Long-Term Correction of Copper Metabolism in Wilson's Disease Mice with AAV8 Vector Delivering Truncated ATP7B.

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by mutations in the ATP7B gene encoding a liver active copper transport enzyme. Gene therapy with adeno-associated virus (AAV) carrying full-length ATP7B, which is about 4.4 kb, was shown to rescue copper metabolism disorder in WD mouse model. However, due to its relatively large size, the AAV vector containing full-length ATP7B could be oversized for its packaging capacity, which could lead to inefficient packaging. To this purpose, we engineered a truncated ATP7B mutant (tATP7B) that is about 3.3 kb in length and used for AAV gene therapy for WD mice. In vitro test showed that the excretion of copper outside the cells could be achieved with tATP7B as efficient as the full-length ATP7B. In vivo delivery of tATP7B to WD mice by AAV8 vectors corrected their copper metabolisms and significantly rescued copper accumulation-related syndromes, including reduced urinary copper excretion, increased serum ceruloplasmin, and improved liver damages. Thus, our study demonstrated that AAV gene therapy based on truncated ATP7B is a promising strategy in the treatment of WD.

Genomic analysis of enterovirus D68, including one strain isolated from a child with Wilson's disease in Taiwan.

North America experienced life-threatening outbreaks of enterovirus D68 (EV-D68) in 2014. We retrospectively detected EV-D68 from a child with Wilson's disease in 2008 in Taiwan. After comparing this EV-D68/Taiwan/2008 strain with EV-D68 genomes obtained from the public domain, it was classified as genome type 1-B; it is phylogenetically related to the predominant EV-D68 viruses that circulated in 2009 in Vietnam. It is necessary to strengthen EV-D68 detection globally, including in children with acute liver failure. Moreover, harmonization of genomic analysis of EV-D68 is desirable to understand global evolution of EV-D68.

Acquired hepatocerebral degeneration in a patient with hepatitis B and hepatitis delta virus coinfection.

Acquired hepatocerebral degeneration is a neurological syndrome with typical clinical (extrapyramidal and neuropsychiatric) symptoms and brain magnetic resonance imaging findings (high T1 signal in the globus pallidus). It occurs mainly in patients with advanced liver disease, such as in patients co-infected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). However, there are no reports relating HBV/HDV coinfection and acquired hepatocerebral degeneration. This report presents the case of a 49-year-old woman with characteristics of acquired hepatocerebral degeneration and liver cirrhosis due to HBV/HDV coinfection, and presents the main theories of the physiopathology of this condition.

Acquired hepatocerebral degeneration in a patient with hepatitis B and hepatitis delta virus coinfection

Abstract Acquired hepatocerebral degeneration is a neurological syndrome with typical clinical (extrapyramidal and neuropsychiatric) symptoms and brain magnetic resonance imaging findings (high T1 signal in the globus pallidus). It occurs mainly in patients with advanced liver disease, such as in patients co-infected with hepatitis B virus (HBV) and hepatitis delta virus (HDV). However, there are no reports relating HBV/HDV coinfection and acquired hepatocerebral degeneration. This report presents the case of a 49-year-old woman with characteristics of acquired hepatocerebral degeneration and liver cirrhosis due to HBV/HDV coinfection, and presents the main theories of the physiopathology of this condition.

Fulminant liver failure in Wilson's disease with histologic features of postinfantile giant cell hepatitis; cytomegalovirus as the trigger for both?

Giant cell hepatitis is a well-known histological feature of several neonatal and infantile liver diseases. In contrast, postinfantile giant cell hepatitis is rarely identified in adult liver biopsies. It has been associated with varying etiologies, mainly viral infections, drug toxicity, and autoimmunity. Here, we report an 18-year-old, previously healthy man with acute liver failure, who showed giant cell hepatitis in a liver biopsy. There was no evidence of viral hepatitis A-E, autoimmunity, and no drug history. Diagnostic work-up revealed Wilson's disease as the underlying disease. As syncytial giant cell formation is thought to be a uniform reaction pattern not related to any specific etiology, copper toxicity in Wilson's disease might cause giant cell formation. In contrast, our patient recalled a recent cytomegalovirus infection, which was confirmed serologically. Therefore, the giant cell formation might also be a fingerprint of an intercurrent cytomegalovirus infection as the common trigger for both giant cell hepatitis and decompensation of Wilson's disease.

Mouse mammary tumour virus-like virus (MMTV-LV) is present within the liver in a wide range of hepatic disorders and unrelated to nuclear p53 expression or hepatocarcinogenesis.

BACKGROUND/AIMS: The human equivalent of mouse mammary tumour virus (MMTV-LV) may have a role in the pathogenesis of primary biliary cirrhosis (PBC) and breast carcinogenesis. We investigated MMTV-LV prevalence in patients with liver disease of diverse aetiology and associations with hepatic expression of hormonal receptors, p53 protein and complicating hepatocarcinogenesis. METHODS: Nested PCR for MMTV-LV envelope was performed using tissue from 210 patients with liver disease and 20 patients with histologically normal liver. Hepatic expression of estrogen receptor-alpha (ER-alpha), progesterone receptor (PgR) and p53 protein was determined by immunohistochemistry. MMTV-LV expression was also determined in hepatocellular carcinoma (HCC) tissue from 21 patients, in 11 of whom paired non-tumourous liver tissue was available for comparison. RESULTS: MMTV-LV envelope sequences were present in 25% (53/210) of liver disease biopsies but not in histologically normal liver (0/20) (P=0.02). There was no association between MMTV-LV presence and hepatic expression of ER-alpha or p53 protein. No liver sections were PgR positive. MMTV-LV prevalence was not significantly different in HCC tissue, paired non-tumourous chronic liver disease tissue from the same patients and liver disease tissue from patients without complicating HCC. CONCLUSIONS: Hepatic expression of MMTV-LV is evident in a wide range of non-cirrhotic and cirrhotic liver diseases, irrespective of ER-alpha, PgR or p53 status, and unrelated to complicating HCC.

Acquired hepatocerebral degeneration in a patient with HCV cirrhosis: complete resolution with subsequent recurrence after liver transplantation.

Acquired (non-Wilsonian) hepatocerebral degeneration (AHD) is a chronic brain disorder caused by liver dysfunction and long-standing portal-systemic shunting. It typically presents with dysathria, ataxia, tremor, involuntary movements and altered mental status, and often does not respond to conventional medical therapy for hepatic encephalopathy. There is scarce and conflicting information regarding the clinical course of AHD after liver transplantation (OLT). We present a case of a 47-year-old woman with hepatitis C (HCV) cirrhosis who developed severe manifestations of AHD after multiple bouts of hepatic encephalopathy. Her first OLT was complicated with primary nonfunction requiring immediate retransplantation. The second OLT led to complete clinical and radiological resolution of the AHD. However the patient developed recurrence of AHD 11 months post-transplant due to recurrent HCV and chronic rejection leading to cirrhosis of the graft. The patient developed severe neurological symptoms, despite mild synthetic graft dysfunction. A third OLT led again to disappearance of the clinical and radiological manifestations of AHD. AHD may show complete resolution after OLT; however it may rapidly recur following recurrent liver disease or graft dysfunction.

Prevalence of GB virus-C/hepatitis G virus infection in patients with cryptogenic chronic liver disease and in patients with primary biliary cirrhosis or Wilson's disease.

OBJECTIVE: To assess the role of hepatitis G virus (HGV) in cryptogenic chronic liver disease (CLD), we investigated the prevalence of HGV RNA among patients with cryptogenic CLD, patients with nonviral CLD (primary biliary cirrhosis [PBC] and Wilson's disease [WD]) and subjects without clinically evident liver disease (controls). METHODS: Ninety patients with cryptogenic CLD (43 with chronic hepatitis, 20 with cirrhosis, and 27 with hepatocellular carcinoma [HCC]), 143 patients with PBC, 22 patients with WD, and 134 controls were recruited. HGV RNA was detected by reverse transcription-polymerase chain reaction (RT-PCR) and antibodies against HGV E2 protein (anti-E2) by an immunoassay test. RESULTS: HGV RNA was detected in 7.8% of patients with cryptogenic CLD (chronic hepatitis, 9.3%; cirrhosis, 5.0%; HCC, 7.4%), in 2.4% of patients with PBC or WD, and in 2.2% of controls. As a consequence, a positive association of HGV infection with cryptogenic CLD was found (odds ratio, 3.1; 95% confidence interval [CI], 1.0-9.7; p = 0.05). No difference was observed between HGV RNA-positive and -negative patients by age, sex, histology, or liver function tests. Anti-E2 prevalence did not differ between patients with cryptogenic CLD (26.5%), patients with PBC (28.1%), and controls (22.1%). Transfusion history was associated with HGV RNA but not with anti-E2 seropositivity. CONCLUSIONS: Although an association was found between cryptogenic CLD and HGV infection, the role of the virus seems far from important, the proportion of cryptogenic CLD attributable to it being only 5.2%.