[Disorders of gut microflora in the pathogenesis of liver cirrhosis and complications of portal hypertension].

A total of 85 patients with alcoholic and viral cirrhosis were included in study to assess the prevalence of dysbiosis and its relationship with the severity of disease, and with development of dyspeptic disorders. Intestinal bacterial over-growth was measured by means of a lactulose breath test, fecal flora was cultured under aerobic and anaerobic conditions. Intestinal bacterial overgrowth and colon dysbiosis were determined in 82.4% of patients with equal prevalence in alcoholic and viral cirrhosis. Intestinal dysbiosis was found to be risk factor of increasing cirrhosis severity and liver dysfunction, as well as development of complications of portal hypertension. It was documented, that intestinal dyspepsia syndrome in cirrhotic patients is strongly associated with the presence of gut microflora disorders.

Medicine. Status and future of applied sciences.

Advances in hepatitis and immunology illustrate the influence of basic research and technologic innovation in shaping the past, present, and future of medical care.

Non-A, non-B hepatitis: ultrastructural evidence for two agents in experimentally infected chimpanzees.

Two different ultrastructural alterations were observed in liver cells of chimpanzees inoculated with plasma derived from two different patients with non-A, non-B hepatitis. During the acute phase of illness in one group of four chimpanzees, peculiar tubular structures, composed of two unit membranes with electron-opaque material in between, were observed in the cytoplasm of hepatocytes. In contrast, these structures were never detected in the liver cells of the second group of five chimpanzees that received the second inoculum, However, nuclear changes, usually associated with aggregates of 20- to 27-nanometer particles, were found in hepatocytes of the latter animals. Although these particles resembled viruses, they were not as uniform as small virus particles often appear. In five other chimpanzees inoculated with non-A, non-B hepatitis material not known to be related to the first two inocula, cytoplasmic structures were found in four, and nuclear structures were found in the remaining one. Thus, all 14 chimpanzees inoculated with transmissible non-A, non-B hepatitis agents could be classified as having either nuclear or cytoplasmic changes. These observations add support to epidemiologic data suggesting that there may be more than one agent of non-A, non-B hepatitis.

Isolation of a cDNA from the virus responsible for enterically transmitted non-A, non-B hepatitis.

Major epidemic outbreaks of viral hepatitis in underdeveloped countries result from a type of non-A, non-B hepatitis distinct from the parenterally transmitted form. The viral agent responsible for this form of epidemic, or enterically transmitted non-A, non-B hepatitis (ET-NANBH), has been serially transmitted in cynomolgus macaques (cynos) and has resulted in typical elevation in liver enzymes and the detection of characteristic virus-like particles (VLPs) in both feces and bile. Infectious bile was used for the construction of recombinant complementary DNA libraries. One clone, ET1.1, was exogenous to uninfected human and cyno genomic liver DNA, as well as to genomic DNA from infected cyno liver. ET1.1 did however, hybridize to an approximately 7.6-kilobase RNA species present only in infected cyno liver. The translated nucleic acid sequence of a portion of ET1.1 had a consensus amino acid motif consistent with an RNA-directed RNA polymerase; this enzyme is present in all positive strand RNA viruses. Furthermore, ET1.1 specifically identified similar sequences in complementary DNA prepared from infected human fecal samples collected from five geographically distinct ET-NANBH outbreaks. Therefore, ET1.1 represents a portion of the genome of the principal viral agent, to be named hepatitis E virus, which is responsible for epidemic outbreaks of ET-NANBH.

Syphilis-related hepatitis in a liver transplant patient.

We herein describe a case of secondary syphilis hepatitis in a liver transplant patient. This homosexual man presented 15 years after an orthotopic liver transplant with nonsquamous papillomacular rash, mild cytolysis, and anicteric cholestasis. Laboratory tests showed syphilis seroconversionwith a VDRL test titer of 1/256, a Treponema pallidum hemagglutination assay of 1/5120, and a positive immunoglobulin M fluorescent Treponemal antibody absorbance. A liver biopsy performed 13 months after the diagnosis showed low-grade hepatitis with a METAVIR score of A1F1; it also showed moderate, nonspecific portal inflammation consisting primarily of neutrophils, with no evidence of cholestasis. The patient was given benzathine-penicillin (2400000 IU) with a transient increase in prednisolone dosages. Cytolysis rapidly, and cholestasis progressively, disappeared. Results of an immunoglobulin M fluorescent Treponemal antibody absorbance test became negative, whereas the VDRL test and the Treponema pallidum hemagglutination assay titers decreased slightly over time.

Cytomegalovirus infection in the normal host.

CMV mononucleosis often resembles EBV infectious mononucleosis; however, certain features of the history and physical may help to distinguish CMV from EBV. While CMV mononucleosis is usually self-limited, certain laboratory abnormalities may persist for months or years after the patient has recovered. Previous reports on CMV in the non-immunocompromised host have rarely described systemic complications. We have reviewed 10 cases of CMV with systemic manifestations at one institution over a 15-year period. These patients had prolonged fevers (often greater than three weeks) and the diagnosis was often unsuspected during the early part of the illness. While two patients required mechanical ventilation, all patients had self-limiting disease and survived. When CMV is suspected and diagnosed early in the course, numerous diagnostic (and potentially dangerous) tests can be avoided in a viral illness in which prolonged fever is common.

Liver disease in renal transplant recipients.

Liver disease is a common complication in renal transplant recipients. Several types of liver disease can occur. The most common are acute and chronic hepatitis. The variety of acute hepatitis include hepatitis A, hepatitis B, cytomegalovirus hepatitis, herpes simplex hepatitis and azathioprine hepatitis. The incidence of azathioprine hepatitis may not be as high as initially suggested. Chronic hepatitis is a serious problem because the disease seems to be progressive despite prednisone therapy. The causes of this chronic hepatitis are not fully known, although hepatitis B, cytomegalovirus and herpes simplex virus have been implicated. Discontinuation of azathioprine therapy has no appreciable effect on the course of chronic hepatitis.

The influence of HLA matching on cytomegalovirus hepatitis and chronic rejection after liver transplantation.

Previous findings in liver transplantation patients have raised the concept that HLA plays a dualistic role. HLA matching will reduce rejection but may augment MHC restricted cellular immune mechanisms of liver allograft injury. To evaluate this concept, we studied CMV hepatitis in 399 FK506-treated liver transplant patients, including 355 cases for which complete HLA-A,B,DR,DQ typing information was available. CMV hepatitis developed in 25 patients, and 17 of them (or 68%) showed a one or two HLA-DR antigen match with the donor. In contrast, HLA-DR matches were found in only 35% of 330 patients without CMV hepatitis (P = 0.005). No significant associations were seen for HLA-A, HLA-B, and HLA-DQ antigens. In pretransplant CMV-seronegative patients with seropositive grafts (n = 39), the frequency of CMV hepatitis was 44% for HLA-DR-matched livers but 14% for HLA-DR-unmatched livers. In seropositive recipients (n = 187), these frequencies were 12% and 2% for HLA-DR-matched and unmatched liver grafts. Chronic rejection developed in 29 patients (or 8%) during a follow-up between 10 and 24 months after transplantation. Its incidence was higher in the CMV hepatitis group (24% vs. 6%) (P = 0.007). Although no associations were found between HLA matching and the incidence of chronic rejection, there was an earlier onset of chronic rejection of HLA-DR-matched livers irrespective of CMV hepatitis. These findings suggest that an HLA-DR match between donor and recipient increases the incidence of CMV hepatitis in both primary and secondary CMV infections. Although HLA compatibility leads to less acute cellular rejection, it is suggested that DR matching may accelerate chronic rejection of liver transplants, perhaps through HLA-DR-restricted immunological mechanisms toward viral antigens, including CMV.

Successful allogeneic bone marrow transplantation in a 2.5-year-old boy with ongoing cytomegalovirus viremia and severe aplastic anemia after orthotopic liver transplantation for non-A, non-B, non-C hepatitis.

BACKGROUND: A 2.5-year-old boy received a cadaveric orthotopic liver transplant for acute liver failure due to non-A, non-B, non-C hepatitis. After transplantation, he developed thrombocytopenia and neutropenia and subsequently severe aplastic anemia. The patient also suffered from recurrent cytomegalovirus (CMV) viremia, treated with foscarnet and ganciclovir. METHODS: For treatment of his aplastic anemia, the patient underwent an allogeneic bone marrow transplantation from his HLA-identical sister after conditioning with cyclophosphamide at 200 mg/kg and antithymocyte globulin at 3 mg/kg for 5 days. Prophylactic acyclovir was given because of ongoing CMV viremia at the time of bone marrow transplantation. RESULTS: The transplant course was uneventful, with rapid engraftment. There were no signs of liver dysfunction, graft-versus-host disease, or reactivation of CMV. The patient is in excellent health, with normal liver and bone marrow function 3 years after bone marrow transplantation. CONCLUSION: This case report shows that allogeneic bone marrow transplantation is feasible and well tolerated in a patient with severe aplastic anemia after liver transplantation for acute fulminant viral hepatitis.

Non-A, non-B viral hepatitis.

Non-A, non-B hepatitis is a newly recognized disease entity. Although initially described as a transfusion related viral infection, the disease can occur in sporadic, endemic, and epidemic settings. There are no confirmed, reproducible serologic tests for associated antigens or antibodies, but electron microscopy has revealed virus-like particles of different sizes. Nonspecific laboratory tests of hepatic dysfunction, especially alanine aminotransferase, are currently utilized to diagnose non-A, non-B hepatitis in patients and may be used to implicate blood donor carriers of this virus. The existence of an infectious non-A, non-B hepatitis agent and proof of a chronic carrier state in humans have been documented by transmission studies in chimpanzees. Cross challenge studies in chimpanzees, as well as some epidemiologic data, suggest that more than one agent causes non-A, non-B hepatitis.

Modern aspects of the morphology of viral hepatitis.

The morphologic pathology of human viral hepatitis and its sequelae are reviewed in this article. Emphasis is placed on new information, including the current status of the pathologic diagnosis of hepatitis non-A, non-B. The article includes a discussion of aspects of the virology that are pertinent to an understanding of the significance of viral markers in the liver. A small contribution of the authors is a brief description of the neocholangiole, a duct of Hering-like structure seen following hepatic necrosis from many causes, including the severe forms of viral hepatitis.

Adenovirus hepatitis in an immunosuppressed adult patient.

The role of adenovirus as an etiologic agent of hepatic damage has been controversial. A fatal case of adenovirus infection with fulminant hepatitis in a young immunosuppressed adult patient is presented. Intranuclear inclusions were confined to the liver. Electron microscopy revealed crystalline arrays of virions within hepatocytes. This is apparently the first reported case of adenovirus hepatitis occurring in an adult. Adenovirus hepatitis represents another hazard for the immunosuppressed patient.

Multiple viral infections in HIV-infected children with chronically-evolving hepatitis.

Hepatic involvement was investigated in 31 children with perinatal HIV-1 infection, who were followed for 2-82 months (mean 30.5). Liver disease, as revealed by increased aminotransferase levels, liver biopsy or necroscopy, was diagnosed in 18 children (58%), of which 7 (22.5%) had acute hepatitis and 11 (35.5%) showed chronic liver disease. Overall, 40 persistently active or recurrent viral infections, as demonstrated by positive culture and/or detection of serum DNA, specific IgM, IgA and high levels of IgG, were revealed in the children with liver disease, while 12 similar infections were detected in 13 children without liver disease (p < 0.001). In particular, the children with liver disease showed a significantly (p < 0.002) higher incidence of cytomegalovirus (CMV) infections than children without liver disease (13 versus 3). Moreover, hepatitis C and B virus infections were revealed only in children with liver disease (5 and 1 patients, respectively). Clinical outcome showed a significantly (p < 0.001) higher mean survival in the children without liver disease than those with liver disease (47.5 versus 18.2 months). In fact, nine of the children with liver disease (50%) died, as opposed to only one of the children without liver disease (7.7%; p = 0.01). Based on these findings, liver disease is indicative of a poor prognosis in children with HIV infection, being related to the presence of multiple active viral infections.

Lassa virus hepatitis: a study of fatal Lassa fever in humans.

In order to explore the significance of a previous observation that the most important pathologic changes in fatal Lassa fever are hepatic, we have studied postmortem liver biopsies from 19 patients with fatal Lassa fever. We observed a vigorous macrophage response to cellular damage, but we found no evidence of lymphocyte infiltration in infected hepatic tissues. Using semi-quantitative estimates of liver cell damage, we found a wide range in the severity and progression of Lassa virus hepatitis in our fatal cases. We have classified for descriptive purposes three general nosopoeitic phases: active hepatocellular injury (less than 20% necrosis), continued damage and early recovery, and mitotic activity representing hepatic recovery. We conclude that the liver goes through cellular injury, necrosis and regeneration and any or all may be present at death. In no instance was the degree of hepatic damage sufficient to implicate hepatic failure, and all three phases were represented among our cases. We conclude that the hepatitis of Lassa fever in humans is not the primary cause of death.

Identification and detection of long incubation non-A, non-B hepatitis virus and associated antigens or antibodies.

Three distinct antigen/antibody systems supposedly associated with an HBV-like virus of non-A, non-B hepatitis have been identified. Because of previously demonstrated cross-reactivity with HBe/3 and HBc antigens and other analogies the following terminology is tentatively used. 1. The previously reported serum antigen has been redesignated non-A, non-B e antigen, since it is equivalent to HBe/3 Ag and cross-reacts with it. Non-A, non-BeAg or Ab were detected in 51/62 post-transfusion and 11/56 sporadic acute non-A, non-B hepatitis cases, and in 12/14 cases affecting staff members. In non-A, non-B chronic persistent or active hepatitis and cryptogenic cirrhosis, the prevalence was similarly high: 14/18, 22/48 and 12/18 respectively. Ten out of 26 implicated blood donors were found positive for non-A, non-BeAg accounting for 7 out of 8 post-transfusion cases. A high prevalence of non-A, non-BeAg was also found in haemophiliacs (11/48) and haemodialysed patients (6/42), whereas anti-non-A, non-Be was respectively detected in 4/48 and 6/42 of these cases. 2. Using immunofluorescence, a second antigen termed non-A, non-BcAg has been identified in liver biopsies from 55/84 non-A, non-B chronic hepatitis or cryptogenic cirrhosis cases. All 8 positive biopsies examined by electron microscopy revealed clusters of 22--25 nm intranuclear particles identical to those described in chimpanzees. Anti-non-A, non-Bc detectable by counter-electrophoresis and indirect immunofluorescence was found in the serum of all patients of which biopsy was positive for non-A, non-BcAg. Anti-non-A, non-Bc was also detected in 5/5 non-A, non-BeAg positive cases of post-transfusion hepatitis, 2--6 weeks after onset end remained positive for the 6 month follow-up period. 3. A third antigen, tentatively designated non-A, non-BsAg, has been found less frequently than non-A, non-BeAg in serum. However, it was detectable in 3/18 and 2/12 washed ultracentrifugation pellets of sera positive for non-A, non-BeAg or anti-non-A, non-Be, respectively.

The agents of non-A, non-B viral hepatitis.

Recent studies have provided physicochemical and electron microscopic evidence for the existence of two distinct agents of posttransfusion non-A, non-B (NANB) hepatitis. One of these agents is chloroform-resistant and is not associated with the formation of unique ultrastructural structures in infected liver. The other agent is CHCl3-sensitive, induces the formation of characteristic hepatocyte cytoplasmic tubules, and interferes with concurrent HAV or HBV infection in experimentally inoculated chimpanzees. The tubuleforming agent (TFA) has also been shown to pass through an 80 nm capillary pore membrane filter, suggesting that it is a small enveloped (or lipid-containing) virus. The TFA can also be recovered from low titer (less than or equal to 10(5) infectious doses/ml) chronic-phase chimpanzee plasma by use of a multi-step purification procedure that assumes the agent is a small enveloped RNA virus with an approximate buoyant density of 1.24 g/cm3 and a sedimentation coefficient of 200-280 S. The apparent lack of nucleic acid homology between the NANB-TFA and HBV further suggests that the NANB-TFA is either Togavirus-like or belongs to another or as yet undefined class of RNA or DNA virus.

Assay of HBV DNA in the plasma of HBV-carrier chimpanzees superinfected with non-A, non-B hepatitis.

A dot hybridisation technique was used to monitor the levels of hepatitis B virus (HBV) DNA in the plasma of two HBV-carrier chimpanzees which had been inocula ed with documented infectious non-A, non-B hepatitis agents. A marked decrease in the quantity of HBV DNA in the plasma during the acute phase of the non-A, non-B hepatitis was observed in both carriers. The possible role of interferon or a similar antiviral agent in modulation of the HBV-carrier state is discussed. Hybridisation may become, in due course, the method of choice for examining blood samples for infectious hepatitis B virus.

The aetiology of acute viral hepatitis in the western region of Saudi Arabia.

Of the 1050 sera of acute viral hepatitis patients admitted to the Infectious Diseases Hospital in Jeddah, Saudi Arabia, over a one-year period, 40.9% were due to hepatitis A, 21.5% to hepatitis B, and 37.6% to non-A, non-B (NANB) hepatitis. The mean age for hepatitis A patients was 4 +/- 2.4 years, with no sex preponderance. The mean ages for hepatitis B and NANB were 26.1 +/- 11.9 and 28.8 +/- 14.2 years, respectively. A male to female ratio of 2:1 was noticed for both. 10% of HBsAg patients were positive for anti-delta. 32% of NANB cases were excluded on the bases of possessing specific IgM against cytomegalovirus (CMV), herpes simplex virus (HSV), Epstein-Barr virus (EBV) or Treponema pallidum. Only 9% of NANB cases had a history of blood transfusion. In conclusion, nearly all cases of acute jaundice in Saudi children are due to hepatitis A, whereas hepatitis B and NANB generally occur in adults. Other viruses such as CMV, HSV, and EBV are highly prevalent and must be excluded in all cases of NANB hepatitis.

IgM responses to hepatitis-A virus and hepatitis-B core antigen in acute and chronic liver disease in Malawi; possible role of non-A, non-B, hepatitis.

Of 33 patients with acute hepatitis in Malawi, 21 had infection by hepatitis-B virus (HBV), five by hepatitis-A virus (HAV) and seven, who had no markers of current HBV or HAV infections, were probably infected by the agent(s) of non-A, non-B, hepatitis. 87 of 88 sera from persons without liver disease contained antibody to HAV and 49 antibody to hepatitis-B surface antigen (anti-HBs) (six were positive for hepatitis-B surface antigen). The diagnosis of recent infection by HAV was made by detecting HAV-specific IGM in single serum samples and, although such tests showed that HAV caused acute hepatitis, its absence in patients with chronic liver disease suggests that, unlike HBV, infection by HAV does not play a role in chronic liver disease in Malawi. Anti-hepatis-B core antigen (anti-HBc)-specific IgM was detected in 19 of 21 patients with acute HBV infection, in three of five HbsAg-positive patients with cirrhosis, but in none of five HbsAg-positive patients with hepatoma.