Luigi Demelia

Uneven hepatic copper distribution in Wilson's disease

BACKGROUND/AIMS Determination of hepatic copper concentration is important in the diagnosis of Wilsons disease. We studied copper distribution in the cirrhotic liver of a patient who died of Wilsons disease. METHODS A liver slice extending from the left to the right lobe was divided into 38 samples. Each sample was analyzed for copper content by Induced Coupled Plasma Atomic Emission Spectroscopy. RESULTS The mean copper concentration in the liver was 1370 micrograms/g dt. A striking variability, up to 2-3-fold, in copper levels was observed between the samples: the copper concentration ranged from 880 to 2100 micrograms/g dt, with significant differences even between adjacent samples. Lobar differences were also observed, with a tendency of the right lobe to accumulate more copper than the left lobe. Histochemical analyses confirmed the uneven distribution of copper even at the acinar level. Copper was mainly stored in periportal hepatocytes (zone 1) and at the periphery of the regenerating nodules. Moreover, we observed some nodules with the majority of hepatocytes full of copper granules, adjacent to areas of parenchyma negative for copper stains. CONCLUSIONS Our data show that: 1) copper is unevenly distributed in Wilsons disease in the cirrhotic stage; 2) a lobar pattern of copper distribution is evident in this case, characterized by a higher copper concentration in the right lobe; 3) the observed lobar pattern is different from that described in the newborn liver, characterized by a higher copper content in the left compartment of the liver; 4) copper content determined in a small liver sample cannot be considered as absolutely representative of the mean hepatic copper concentration. From a practical point of view, our data show that sampling variability deserves more consideration in the diagnosis and in the monitoring of Wilsons disease. The use of hepatic copper concentration in monitoring the efficacy of the copper-chelating therapy may be unreliable, particularly in the cirrhotic stage, because of the patchy distribution of copper, as demonstrated in this study.

A randomized controlled trial of pegylated interferon-α2a 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.

Value of histochemical stains for copper in the diagnosis of Wilson's disease

Aims: The histochemical demonstration of hepatic copper is important in the diagnosis of Wilsons disease (WD). Conflicting results have been published with regard to the ability of different histochemical methods to demonstrate copper storage in the liver. Therefore, we evaluated the diagnostic value of three available histochemical methods in a large series of patients affected by WD.

Comparison of MRI, EEG, EPs and ECD-SPECT in Wilson's disease

Objectives – The purpose of this study is to evaluate the efficiency of a few methodologies in detecting anatomo‐functional brain abnormalities in patients with Wilsons disease. Materials and methods – Twenty‐three patients with Wilsons disease underwent almost simultaneously brain magnetic resonance imaging (MRI), computerized electroencephalography (EEG), multimodal evoked potentials (EPs) and ECD single photon computerized tomography (SPECT) evaluation. The clinical picture was of the neurologic type in 8 patients and of the hepatic type in 15. Results – MRI was abnormal in 7 patients with neurological manifestations. The EPs proved pathologic in 7 neurologically symptomatic patients and in 4 cases with hepatic form. These results agree with those reported in other case studies. The EEG records were abnormal only in 3 cases. Nevertheless, the most interesting finding of this study is the particular frequency (86%) of diffuse or focal decrease of ECD uptake shown by brain SPECT. Conclusion – We highlight the use of this interesting procedure in the therapeutic monitoring of this disease.

Bipolar disorders and Wilson’s disease

BackgroundThe 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.MethodsThis 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.ResultsCompared 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.ConclusionsThis 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.

Brain MRI and SPECT in the diagnosis of early neurological involvement in Wilson’s disease

PurposeTo evaluate the impact of brain MRI and single-photon emission computed tomography (SPECT) in early detection of central nervous system abnormalities in patients affected by Wilson’s disease (WD) with or without neurological involvement.MethodsOut of 25 consecutive WD patients, 13 showed hepatic involvement, ten hepatic and neurological manifestations, and twp hepatic, neurological, and psychiatric symptoms, including mainly movement disorders, major depression, and psychosis. Twenty-four healthy, age-gender matched subjects served as controls. All patients underwent brain MRI and 99mTc-ethyl-cysteinate dimer (ECD) SPECT before starting specific therapy. Voxel-by-voxel analyses were performed using statistical parametric mapping to compare differences in 99mTc-ECD brain uptake between the two groups.ResultsBrain MRI showed T2-weighted hyperintensities in seven patients (28%), six of whom were affected by hepatic and neurological forms. Brain perfusion SPECT showed pathological data in 19 patients (76%), revealing diffuse or focal hypoperfusion in superior frontal (Brodmann area (BA) 6), prefrontal (BA 9), parietal (BA 40), and occipital (BA 18, BA 39) cortices in temporal gyri (BA 37, BA 21) and in caudatus and putamen. Moreover, hepatic involvement was detected in nine subjects; eight presented both hepatic and neurological signs, while two exhibited WD-correlated hepatic, neurological, and psychiatric alterations. All but one patient with abnormal MRI matched with abnormal ECD SPECT. Pathologic MRI findings were obtained in six out of ten patients with hepatic and neurological involvement while abnormal ECD SPECT was revealed in eight patients. Both patients with hepatic, neurological, and psychiatric involvement displayed abnormal ECD SPECT and one displayed an altered MRI.DiscussionThese findings suggest that ECD SPECT might be useful in detecting early brain damage in WD, not only in the perspective of assessing and treating motor impairment but also in evaluating better the less investigated disorders in the cognitive domain.

HCV transmission in family members of subjects with HCV related chronic liver disease

To investigate the risk of sexual and intrafamilial transmission of HCV, 220 family members of 76 patients (index cases) with chronic type C viral liver disease were tested for serological markers of HCV Of the family members, 129 were offspring, 64 sexual partners, 15 parents and 12 siblings of the index cases. Anti-HCV was tested in all the household contacts; HCV-RNA was tested in antibody positive samples. The serologic markers of HCV were tested in a control group of 168 family members of 81 patients with chronic hepatitis unrelated to HCV. The overall prevalence of anti-HCV was 8.2% compared to 0.6% in the control group (p < 0.001). Sexual partners were anti-HCV positive more frequently than the other contacts (20% vs 2.2%; p < 0.001), without any difference in males or females. No correlation was observed between the occurrence of HCV infection in contacts and age, severity of liver disease or risk factor for the acquisition of HCV in the index cases. Seven of the 18 (39%) anti-HCV positive family contacts had biochemical evidence of chronic liver disease, histologically confirmed in the 6 patients who underwent a liver biopsy. Liver chemistry was normal in all the HCV-negative contacts. Ten of the 18 anti-HCV positive contacts (55%) were HCV-RNA positive. Genotypes were the same (lb) in 4 of the 7 viremic couples of subjects: in 3 of the 6 couples of sexual partners and in the only mother/son couple. These data suggest the occurrence of intraspousal transmission of HCV, while intrafamiliar acquisition of HCV in non-sexual contacts seems to be rare.

Quality of Life and Psychiatric Symptoms in Wilson's Disease: the Relevance of Bipolar Disorders.

Introduction: Wilson’s disease is an inherited disorder caused by a gene located on chromosome 13, which involved copper transportation across cell membranes. The disease can cause a reduced incorporation of copper into ceruloplasmin resulting in accumulation of this metal in the liver, central nervous system, kidneys and other organs. The objective is to define the frequencies of psychiatric disorders in WD, the amount of impairment of Quality of Life [QoL] in patients with WD and the relevance of the psychiatric disorders in the QoL of people suffering by WD. Methods: This is a systematic review. The search of the significant articles was carried out in PubMed using specific key words. Results: Such other neurological diseases, WD is characterized by chronic course and need of treatments, impairment of functional outcomes and high frequency of psychiatric symptoms, although a specific association between Bipolar Disorders and WD was recently found. Despite this, since today few studies are carried on WD patients’ quality of life related to psychiatric symptoms. Some new reports showed a link between presence of Bipolar Disorders diagnosis, cerebral damage and low Qol. Conclusion: Prospective studies on large cohorts are required to establish the effective impact of psychiatric disorders comorbidity, particularly Bipolar Disorders, on quality of life in WD and to clarify the causal link between brain damage, psychiatric disorders and worsening of QoL.

TT virus infection in Italy: prevalence and genotypes in healthy subjects, viral liver diseases and asymptomatic infections by parenterally transmitted viruses

This study was aimed to evaluate TT virus prevalence in subjects with hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections in patients affected by hepatitis of unknown origin (non‐A–non‐E hepatitis) and in healthy subjects who had not been exposed to HBV, HCV and HIV. A total of 317 subjects were tested; 40 were HBsAg asymptomatic carriers, 57 subjects were anti‐HCV positive (45 without chronic hepatitis and 12 with HCV‐related chronic hepatitis), and 27 had chronic non‐A–non‐E hepatitis. Fifty‐seven subjects were intravenous drug users (IVDUs) (52 with HCV or/and HIV infections), seven patients underwent a liver transplant for fulminant hepatitis and 137 were healthy subjects from the general population. Overall, TTV‐DNA was detected in 62 subjects (19.6%): in 17.9% of the HBsAg carriers, in 14% of the anti‐HCV‐positive patients (in 8.3% and in 15.5% of patients with and without chronic hepatitis, respectively), in 22.2% of non‐A–non‐E hepatitis patients, in 22.8% of IVDUs, in 57.1% of fulminant hepatitis patients. TTV‐DNA was also found in 20.4% healthy subjects. The prevalence in the different subgroups was not statistically different. The genotypes were identified in 40 of the 62 (64.5%) TTV‐DNA positive samples: genotype 1a in 17.5%, 1b in 27.5%, genotype 2 in 27.5%, genotype 3 in 15.0%, genotype 4 in 5.0% and genotype 5 in 7.5%; the genotype distribution in the subsets of patients was not significantly different. In conclusion, this study showed that TTV infection is common in Italy; it is widespread throughout the entire population and five genotypes are present in Sardinia. Our results further dismiss the role of TTV as cofactor in influencing the clinical course of infections with other hepatitis viruses as well as the role of HIV in enhancing TTV transmission and replication.

Idiopathic adulthood ductopenia presenting with chronic recurrent cholestasis: A case report

The paucity of the intrahepatic bile ducts, also known as ductopenia, is a well recognized disorder in pediatric patients. Recently, however, a similar disorder has been reported in adults and termed idiopathic adulthood ductopenia (IAD). We describe a 30-year-old patient with a 15 year history of episodes of jaundice. During icteric episodes, serum levels of bilirubin and alkaline phosphatase were markedly elevated. Between attacks, totalling more than 30, the patient was asymptomatic, but bilirubin and alkaline phosphatase levels were mildly elevated. No neonatal jaundice was present in the patients history. PBC, PSC and drug-induced cholestasis were excluded. Two needle biopsies of the liver, taken within a 13 year interval, were available. The lobular architecture appeared progressively disturbed by porto-centro-portal bridging septa. In both biopsies, a destructive cholangitis was found. In the last biopsy, the majority of the septal and interlobular ducts appeared severely damaged and, in three out of seven portal tracts, the interlobular bile duct had disappeared. In the parenchyma, the main feature was a severe mainly canalicular bilirubinostasis. The patient described illustrates that IAD may have a clinical picture indistinguishable from benign recurrent intrahepatic cholestasis. The etiology of the disease, in this as in other patients, remains unknown.