Clot wave analysis and thromboembolic score in liver cirrhosis: two opposing phenomena.

INTRODUCTION: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are abnormal but unreliable in cirrhotic patients to express their risk of bleeding. However, these patients may also suffer from thrombotic episodes. In order to investigate the dynamics of the formation of fibrin, the clot waveform analysis (CWA) of aPTT was studied together with a score for the evaluation of the thromboembolic risk. METHODS: CWA in terms of velocity (1st derivative), acceleration (2nd derivatives) and density (Delta) of aPTT and the Padua Prediction Score (PPS) for venous thromboembolism were studied in 191 cirrhotic patients. RESULTS: CWA values were lower in the cirrhotic patients when compared to the control groups. However, Delta, 1st and 2nd derivatives were higher in cirrhotic patients with elevated PPS in comparison to those with a low PPS. The 1st derivative was significantly associated with a high PPS score (>4): OR: 2.66, CI: 95% 1.23-5.78. CONCLUSIONS: Two opposing tendencies seem to be present in cirrhotic disease: the first shows a weakness of clot formation while the second a predisposition towards thrombosis, identified by the PPS.

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.

Kayser-Fleischer ring in Wilson's disease: a cohort study.

AIMS: To evaluate Wilson's disease (WD) features in Sardinian patients with Kayser-Fleischer (KF) ring and to evaluate correlations between modifications in KF and anti-copper therapy and systemic WD evolution. PATIENTS AND METHODS: Sixty-seven WD patients (35 m/32 f; mean age 41 years) were retrospectively studied. At diagnosis and during follow up comprehensive ophthalmologic and neurologic examinations, brain RMN and ECD SPECT, detailed objective laboratory studies and hepatic histological examination were performed on all patients for analysis. All patients were given anti-copper therapy with d-Penicillamine in mono-therapy or in combination with Zinc Salts. RESULTS: At diagnosis, KF was observed in 27% of patients with equal distribution in all age groups. Significant correlations between KF at diagnosis, neuro-psychiatric manifestations and pathologic features in brain RMN and in brain ECD SPECT were found at diagnosis. During follow up, a decrease in, or regression of KF was seen in 14% of patients. Anti-copper therapy leads to KF regression and prevents the appearance of KF. No significant correlations were observed between KF regression and clinical neurological or neuro-imaging improvement nor between KF modifications and clinical hepatic improvement. CONCLUSIONS: Our study highlights the peculiar features of Sardinian WD patients: low representation of KF, its equal distribution in all age groups, significant correlation between KF at diagnosis and clinical neurological manifestations, pathologic brain RMN and brain ECD-SPECT are highlighted by our study. Anti-copper therapy induces KF regression and prevents its onset. Therefore, KF ring does appear to be a predictive factor in the neurological and hepatic evolution of WD.

[Late onset Wilson's disease]. / Morbo di Wilson ad esordio tardivo.

BACKGROUND: Wilson's disease (W.D.) is a metabolic disorder that occurs predominantly in children, adolescents, young adults and, rarely, in patients over 35 years. AIMS: In order to verify the prevalence of the clinical presentation of W.D. in adulthood, we analyzed a wide number of clinical presentation of W.D. with particular attention to the age of onset and to the evolutive stage of liver disease at presentation. PATIENTS: Our study is relative to 11 Sardinian adult subjects, aged 36-57 years, 6 males and 5 females, selected from a series of 120 patients affected by W.D. The only criterion utilized to select the patients was their age at presentation, with a cut off of 35 years. METHODS: Liver biopsies were routinely processed and stained with rhodanine, rubeanic acid, orcein and Timm's methods. On the basis of the histological picture, liver biopsies were subdivided into four evolutive stages: stage I = steatosis; stage II = interface hepatitis; stage III = bridging fibrosis; stage IV = cirrhosis. Molecular characterization of W.D. for gene mutations in the Sardinian population was performed in 7 out of 11 cases (-441/-427 del, 5' UTR and 3436 G > A Exon 16). RESULTS: 3 patients showed histological features of the first evolutive stage, 2 of the second, 1 of the third, and 5 of the fourth stage. Histochemistry for copper resulted positive in 9 of 11 cases at least with one of the four employed methods. In the seven patients in whom molecular characterization was perfomed, the gene mutation of W.D. was the same observed more frequently in the Sardinian population (-441/-427 del, 5'UTR). CONCLUSIONS: Our data show that: 1) W.D. with late onset is not rare in Sardinian population; 2) in spite of the late clinical presentation, W.D. may present in the first (3/10) and in the second evolutive stage (2/10) with mild to moderate changes of the liver architecture; 3) patients may show, at presentation, a severe liver disease, characterized by bridging fibrosis or cirrhosis; 4) from a practical point of view, we ask to consider the diagnosis the W.D. in all patients with chronic liver disease of unknown etiology, even if aged over 35 years.

A randomized controlled trial of amantadine plus interferon-alpha2a vs. interferon-alpha2a alone in naive patients with chronic hepatitis C randomized according to the early virological response to interferon-alpha2a monotherapy.

BACKGROUND: An early virological response to interferon-alpha treatment is a strong predictor of sustained response, but it has never been exploited to stratify patients in clinical trials. AIM: To evaluate the efficacy of amantadine plus interferon-alpha compared with interferon-alpha alone in naive patients with chronic hepatitis C who were randomized on the basis of the early virological response to interferon-alpha. METHODS: One hundred and eighty-one patients received recombinant interferon-alpha2a (3 MU three times weekly) for 2 months and 164 were evaluated for early (i.e. month 2) virological response. Hepatitis C virus (HCV) RNA-negative patients (n = 66) were randomized to receive 3 MU of interferon-alpha three times weekly, with or without amantadine (200 mg/day); HCV RNA-positive patients (n = 98) were randomized to receive 6 MU of interferon-alpha three times weekly, with or without amantadine (200 mg/day). HCV RNA-positive patients at 6 months discontinued treatment, and all others completed 12 months. RESULTS: At month 6, HCV RNA-negative patients made up 54.2% of the interferon + amantadine group and 42.0% of the monotherapy group (P = 0.07). At month 12, HCV RNA-negative patients made up 38.5% of the interferon + amantadine group and 28.4% of the monotherapy group (N.S.). The sustained virological response rates were 21.6% and 20.9%, respectively (N.S.). CONCLUSION: The addition of amantadine does not enhance the sustained virological response to interferon-alpha in naive patients with chronic hepatitis C; however, an additive effect of amantadine occurs in the first 6 months, mainly in patients without an early response to monotherapy. Early response to interferon-alpha is a strong predictor of sustained virological response.

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.

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 Wilson's disease. MATERIALS AND METHODS: Twenty-three patients with Wilson's 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.

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 Wilson's 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. METHODS AND RESULTS: Seventy-nine consecutive liver needle biopsies, from 74 patients, 39 males and 35 females, aged 4-60 years (mean age 28.5 years) were stained with orcein, rhodanine and using Timm's method. On the basis of the histological picture, liver biopsies were subdivided into three groups: group A, steatosis; group B, interface hepatitis; group C, chronic hepatitis with bridging fibrosis and/or cirrhosis. In group A, 30.4% of the cases were positive using Timm's method, vs 13.2% using the rhodanine and 17.5% using the orcein method. In group B, Timm's method was positive in 40.1% while rhodanine and orcein showed positivity in 26.7%. In group C, the Timm's method stained 58.6%, rhodanine 36.6% and orcein 29.3% positively. CONCLUSIONS: Our data show that: (1) Timm's silver stain is the most sensitive method for the demonstration of copper in all cases of WD; (2) rhodanine and orcein have minor value in the diagnosis of WD, especially in the early stages of the disease; (3) to increase the diagnostic value of histochemistry for copper multiple histochemical stains in serial sections are required; and (4) although hepatic copper concentration is highest in the early stages of WD, the histochemical demonstration fails in a large number of cases.

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 bio-chemical 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 (1b) 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.

Uneven hepatic copper distribution in Wilson's disease.

BACKGROUND/AIMS: Determination of hepatic copper concentration is important in the diagnosis of Wilson's disease. We studied copper distribution in the cirrhotic liver of a patient who died of Wilson's 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 Wilson's 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 Wilson's 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.

Predictive testing for Wilson's disease using tightly linked and flanking DNA markers.

We studied DNA polymorphisms for five new chromosome 13 markers in 52 Wilson's disease (WD) families from Europe, North America, and the Middle East. There was significant evidence for linkage between the Wilson's disease locus (WND) and all the marker loci. Multilocus linkage analysis, using a genetic linkage map established from reference pedigrees, suggested that WND is most likely between D13S31 and D13S59, at distances of 0.4 and 1.2 centimorgans, respectively. Our results suggest that the chromosomal location of the Wilson's disease gene is the same in all families from the populations studied. This evidence and the availability of many close, flanking, and polymorphic DNA markers make possible accurate and informative testing of potential carriers and WD homozygotes in families with at least one previously affected child. An advantage of a genetic linkage test over other laboratory methods for prediction of genotype in WD is that a reliable diagnosis can be made at a much earlier stage in life, including prenatally. In addition, DNA testing can be used in place of an invasive liver biopsy procedure to confirm a diagnosis in patients with borderline serum ceruloplasmin levels. Presymptomatic identification will also allow therapeutic intervention to prevent symptoms before irreparable liver or neurologic damage occurs. We describe the implementation of prenatal and preclinical diagnosis for two families with WD.

[Hypothalamo-pituitary-adrenal function in liver cirrhosis of viral etiology]. / Studio della funzione ipotalamo-ipofiso-surrenalica nella cirrosi epatica di origine virale.

With the aim of evaluating the glucocorticoid function and the role of the adrenal gland in hypogonadism and feminization of cirrhotic patients, we examined 11 patients with virus-induced liver cirrhosis and 8 normal subjects as controls. In each subject serum levels of cortisol (C), progesterone (P), dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulphate (DHEAS), delta 4-androstenedione (A), estrone (E1), testosterone (T), luteinizing hormone (LH) were assayed in basal conditions and after adrenocorticotropic hormone (ACTH) stimulation. Serum levels of ACTH, C, E1, estradiol (E2), T were assayed in basal condition and after dexamethasone suppression test. Moreover, a circadian study of ACTH, C and corticosteroid-binding globulin (CBG) was performed, with blood samples drawn at 8:00 and 20:00 on two consecutive days. Our results demonstrate that in cirrhosis: 1) normal levels of C, when metabolism is altered and CBG levels are reduced, are maintained by inhibition of ACTH secretion; 2) circadian rhythmicity of the pituitary-adrenal axis is well preserved; 3) in non-alcoholic cirrhosis, too, there is a reduction of androgens (T, DHEA, DHEAS, A) and a rise of estrogens (E2 and, more markedly, E1) and P; 4) in cirrhotic men E1 is mainly of adrenal origin and contributes, through negative feedback on LH secretion, to low levels of T.

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 patient's 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.

Epidemiologic study of hepatolenticular degeneration (Wilson's disease) in Sardinia (1902-1983).

From 1902 to 1983, 68 cases of hepatolenticular degeneration (HLD) were discovered in Sardinia, with a mean frequency, in reference to number of live births, of 27.7 and a sex ratio of 1.83. The prevalence of the disease was seen to be higher over the last few decades. With regard to the geographic distribution of the disease, 3 high-frequency areas were evident, in Barbagia, in Campidano, and in the area surrounding the city of Sassari. In 38.23% of cases, the clinical picture was of hepatoneurologic type; hepatic forms have become more frequent over the last decades. The first symptoms were observed at mean age of 15 years 8 months. The number of asymptomatic cases was fairly consistent (22.05%). The median survival rate in subjects who received inadequate therapy was 6 years 4 months. Only 3 patients of the 45 treated with adequate therapy died. The gene frequency, calculated by the application of Dahlberg's formula, was extremely high.

alpha 2 Antiplasmin and disseminated intravascular coagulation in liver cirrhosis.

Subnormal concentrations of alpha 2 Antiplasmin (alpha 2 AP) in liver cirrhosis may be due to an impaired hepatic synthesis and/or to a fibrinolysis activation in disseminated intravascular coagulation (DIC). In order to clarify this problem, in 26 cirrhotic patients (15 compensated and 11 decompensated) alpha 2 AP plasma activity and plasma Fibrinopeptide A (FPA) were measured. Serum albumin, p-Cholinesterase (p-CHE), Fibrinogen and Fibrinogen Degradation Products (FDP) were also carried out. Our data show that alpha 2 AP and FPA were equally abnormal in compensated and decompensated cirrhosis. The significant negative correlation obtained between alpha 2 AP and FPA as well as the lack of correlation between alpha 2 AP and albumin, alpha 2 AP and p-CHE in both groups suggests that, in our patients, alpha 2 AP decrease may be due to a fibrinolysis activation induced by a DIC which appears chronic since Fibrinogen and FDP were normal. These findings are in agreement with the results obtained in the four subgroups a posteriori selected on the basis of FPA levels: alpha 2 AP in subgroups with high FPA was significantly different from controls while it did not differ in subgroups with normal FPA.

Computerized cranial tomography in presymptomatic and hepatic form of Wilson's disease.

Computerized cranial tomography was performed in 14 patients affected with hepatolenticular degeneration (4 presymptomatic and 10 with a hepatic form). 1 case showed brain stem atrophy with atypically located hypodense areas and another subject showed frontal atrophy with prevalence to the right side. The abnormalities found in another 7 cases were slight. In 5 patients, CT was normal.