This case report describes the case of a young adult patient who developed ALF that was facilitated by a context of immunoparesis. This patient’s malnutrition and alcohol consumption are susceptibility factors to infection and to liver toxicity. Malnutrition influences the immune system through epigenetic changes, impaired T-cell function, and disruption of the gut microbiota. These effects lead to a compromised immune system, increasing individuals’ vulnerability to infections and other diseases [13]. Additionally, binge drinking increases the risk of infection [14].

Since we have detected HHV-6B in peripheral blood and in liver tissue, this infection was considered the possible cause of the ALF. This patient’s fever, thrombocytopenia, leukopenia, anemia, and hepatitis are manifestations consistently associated with HHV-6 infections [4]. The temporal association between the acute phase of illness and the evidence of viremia by PCR supports an active infection by HHV-6B. Viral loads above 1,000 copies per mL of whole blood correspond to active infections [4]. However, one must exclude chromosomally integrated HHV-6 (ciHHV-6; found in 0.2–1% of the adult population), which is usually associated with viremia exceeding 1 million copies per mL [4]. Although this patient’s viral load was not in this range of values, we did not test for the presence of ciHHV-6, and this can be a limitation of our case. Immunosuppression is the major factor promoting endogenous HHV-6 reactivations, with possible hepatic injury [4]. However, we cannot determine if this is a primary infection (though unlikely given the patient’s age), an endogenous reactivation, or an exogenous reinfection. Also, the unavailability of HHV-6 antibody testing at our center did not help us in this issue.

Therefore, the patient’s immunoparesis in the context of malnutrition and binge drinking, the chronology of clinical symptoms associated with an HHV-6B viral load compatible with active infection, the correspondence between the nature of symptoms and the known tropism of the virus for liver tissue, the association between active infection and disease in comparable contexts, and the absence of other causative pathogens all support a causative relationship between HHV-6B and the ALF. However, there is a recognized difficulty in ascribing causality to HHV-6 in clinical manifestations concomitant with active infections. In this case, in particular, we must not oversee the other factors implicated and facilitating this ALF. Also, we cannot rule out a synergistic pathogenic role.

This patient took paracetamol shortly before presenting to the ED, and her usual dose was 3 g, three times a week. Although asymptomatic elevations of aminotransferase levels are sometimes seen with chronic use at the maximum recommended daily dose of 4 g, these elevations are typically less than three times the ULN [12]. However, our patient was in greater risk of hepatotoxicity due to malnutrition and excessive alcohol consumption [12, 15, 16]. For at-risk patients, the threshold for referral for further evaluation is lower than for patients without risk factors and is advised for ingestion of more than 4 g or 100 mg/kg within 24 h, whichever is less [12, 15]. Accordingly, this patient’s limit to further clinical evaluation would be 3.9 g within 24 h, slightly more than her usual 3 g. Even so, we decided to initiate NAC, given the highly increased transaminases, a paracetamol level exceeding 10 µg/mL (the recommended threshold for management of repeated supratherapeutic ingestion [12]) and its benefits in patients with hepatotoxicity.

Supportive treatment for ALF and cessation of hepatic offending agents (malnutrition, alcohol, paracetamol) were decisive in the patient’s outcome. As previously mentioned, in this case antiviral drugs active against HHV-6 were not started also due to an already favorable evolution when the virus was identified. Since the infections by HHV-6 are rare, an unambiguous causative role is frequently difficult to establish, and active HHV-6 infections are often spontaneously controlled, it remains unclear in which circumstances an antiviral treatment should be started [4, 9]. However, it is essential to reverse immunosuppression, when it is present and can be medically modulated [4].

The most common culprits for the histologic pattern described in this case are medications, illicit drugs, herbal products, and viruses. Regarding the suspicion of paracetamol, it fits in this pattern when taken in high doses, often in cases of attempted suicide, which is not compatible with the patient’s reported history. As mentioned, viruses can also be responsible for this pattern [2, 3, 17], in particular HSV (although the negative immunohistochemistry does not favor), adenovirus, and HHV-6. However, the pattern of necrosis of the first two is non-zonal, while in HHV-6, it is centrilobular [18], as observed in our case. All of these were tested, and only HHV-6 was detected. In a recent paper by Wang et al. [18], 5 patients with HHV-6-associated liver injury were studied, and they presented centrilobular necroinflammation, likely due to an immune-mediated process triggered by the virus. Acute graft hepatitis with a periportal pattern of confluent necrosis can be caused by HHV-6 reactivation in immunosuppressed liver transplant recipients [2]. In a study by Härmä et al. [6] on HHV-6 infection and ALF, the predominant histologic findings included hepatocyte necrosis and moderate to severe portal lymphocytic infiltration. In a report of 2 cases of ALF and HHV-6 by Cacheux et al. [3], histology revealed submassive hepatic necrosis and moderate inflammatory cell reaction in 1 case, while the other showed acute hepatitis with bridging necrosis, spotty necrosis, and minimal cholestasis. Charnot-Katsikas et al. [8] described a case in which liver biopsy revealed massive necrosis with a plasma cell infiltrate in the portal areas and no viral inclusions. The liver biopsy of the case reported by Szewc et al. [11] described hepatic necrosis and a marked inflammatory infiltrate. Both HHV-6 and paracetamol can be associated with a scant inflammatory infiltrate [2]. The presence of associated steatosis is described in paracetamol, although other concurrent etiologies cannot be excluded, such as malnutrition and alcohol. The diagnosis in this case report probably results from an ALF of viral cause due to a possible reactivation of HHV-6 in the context of immunoparesis secondary to malnutrition and binge drinking, though we cannot exclude a contribution from a toxic cause due to paracetamol overuse, facilitated by these same susceptibility factors.

Although the pathology of HHV-6 is not fully understood, this virus is associated with ALF in adults, with potentially serious prognosis and should be included in the differential diagnosis of ALF of undetermined cause, particularly in immunocompromised patients. In cases of ALF of unclear etiology, monitoring and supportive treatment should not be delayed, as organ failures may progress rapidly, and patients should be prepared for potential liver transplantation. With this case report, we alert to the possibility of a causative role of HHV-6 in ALF, even in apparently immunocompetent adults, who may harbor an underlying state of immunoparesis, possible to identify after a careful evaluation.