Rat Hepatitis E - J of Hepatology-Jan.26

Rat Hepatitis E (rHEV), also known as Rocahepevirus ratti, is an emerging zoonotic pathogen that has garnered significant attention in recent years due to its potential to infect humans and cause clinical disease. It was first identified in wild rats in Germany in 2009 and has since been detected in rodents and other small mammals across the globe. Although it was initially believed to be confined to rodents, subsequent studies have revealed its zoonotic potential, with confirmed human cases reported in multiple countries.

### Differences Between Rat Hepatitis E (rHEV) and Human Hepatitis E (HEV)

Human Hepatitis E is primarily caused by the Paslahepevirus balayani genus, which includes genotypes HEV-1 to HEV-4. In contrast, Rat Hepatitis E belongs to the Rocahepevirus genus. While both viruses share structural similarities, including a ~7 kb positive-sense single-stranded RNA genome organized into four open reading frames (ORFs), they differ significantly in genetic composition. rHEV shares only about 50–60% nucleotide identity with human HEV, making it genetically distinct.

Key differences include:

1. **Host Range**:

• Human HEV (HEV-1 to HEV-4) primarily infects humans, pigs, and other animals.
• rHEV was initially thought to be rodent-specific but has now been shown to infect humans as well, indicating its zoonotic potential.

2. **Genomic Differences**:

• Despite structural similarities, rHEV exhibits significant genetic divergence from human HEV, particularly in nucleotide sequences.

3. **Diagnostic Challenges**:

• Routine hepatitis E diagnostics often fail to detect rHEV infections, as they are designed for Paslahepevirus. Diagnosis of rHEV requires specialized pan-hepevirus PCR assays, highlighting the limitations of current diagnostic methods.

4. **Clinical Presentation**:

• Human HEV infections can cause a spectrum of disease ranging from asymptomatic to severe acute hepatitis, particularly in pregnant women and immunocompromised individuals.
• rHEV infections in humans have also shown a wide range of clinical manifestations, from asymptomatic cases to severe acute and chronic hepatitis. Extrahepatic complications, such as acute renal failure, glomerulonephritis, acute pancreatitis, and meningoencephalitis, have also been reported.

### Clinical Impact of Rat Hepatitis E

The emergence of rHEV as a zoonotic pathogen raises several important clinical and public health concerns:

1. **Human Cases**:

• Since the first human case of rHEV was identified in 2017 in a liver transplant recipient in Hong Kong, a total of 48 human infections have been reported across Hong Kong, Spain, mainland China, France, Germany, and Canada. These cases involved individuals of both sexes and a wide age range (7–89 years).

2. **Chronic Hepatitis**:

• Chronic hepatitis, which can potentially progress to cirrhosis, has been observed in immunocompromised individuals infected with rHEV. In the Hong Kong cohort, 12 out of 22 identified cases developed chronic hepatitis.

3. **Treatment**:

• No virus-specific therapies are currently available for rHEV. However, ribavirin, a drug commonly used to treat human HEV infections, has shown efficacy in some rHEV cases.

4. **Extrahepatic Manifestations**:

• rHEV infections have been associated with severe complications beyond the liver, including acute renal failure, glomerulonephritis, acute pancreatitis, and meningoencephalitis.

5. **Global Circulation**:

• Phylogenetic analyses suggest that rHEV strains are circulating globally, likely facilitated by the movement of rodents or contaminated materials. Strains from a single geographic region do not always form monophyletic groups, indicating ongoing global transmission.

### Future Clinical and Public Health Implications

1. **Zoonotic Risk**:

• rHEV's ability to infect humans without requiring major genetic changes underscores its zoonotic potential. Broader genomic surveillance in both human and animal populations is essential to better understand transmission routes and zoonotic risks.

2. **Diagnostic Improvements**:

• Incorporating rHEV-specific assays into routine diagnostic protocols for unexplained hepatitis is critical to identifying and managing cases. This approach has already proven effective in Hong Kong, where 22 human cases were identified over seven years.

3. **Evolutionary Insights**:

• Molecular clock analyses suggest that rHEV originated a few hundred years ago, with some strains circulating in rodents and potentially humans for decades before being recognized. Understanding its evolutionary history can help distinguish between newly emerging threats and long-standing but overlooked pathogens.

4. **Molecular Adaptation**:

• Studies indicate that rHEV is well-adapted to human hosts, with codon usage patterns and selective pressures suggesting that most rHEV lineages possess the translational capacity to replicate efficiently in human cells. Ongoing research is needed to identify molecular adaptations that facilitate cross-species transmission.

5. **Surveillance and Public Health Strategies**:

• Expanding genomic surveillance and developing standardized classification systems, such as the open-access tool created by researchers, will enable better tracking of rHEV strains and their public health impact. Enhanced surveillance will also help identify genetic determinants of human adaptation and monitor the emergence of new strains.

6. **Infection Prevention**:

• As rodents are the primary reservoir for rHEV, controlling rodent populations and minimizing human exposure to contaminated environments are crucial for preventing infections.

### Conclusion

Rat Hepatitis E (rHEV) is an emerging zoonotic pathogen with significant clinical and public health implications. While it shares some similarities with human HEV, its genetic distinctiveness and zoonotic potential make it a unique public health concern. The identification of human cases, particularly in immunocompromised individuals, highlights the need for improved diagnostic tools, expanded surveillance, and further research into its transmission dynamics and molecular adaptations. Understanding the full extent of rHEV's impact will be critical for anticipating future risks and developing effective prevention and treatment strategies.