Are prothrombin time and clot waveform analysis useful in detecting a bleeding risk in liver cirrhosis?

INTRODUCTION: Prothrombin time is thought to be unreliable in cirrhotic patients to predict the risk of bleeding. We investigated whether prothrombin time ratio was an independent risk factor for bleeding alongside its clot waveform analysis. METHODS: We studied 307 consecutive cirrhotic patients and 115 healthy subjects. A coagulometer was used for detecting both prothrombin time and clot waveform analysis which included velocity (1st derivative) and acceleration (2nd derivative) of clot formation, and area of parabolic segment of the 1st and 2nd derivatives of prothrombin time (entire cycle of the clot formation). RESULTS: Logistic regression shows that prothrombin time ratio was the only variable significantly associated with the history of bleeding. Using a hemorrhagic score, the stepwise model included prothrombin time ratio and the area of parabolic segment of the 1st derivative of Prothrombin Time. Odds ratio was used to create a new score to be challenged against the hemorrhagic score in a ROC analysis. The AUC was 0.72, 95% CI: 0.67-0.77. CONCLUSION: Prothrombin time ratio is associated to an increased bleeding risk. Its role may be further emphasized considering clot waveform analysis. The new score, if aggregated to prothrombin time ratio, could be useful to provide a single parameter immediately ready to assess the bleeding risk in the individual cirrhotic patient.

Proteomic investigation of whole saliva in Wilson's disease.

Wilson's disease is a rare inherited disorder of copper metabolism, manifesting hepatic, neurological and psychiatric symptoms. Early diagnosis is often unfeasible and a unique diagnostic test is currently inapplicable. We performed the qualitative/quantitative characterization of the salivary proteome/peptidome of 32 Wilson's disease patients by an integrated top-down/bottom-up approach. Patients exhibited significant higher levels of S100A9 and S100A8 proteoforms, and their oxidized forms with respect to controls. Oxidation occurred on methionine and tryptophan residues, and on the unique cysteine residue, in position 42 in S100A8, and 3 in S100A9, that generated glutathionylated, cysteinylated, sulfinic, sulfonic, and disulfide dimeric forms. Wilson's disease patient saliva showed high levels of two new fragments of the polymeric immunoglobulin receptor, and of α-defensins 2 and 4. Overall, the salivary proteome of Wilson's disease patients reflected oxidative stress and inflammatory conditions characteristic of the pathology, highlighting differences that could be useful clues of disease exacerbation.

Homogeneous magnetic resonance imaging of brain abnormalities in bipolar spectrum disorders comorbid with Wilson's disease.

BACKGROUND: The purpose was to determine if brain damage in Wilson's disease (WD) is different in comorbid bipolar spectrum disorders (BDs), comorbid major depressive disorder (MDD) or without any mood disorders. METHODS: An observational study was conducted on consecutive patients from a center for WD care. The study sample was divided by psychiatric assessment into WD without any mood disorders, WD with BDs and WD with MDD negative at Mood Disorder Questionnaire (MDQ). RESULTS: Thirty-eight WD patients were recruited (53.2% females): 21 without mood disorders (55.2%), 9 with comorbid BDs (26.7%) and 8 with MDD without MDQ+ (21.1%). The BDs showed a higher frequency of brain damage, reaching statistically significant differences in the basal ganglia (P<.001), in the overall brain (P<.003) and at the limit in the white matter (P<.05). CONCLUSIONS: In WD, comorbidity with BDs is associated with earlier evidence of brain damage, especially in the basal ganglia. The results confirm the importance of screening and early diagnosis of BDs in WD. Future follow-up studies on large samples are required to confirm if detection of BDs may be an early marker of brain damage and if a good therapeutic response in BDs may improve the prognosis of WD.

Uneven distribution of hepatic copper concentration and diagnostic value of double-sample biopsy in Wilson's disease.

BACKGROUND AND AIMS. Determination of hepatic copper (Cu) concentration is important in Wilson's disease (WD) diagnosis. The aim of this study was to evaluate uneven distribution of liver Cu concentration and the utility of double-sample biopsy in WD diagnosis. METHODS. Thirty-five WD patients (20 male; mean age 41 ± 9 years) were enrolled in the study and double-liver samples for biopsy were obtained. A further 30 WD patients, in whom Cu determination was performed using single-liver samples, were also enrolled as controls. RESULTS. A marked difference in hepatic Cu concentration was observed between the two sample groups (p < 0.0001). This difference is statistically significant for all levels of liver fibrosis (p < 0.001) and for the comparison of hepatic and neurological phenotypes (p < 0.01). The sensitivity of the Cu concentrations obtained from the double-sample biopsies for the conventional cut-off value of 250 mg/g dry weight of tissue was 85.7% compared to 80% in the single-sample biopsies. By lowering the cut-off value from 250 to 50 µg/g of dry weight of tissue, the sensitivity of Cu content to diagnose WD increased to 97% for double-sample liver biopsy compared to 93% for single-sample liver biopsy. CONCLUSIONS. Liver Cu content was unevenly distributed in the WD subjects, irrespective of fibrosis levels and disease phenotypes; hence WD can be misdiagnosed using single-sample liver Cu measurement. Double-sample biopsy sensitivity is greater than that obtained with single-sample biopsy and should therefore be considered to evaluate liver Cu concentration at initial diagnosis in all patients.

Histologic evolution and long-term outcome of Wilson's disease: results of a single-center experience.

BACKGROUND/AIMS: Wilson's disease (WD) is a rare inborn disease related to copper storage, leading to liver cirrhosis and neuropsychological deterioration. The aim of this study was to determine the clinical presentation and long-term outcome, and to examine the progression of hepatic histopathology in serial liver biopsies from WD patients. MATERIALS AND METHODS: We carried out a retrospective analysis of 60 patients with WD treated with zinc and/or penicillamine. Demographic, clinical, and laboratory data were gathered and 40 patients underwent an initial biopsy and at least one repeat biopsy. Patients were divided into two groups: progressors (patients who presented worsening of at least one unit of fibrosis) and nonprogressors (patients who presented stable or improved fibrosis scores). RESULTS: A total of 33/40 (83%) patients (nonprogressors) showed stable hepatic histology or improvement. Seven of 40 (17%) patients (progressors) showed worsening of fibrosis. There was no significant correlation between the histological findings and clinical parameters or initial presentation. CONCLUSION: In our study cohort, liver disease was stable or improving in most of the patients, and development of progressive hepatic symptoms while under treatment was a rare event. The development of new symptoms while under treatment or progression of pre-existing symptoms was more often recorded for neurological than for hepatic symptoms.

The relationship between copper and steatosis in Wilson's disease.

BACKGROUND AND AIMS: The histological similarities seen in Wilson's disease (WD) and non-alcoholic steatohepatitis (NASH) led us to verify possible correlations between glucose and/or lipid and/or iron metabolism alterations and hepatic steatosis in WD patients. METHODS: Thirty-five WD patients (20 females, 15 males, mean age 40.1 ± 5.4 years), and 44 NASH patients (25 females, 19 males, mean age 42.8 ± 6.7 years) were enrolled in the study. BMI, total/HDL/LDL-cholesterol, triglycerides and glucose serum levels were established in all subjects. HOMA index was calculated. Percutaneous liver biopsy with quantitative evaluation of steatosis and copper tissue content was performed in all WD patients and in NASH control group. RESULTS: Significant difference was seen in baseline serum levels of glucose, HOMA index, total cholesterol, triglycerides, and ferritin between the WD group and NASH group (P<0.05) but steatosis scored was similar between two groups. No correlation between the level of steatosis and metabolic factors studied was highlighted. In WD, hepatic parenchymal copper concentration was 753 ± 65.3 mcg/g dry weight against 54.5 ± 16.9 mcg/g dry weight in NASH patients (P<0.05). Higher liver copper concentrations were seen in patients with severe steatosis compared to those with mild (P=0.004) and moderate, (P=0.038) steatosis. Positive significant correlation between liver copper content and steatosis scores (r=0.87; r(2)=0.76) was observed. CONCLUSIONS: The hepatic steatosis in WD is not induced by metabolic comorbidities but by the accumulation of copper in the liver tissue. The hypothesise that the metabolic alterations could be co-factors in the pathogenesis of steatosis in these patients cannot be excluded.

A randomized controlled trial of sequential pegylated interferon-α and telbivudine or vice versa for 48 weeks in hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: Short-term treatment for hepatitis B e antigen (HBeAg)-negative chronic hepatitis B remains unsatisfactory. The aim of our study was to compare the efficacy and safety of two sequential regimens of pegylated interferon (PEG-IFN)-α and telbivudine (LdT). METHODS: Adult patients with biopsy-proven HBeAg-negative chronic hepatitis B, elevated alanine aminotransferase (ALT) and serum HBV DNA ≥ 2,000 IU/ml were randomized 1:1 at baseline to receive PEG-IFN 180 µg/week for 24 weeks followed by LdT 600 mg/day for 24 weeks (PEG-IFN first), or vice versa (LdT first), plus 24-week follow-up; individuals with HCV, HDV or HIV coinfections and lamivudine resistance were excluded. Primary end points were serum HBV DNA<2,000 IU/ml and normal ALT at week 72. RESULTS: A total of 30 patients (86% male, median age 48 years) were enrolled: mean ±sd baseline serum HBV DNA was 5.56 ± 1.4 log IU/ml and ALT was 2.9 ± 2.5× upper limit of normal. At end of follow-up (week 72), HBV DNA<2,000 IU/ml was achieved in 13.3% of participants in the PEG-IFN first group versus 46.7% of those in the LdT first group (P=0.046). Mean ±sd ALT levels were significantly lower in the LdT first group (1.3 ± 0.9 versus 3.2 ± 2.7× upper limit of normal; P=0.03). PEG-IFN dose was reduced in 2 (7%) patients and 1 (7%) patient dropped out due to myalgia. CONCLUSIONS: Sequential treatment with 24 weeks PEG-IFN followed or preceded by 24 weeks of LdT is safe. Virological response rate at week 72 was significantly higher in patients treated with LdT followed by PEG-IFN than vice versa. A sequential antiviral regimen of LdT followed by PEG-IFN, if confirmed in larger series, could improve response rates compared with standard PEG-IFN monotherapy.

Bipolar disorders and Wilson's disease.

BACKGROUND: The aim of this study was to determine the risk for Bipolar Disorder (BD) in Wilson's disease (WD) and to measure the impaired Quality of Life (QL) in BD with WD using standardized psychiatric diagnostic tools and a case control design. METHODS: This was a case control study. The cases were 23 consecutive patients with WD treated at the University Hospital in Cagliari, Italy, and the controls were 92 sex- and age-matched subjects with no diagnosis of WD who were randomly selected from a database used previously for an epidemiological study. Psychiatric diagnoses according to DSM-IV criteria were determined by physicians using structured interview tools (ANTAS-SCID). QL was measured by means of SF-12. RESULTS: Compared to controls, WD patients had lower scores on the SF-12 and higher lifetime prevalence of DSM-IV major depressive disorders (OR = 5.7, 95% CI 2.4-17.3) and bipolar disorders (OR = 12.9, 95% CI 3.6-46.3). BD was associated with lower SF-12 in WD patients. CONCLUSIONS: This study was the first to show an association between BD and WD using standardized diagnostic tools and a case control design. Reports in the literature about increased schizophrenia-like psychosis in WD and a lack of association with bipolar disorders may thus have been based on a more inclusive diagnosis of schizophrenia in the past. Our findings may explain the frequent reports of loss of emotional control, hyperactivity, loss of sexual inhibition, and irritability in WD patients. This study was limited by a small sample size.

Non-invasive assessment of hepatic fibrosis in a series of patients with Wilson's Disease.

BACKGROUND/AIMS: Liver biopsy has always represented the standard of reference in hepatic fibrosis assessment. Recently, blood markers and instrumental methods have been proposed for non-invasive assessment. The aim of this study was to validate transient elastography and other non-invasive tests compared to liver histology in Wilson's Disease. METHODS: Liver stiffness in 35 Wilson's Disease patients was evaluated by Fibroscan, serum fibrosis markers (AST-to-platelet-ratio index and FIB-4) and biopsy. RESULTS: Compared to liver histology, the FibroScan values increased proportionally with progression of the histological fibrosis stage. Significant fibrosis could be predicted with a Fibroscan cut-off value of 6.6 kPa. Advanced fibrosis could be predicted with a FibroScan cut-off value of 8.4 kPa. Serum fibrosis marker values gave good correlation with hepatic stage. CONCLUSIONS: A FibroScan value of 6.6 kPa was found to be a significant separation limit for differentiating significant fibrosis stages from milder stages and a fibroscan value of 8.4 kPa was found to be a significant separation limit for differentiating advanced fibrosis stages from milder stages. FibroScan values are clinically useful for predicting fibrosis stages and helpful in managing chronic therapy in Wilson's Disease patients.

Hemochromatosis gene mutations: prevalence and effects on pegylated-interferon and ribavirin therapy response in chronic hepatitis C in sardinia.

BACKGROUND/AIMS: Considerable evidence suggests that iron could be a comorbid factor for liver injury in chronic hepatitis C (CHC). Elevated iron indices are frequently described in CHC and may impact negatively on the course of liver disease and on the response to interferon alfa therapy. The aim of this study was to evaluate the frequency of hemochromatosis gene mutations in Sardinian CHC patients, the association with iron overload and the impact on response to therapy. METHODS: Sixty-nine CHC patients were enrolled. Iron indices, hepatic and viral parameters were detected. C282Y, H63D and S65C mutations were identified through a PCR. Liver biopsy was performed for hepatic fibrosis evaluation. All patients were treated for 6 months (viral genotype 2/3) or 12 months (viral genotype 1/4) with pegylated-interferon 180 mcg once weekly and ribavirin 1000-1200 mg/daily. Sustained virological response (SVR) was defined as undetectable HCV RNA 24 weeks after the end of treatment. RESULTS: HFE gene mutation was detected in 29 patients (42%). The presence of HFE mutations was significantly associated with elevated transferrin saturation (P < 0.01). Hepatic fibrosis was more advanced in HFE mutation carriers (χ (2), P = 0.04). Among mutation carriers 27.5% achieved responses at the end of treatment compared with 60% of non-carriers (P = 0.005). Patients with HFE wildtype produced significant SVR compared with patients with HFE mutations (P = 0.03). CONCLUSIONS: The literature shows discordant results about the prevalence, hepatic distribution and possible therapeutic implications of iron overload in chronic hepatitis C. Our findings shows that HFE gene mutations could favor, synergically with CHC and other genetic or acquired factors, the development of liver damage and could influence the outcome of interferon treatment with higher rate of non-response.

Resolved Psychosis after Liver Transplantation in a Patient with Wilson's Disease.

A psychiatric involvement is frequently present in Wilson's disease. Psychiatric symptoms are sometimes the first and only manifestation of Wilson's disease. More often a psychiatric involvement is present beside a neurologic or hepatic disease.We describe the case of a 18 years-old male patient who shows a clinic and laboratoristic pattern of cirrhosis and an history of subchronic hallucinatory psychosis, behavioral symptoms and mood disturbances with depressed mood. He hadn't familiar history of liver or psychiatric disease. Laboratory and imaging tests confirmed the diagnosis of Wilson's disease with psichiatric involvement. After liver transplantation copper metabolism and liver function normalised and we noticed no recurrency of the psichiatric illness. Very few cases of psychiatric improvement after orthotopic liver transplantation (OLT) has been described until now.

Patterns of chronic hepatitis B in Central Italy: a cross-sectional study.

We investigated the patterns of chronic hepatitis B virus (HBV)-related disease in a large cohort of HBsAg-positive patients, in Central Italy, by collecting a screening form with demographic, clinical and laboratory data. Overall, 737 HBsAg-positive cases were included (70% male; median age 52 years): 30% were inactive HBsAg carriers, 51% had chronic hepatitis B (CHB) and 19% had HBV-related cirrhosis. Patients from non-European Union (EU) countries (n = 65) were significantly younger, had a higher prevalence of HBeAg-positive infection and hepatitis delta virus (HDV) co-infection than patients of Italian origin. Therefore, as immigration from non-EU countries continues to grow, we can expect a change in the landscape of HBV-related disease in our area.

HFE gene mutations and Wilson's disease in Sardinia.

BACKGROUND: Hypocaeruloplasminaemia can lead to tissue iron storage in Wilson's disease and the possibility of iron overload in long-term overtreated patients should be considered. The HFE gene encodes a protein that is intimately involved in intestinal iron absorption. AIMS: The aim of this study was to determine the prevalence of the HFE gene mutation, its role in iron metabolism of Wilson's disease patients and the interplay of therapy in copper and iron homeostasis. METHODS: The records of 32 patients with Wilson's disease were reviewed for iron and copper indices, HFE gene mutations and liver biopsy. RESULTS: Twenty-six patients were negative for HFE gene mutations and did not present significant alterations of iron metabolism. The HFE mutation was significantly associated with increased hepatic iron content (P<0.02) and transferrin saturation index (P<0.03). After treatment period, iron indices were significantly decreased only in HFE gene wild-type. CONCLUSIONS: The HFE gene mutations may be an addictional factor in iron overload in Wilson's disease. Our results showed that an adjustment of dosage of drugs could prevent further iron overload induced by overtreatment only in patients HFE wild-type.

A randomized controlled trial of pegylated interferon-alpha2a plus adefovir dipivoxil for hepatitis B e antigen-negative chronic hepatitis B.

BACKGROUND: Pegylated interferon (PEG-IFN)-alpha monotherapy is the current standard of care for short-term antiviral treatment of hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). We aimed to assess the safety and efficacy of PEG-IFN-alpha plus adefovir dipivoxil (ADV) versus PEG-IFN-alpha monotherapy for compensated HBeAg-negative CHB. METHODS: A multicentre randomized controlled trial was performed in eight outpatient hepatology/infectious disease clinics in central Italy. A total of 60 patients (67% male and median age 48 years) with biopsy-proven HBeAg-negative compensated CHB (mean alanine aminotranferase [ALT] levels 3.3 +/-3x the upper normal limit and serum hepatitis B virus [HBV] DNA 5.8 +/-0.9 log(10) IU/ml) were randomized at baseline to receive PEG-IFN-alpha2a 180 microg/week plus ADV 10 mg/day or PEG-IFN-alpha2a monotherapy for 48 weeks. Post-treatment follow-up was for 24 additional weeks. The primary end point was sustained HBV DNA suppression defined as serum HBV DNA<2,000 IU/ml after 24 weeks of post-treatment follow-up. The secondary end point was ALT normalization at the end of follow-up. RESULTS: At week 48, HBV DNA was undetectable in 20/30 (67%) in the combination group versus 11/30 (37%) patients in the monotherapy group (P=0.02). ALT normalization was achieved in 17/30 (57%) versus 10/30 (30%) patients, respectively (P=0.03). At week 72, sustained virological response was achieved in 7/30 (23.3%) in the combination group versus 6/30 (20%) patients in the monotherapy group (P=0.75); 5 (16%) patients in each group dropped out because of adverse events or non-compliance. CONCLUSIONS: In HBeAg-negative CHB, combination PEG-IFN-alpha2a plus ADV for 48 weeks is safe and resulted in greater on-treatment efficacy than PEG-IFN-alpha2a monotherapy. No difference in sustained virological and biochemical response rates were observed between the two treatment regimens.

Peginterferon alpha-2a and ribavirin versus peginterferon alpha-2a monotherapy in early virological responders and peginterferon alpha-2a and ribavirin versus peginterferon alpha-2a, ribavirin and amantadine triple therapy in early virological nonresponders: the SMIEC II trial in naïve patients with chronic hepatitis C.

OBJECTIVE: The objective of this study was to compare the efficacy of anti-hepatitis C virus (anti-HCV) treatment schedules on the basis of an early virological response (EVR), defined as undetectable serum HCV-RNA (<50 IU/ml) after a 12-week induction course of peginterferon alpha-2a (PEG-IFN) 180 mcg/week. METHODS: A total of 210 interferon-naïve patients (69% male; median age, 42 years) with histologically proven chronic hepatitis C infection (genotype 1: 62%) received PEG-IFN 180 mcg/week for 12 weeks. Patients with EVR (58%) were randomized to continue PEG-IFN monotherapy (n=64) or to add ribavirin (RBV), 800 mg/day (n=57), for 36 additional weeks. Patients without EVR (42%) were randomized to add RBV (n=42), or RBV plus amantadine, 200 mg/day (n=47), for 36 additional weeks. Sustained virological response (SVR, undetectable HCV-RNA 24 weeks after treatment completion) was compared among treatment groups. RESULTS: Patients with EVR: SVR rate was 60.3% in the PEG-IFN group versus 67.2% in the PEG-IFN+RBV group (NS). In genotypes 2/3, SVR rates were 66.7 versus 73.1% (NS); in genotypes 1/4, SVR rates were 51.6 versus 61.3%, respectively (NS). Patients without EVR: SVR was 16.7% in the PEG-IFN+RBV group versus 31.9% in the triple therapy group (P=0.07). In patients with genotypes 1/4, SVR rates were 9.4 versus 29.7% (P=0.041). CONCLUSION: In genotypes 1/4 patients without EVR, triple therapy results in higher SVR rates than standard dual therapy. This study confirms that addition of amantadine is beneficial in early-recognized 'difficult-to-treat' patients.

Interferon beta-1a alone or in combination with ribavirin: a randomized trial to compare efficacy and safety in chronic hepatitis C.

AIM: To compare the efficacy and safety of recombinant human IFN beta-1a alone or in combination with ribavirin in treatment-naive subjects with chronic hepatitis C. METHODS: Open, randomized trial was performed in 6 Italian tertiary centers: 102 of the 108 patients screened were randomized to receive 6 MIU of recombinant human IFN beta-1a subcutaneously daily for 24 wk, alone (Group 1, n = 51) or in combination with ribavirin 1,000 to 1,200 mg/d (Group 2, n = 51). RESULTS: The end-of-treatment virologic response rate was 29.4% in Group 1 and 41.2% in Group 2 (non-significant). Twenty-four weeks after stopping therapy, sustained virologic response rate was 21.6% in Group 1 and 27.4% in Group 2 (non-significant). All subjects in Group 1 completed treatment, while two subjects in Group 2 stopped therapy due to treatment-related adverse events. CONCLUSION: Recombinant human IFN beta-1a, alone or in combination with ribavirin, has an excellent safety profile and, may represent an alternative for chronic hepatitis C patients who are unable to tolerate pegylated alpha-interferon.