Primary human herpesvirus 6 (HHV-6) infection is a frequent cause of acute febrile illness in small children, accounting for 20-30% of cases, mainly within the first two years of life. HHV-6 is the collective name used for two distinct viruses, HHV-6A and HHV-6B. While HHV-6A is mainly found in immunocompromised hosts, HHV-6B is a ubiquitous virus and the causative agent of a childhood disease named roseola infantum. Although it is considered a benign virus in immunocompetent patients, some cases of gastroenteritis, hepatitis and encephalitis have been described in this group(1,2).
The virus can replicate in human liver cells and may have direct cytopathic effects, as demonstrated by some in vitro studies. Hepatitis cases range from mild to severe, and in some patients it can lead to acute liver failure(2).
We report the cases of two twin sisters who presented in our hospital for fatigability, jaundice, acholic stools and hyperchromic urine. In the first patient, the symptoms began 10 days before the admission, and her sister followed five days later. They had no prior medical history. The clinical examination of both patients revealed jaundice, more evident on the face. The weight, height, blood pressure, heart and respiratory rate were within normal range. They presented sensibility in the upper right abdominal quadrant, without hepatosplenomegaly. The intestinal transit was adequate, with acholic stools, and they presented hyperchromic urine.
The laboratory tests revealed elevated liver enzymes (alanine aminotransferase 1184 IU/L and 1272 IU/L, and aspartate aminotransferase 1198 IU/L and 980 IU/L), elevated cholestasis enzymes (gamma-glutamyl transferase 69 IU/L and 88 IU/L) and hyperbilirubinemia (total bilirubin 7.18 mg/dL and 3.41 mg/dL, and direct bilirubin 4.98 mg/dl and 2.23 mg/dl). They had no coagulation abnormalities, inflammatory syndrome and electrolyte imbalances, having a normal kidney function. We excluded the infection with hepatitis viruses A, B, C and E, herpes simplex virus 1/2, Epstein-Barr virus (EBV), cytomegalovirus (CMV), Toxoplasma gondii and alpha-1 antitrypsin deficiency. The serum amino acids, urinary organic acids and serum acylcarnitine profile were within the normal range, excluding an inborn error of metabolism. We did not detect specific antibodies for autoimmune hepatitis (antinuclear, anti-smooth muscle or anti-liver-kidney microsomal antibodies). We performed further testing for enteroviruses infections that were negative and HHV-6 antibody testing, which was positive. HHV-6 infection was confirmed in each case by the detection of HHV-6 DNA in blood samples. The liver ultrasound was within normal ranges in both patients.
Based on the clinical picture and the laboratory examinations, we established the diagnosis of HHV-6 associated hepatitis. As the disease severity was moderate and the liver function was normal, there was no need for antiviral therapy. We administered combined treatment with pyridoxine and aspartic acid to sustain the functionality of the liver and ursodeoxycholic acid for the cholestasis syndrome. The evolution was excellent, with the normalization of the hepatic enzymes in about one week and the resolution of jaundice in about 10 days. They were discharged afterward with the first follow-up appointment in one month.
HHV-6 is a lymphotropic virus, part of the beta-herpesvirus family, alongside Epstein-Barr virus and cytomegalovirus. It is a ubiquitous virus that uses humans as the only host. The actual incidence of HHV-6 infection is difficult to appreciate due to the lack of active screening for this virus. Primary infection usually occurs between 6 and 12 months of life and may present as asymptomatic or as an acute febrile illness accompanied by a maculopapular rash. HHV-6 infection can be less frequently responsible for a more severe presentation, including hepatitis, meningoencephalitis or macrophage activation syndrome(3-5).
In immunocompetent hosts, like our patients, the primary infection can manifest as hepatitis, associated or not with exanthem subitum. HHV-6 infections often evolve asymptomatically, especially in immunocompetent hosts, or may present with maculopapular rash (exanthem subitum) accompanied by fever, especially in HHV-6B infection. Sometimes, HHV-6 can determine other manifestations like pneumonia, otitis, gastrointestinal symptoms, seizures, encephalitis, autoimmune conditions, Stevens-Johnson syndrome, drug-induced hypersensitivity syndrome, myocarditis, hepatitis or acute liver failure (ALF). But it is proven that HHV-6 may cause fulminant hepatic failure and acute decompensation of chronic liver disease in children. Studies in groups of children with ALF initially of unspecified etiology have shown significantly higher viral loads of HHV-6. These severe infections are mainly determined by HHV-6A and occur with predilection in immunosuppressed hosts or with preexisting chronic liver disease(6-9). ALF secondary to HHV-6 infection is very rare (less than 1% of ALF cases) but can be extremely severe, with a mortality of over 85% in the absence of treatment. Severe HHV-6 infection associated with fulminant hepatitis is due to the direct action of the virus and secondary to massive apoptosis of the liver cells by excess production of cytokines and free radicals. The first case of ALF secondary to HHV-6 infection was described in a 3-year-old Japanese girl, in 1990. Since then, several other cases have been reported, especially in older children or teenagers, but without studies in larger patients groups. Other hepatobiliary disorders which can occur in HHV-6 infection are acute decompensation of chronic liver disease in children, giant cell hepatitis, cholestatic hepatitis or specific manifestations of mononucleosis(6-10).
HHV-6 is an important complication in patients with a liver transplantation, proving the presence of the viral DNA in hepatic graft in the areas of confluent necrosis. A study performed on a large group of patients (173 liver transplants) comes from Germany. The high level of intrahepatic HHV-6 DNA is associated with decreased graft survival. In these cases, the detection of HHV-6 IgM antibodies is not significant. According to some authors, not even HHV-6 DNA in blood samples is significant, therefore the diagnosis of HHV-6 infection in transplant recipients should be made by liver biopsy. This theory is supported by the fact that high intrahepatic levels of HHV-6 DNA (more than 11.27 copies/1000 cells) was associated with decreased graft survival after liver transplant, while low levels of intrahepatic HHV-6 DNA (latent viral infection) were not. Also, large amounts of CMV and EBV may be present in the liver, but the viral load did not correlate with the graft survival(6-9).
After an acute infection, the virus enters a latent state, with the risk of reactivation under certain circumstances, like human immunodeficiency virus infection, stem cells or solid organ transplantation. The manifestations associated with viral reactivation include cytopenia, hepatitis, pneumonitis, central nervous system involvement or graft rejection(1-3). HHV-6 hepatitis in transplant recipients is more often secondary. Approximately 40-50% of patients develop HHV-6 infection around 2 to 4 weeks after transplantation(6).
The infection’s pathophysiology consists of the penetration of the virus into the cells and the integration of the DNA into the nucleus, where the replication takes place. The next step is the acquisition of the nucleocapsid and viral envelope, and then the virions are released by exocytosis into the cell membrane. The cycle results in the death of the affected cells and the replication of the virus. After the acute infection, the virus persists in various cells, especially macrophages. Another phenomenon attributed exclusively to the herpes viruses is chromosomal integration, which consists of binding the viral genome to the cell DNA in the telomeric region of a chromosome. The infection produces a cellular immune response of the CD4+ and CD8+ T cells(3,11-13).
Liver biopsy is rarely performed during HHV-6 related hepatitis, therefore there is a small amount of data about the microscopic aspect of liver inflammation. One case report of HHV-6 hepatitis in a heart transplant recipient described mild portal inflammatory infiltrates and syncytial transformation with giant cell formation in the biliary epithelium. Another report showed no difference between hepatitis caused by HHV-6 and the one related to EBV and CMV(15). In post-liver transplantation acute hepatitis, the presence of periportal confluent necrosis was associated with high viral load HHV-6 infection and not with other viruses who presented lobular necrotico-inflammatory activity without periportal necrosis. The periportal confluent necrosis may be useful for HHV-6 diagnosis(16).
For diagnostic purposes, it is difficult to differentiate between an acute infection and a reactivation. The most frequently used are serologic studies using immunofluorescence assay (IFA) and enzyme-linked immunosorbent assay (ELISA). Still, they cannot differentiate between the HHV-6 A and HHV-6 B subtypes, as it was in the cases presented above. Other methods, like real-time polymerase chain reaction (PCR), antigen studies or viral cultures, are less often used in immunocompetent patients. Still, they can be a helpful tool in cases of infection in transplant recipients(5).
There is no consensus about the proper treatment for HHV-6 infection. In mild cases, the symptom relief treatment is enough, but in other cases, like in transplant recipients presenting with severe disease, the use of antiviral agents is accepted. Foscarnet, cidofovir and ganciclovir are the viral polymerase DNA inhibitors that have shown the inhibition of viral replication in vitro. The efficacy of the antiviral treatment initiated must be monitored by measuring the viral load using the PCR technique(3,17).
The HHV-6 is known for causing systemic illness in immunocompromised hosts, but some mild-to-moderate hepatitis cases can be found in immunocompetent persons. The severity of cases is heterogeneous due to the association with other infections and illnesses, but it must be considered in cases of hepatitis of unknown cause.
Conflicts of interests: The authors declare no conflict of interests.