Cytomegalovirus hepatitis in liver transplantation: prospective analysis of 93 consecutive orthotopic liver transplantations

Ninety-three consecutive orthotopic liver transplantations in 78 patients were followed prospectively to study the incidence of cytomegalovirus (CMV) hepatitis. CMV hepatitis occurred in 13 (17%). The diagnosis was established by both histology and culture in 5, only by histology in 6, and only by culture in 2. All 13 patients had CMV viruria and 9 had viremia at diagnosis. CMV hepatitis developed in 64% of CMV-seronegative (pretransplantation) patients who received a liver from a CMV-seropositive donor, compared with 3% or 6% of CMV-seropositive patients who received a liver from a CMV-seronegative or CMV-seropositive donor, respectively (P less than .001). CMV hepatitis was not a cause of fulminant or irreversible liver dysfunction in any of the 13 cases. Ganciclovir was administered to 6 of the 13 patients and was associated with clinical and virologic cure in 5. CMV hepatitis was self-limited in patients not treated with ganciclovir (illness less severe). The presence of inclusions within the liver tissue correlated with active disease.     

The spectrum of liver disease in systemic lupus erythematosus: Report of 33 histologically-proved cases and review of the literature

The charts of 238 patients with systemic lupus erythematosus (SLE) were reviewed. Although not routinely screened for biochemical evidence of liver disease, 124 of 206 patients tested had at least one abnormal result, and 43 met strict criteria for the existence of liver disease. In most patients, a specific viral or drug etiology could not be implicated. The spectrum of liver disease in 33 patients from whom liver tissue was available included cirrhosis, chronic active hepatitis, granulomatous hepatitis, chronic persistent hepatitis and steatosis. Three of four cirrhotic patients demonstrated a peculiar form of cholestasis which resembled a “canalicular cast” of bile. Of the nine patients who had serial liver biopsies, four showed progression of their disease. Three patients died of liver failure. Liver involvement in SLE is more common than previously recognized. Severe and even fatal liver disease can occur.     

Detection by immunofluorescence of an antigen-antibody system in patients with acute and chronic non-A,non-B hepatitis

ABSTRACT— An antigen-antibody system has been identified by immunofluorescence in patients with non-A, non-B hepatitis. The non-A, non-B antigen was localized in the hepatocyte nuclei of liver biopsies from patients with acute post-transfusion or sporadic non-A, non-B hepatitis and in those from patients with chronic post-transfusion non-A, non-B hepatitis, the percentage of positive cells being most prominent in patients receiving immunosuppressive treatment. Absence of the antigen in normal livers and in livers from patients with type B hepatitis infection indicated its specific association with non-A, non-B infection. Antibody reacting with the nuclear antigen became detectable in serum during post-transfusion acute non-A, non-B hepatitis in 11 out of 15 cases; it was absent before transfusion. Six out of 12 cases of sporadic acute non-A, non-B hepatitis were also found to produce the antibody, which was repeatedly found to be absent during the acute phase in five patients with type A and in eight with type B hepatitis. The non-A, non-B antibody, mainly an IgM antibody, persisted in serum for prolonged periods of time after onset, both in patients showing biochemical resolution of their illness and in those who continued to have liver damage after the acute phase. Accordingly, eight out of nine patients withchronic non-A, non-B hepatitis were found positive for the antibody in serum, seven at the time the non-A, non-B antigen was detected in their liver. Thus this non-A, non-B associated antigen-antibody system shares remarkable similarities of behaviour with the “core” system of the hepatitis B virus.     

Cytomegalovirus hepatitis after bone marrow transplantation: An autopsy study with clinical,histologic and laboratory correlates

Mortality from cytomegalovirus disease after marrow transplantation can be reduced by treatment with antiviral drugs based on the detection of viremia and organ involvement. We examined autopsy liver specimens to determine the frequency, extent and outcome of cytomegalovirus hepatitis and whether cytomegalovirus hepatitis occurred in the absence of cytomegalovirus disease elsewhere. Autopsy specimens from 50 transplant patients were evaluated for cytomegalovirus‐infected cells, in five groups of 10, according to extent of CMV during life and at autopsy. Liver sections were examined by routine light microscopy, immunohistochemistry and in situ DNA hybridization. Clinical and laboratory data collected during the last 30 days of life were analysed as markers of liver cytomegalovirus infection. Cytomegalovirus‐infected cells were detected in the livers of 10/10 patients with cytomegalovirus infection during life and widespread cytomegalovirus at autopsy; in 3/20 livers from patients with cytomegalovirus infection during life but negative liver cultures at autopsy; and in 1/10 livers from cytomegalovirus‐seropositive patients who had been without other evidence of cytomegalovirus infection. Histology detected a lower density of cytomegalovirus‐bearing cells per unit area of liver, compared to immunohistochemistry and in situ hybridization. No cytomegalovirus‐infected cells were detected in livers from cytomegalovirus‐seronegative controls. No distinctive clinical or laboratory findings correlated with liver cytomegalovirus detection. CMV liver disease is common in allografted patients with disseminated CMV but may rarely be isolated to the liver, best demonstrated with IHC and ISH. Massive hepatic necrosis from CMV was not seen in any autopsy liver in this study.     

Liver disease in renal transplant recipients.

Significant liver disease developed in 14 patients after renal transplantation. Nine patients had morphologic and functional evidence of chronic active hepatitis. In general, these patients had few symptoms of liver disease, even though the course of chronic active hepatitis was progressive. Despite large doses of prednisone, cirrhosis ultimately developed in five patients. The cause of chronic active hepatitis could not be related to azathioprine or methyldopa therapy because there was no perceptible change in the course of liver disease after treatment with these drugs was stopped. Three patients were persistently positive for hepatitis B surface antigen. Isolated instances of granulomatous hepatitis (Mycobacterium kansasii) and of prolonged intrahepatic cholestasis were encountered in patients with chronic active hepatitis. Two patients had acute cytomegalovirus hepatitis. There was one episode each of fulminant herpes simplex hepatitis and severe fatty metamorphosis.     

婴儿巨细胞病毒性肝炎临床病理分析

目的 分析婴儿巨细胞病毒(CMV)性肝炎的临床病理表现,以提高对该病的认识.方法 30例CMV性肝炎患儿临床资料分析并行肝穿刺活组织检查,光镜及电镜观察肝细胞的特征性改变.结果 婴儿CMV肝炎的临床主要表现为黄疸、肝脾肿大及伴发症状、体征;实验室检查肝功能异常、CMV相关病毒检查阳性;影像学检查显示肝脏增大;肝穿刺活组织光镜观察显示肝细胞变性,坏死、纤维化、淤胆等一般性损伤,特征性改变为肝细胞内病毒包涵体、巨细胞样肝细胞形成和局部"假腺管"样排列,电镜观察找到病毒颗粒.结论 CMV DNA和抗体检查对于婴儿CMV性肝炎的诊断应用有限,疑似病例的肝穿刺活组织检查有助于明确CMV性肝炎的诊断.     

Clinical, histologic and serologic evaluation of patients with acute non-A-E hepatitis in north-eastern Brazil: is it an infectious disease?

Non-A-E hepatitis and acute cryptogenic hepatitis are the names given to the disease of patients with clinical hepatitis, but in whom serologic evidence of A-E hepatitis has not been found. Over a period of 8 years, we evaluated in Brazil 32 patients who fulfilled the criteria for this diagnosis in order to determine patterns of the clinical illness, laboratory parameters, or histologic features. Each patient was subjected to virologic tests to exclude A-E hepatitis and cytomegalovirus/Epstein-Barr virus infection. Drug-induced hepatitis and autoimmune disease were also excluded. Wilson's disease was excluded in young patients. The course of the disease was clinical/biochemical recovery in 3 months in 25 patients and persistent alanine aminotransferase (ALT) elevation in 7 patients. Three of these had chronic hepatitis, and one had severe fibrosis on liver biopsy. During the acute illness, mean peak ALT was 1267 IU/L, bilirubin was 4.0 mg/dL, and ferritin was 1393 IU/mL. GB virus type C (GBV-C) was found in six patients, and TT virus (TTV) in five patients. We conclude that, in Brazil, non-A-E hepatitis probably originates from still unidentified viruses. The course of the disease and the histologic patterns are similar to those recorded for known viruses. Continuous survey for the specific etiologic agents is needed.     

Fulminant hepatitis after allogenic bone marrow transplantation caused by reactivation of hepatitis B virus with gene mutations in the core promotor region

Under immunosuppressive conditions after hematopoietic stem cell transplantation (HSCT), even if hepatitis B virus (HBV) antigen is negative but hepatitis B surface antibody (HBsAb) or hepatitis B core antibody (HBcAb) is presented, HBV reactivates and sometimes causes fulminant hepatitis. However, it remains unclear which patients will develop fulminant hepatitis, or whether fulminant hepatitis is caused by host-related factors or by virus-related factors. A 30-yr-old man with a history of aplastic anemia since 3 yr of age underwent allogenic BMT, when HBsAb and HBcAb were positive but HBs antigen (HBsAg) was negative. The donor was negative for HBsAg, HBsAb and HBcAb. After transplantation, the patient was complicated by acute graft-vs.-host disease (GVHD), cytomegalovirus infection, intestinal thrombotic microangiopathy and aspergillus colitis. Chronic GVHD was well controlled by FK506 and prednisolone. Twenty months after transplantation, the patient was admitted with general fatigue and liver dysfunction and was found to be positive for HBsAg and HBeAg. His serum HBV-DNA level was >8.8 log of the genome equivalent (LGE)/mL. Therefore, he was diagnosed as having hepatitis B caused by HBV reactivation and 100 mg/d lamivudine treatment was started. However, jaundice and hepatic failure deteriorated and became fatal. On analysis of the HBV-DNA, two adjacent gene mutations in the core promoter region (T1762/A1764) were detected. Increased replication of the mutated HBV might have caused HBV reactivation which progressed to fulminant hepatitis.     

Impact of human herpes virus 6 in liver transplantation

Human herpes virus 6 (HHV-6) infects > 95% of humans. Primary infection which occurs mostly during the first 2 years of life in the form of roseola infantum, non-specific febrile illness, or an asymptomatic illness, results in latency. Reactivation of latent HHV-6 is common after liver transplantation. Since the majority of human beings harbor the latent virus, HHV-6 infections after liver transplantation are most probably caused by endogenous reactivation or superinfection. In a minority of cases, primary HHV-6 infection may occur when an HHV-6-seronegative individual receives a liver allograft from an HHV-6-seropositive donor. The vast majority of HHV-6 infections after liver transplantation are asymptomatic. Only in a minority of cases, when HHV-6 causes a febrile illness associated with rash and myelosuppression, hepatitis, gastroenteritis, pneumonitis, and encephalitis after liver transplantation. In addition, HHV-6 has been implicated in a variety of indirect effects, such as allograft rejection and increased predisposition to and severity of other infections, including cytomegalovirus, hepatitis C virus, and opportunistic fungi. Because of the uncommon nature of the clinical illnesses directly attributed to HHV-6, there is currently no recommended HHV-6-specific approach prevention after liver transplantation. Asymptomatic HHV-6 infection does not require antiviral treatment, while treatment of established HHV-6 disease is treated with intravenous ganciclovir, foscarnet, or cidofovir and this should be complemented by a reduction in immunosuppression.     

晚期血吸虫病患者肝细胞核内嗜酸性包涵体的观察

对155例晚期血吸虫病病例肝脏活检组织进行病理观察,并检测肝内乙肝表面抗原(HBsAg)和乙肝核心抗原(HBcAg)。结果,88例(56.8％)乙肝抗原(HBAg)阳性;30例(19.4％)肝细胞核内存在嗜酸性包涵体,其中18例(60％)HBAg也阳性。这些包涵体可能是巨细胞病毒、单纯疱疹病毒等肝内感染的标志。肝内HBAg或包涵体阳性患者的肝实质病变显著加重。表明合并其它病毒的肝内感染也可加重晚期血吸虫病的肝脏病变,并可能是发生门脉性肝硬化的原因之一。     

Cytomegalovirus infection of the liver in transplant recipients

Thirty-two transplant recipients with cytomegalovirus (CMV) infection documented by positive culture of blood and/or organs other than the liver were evaluated for hepatic involvement. Thirteen of the 32 (41%) had evidence of hepatic involvement with CMV. Inclusions alone were present in three patients; liver cultures alone were positive for CMV in three; and both were present in seven. Although the presence of CMV inclusions was the only histological feature that clearly separated the groups with and without hepatic involvement, two items helpful in finding inclusions were lobular aggregates of polymorphonuclear cells and portal karyorrhexic debris. The presence of liver involvement had a significant correlation with multiple organ infection, indicating it is a good marker of widely disseminated disease. This study indicates that liver histology and culture are useful and complementary methods for documentation of hepatic involvement (hence, tissue invasion) in immunocompromised patients with CMV infection.     

Diagnostic criteria of acute liver failure: A report by the Intractable Hepato-Biliary Diseases Study Group of Japan

The diagnostic criteria of fulminant hepatitis in Japan are different from those of acute liver failure in Europe and the United States, both in regard to the histological features in the liver and the cutoff values of the prothrombin time. Thus, the Intractable Hepato‐Biliary Disease Study Group established novel diagnostic criteria for “acute liver failure” in Japan based on the demographic and clinical features of the patients. Patients showing prothrombin time values of 40% or less of the standardized values or international normalized ratios of 1.5 or more caused by severe liver damage within 8 weeks of onset of the symptoms are diagnosed as having “acute liver failure”, where the liver function prior to the current onset of liver damage is estimated to be normal. Acute liver failure is classified into “acute liver failure without hepatic coma” and “acute liver failure with hepatic coma,” depending on the severity of the hepatic encephalopathy; the latter is further classified into two types, the “acute type” and the “subacute type”, in which grade II or more severe hepatic coma develops within 10 days and between 11 and 56 days, respectively, after the onset of disease symptoms. Patients without histological findings of hepatitis, such as those with liver damage caused by drug toxicity, circulatory disturbance or metabolic disease, are also included in the disease entity of “acute liver failure”, while acute‐on‐chronic liver injuries, such as liver injury caused by alcohol, are excluded. A nationwide survey of “acute liver failure” in Japan based on the novel criteria is proposed.     

Polymerase chain reaction to detect human cytomegalovirus in livers of infants with neonatal hepatitis.

Neonatal hepatitis is closely related to human cytomegalovirus infection in Taiwan, a conclusion based on serological and urine culture studies. To obtain more direct evidence further relating cytomegalovirus to the pathogenesis of neonatal hepatitis, the cytomegalovirus genome was studied in the liver tissues of 50 infants with neonatal hepatitis using the polymerase chain reaction (PCR). Liver tissues from 26 infants with biliary atresia and another 30 infants and children with diagnoses other than neonatal hepatitis, cholestasis, or hepatitis were also studied for comparison. Sequences from the immediate early gene 1 and 2 regions were used as primers. The liver tissues from 23 (46%) of the 50 infants with neonatal hepatitis were positive for cytomegalovirus genome, whereas those of 2 of the 26 infants with biliary atresia and none of the liver tissues from 30 infants and children without neonatal hepatitis were positive for cytomegalovirus genome, by PCR. The results of PCR correlated well with that of serology and urine culture. This study provides further evidence of cytomegalovirus in the pathogenesis of neonatal hepatitis.     

Cytokeratin inclusions in alcoholic liver disease and their relation to the amount of alcohol intake

ABSTRACT: In the present study, the frequency and the distribution pattern of immunoreactive hepatocytic cytokeratin (CK) inclusions was investigated using the monoclonal antibody (MAb) CAM 5.2 detecting CKs 8, 18 and 19. The CK antigenicity of the inclusions was confirmed on frozen sections with MAbs for the CKs 7, 8, 17, 18 and 19. The frequency of hepatocytic CK aggregates was compared to the presence of non-alcoholic and alcoholic liver disease (ALD) as well as to the average all-year daily ethanol intake of 195 consecutive males subjected to medicolegal autopsy. Hepatocytic CK inclusions were infrequent in patients with normal liver histology, portal fibrosis and/or portal inflammation. In ALD, however, inclusions were observed in 35.6% of patients with fatty liver, in 63.2% of patients with alcoholic hepatitis, in 30.8% of patients with bridging fibrosis and in 60.0% of patients with liver cirrhosis. In all specimens studied, the inclusions were reactive only for CKs 8 and 18, CKs 7, 17, and 19 being unreactive. The frequency of inclusion bodies increased, paralleling increasing average all-year daily alcohol consumption. Compared to non-drinkers, a daily intake of between 40 and 80 g of absolute alcohol was associated with a statistically significantly (relative risk, RR=6.6) increased risk of formation of aggregates. Similarly, daily consumption exceeding 80 g was related to increased (RR=6.0) frequency of CK aggregates. The frequency of full-blown “classical” Mallory bodies (MBs) was, however, increased (RR=8.9) only in patients with a daily intake exceeding 160 g. These results indicate that CK inclusions are unequivocally related to the presence of ALD in longitudinal autopsy series. Their frequency in autopsy series was, however, significantly lower than their frequency in previous studies comprising hospitalised patients diagnosed as having alcoholic liver disease. Furthermore, our results suggest that a daily ethanol intake between 40 and 80 g can increase the risk of appearance of smaller CK inclusions, although the risk of occurrence of “classical” full-blown MBs was associated only with heavy drinking exceeding 160 g of absolute alcohol daily.     

A case of dermatomyositis with “liver disease associated with rheumatoid diseases” positive for anti-liver–kidney microsome-1 antibody

We reported a case of dermatomyositis (DM) with liver disturbance in a 50-year-old Japanese female. She presented with fever, muscle weakness, and typical DM rashes. On clinical and serological examinations, the liver impairment was initially diagnosed as probable autoimmune hepatitis, which was denied by a histological study despite positive anti-liver–kidney microsome-1 antibody. Finally, she was diagnosed as having DM with “liver disease associated with rheumatoid diseases”, and treatment with oral prednisone (40 mg/day) achieved normalization of liver and muscle enzyme levels as well as improvement of symptoms associated with DM. Liver involvement in patients with polymyositis (PM)/DM has not been well described and is considered to be uncommon. Full clarification of the etiology of liver impairment with a histological examination in collagen diseases including PM/DM is useful to determine the proper dose of corticosteroids for the treatment of collagen diseases and their liver complications.     

Interferon-gamma production by peripheral blood mononuclear cells of patients with chronic liver disease

We investigated the role of the interferon system in the pathogenesis of chronic liver disease. Interferon-gamma production by peripheral blood mononuclear cells was measured with an ELISA. While concanavalin A-stimulated and recombinant interleukin 2-stimulated production of interferon-gamma in patients with chronic active hepatitis and liver cirrhosis was significantly decreased when compared with that of controls (518 +/- 189 and 729 +/- 195 units per ml, mean +/- S.D.), there was also a lot of overlap. Addition of indomethacin to the cultures partially restored interferon-gamma production in patients with chronic active hepatitis and liver cirrhosis, indicating that suppressor function of monocytes was, in part, responsible for the diminished interferon-gamma production. Serial studies showed that interferon-gamma production rose during acute deterioration of illness, during treatment with interleukin 2 and with the improvement of clinical course. Interferon-gamma production was not different among hepatitis B e antigen or antibody positive, and non-A, non-B patients with chronic active hepatitis and liver cirrhosis. Our findings suggest that diminished interferon-gamma production is associated with disease severity in chronic liver disease, irrespective of the hepatitis B virus carrier state. It would be interesting to compare the efficacy of treatment with interferon-gamma or interferon-gamma inducers such as interleukin 2 in chronic hepatitis B patients with and without decreased in vitro interferon-gamma production.     

Green neutrophil and monocyte inclusions – time to acknowledge and report

Bright green inclusions in neutrophils have been reported as a sign of impending patient death. Here we report a series of 20 patients in whom green inclusions were identified in neutrophils or monocytes. Thirteen (65%) of the patients died within days of the detection of the inclusions. A common feature to almost all patients was ischaemic or hypoxic hepatitis which, in fatal cases, was associated with lactic acidosis. Light and electron microscopy indicated that the inclusions were lipid‐rich, probably derived from lipofuscin‐like material released from necrotic liver parenchymal cells. The majority of patients were known to be seriously ill at the time of detection of neutrophil inclusions. We recommend that the detection of green inclusions, which we refer to as ‘critical green inclusions’, is acknowledged and reported by laboratories and correlated with clinical findings.     

LUPOID HEPATITIS: COMPUTER ANALYSIS DEFINING “HEPATITIS” AND “CIRRHOSIS” PHASES AND RELATIONSHIPS BETWEEN HEPATOCELLULAR DAMAGE AND IMMUNE REACTIONS IN THE LIVER

The interrelationships between histopathological, clinical, biochemical, and serological indices in 30 patients with lupoid hepatitis were analysed by a digital computer which was used to calculate 225 correlation coefficients. First, the study defined two groups of significantly interrelated histological indices corresponding to “hepatitis” and “cirrhosis” phases of the disease. The hepatitis phase comprised liver cell necrosis, Kupffer cell hyperplasia and plasma cell accumulation, and the cirrhosis phase comprised loss of architecture, fibrosis, bile duct proliferation, and lymphocyte and plasma cell accumulation. Secondly, the study defined significant interrelationships in the hepatitis phase between hepatocellular damage and an immune reaction as shown by plasma cell accumulation in the liver, gamma globulin increase in the serum and lupus erythematosus (LE) cell positivity. The immune reaction is, in part at least, to antigens of damaged liver cells; it may be entirely a consequence of damage from a primary process, such as a virus infection, or it may be an autoimmune cause of continuing cell injury. The analysis did not discriminate between these two possibilities.     

Acute hepatitis A virus infection: a review of prognostic factors from 25 years experience in a tertiary referral center

BACKGROUND/AIMS: Hepatitis A is usually a mild, self-limiting illness but can result in severe or fatal disease. We reviewed 25 years experience to determine what factors predispose to severe or fatal disease. METHODOLOGY: We identified 97 patients admitted between 1974-1999 with acute hepatitis A. Clinical, biochemical and histological data were correlated with outcome and patients were screened for evidence of hepatitis B or C virus coinfection and coexisting autoimmunity. RESULTS: Fifty-five patients had liver failure with hepatic encephalopathy of whom 29 died and 6 underwent liver transplantation. Patients with liver failure were significantly older than those without (mean age: 42.2 +/- 13.3 vs. 29.2 +/- 7.8, P = 0.0001), and liver failure patients who died were older than those surviving (47.5 +/- 12.7 vs. 36.3 +/- 11.6, P = 0.0001). Hyperacute liver failure predicted good outcome (P = 0.0001). Three patients with viral coinfection had established cirrhosis and died. Detectable autoantibodies did not correlate with outcome or severity. Patients acquiring infection abroad were more likely to have liver failure than those acquiring infection in the UK (P = 0.023). CONCLUSIONS: Age is the best predictor for outcome in patients with liver failure from hepatitis A. Underlying chronic liver disease, and the time of onset of encephalopathy are also factors affecting outcome. Infection acquired abroad has a worse prognosis.     

Human herpesvirus 6 infections after liver transplantation

Human herpesvirus 6 （HHV-6） infections occur in 〉 95% of humans. Primary infection, which occurs in early childhood as an asymptomatic illness or manifested clinically as roseola infantum, leads to a state of subclinical viral persistence and latency. Reactivation of latent HHV-6 is common after liver transplantation, possibly induced and facilitated by allograft rejection and immunosuppressive therapy. Since the vast majority of humans harbor the virus in a latent state, HHV-6 infections after liver transplantation are believed to be mostly due to endogenous reactivation or superinfection （reactivation in the transplanted organ）. In a minority of cases, however, primary HHV-6 infection may occur when an HHV-6 negative individual receives a liver allograft from an HHV-6 positive donor. The vast majority of documented HHV-6 infections after liver transplantation are asymptomatic. In a minority of cases, HHV-6 has been implicated as a cause of febrile illness with rash and myelosuppression, hepatitis, pneumonitis, and encephalitis after liver transplantation. In addition, HHV-6 has been associated with a variety of indirect effects such as allograft rejection, and increased predisposition and severity of other infections including cytomegalovirus （CMV）, hepatitis C virus, and opportunistic fungi. Because of the uncommon nature of the clinical illnesses directly attributed to HHV-6, there is currently no recommended HHV-6- specific approach to prevention. However, ganciclovir and valganciclovir, which are primarily intended for the prevention of CMV disease, are also active against HHV-6 and may prevent its reactivation after transplantation. The treatment of established HHV-6 disease is usually with intravenous ganciclovir, cidofovir, or foscarnet, complemented by reduction in the degree of immunosuppression. This article reviews the current advances in the pathogenesis, clinical diagnosis, and therapeutic modalities against HHV6 in the setting of liver transplantation.