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There is a veritable alphabet soup of hepatitis viruses. Hepatitis D or delta agent is a defective RNA virus which requires co-infection with hepatitis B virus. It is covered in the hepatitis B section. Hepatitis E is a water-borne infection, similar to hepatitis A. Hepatitis G has been described as a "virus looking for a disease". It is unclear of its role in the liver.


Histopathological Features and Variants

Hepatitis E
Hepatitis G
Hepatitis TTV

Additional Variants Alcoholic
Commonly Used Terms  
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Hepatitis E virus: a global view of its seroepidemiology and transmission pattern.

Irshad M.

Department of Laboratory Medicine, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, India.

Trop Gastroenterol 1997 Apr-Jun;18(2):45-9 Abstract quote

Hepatitis E virus (HEV) infection causes epidemic outbreaks as well as sporadic disease in many parts of the world. It has been detected in travellers from endemic regions and also in native citizens of developed countries. In contrast to epidemics where predominantly adults are infected, HEV is found to be a common cause of acute sporadic hepatitis in children as well. A high incidence of HEV infection has been noted in pregnant ladies. Further, HEV has an association with other hepatotropic viruses and induces fulminant hepatic failure both with and without the simultaneous presence of other viruses.

Transmission of HEV occurs predominantly by the faeco-oral route. However, the parenteral route has also been implicated. There is evidence to suggest vertical transmission of HEV via the intrauterine and perinatal routes. However, a number of questions remain unanswered.

The available data do not explain the occurrence of HEV infection predominantly in adults during epidemics, possibility of contact transmission and means of protection against this infection. More detailed studies are needed to provide the actual status of HEV epidemiology in different parts of the world.

Seroepidemiology of hepatitis E virus infection in Mexican subjects 1 to 29 years of age.

Alvarez-Munoz MT, Torres J, Damasio L, Gomez A, Tapia-Conyer R, Munoz O.

Unidad de Investigacion Medica en Enfermedades Infecciosas, Instituto Mexicano del Seguro Social (IMSS), D.F., Mexico.

Arch Med Res 1999 May-Jun;30(3):251-4 Abstract quote

BACKGROUND: Hepatitis E virus (HEV) infection causes an acute, self-limited hepatitis associated with high mortality in pregnant women. Community-based surveys are scarce and information on HEV infection in populations is needed. The aim of this work was to study seroprevalence to HEV in young adults and children in Mexico, using a community-based survey.

METHODS: Serum samples from 3,549 individuals were studied; the population included subjects from 1 to 29 years old from all regions of the country representing all socioeconomic levels. IgG anti-HEV was determined by ELISA.

RESULTS: Anti-HEV antibodies were found in 374 (10.5%) individuals. Seroprevalence increased with age from 1.1% in children younger than 5 years to 14.2% in persons 26 to 29 years of age (p = 0.006). Risk factors for infection included living in rural communities and a low educational level. Seroprevalence was not associated with the level of regional development.

CONCLUSIONS: HEV infection is endemic in Mexico. Age, type of community, and educational level were identified as risk factors for infection.

Hepatitis E virus infection in travelers.

Schwartz E, Jenks NP, Van Damme P, Galun E.

Sheba Medical Center, Tel-Hashomer, and the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel.

Clin Infect Dis 1999 Nov;29(5):1312-4 Abstract quote

Hepatitis E virus (HEV) is a major cause of clinical hepatitis in regions of endemicity, affecting primarily young adults and travelers to these areas. We present 5 cases of acute HEV infection in travelers and review 143 cases of HEV infection found by a literature search that were contracted in areas of endemicity. Fulminant hepatitis occurred in 2.7% of the reported cases; 2 of these were fatal. The destination of most of the travelers with acute HEV infection was the Indian subcontinent.

The overall risk of contracting HEV infection for travelers appears to be lower than the risk for hepatitis A virus infection. Pregnant women and individuals with underlying liver disease may be a risk for severe infection.

Novel hepatitis E virus (HEV) isolates from Europe: evidence for additional genotypes of HEV.

Schlauder GG, Desai SM, Zanetti AR, Tassopoulos NC, Mushahwar IK.

Virus Discovery Group, Abbott Laboratories, North Chicago, Illinois 60064, USA.

J Med Virol 1999 Mar;57(3):243-51 Abstract quote

Hepatitis E infection is associated with areas in which hepatitis E virus (HEV) infection is endemic. Acute infections in industrialized nations are usually linked to travel to endemic areas. Recently, an acute hepatitis infection in a patient from the United States (US), with no recent foreign travel history, was linked to a novel strain of HEV. Although a few additional cases have been reported from patients who have not traveled to endemic areas, the source of these infections has not been determined.

The objective of this study was to identify additional HEV isolates from patients with acute infection who had no recent history of travel to areas where HEV is considered endemic, and to determine the genetic relationship between these and other HEV isolates.

Viral RNA was isolated from serum and polymerase chain reaction (PCR) was performed using consensus primers based on a number of HEV isolates. HEV sequence in open reading frame (ORF) 1 and ORF2 was identified in three patients from nonendemic areas, one from Italy and two from Greece. Comparative and phylogenetic analyses were performed. The Greek and Italian isolates were significantly divergent from two isolates from the US and isolates identified previously from HEV-endemic regions. The Italian isolate was distinct from the two Greek isolates. In addition, the two Greek isolates were significantly divergent from each other. Phylogenetic analysis indicated that the Italian and two Greek isolates represent three new genotypes of HEV, distinct from the Burmese, Mexican, and US genotypes.

Prevalence of hepatitis E antibodies in immigrants from developing countries.

Tarrago D, Lopez-Velez R, Turrientes C, Baquero F, Mateos ML.

Microbiology Department, Hospital Ramon y Cajal, Madrid, Spain.

Eur J Clin Microbiol Infect Dis 2000 Apr;19(4):309-11 Abstract quote

The aim of the present study was to investigate the prevalence of anti-hepatitis E virus (HEV) antibodies among indigenous Spanish blood donors and immigrants from developing countries in order to determine whether immigrants pose a significant risk for the transmission of HEV to the healthy Spanish population.

The seroprevalence of HEV was determined in a cohort of 90 asymptomatic immigrants (mostly from countries in sub-Saharan Africa) who had recently arrived in Madrid, Spain, and in 863 blood donors, who represented the healthy Spanish population. The results showed that the prevalence of HEV antibodies was 1.9 times higher in the immigrants than in the blood donors (5.5% in immigrants, 95% CI 1.8-12.4; 2.9% in blood donors, 95% CI 1.9-4.2).

Combined with the estimated population figures of 300,000 undocumented immigrants versus 39,000,000 Spaniards, these results indicate that sub-Saharan immigrants cannot currently be considered a major risk source for the transmission of HEV in Spain.

Hepatitis E: an overview and recent advances in clinical and laboratory research.

Aggarwal R, Krawczynski K.

Hepatitis Branch, Division of Viral and Rickettsial Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.

J Gastroenterol Hepatol 2000 Jan;15(1):9-20 Abstract quote

Hepatitis E virus (HEV) is a non-enveloped RNA (7.5 kb) virus that is responsible for large epidemics of acute hepatitis and a proportion of sporadic hepatitis cases in southeast and central Asia, the Middle East, parts of Africa and Mexico.

Hepatitis E virus infection spreads by the faecal-oral route (usually through contaminated water) and presents after an incubation period of 8-10 weeks with a clinical illness resembling other forms of acute viral hepatitis. Clinical attack rates are the highest among young adults. Asymptomatic and anicteric infections are known to occur. Chronic HEV infection is not observed. Although the mortality rate is usually low (0.07-0.6%), the illness may be particularly severe among pregnant women, with mortality rates reaching as high as 25%. Recent isolation of a swine virus resembling human HEV has opened the possibility of zoonotic HEV infection.

Studies of pathogenetic events in humans and experimental animals reveal that viral excretion begins approximately 1 week prior to the onset of illness and persists for nearly 2 weks; viraemia can be detected during the late phase of the incubation period. Immunoglobulin M antibody to HEV (anti-HEV) appears early during clinical illness but disappears rapidly over a few months. Immunoglobulin G anti-HEV appears a few days later and persists for at least a few years. There is no specific treatment available for hepatitis E virus infection. Ensuring a clean drinking water supply remains the best preventive strategy.

Recombinant vaccines are being developed that may be particularly useful for travellers to disease-endemic areas and for pregnant women.

Recombinant vaccines for hepatitis E.

Emerson SU, Purcell RH.

Molecular Hepatitis and Hepatitis Viruses Sections, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 20892, Bethesda, Maryland, USA

Trends Mol Med 2001 Oct;7(10):462-6 Abstract quote

Hepatitis E virus causes epidemics of acute hepatitis in many developing countries. It infrequently causes disease in developed countries, but avirulent strains might circulate. Some evidence suggests that hepatitis E might be a zoonosis.

There is probably only a single serotype. A candidate vaccine consisting of baculovirus-expressed recombinant capsid protein protected macaques from hepatitis E - it passed phase I clinical trials and is currently scheduled for phase II/III clinical trials.

Acute hepatitis caused by a novel strain of hepatitis E virus most closely related to United States strains.

Kabrane-Lazizi Y, Zhang M, Purcell RH, Miller KD, Davey RT, Emerson SU.

Hepatitis Viruses and Molecular Hepatitis Sections, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA.

J Gen Virol 2001 Jul;82(Pt 7):1687-93 Abstract quote

A unique hepatitis E virus (HEV) strain was identified as the aetiological agent of acute hepatitis in a United States (US) patient who had recently returned from vacation in Thailand, a country in which HEV is endemic.

Sequence comparison showed that this HEV strain was most similar, but not identical, to the swine and human HEV strains recovered in the US. Phylogenetic analysis revealed that this new HEV isolate was closer to genotype 3 strains than to the genotype 1 strains common in Asia.

The fact that this HEV was closely related to strains recovered in countries where HEV is not endemic and was highly divergent from Asian HEV strains raises the questions of where the patient's infection was acquired and of whether strains are geographically as localized as once thought.


Comparative histologic features of liver biopsy specimens from patients coinfected with hepatitis G and C viruses with chronic hepatitis C virus alone: an age-, sex-, disease duration-, and transmission-matched controlled study of chronic hepatitis.

Goldstein NS, Underhill J, Gordon SC, Bayati N, Silverman A.

Department of Anatomic Pathology, William Beaumont Hospital, Royal Oak, Michigan 48324, USA.

Am J Clin Pathol 1997 Dec;108(6):625-32 Abstract quote

Hepatitis G virus (HGV) is a recently described, parenterally spread, positive-strand RNA virus of the Flaviviridae family. There is a high rate of HGV coinfection in patients with hepatitis C virus (HCV). Whether HGV can cause or is pathogenetically related to clinically apparent chronic liver disease, or whether HGV alters the course of hepatitis C in patients who are coinfected with both viruses is unknown.

We studied 13 biopsy specimens from 11 patients coinfected with HGV and HCV and compared them with 15 biopsy specimens from a group of patients infected only with HCV who were matched for age, sex, disease duration, and transmission mode to characterize the histologic features of coinfected liver biopsy specimens and to look for any histologic features that might allow identification of coinfected patients.

Three of the biopsy specimens from coinfected patients had a modified histologic activity index score of minimal chronic hepatitis, three of mild, two of mild/moderate, and five of moderate chronic hepatitis. Bile duct injury was absent in seven specimens, minimal in five, and mild in one. The biopsy specimens from patients who were coinfected with HGV and HCV had similar histologic features to the biopsy specimens of patients infected with HCV alone. There were no detectable histologic differences between the biopsy specimens from the two patient groups. The P values for the statistical comparisons confirmed this impression. In addition, no group of histologic features distinguished the coinfected patient group from the control group. Any suspicion that a clinician might have about the presence of HGV requires confirmation by reverse transcriptase-polymerase chain reaction testing of serum samples.

Our results suggest that HGV most likely does not actively participate in the cytotoxic effects of chronic hepatitis or does so by a mechanism as yet undefined. Although HGV can cause chronic infection, the present study provides no evidence that it causes or contributes to chronic hepatitis.

Hepatitis G virus infection in chronic dialysis patients and kidney transplant recipients.

Fabrizi F, Lunghi G, Bacchini G, Corti M, Guarnori I, Raffaele L, Erba G, Pagano A, Locatelli F.

Nephrology and Dialysis Unit, Hospital, Lecco, Italy.

Nephrol Dial Transplant 1997 Aug;12(8):1645-51 Abstract quote

BACKGROUND: The cloning of the hepatitis G virus (HGV), a novel RNA virus of the Flaviviridae family, has been very recently developed. HGV is known to be parenterally transmitted and has been detected in several patients with cryptogenic hepatitis. However, little information exists about the epidemiology of HGV infection in renal patients. We studied 178 chronic dialysis patients and 11 renal transplant individuals to evaluate prevalence, risk factors, and clinical manifestations of HGV infection in this population.

METHODS: Hepatitis G virus infection has been detected by a modified PCR technology which incorporates digoxigenin-labelled nucleotides into the amplicon. Primers from the non-coding region and the NS-5 region of HGV are utilized for a single round amplification. Using a streptavidin surface and a biotin-labelled capture probe, the labelled nucleic acid is bound through the capture probe to the surface, and the amplified nucleic acid is detected using antibody to digoxigenin.

RESULTS: HGV RNA was detected in 6% of chronic haemodialysis (HD) patients (11/172), 36% of renal transplant recipients (4/11), and 17% (1/6) of patients on peritoneal dialysis treatment (CAPD). There were no significant differences between HGV positive and negative patients on chronic HD treatment with regard to several demographic, biochemical and virological features. However, the frequency of anti-HCV antibody was significantly higher in HGV-positive than HGV-negative patients (9/11 (82%) vs 51/161 (32%), P = 0.006). In the whole group of HGV RNA-positive patients, 78% (11/14) had a history of blood transfusion requirements, 14/16 (87%) had co-infection with HCV, and 1 (6%) had co-infection with HBsAg. There was no significant association between HCV genotypes and HGV RNA positivity. Six (37.5%) of 16 HGV RNA-positive patients showed raised aminotransferase values in serum.

CONCLUSIONS: Patients on maintenance dialysis and kidney transplant recipients are at increased risk of HGV infection; HGV is very frequently associated to hepatitis C co-infection, regardless of HCV genotype. HGV may be transmitted by blood transfusions but transmission routes other than transfusion are possible; 37.5% of HGV RNA-positive patients showed raised serum aminotransferase levels. Further investigations are necessary to clarify the role of HGV infection in the development of liver disease in this clinical setting.

Identification, prevalence and aspects of molecular biology of hepatitis G virus.

Thomas HC, Pickering J, Karayiannis P.

Department of Medicine, Imperial College School of Medicine at St Mary's London, UK. .

J Viral Hepat 1997;4 Suppl 1:51-4 Abstract quote

Hepatitis G virus (HGV) is a newly identified member of the Flaviviridae family.

The positive-sense RNA genome of the virus contains a single open reading frame that encodes the viral polyprotein. Its genomic organization is similar to that of the hepatitis C virus (HCV) with which it has only 25% homology at the nucleotide level. Nucleotide sequences from the NS-3 helicase region of HCV varied by 10-30%. HGV is therefore much less variable than HCV. Construction of phylogenetic trees, and calculation of mean distances between possible subtypes, indicated one level of variation in NS-3 sequences: the degree of variation between isolates was similar to that observed between HCV subtypes. Thus no evidence for clustering of sequences into multiple genotypes was found. The virus is transmissible through blood transfusion and by exposure to blood products or intravenous drug use, and may result in acute or chronic hepatitis.

A causative role of HGV in acute and chronic hepatitis is not yet established. Concurrent infection with hepatitis B virus (HBV) and HCV is common and persistent viraemia has been documented for many years, in many cases, in the absence of transaminase elevations.

Short report: evidence of worldwide transmission of hepatitis G virus.

Corwin AL, Hyams KC, Kim JP, Wages J, Doss R, Sulaiman A, Mitchell B, Arthur R, Bassily S, Punjabi NH, Laras K, Duc DD,Watts D.

U.S. Naval Medical Research Unit No. 2, Jakarta, Indonesia.

Am J Trop Med Hyg 1997 Oct;57(4):455-6 Abstract quote

Hepatitis G virus (HGV) has been recently documented in the Americas, Europe, and Australia. Distinct risk populations from North Africa, South America, and Southeast Asia were screened for HGV, in addition to hepatitis B and C viruses.

First time recognition of HGV is described from Egypt and Indonesia. Notable is the high proportion of HGV positive individuals among multiply transfused children, ranging from 24% of those sampled from Egypt to 32% in Indonesia. Also, data from Peru suggest the likely association of HGV infection with progressive liver disease.

Hepatitis G virus should be considered a world-wide health concern.

High prevalence of hepatitis G virus after liver transplantation without apparent influence on long-term graft function.

Haagsma EB, Cuypers HT, Gouw AS, Sjerps MC, Huizenga JR, Slooff MJ, Jansen PL.

Department of Gastroenterology and Hepatology, University Hospital, Groningen, The Netherlands.

J Hepatol 1997 Apr;26(4):921-5 Abstract quote

BACKGROUND/AIMS: Hepatitis G virus is a recently characterized transfusion-transmissible RNA virus. Its pathogenicity remains to be established. We studied its prevalence in liver transplant patients and assessed the long-term influence on the liver graft.

METHODS: Thirty-nine adult patients without hepatitis B or C were included; median follow-up was 8 years (range 1-17). Serum samples from before and late after transplantation were investigated for the presence of HGV-RNA. HGV-RNA was detected by cDNA-PCR, using primers from the NS3 region of the viral genome. The latest available yearly liver biopsy was assessed in a coded fashion according to established histological criteria. The outcome in the HGV-positive patients was compared with the outcome in the HGV-negative patients with respect to liver tests and liver histology.

RESULTS: The prevalence before and after transplantation was 15.4 and 43.6%, respectively. Liver test results and liver histology did not differ between the HGV and non-HGV groups. In both groups more than 50% of the patients showed normal histology. Mild portal and/or lobular inflammation tended to be more prevalent in the non-HGV group (no statistical difference).

CONCLUSIONS: HGV infection is highly prevalent in liver transplant patients. In the absence of co-infection with hepatitis B or C virus, no long-term negative influence on the graft occurs.

HGV: the identification, biology and prevalence of an orphan virus.

Mphahlele MJ, Lau GK, Carman WF.

Department of Virology, Medical University of Southern Africa, Gauteng.

Liver 1998 Jun;18(3):143-55 Abstract quote

Hepatitis G virus (HGV) and GB virus C (GBV-C) (both hereinafter referred to as HGV) were independently identified in patients with hepatitis of unknown aetiology. HGV is a positive-sense RNA virus of the family Flaviviridae. The virus can establish both acute and chronic infection and appears to be sensitive to interferon. Horizontal transmission is mainly parenteral, although other routes such as vertical have been well documented. High risk groups include intravenous drug users (i.v.DUs), the multiply transfused, haemodialysis patients and haemophiliacs. Up to 90% of i.v.DUs are positive for either HGV-RNA or antibodies to HGV envelope-2 protein (anti-E2). HGV is frequently detected in patients with HBV and HCV infection. Its link to hepatitis has now become less certain. Only around 3-6% of non-A E hepatitis cases are HGV viraemic, clearly showing that HGV is not the major cause of idiopathic hepatitis as originally hoped. Around 1-5% of volunteer blood donors in developed countries are HGV viraemic, but the prevalence is 10-20% in the general population in some developing countries.

At present, it is not known whether HGV is associated with other diseases in humans, is a passenger virus, or only becomes virulent under certain conditions.

The significance of hepatitis G virus in serum of patients with sporadic fulminant and subfulminant hepatitis of unknown etiology.

Munoz SJ, Alter HJ, Nakatsuji Y, Shih JW, Reddy RK, Jeffers L, Schiff ER, Reid AE, Marrone A, Rothstein K, Manzarbeitia C, Liang TJ.

Center for Liver Diseases, Albert Einstein Medical Center, Philadelphia, PA, USA.

Blood 1999 Aug 15;94(4):1460-4 Abstract quote

Excluding acute hepatic failure caused by drugs, the etiology of fulminant hepatitis (FH) remains unknown in many patients. There are conflicting data about a possible pathogenic role for the hepatitis G virus (HGV) in patients with cryptogenic fulminant hepatitis (non-A-E FH).

We investigated the presence of circulating HGV in 36 patients with well-documented non-A-E fulminant and 5 patients with subfulminant hepatitis from 3 geographic locations in the United States.

Serum HGV RNA was determined by reverse transcriptase-polymerase chain reaction using primers from the NS5 region of the HGV genome. HGV RNA was also measured before and after liver transplantation in 5 patients and at different time points in 7 patients. Serum samples were recoded and reanalyzed for HGV RNA using different primer sets to assess the validity of the HGV RNA assay. HGV was present in serum of 14 of the 36 patients (38.8%) with non-A-E fulminant hepatitis. Twenty percent of patients from the Northeast, 11% of the patients from the Southeast, and 50% from the Mid-Atlantic regions of the United States had circulating HGV RNA. The use of therapeutic blood products was significantly associated with the presence of serum HGV RNA (P <.02). Retesting for HGV RNA with different primers was positive in all but 1 case. HGV RNA is not causally related to non-A-E fulminant hepatitis.

The finding of HGV RNA in serum from these patients is likely related to the administration of blood product transfusion after the onset of fulminant hepatitis.

Persistence and clinical outcome of hepatitis G virus infection in pediatric bone marrow transplant recipients and children treated for hematological malignancy.

Yamada-Osaki M, Sumazaki R, Tsuchida M, Koike K, Fukushima T, Matsui A.

Department of Pediatrics, University of Tsukuba, Tsukuba, Japan.

Blood 1999 Jan 15;93(2):721-7 Abstract quote

The natural course and the clinical significance of hepatitis G virus (HGV) infection were investigated in 106 pediatric patients who received chemotherapy for hematological malignancy or underwent bone marrow transplantation (BMT) using HGV-RNA and antibodies to the HGV-E2 protein (anti-E2).

HGV markers were detected in 21 patients (19.8%; HGV-RNA in 19 and anti-E2 in 2). Longitudinal analysis of these HGV-infected patients showed that 1 had anti-E2 before the initial blood transfusion, 14 had persistent viremia, and 6 became clear of circulating HGV-RNA after completion of therapy, although 5 of the 6 HGV-cleared patients never developed anti-E2. Reactivation of HGV infection during chemotherapy was observed in two anti-E2-positive, HGV-RNA-negative patients; the reappearance of the same HGV strain was confirmed by phylogenetic analysis. Among BMT survivors without other known causes of liver dysfunction, HGV-RNA-positive patients had a higher peak serum alanine amino transferase (ALT) value than negative patients.

Contrary to previous reports, immunosuppressed patients can apparently recover from HGV infection without detectable anti-E2 and some patients who supposedly recovered from HGV infection can nonetheless suffer exacerbation when subsequently immunosuppressed.

Hepatitis G virus biology, epidemiology, and clinical manifestations: Implications for blood safety.

Kleinman S.

University of British Columbia, Vancouver, British Columbia, Canada.

Transfus Med Rev 2001 Jul;15(3):201-12 Abstract quote

Hepatitis G virus (HGV), also called GBV-C, is a single positive-standard RNA virus belonging to the Flaviviridae family.

In 50 % to 75 % of infections, HGV is cleared with plasma RNA disappearing as anti-E2 becomes detectable; in other cases, HGV infection becomes chronic. The prevalence of HGV RNA in blood donors ranges from 1 % to 4 %, and the rate of anti-E2, indicating resolved infection, ranges from 3 % to 14 %. HGV is transmitted by transfusion of blood components and has been transmitted by nonvirally inactivated factor VIII concentrate. Despite extensive study, HGV has not been identified as a causative agent of any type of liver disease or any other known clinical condition. Molecular biology data show a lack of hepatotropism; preliminary data indicate that the site of HGV replication may be in mononuclear cells in bone marrow or spleen but not in peripheral blood or lymph nodes.

The combined clinical and laboratory data strongly support the contention that HGV is not a hepatotropic virus and that this virus was inappropriately named hepatitis G. Because the data do not indicate any pathologic effects of HGV, it is not appropriate to screen the blood supply for HGV RNA.


The role of TT virus infection in acute viral hepatitis.

Kanda T, Yokosuka O, Ikeuchi T, Seta T, Kawai S, Imazeki F, Saisho H.

First Department of Medicine, Chiba University School of Medicine, Chiba, Japan.

Hepatology 1999 Jun;29(6):1905-8 Abstract quote

Recently, transfusion-transmitted virus (TTV) was discovered to be a potential causative agent for non-A-E hepatitis. Little is known about the relation between TTV and the clinical courses of various types of acute viral hepatitis.

One hundred twenty-five patients with acute viral hepatitis who were admitted to the Chiba University Hospital between 1984 and 1998 and 100 persons with normal liver function tests were tested for the presence of TTV in their sera. Serum samples were tested for TTV DNA and genotype by polymerase chain reaction (PCR). TTV DNA was detected in 15 of 35 patients (43%) with non-A-E hepatitis, 14 of 33 patients (42%) with hepatitis C, 8 of 28 patients (29%) with hepatitis A, 7 of 29 patients (24%) with hepatitis B, and 37 of 100 subjects with normal liver function tests (37%). The detection rate did not differ statistically between non-A-E hepatitis and hepatitis A, B, C, or controls. The distribution of TTV genotypes was similar in non-A-E, A, B, C types, and controls.

The clinical characteristics of the acute illnesses were similar for patients with or without TTV in hepatitis non-A-E, A, B, or C. Although TTV was detected frequently in non-A-E acute hepatitis, no etiologic role for TTV could be established.

TTV infection in patients with acute hepatitis of defined aetiology and in acute non-A-E hepatitis.

Fabris P, Biasin MR, Infantolino D, Tositti G, Venza E, Floreani A, Zanetti A, de Lalla F.

Department of Infectious Diseases, Ospedale S. Bortolo, Vicenza, Italy.

J Hepatol 2000 Apr;32(4):661-5 Abstract quote

BACKGROUND/AIMS: Recently, the presence of a novel nonenveloped single-stranded DNA virus (TTV) has been associated with either acute or chronic hepatitis of unknown aetiology, suggesting a possible aetiological role. The aim of this study was to evaluate the prevalence, the significance and the clinical impact of TTV infection in patients with acute viral hepatitis of defined aetiology and in patients with non-A-E acute hepatitis.

METHODS: TTV-DNA was tested by hemi-nested PCR in serum samples collected from 121 patients during and after acute hepatitis (103 with acute viral hepatitis of defined aetiology and 18 with acute non-A-E hepatitis) and in 30 healthy controls.

RESULTS: Overall, the rate of TTV infection was 12.6% (13/103) in patients with acute hepatitis of defined aetiology, 16.6% (3/18) in patients with non-A-E acute hepatitis and 6.6% (2/30) in the healthy control group, (p=n.s). TTV-DNA was detected in the following proportions: hepatitis B, 13.2% (7/53); hepatitis C, 16.6% (4/24); hepatitis A, 4.7% (1/21); hepatitis E 20% (1/5). Moreover, acute hepatitis with and without TTV infection/coinfection were comparable in terms of both liver biochemistry and chronicity rate. The results of TTV re-testing after serial dilutions of six TTV-DNA positive serum samples during and after the peak of liver transaminases failed to demonstrate a correlation between liver damage and viral titre.

CONCLUSIONS: The prevalence of TTV infection appeared to be comparable in patients with non-A-E hepatitis, in acute hepatitis of defined aetiology and in the control group. Hence, an aetiological role of TTV for acute hepatitis of unknown aetiology seems questionable. Moreover, TTV infection does not modify the natural history of acute hepatitis of defined aetiology.

Effect of interferon on a nonenveloped DNA virus (TT virus) associated with acute and chronic hepatitis of unknown etiology.

Akahane Y, Sakamoto M, Miyazaki Y, Okada S, Inoue T, Ukita M, Okamoto H, Miyakawa Y, Mayumi M.

First Department of Internal Medicine, Yamanashi Medical University, Japan.

J Med Virol 1999 Jul;58(3):196-200 Abstract quote

An unenveloped DNA virus named TT virus (TTV) has been reported in association with acute and chronic hepatitis of unknown etiology.

The effect of interferon on TTV was evaluated in the patients with chronic hepatitis C who were coinfected with TTV. TTV DNA was determined by a polymerase chain reaction with heminested primers in the 96 patients with chronic hepatitis C who received interferon-alpha (516 million units in 26 weeks) and followed for 24 months thereafter. TTV DNA was detected in 31 (32%) patients before therapy. TTV DNA became undetectable during interferon therapy and remained absent in 14 (45% of the 31 patients) through 24 months thereafter. The four patients with pretreatment TTV DNA titer > or =10(3)/ml did not respond.

These results indicate that TTV is sensitive to interferon, and the response would be inversely correlated with pretreatment viral titers.

Age-specific prevalence and transmission of TT virus.

Saback FL, Gomes SA, de Paula VS, da Silva RR, Lewis-Ximenez LL, Niel C.

Department of Virology, Oswaldo Cruz Institute, Rio de Janeiro, Brazil.

J Med Virol 1999 Nov;59(3):318-22 Abstract quote

TT virus (TTV) is an unenveloped, single-stranded DNA virus that was discovered recently in the sera of Japanese patients with posttransfusion hepatitis of unknown etiology. A high prevalence of TTV infection in blood donors of several countries, including Brazil, has been demonstrated.

To study the variation in TTV prevalence between different age groups, sera from 223 individuals without liver disease, aged 0-80 years, were tested by the polymerase chain reaction for the presence of TTV DNA.

All subjects were inhabitants of the city of Rio de Janeiro, Brazil. The prevalence increased continuously with age (P <.001), from 17% among children under the age of 11 years, to 57% in people older than 50 years. To assess vertical transmission, sera from 105 unselected, consecutive parturient women attending a public maternity hospital were paired with cord bloods and examined for the presence of TTV DNA. Thirty-seven (35%) mothers were found to be TTV infected. Seven cord bloods were also positive, suggesting the possible transplacental transmission of the virus. Furthermore, a direct correlation between TTV viremia and presence of antibodies to the enterically transmissible hepatitis A virus (HAV) was observed in this group of women, with a relative risk of TTV infection of 5.09 (95% confidence interval 0.76-34.03) for women with anti-HAV, compared with women without.

This finding suggested that the fecal-oral route might be an important route of TTV transmission.

Lack of association between TTV viral load and aminotransferase levels in patients with hepatitis C or non-B-C.

Kato H, Mizokami M, Orito E, Ohno T, Hayashi K, Nakano T, Kato T, Tanaka Y, Sugauchi F, Mukaide M, Ueda R.

Second Department of Medicine, Nagoya City University Medical School, Mizuho, Nagoya, Japan.

Scand J Infect Dis 2000;32(3):259-62 Abstract quote

TT virus (TTV) is a newly identified un-enveloped single-stranded DNA virus. Although TTV was initially thought to be a new hepatitis virus, it is still unclear whether it causes hepatitis.

To clarify the natural history and pathogenesis of TTV infection, serial serum samples from patients with chronic hepatitis were analysed.

TTV DNA was quantified by real-time detection polymerase chain reaction assay (RTD-PCR), which was adapted for TTV. Five patients with chronic hepatitis, 4 with hepatitis C and 1 with non-B-C, were studied. The study period ranged from 9 to 50 months. In 3 patients there were frequent increases in TTV DNA titres, but no concomitant elevation of the aminotransferase (ALT) levels. In 2 patients who were treated with interferon, the changes in TTV titres were not synchronized with those of the ALT levels.

Thus, in cases of chronic hepatitis, no correlation was observed between the serum TTV DNA titres and the ALT levels.


The immunology of fibrogenesis in alcoholic liver disease.

Chedid A, Arain S, Snyder A, Mathurin P, Capron F, Naveau S.

Department of Pathology, Rosalind Franklin University/Chicago Medical School, North Chicago, Ill 60064, USA.
Arch Pathol Lab Med. 2004 Nov;128(11):1230-8. Abstract quote  

CONTEXT: Alcoholic liver disease in humans frequently leads to cirrhosis. Experimental models of hepatic fibrogenesis are available, but extrapolation of those findings to human ethanol-induced liver injury is difficult. Hepatic ethanol-induced fibrosis in humans has often been studied in relatively small patient populations. During the past decade, several animal models and human studies have attributed fibrogenesis in the liver to the role played by hepatocytes, Kupffer cells, endothelial cells, and especially stellate cells.

OBJECTIVE: To determine the contribution of the main liver cell types to ethanol-induced fibrogenesis. For that purpose, we studied the expression of the following immunologic parameters: smooth muscle-specific alpha actin (SMSA), CD68, CD34, transforming growth factor beta1, intercellular adhesion molecule 1, and collagen types 1 and 3. The Dako LSAB+ kit (peroxidase method) was used.

DESIGN: We recently studied a large cohort of patients with alcoholic liver disease in France. In this cohort, we found 87 cases in which liver biopsies revealed only pericentral injury with nonpathologic portal areas. We compared cases in which the portal areas were nonpathologic with 324 patients in whom staging ranged from F0 to F3. Patients with cirrhosis (F4) were excluded from evaluation. To stage fibrosis, we used the METAVIR system. Furthermore, we selected 40 cases in which the biopsies measured at least 25 mm in length for further histochemical evaluation. Ten additional normal cases from our archives were used as controls. We divided this patient population into the following 5 groups of 10 patients each: group 1A, F0 with steatosis; group 1B, F0 without steatosis; group 2, F0 to F1, central injury; group 3, F3, fibrosis with multiple septa; and group 4, nonpathologic livers (controls).

RESULTS: Smooth muscle-specific alpha actin was expressed by stellate cells, pericentrally, with increasing severity and intensity in the advanced stage of fibrosis of group 3, less intense expression was noted in group 2, and expression was practically absent in group 1 and in nonpathologic controls. CD68 was the best marker for Kupffer cells and was expressed diffusely within the lobules in all groups. Its expression correlated directly with the degree of disease severity, progressing from stage I through stage III, but was absent in nonpathologic livers. CD34 was consistently expressed by endothelial cells in the periportal areas in all groups. The expression of collagen type 1 was intense in the bands of fibrosis or bridging, while type 3 expression was poor. Transforming growth factor beta1 and intercellular adhesion molecule 1 were not expressed in any group.

CONCLUSIONS: In this study, stellate cell activation (SMSA) was most intense pericentrally in the early stages and diffusely with progression to fibrosis and maximum intensity in stage III. Kupffer cell activation, as determined by CD68 expression, was intense and diffuse, while endothelial cells expressed CD34 periportally in a similar manner in all stages. Fibrogenesis in human ethanol injury is due to the activity of stellate cells, Kupffer cells, and to a lesser extent, to endothelial cells.

Autoimmune hepatitis with centrilobular necrosis.

Misdraji J, Thiim M, Graeme-Cook FM.

James Homer Wright Pathology Laboratories, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Am J Surg Pathol. 2004 Apr;28(4):471-8. Abstract quote  

Autoimmune hepatitis (AIH) is usually a chronic portal-based hepatitis with prominent plasma cells. Although necroinflammatory activity throughout the lobule is described, centrilobular necrosis (CN) is only rarely the predominant pattern of injury. Recognition of the possibility of AIH in zone 3 hepatitis will lead to prompt steroid therapy and may avert cirrhosis.

We report the clinicopathologic features of 6 cases of AIH with CN. The 3 females and 3 males averaged 48 years of age (range 32-66 years). Four patients had a history of autoimmune disorders. All had elevated transaminases and negative serology for viral hepatitis B and C. One had a history of ethanol use. One patient was taking interferon-beta and 1 patient was taking atorvastatin, but none of the patients was taking medication with a temporal relationship to suggest a drug hypersensitivity hepatitis. All patients had positive antinuclear antibody, anti-smooth muscle antibody, or both, although 1 patient was negative for autoantibodies at initial laboratory testing.

Four biopsies showed confluent zone 3 necrosis, whereas two biopsies showed spotty CN. Portal inflammation was relatively mild in all cases. Plasma cells were few to numerous in both zone 3 and portal tracts in four biopsies; they were absent in 2 cases. All patients responded to steroid therapy. Two patients relapsed, and rebiopsy in 1 of them showed CN, bridging necrosis, and an increase in the degree of portal-based hepatitis. Another patient was not treated initially; a second biopsy 35 months after presenting revealed periportal hepatitis as well as CN.

The histologic spectrum of AIH should be expanded to include zone 3 hepatitis. As with classic AIH, most patients with CN demonstrate serologic and clinical evidence of autoimmunity. Subsequent biopsies in patients with a centrilobular pattern may show evolution to portal-based hepatitis characteristic of AIH but may also show persistence of the zone 3 hepatitis. Unlike other causes of zone 3 hepatitis, AIH is steroid responsive; therefore, timely diagnosis is important.

Depletion of mitochondrial DNA in the liver of an infant with neonatal giant cell hepatitis.

Muller-Hocker J, Muntau A, Schafer S, Jaksch M, Staudt F, Pongratz D, Taanman JW.

Institute of Pathology, Ludwig-Maximilians-Universitat Munchen, Munchen; Kinder-/Kinder-Poliklinik, Ludwig-Maximilians-Universitat Munchen, Munchen; Stoffwechselzentrum und Institut fur Klinisch-Chemische Diagnostik, Krankenhaus, Munchen-Schwabing; Kinderklinik, Dritter Orden, Passau; Friedrich-Baur-Institut bei der Medizinischen Klinik und Neurologischen Klinik der Ludwig-Maximilians-Universitat Munchen, Munchen, Germany; and the Department of Clinical Neurosciences, Royal Free and University College Medical School, London, England

Hum Pathol 2002 Feb;33(2):247-253 Abstract quote

A boy presented with lactic acidosis, hepatomegaly, hypoglycemia, generalised icterus, and muscle hypotonia in the first weeks of life. At the age of 2 months, neonatal giant cell hepatitis was diagnosed by light microscopy.

Electron microscopy of the liver revealed an accumulation of abnormal mitochondria and steatosis. Skeletal muscle was normal on both light and electron microscopy. At the age of 5 months, the patient died of liver failure. Biochemical studies of the respiratory chain enzymes in muscle showed that cytochrome-c oxidase (complex IV) and succinate-cytochrome-c oxidoreductase (complex II + III) activities were (just) below the control range. When related to citrate synthase activity, however, complex IV and complex II + III activities were normal. Complex I activity was within the control range.

The content of mitochondrial DNA (mtDNA) was severely reduced in the liver (17% to 18% of control values). Ultracytochemistry and immunocytochemistry of cytochrome-c oxidase demonstrated a mosaic pattern of normal and defective liver cells. In defective cells, a reduced amount of the mtDNA-encoded subunits II-III and the nuclear DNA-encoded subunits Vab was found. Cells of the biliary system were spared. Immunohistochemistry of mtDNA replication factors revealed normal expression of DNA polymerase gamma. The mitochondrial single-stranded binding protein (mtSSB) was absent in some abnormal hepatocytes, whereas the mitochondrial transcription factor A (mtTFA) was deficient in all abnormal hepatocytes.

In conclusion, depletion of mtDNA may present as giant cell hepatitis. mtTFA and to a lesser degree mtSSB are reduced in mtDNA depletion of the liver and may, therefore, be of pathogenetic importance. The primary defect, however, is still unknown.

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