FHF, fulminant hepatic failure; EIA, enzyme immune assay; RT-PCR, real-time polymerase chain reaction.
Hepatitis-Associated Aplastic Anaemia
Hepatitis-associated aplastic anaemia (HAAA) is a syndrome in which an episode of hepatitis not linked to a major hepatotropic virus precedes the onset of severe anaemia due to bone marrow failure, possibly mediated by immunological mechanisms such as interferon-γ or the cytokine cascade. Although HAAA is a rare event, it occurs in 28% of young adults after liver transplantation for non-A–E hepatitis. Parvovirus B 19 has been isolated from the liver and the bone marrow of patients, mostly children, with HAAA, but its causal role is not established [1].
HAAA may be treated by immunosuppression with a response of 70% but relapses are frequent after treatment withdrawal and haematopoietic cell transplantation, with a reported survival of 82%.
Hepatotropic Viruses
Flaviviridae Other Than HCV
GB Virus C/ Hepatitis G Virus
Virology, Pathogenesis and Diagnosis
GB virus C (GBV-C) and hepatitis G virus (HGV) were described independently by Linnen et al. [2] and by Simons et al. [3] in patients with non-A–E hepatitis and were initially considered separate major aetiological agents of hepatitis. Sequence comparison of GBV-C and HGV subsequently showed them to be different isolates of one viral species, bearing a nucleotide and amino acid homology of 86 and 96%, respectively [4]. It is now referred to as GBV-C.
Based on sequence relatedness and overall genome structure, GBV-C is classified in the Flaviviridae family, like HCV and yellow fever virus (YFV). It has a linear, single-stranded RNA with positive polarity, containing approximately 9400 nucleotides, and one open reading frame (ORF), encoding a polyprotein of approximately 2840 amino acids. The GBV-C genome is similar to HCV in its organization. The ORF of GBV-C has a 30% amino acid sequence homology with HCV, with the greatest similarity in the NS3 and NS5b regions.
GBV-C is primarily a lymphotropic agent, which replicates in the bone marrow and spleen [5] but also in peripheral blood mononuclear cells and in the vascular endothelial cells [6]. Despite its association with hepatitis of unknown aetiology, the hepatotropism of GBV-C has been questioned [7]. Overall, it seems that GBV-C can replicate in the liver in a small proportion of infected patients and cause minor and transient liver damage.
Detection of GBV-C infection is performed by testing for antibodies against the E2 glycoprotein of GBV-C (anti-E2 antibodies) with an enzyme immunoassay. Confirmation of an active GBV-C infection is based on detection of viral genome by nested real-time polymerase chain reaction (RT-PCR) [8].
GBV-C viraemia may persist for years without hepatitis or other specific disease. However, spontaneous clearance of the virus occurs in 60 to 75% of immunocompetent subjects with seroconversion to anti-E2 antibodies. Most healthy individuals and patients with non-A–E acute hepatitis who are anti-GBV-C E2 positive are GBV-C RNA negative. Overall, the development of anti-E2 is an indication of previous infection and immunity.
Epidemiology
GBV-C infection has a worldwide distribution, with a prevalence 10-fold higher in African than in non-African countries. Phylogenetic analysis of GBV-C isolates demonstrated six genotypes [9,10].
The detection rate of GBV-C viraemia among healthy blood donors averages 2% (0.9–5.3%). Prevalence rates of anti-E2 antibodies (between 3.0 and 42.1% in different countries) are much higher than those of viraemia. Transmission via the blood-borne route and through sexual intercourse is the most common, although less frequently mother to child transmission occurs. High rates of active GBV-C infection are found in subjects with repeated parenteral exposures such as intravenous drug users (13 to 35%), in groups at high risk of exposure to blood and blood products (3.1 to 55% of patients on haemodialysis, 14 to 28% of those with haemophilia) and in sexually promiscuous individuals (13 to 63% of male homosexuals, 14 to 25% of female prostitutes).
Due to the common pathways of transmission, GBV-C RNA is also detected frequently among anti-HCV positive individuals, with a rate of coinfection of approximately 20%. The prevalence of GBV-C coinfection in patients infected with human immunodeficiency virus (HIV) varies between 14 and 45%, with a higher rate in male homosexuals and drug abusers [11].
Interaction with HIV
A first report [12] in a cohort of HIV-infected haemophilia patients suggested an improved survival in patients coinfected with GBV-C. Others studies have confirmed that coinfection with GBV-C and HIV is linked to a better outcome of HIV infection in terms of reduction in mortality rates and disease progression, together with higher CD4 cell counts and lower HIV viral load, independent of sex, age or race. Tillmann et al. [13] found that GBV-C viraemia was associated with better survival even after the development of acquired immunodeficiency syndrome (AIDS) and continued to be predictive of longer survival after the introduction of highly active antiretroviral therapy, and showed an inverse correlation between GBV-C and HIV viral loads. More recently, Williams et al. [14] found that GBV-C infection was detected in 85% of HIV-infected men in the Multicenter AIDS Cohort Study, and was associated with longer survival. Loss of GBV-C viraemia was a strong predictor of death, suggesting that survival benefit was dependent on the persistence of GBV-C viraemia in HIV-infected patients.
GBV-C may interact with HIV through a mechanism of viral interference. Other possible mechanisms could be the up-regulation of T-helper 1 (Th1) cytokine, down regulation of T-helper 2 (Th2) cytokine [15] or inhibition of the entry of HIV into target cells [16].
Clinical Features
Although acute GBV-C infection rarely becomes chronic, the duration of GBV-C infection probably depends on the immune status of the host. Childhood acquisition of GBV-C commonly evolves into chronic infection, whereas sexual transmission in immunocompetent adults usually leads to rapid clearance of the virus [17]. HIV-infected subjects are less likely to clear GBV-C [18].
An active GBV-C infection can be detected in a high proportion of patients with non-A–E acute or chronic hepatitis, but no convincing evidence linking it directly to liver damage is available, regardless of the immune status of the patients [19,20].
Patients with chronic hepatitis B [21] or chronic hepatitis C [22] have a comparable severity of liver disease and response to treatment regardless of their GBV-C status. Similarly, the outcome of liver transplantation for hepatitis C is not affected by GBV-C [23].
No association between GBV-C and hepatocellular carcinoma has ever been reported.
Yellow Fever Virus (YFV)
Epidemiology and Viral Features
Yellow fever is a life-threatening, mosquito-borne flaviviral haemorrhagic fever characterized by severe hepatitis, renal failure, haemorrhage and rapid terminal events with shock and multiorgan failure [24–26]. Before the development of an effective vaccine it was among the most feared infectious diseases, and still affects as many as 200 000 persons annually in the two endemic regions of South America and equatorial Africa.
Yellow fever is transmitted in a cycle involving monkeys and mosquitoes in the jungle variety, but human beings can also serve as the viraemic host for mosquito infection in urban yellow fever. Recent increases in the density and distribution of the urban mosquito vector, Aedes aegypti, as well as the rise in air travel increase the risk of introduction and spread of yellow fever to North and Central America, the Caribbean and Asia.
YFV has a single serotype but, at the genome level, five genotypes can be distinguished (three in Africa and two in South America). The YFV positive-sense, single-stranded RNA genome contains a single open reading frame of 10 233 nucleotides, encoding three structural and seven non-structural proteins. The viral envelope (E) protein attaches to cell receptors and is a principal target for the immune response.
Pathology and Pathogenesis
The hepatic injury of yellow fever has a typical midzonal pattern, with sparing of hepatocytes around the central vein and portal tracts. This could reflect low-flow hypoxia due to shock, but YFV antigens and YFV RNA have been observed principally in hepatocytes in the midzone, suggesting that these cells are most susceptible to virus infection. The infected hepatocytes undergo apoptotic cell death signalled by eosinophilic degeneration with condensed nuclear chromatin (Councilman bodies). Cell death by apoptosis rather than necrosis explains the reduced number of inflammatory cells in YFV hepatitis and the preservation of the reticulin framework. Intranuclear inclusions (Torres bodies) are diagnostic. With recovery, regeneration is complete without chronicity.
The pathogenesis of hepatic damage in YFV infection is controversial. Hypotension and shock mediated by cytokine dysregulation may cause ischaemic damage. Tumour necrosis factor-α (TNF-α) and other cytokines produced by Kupffer cells and splenic macrophages in response to direct virus injury and cytotoxic T cells involved in viral clearance might be responsible for hepatocyte injury.
Clinical Features and Diagnosis
Following an incubation period of 3–6 days, onset is sudden with fever, chills, headache, backache, prostration and vomiting, often of altered blood. The blood pressure falls, haemorrhages become widespread, jaundice and albuminuria are conspicuous and there is a relative bradycardia. Delirium proceeds to coma and death may occur within 9 days. With recovery, the temperature becomes normal and convalescence progresses rapidly. There are no sequelae and life-long immunity follows. The majority of infections are probably milder, with no detectable jaundice and only a few constitutional symptoms.
Laboratory confirmation is by demonstrating specific IgM antibodies to YFV. Yellow fever antigen may be detected in formalin-fixed, paraffin-embedded tissue cut from blocks made as long as 8 years before [27].
Prevention and Treatment
Prevention consists of vaccination at least 10 days before arrival in an endemic area and by control of mosquitoes. A live, attenuated vaccine (YF 17D) has been in use for over 60 years but may cause a disease identical to wild-type virus at an incidence of 1 in 2.5 million [28].
Death in patients with YFV results principally from renal damage. The hepatic lesion is self-limited and short-lived and does not require special treatment. Some antivirals [26] have been evaluated but none have been shown to be effective. Studies on specific inhibitors of flaviviruses proteases and polymerases or with viral entry and assembly inhibitors are in progress.
The ‘cytokine storm’ represents also a potential target for therapeutic interventions with specific monoclonal antibodies.
Circoviridae: Torque Teno Virus (TTV) and Others
Virology, Pathogenesis and Diagnosis
The prototypic agent in this group was isolated in 1997 [29] from the blood of a Japanese patient with post-transfusion hepatitis of unknown aetiology, and was called TT virus (TTV) after the patient’s initials. TTV is now know as torque teno virus, from the Latin torques (necklace) and teno (thin), thus maintaining the initial denomination TTV. It was the first human virus found to have a single-stranded circular DNA genome and was classified in the family Circoviridae, genus Anellovirus.
The TTV genome consists of a negative, single-stranded DNA with a circular structure and a total genomic length of approximately 3.8 kb. After the description of the original TTV isolate, many TTV-like variants were found in humans and were classified into five major phylogenetic groups (group 1 to 5), including SEN, Sanban and Yonban viruses. In 2000, Takahashi et al. [30] discovered a new group of viruses with a single-stranded, circular DNA that were termed TTV-like mini virus (TTMV), because of a genomic size of less than 2.9 kb. Later, two new TTV-like viruses were isolated from the blood of patients with acute viral infections and named small anellovirus 1 (SAV1) and small anellovirus 2 (SAV2) [31]. Finally, Ninomiya et al. [32] in 2007 isolated another agent with a genomic organization akin to that of TTV and TTMV and a full-length genome of 3.2 kb that was named torque teno midi virus (TTMDV).
The heterogeneous TTV group, including TTMV and TTMDV, is characterized by an extreme genetic diversity, not only due to genetic evolution but also to recombination between related isolates. Despite a marked divergence, there is a specific region of 130 nucleotides that is highly conserved, allowing the development of a PCR assay which can detect all members of the TTV group [33].
Infection with TTV is characterized by lifelong viraemia in up to 80% of subjects. Antibodies against TTV virions or recombinant ORF1 protein are detected in viraemic and non-viraemic individuals, suggesting that the humoral immune response is inadequate to clear the virus. The tissue tropism of TTV is rather broad. TTV genomes can replicate in the liver, bone marrow, spleen, lung and peripheral blood mononuclear cells.
Epidemiology and Pathogenesis
TTV, TTMV and TTMDV infection have a worldwide distribution. Ninomiya et al. [33] reported extremely high prevalence rates of viraemia for TTV (100%), TTMV (82%) and TTMDV (75%) in the general population in Japan. The prevalence of TTV, TTMV and TTMDV infection increases with age and dual or triple infection is common. The detection of TTV and TTMV genomes in saliva, faeces and breast milk strongly suggest that the human Anelloviridae are transmitted by a horizontal route during early childhood.
TTV was originally described as a hepatitis agent. Shibata et al. [34] reported that TTV genotype 1 might be a cause of non-A, non-C fulminant hepatic failure. Japanese [35] and French researchers [36] found a direct relation between TTV infection, TTV viral load and various liver diseases but these findings were not confirmed by other investigators [37–40]. Although TTV is known to replicate in the liver, it does not fulfil the criteria for being a hepatitis virus, such as direct causal association between hepatic necroinflammation and TTV replication or an epidemiological association with acute or chronic liver disease [41]. There is even less evidence for hepatic pathogenicity of the other viral agents in this group.
Systemic Viral Infections that Often Cause Transient Liver Involvement
Herpesviridae: EBV, CMV, HSV, VZV
Epstein–Barr Virus
Epidemiology and Clinical Features
The Epstein–Barr virus (EBV), a member of the Gammaherpesvirinae subfamily, infects more than 90% of the world’s population, thus representing one of the most prevalent human viral infections. EBV excites a generalized reticuloendothelial reaction [42] and causes infectious mononucleosis. Although mortality is minimal, liver failure is the cause of death in about half of the patients with fatal infectious mononucleosis [43].
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