Insight into the distinctive paradigm of Human Cytomegalovirus associated intrahepatic and extrahepatic cholestasis in neonates.

Human Cytomegalovirus has been implicated as a probable cause for the development of hepatic cholestasis among neonates. Our study tried to ascertain the exact demographic, biochemical and immunological markers to differentially diagnose patients with HCMV associated intrahepatic and extrahepatic cholestasis and also decipher the phylogenetic variability among the viral strains infecting the two groups. A total of 110 neonates collected over a span of 2 years were selected for the study classified into four different groups based on the presence of hepatic cholestasis and active HCMV infection. Our analysis predicted that total Cholesterol, GGT, ALP and TNFα were the only significant biological markers with exact cut-off scores, capable of distinguishing between HCMV associated intrahepatic and extrahepatic cholestasis. We confirmed that in patients belonging to both of these groups, the inflammasome is activated and the extent of this activation is more or less same except for the initial activators NLRP3 and AIM2 respectively. When we performed two separate phylogenetic analyses with HCMV gM and gN gene sequences, we found that in both cases the sequences from the IHC and EHC groups formed almost separate phylogenetic clusters. Our study has shown that the HCMV clinical strains infecting at intrahepatic and extrahepatic sites are phylogenetically segregated as distinct clusters. These two separate groups show different physiological as well as immunological modulations while infecting a similar host.

Biliary atresia: the animal models.

Biliary atresia (BA) is a progressive fibrosing process of the neonatal biliary tree and liver, of unknown origin, and an as-yet unexplained pathologic mechanism. The crucial point is to elucidate the origin of this rare disease to change palliative surgery to etiology-related procedures. Patient-based research can only begin at the time of the Kasai procedure and does not allow retracing of the pathology back to its origin. Basic research has focused on similar diseases in the veterinary literature and started to simulate BA in animal models. Unfortunately, even after 50 years of research, no knowledge has been gained from such models, which has led to a single clinical application. This article reviews BA in the context of the animal models available and discusses whether future studies are promising or futile.

High frequency of human cytomegalovirus DNA in the liver of infants with extrahepatic neonatal cholestasis.

BACKGROUND: Biliary atresia (BA) is the most severe hepatic disorder in newborns and its etiopathogenesis remains unknown. Viral involvement has been proposed, including the human cytomegalovirus (HCMV). The aims of the study were to use the polymerase chain reaction (PCR) to screen the liver tissue of infants with extrahepatic cholestasis for HCMV and to correlate the results with serological antibodies against HCMV and histological findings. METHODS: A retrospective study in a tertiary care setting included 35 patients (31 BA, 1 BA associated with a choledochal cyst, 2 congenital stenosis of the distal common bile duct and 1 hepatic cyst). HCMV serology was determined by ELISA. Liver and porta hepatis were examined histologically. Liver samples from infants and a control group were screened for HCMV DNA. RESULTS: Twelve patients had HCMV negative serology, 9 were positive for IgG antibodies and 14 were positive for IgG and IgM. Nine liver and seven porta hepatis samples were positive for HCMV DNA but none of the control group were positive (general frequency of positivity was 34.3%-12/35). There was no correlation between HCMV positivity by PCR and the histological findings. The accuracy of serology for detecting HCMV antibodies was low. CONCLUSION: These results indicate an elevated frequency of HCMV in pediatric patients with extrahepatic neonatal cholestasis. They also show the low accuracy of serological tests for detecting active HCMV infection and the lack of correlation between HCMV positivity by PCR and the histopathological changes.

Aetiological factors in neonatal cholestasis.

UNLABELLED: The aim of the study was to investigate factors of possible importance for the aetiology of neonatal cholestasis. The medical records of 85 cholestatic infants were retrospectively reviewed. The most common diagnoses were extrahepatic biliary atresia (n = 30 patients), alpha1-antitrypsin deficiency (n = 11) and progressive familial intrahepatic cholestasis (n = 11). The mothers of the patients with biliary atresia had a higher mean age and were more commonly treated for gestational diabetes than the mothers of patients with intrahepatic neonatal cholestasis. The morbidity and mortality in the siblings of patients with biliary atresia were also greater than expected. There was a seasonal variation of the birth months in the biliary atresia group. possibly indicating an association to viral infections. Signs of ongoing cytomegalovirus infection were more common in both the extrahepatic and the intrahepatic group. CONCLUSIONS: Progressive familial intrahepatic cholestasis may be a more common cause of neonatal cholestasis in Sweden than reported elsewhere. A maternal vulnerability, of genetic or other origin, is suggested in the aetiology of biliary atresia. The true pathogenetic importance of cytomegalovirus infection in patients with neonatal cholestasis of different origins remains to be established.

The viral association of neonatal cholestasis in Sweden: a possible link between cytomegalovirus infection and extrahepatic biliary atresia.

BACKGROUND: In addition to earlier reports on the association between viral infections and intrahepatic neonatal cholestasis, in recent studies, investigators have suggested a similar link to extrahepatic biliary atresia. METHODS: Fifty-nine cholestatic infants (mean age 8 weeks) were investigated for signs of infection with a large spectrum of viruses. Twenty-one infants had extrahepatic biliary atresia, 38 had intrahepatic cholestasis. The virologic methods included serologic investigation in 59 infants and 54 mothers, virus isolation from stools (49 infants), urine (58 infants) and liver biopsies (40 infants). Polymerase chain reaction was used to detect cytomegalovirus DNA in 25 of the liver biopsy specimens. Two control groups, one with 35 noncholestatic infants and one with 111 healthy, pregnant women were checked for serologic signs of cytomegalovirus. RESULTS: Nineteen of 59 (32%) cholestatic infants, including 8 of 21 (38%) with extrahepatic biliary atresia, compared with 2 of 35 (6%) control infants had cytomegalovirus-immunoglobulin (Ig) M detected in serum (p < 0.01). Fifty-one of 54 (94%) tested mothers of cholestatic infants were seropositive for cytomegalovirus, compared with 83 of 111 (75%) control mothers (p < 0.01). Cytomegalovirus DNA in liver specimens was detected by polymerase chain reaction in 9 of 18 (50%) analyzed patients with biliary atresia and in specimens from 3 of 7 patients with intrahepatic cholestasis. CONCLUSIONS: Cytomegalovirus infection may play a role, not only in intrahepatic neonatal cholestasis, as was suggested earlier, but also in extrahepatic biliary atresia. The pathogenetic mechanism for this link remains to be established.

Extrahepatic biliary stricture associated with cytomegalovirus in a liver transplant recipient.

We describe a patient who developed a stricture in the distal common bile duct 6 weeks after orthotopic liver transplantation. Histopathologic examination of the bile duct epithelium in the region of the stricture showed characteristic cytomegalovirus (CMV) inclusions. CMV was also identified in pulmonary alveoli and in the duodenum. Although CMV has been demonstrated in the biliary epithelium of AIDS patients with extrahepatic biliary strictures and biliary obstruction, this entity has not, to our knowledge, been described in liver transplant recipients. This report confirms that CMV infection should be included as a probable cause of extrahepatic biliary strictures and bile duct obstruction in liver transplant patients.