonstrates comparable operating characteristics to previously described APRI. Furthermore, CAPRI, compiled as product of CEC to APRI showed outstanding ability to distinguish patients with cirrhosis from controls, although larger studies are necessary for validation.

Medical Comorbidity of Full and Partial Posttraumatic Stress Disorder in US Adults

This study examined associations between lifetime trauma exposures, PTSD and partial PTSD, and past-year medical conditions in a nationally representative sample of US adults. Face-to-face interviews were conducted with 34,653 participants in the Wave 2 National Epidemiologic Survey on Alcohol and Related Conditions. Logistic regression analyses evaluated associations of trauma exposure, PTSD, and partial PTSD with respondent-reported medical diagnoses. After adjustment for sociodemographic characteristics and comorbid Axis I and II disorders, respondents with full PTSD were more likely than traumatized respondents without full or partial PTSD (comparison group) to report diagnoses of diabetes mellitus, noncirrhotic liver disease, angina pectoris, tachycardia, hypercholesterolemia, other heart disease, stomach ulcer, human immunodeficiency virus seropositivity, gastritis, and arthritis (odds ratios [ORs] = 1.2-2.5). Respondents with partial PTSD were more likely than the comparison group to report past-year diagnoses of stomach ulcer, angina pectoris, tachycardia, and arthritis (ORs = 1.3-1.6). Men with full and partial PTSD were more likely than controls to report diagnoses of hypertension (both ORs = 1.6), and both men and women with PTSD (OR = 1.8 and OR = 1.6, respectively) and men with partial PTSD (OR = 2.0) were more likely to report gastritis. The total number of lifetime traumatic event types was associated with many assessed medical conditions (ORs = 1.04-1.16), reducing the magnitudes and rendering some of the associations between PTSD status and medical conditions nonsignificant. Greater lifetime trauma exposure and PTSD are associated with numerous medical conditions, many of which are stress-related and chronic, in US adults. Partial PTSD is associated with intermediate odds of some of these conditions.

Differences in the Disposition of Silymarin between Patients with Nonalcoholic Fatty Liver Disease and Chronic Hepatitis C

Silymarin, derived from the milk thistle plant Silybum marianum and widely used for self-treatment of liver diseases, is composed of six major flavonolignans including silybin A and silybin B, which are the predominant flavonolignans quantified in human plasma. The single- and multiple-dose pharmacokinetics of silymarin flavonolignans were examined in patients with nonalcoholic fatty liver disease (NAFLD) or hepatitis C virus (HCV) to determine whether the disposition of silymarin and therefore its potential efficacy vary among liver disease populations. Cohorts of eight subjects with noncirrhotic liver disease were randomized 3:1 to oral silymarin or placebo (280 or 560 mg) every 8 h for 7 days. Forty-eight-hour blood sampling was conducted after the first and final doses. In general, plasma concentrations of silybin A and silybin B were higher, whereas concentrations of conjugates were lower in NAFLD compared with HCV. After adjustment of the area under plasma concentration-time curve from 0 to 8 h (AUC(0-8 h)) for weight and dose, only silybin B and silybin B conjugates differed significantly between disease types. For NAFLD, the adjusted mean AUC(0-8 h) was higher for silybin B (p < 0.05) but lower for silybin B conjugates (p < 0.05) compared with that for HCV. At the 280-mg dose, steady-state plasma concentrations of silybin B conjugates for NAFLD subjects were characterized by 46% lower AUC(0-8 h) (p < 0.05) and 42% lower C(max) (p < 0.05) compared with HCV subjects. Evidence of enterohepatic cycling of flavonolignans was only observed in NAFLD subjects. In summary, the efficacy of silymarin may be more readily observed in NAFLD patients because of their higher flavonolignan plasma concentrations and more extensive enterohepatic cycling compared with those in HCV patients.