Beyond the Liver, Hepatitis E Can Affect the Nerves, Pancreas, and Blood Vessels. Extrahepatic Manifestations of Hepatitis E: A Comprehensive Literature Review

Extrahepatic manifestations of Hepatitis E, though rare, are being increasingly reported in the medical literature. In this review article, we will discuss the extrahepatic manifestations of hepatitis E, such as Guillain-Barre syndrome, pancreatitis, and cryoglobulinemia, their clinical association with hepatitis E, and their management.


Introduction And Background
Hepatitis E virus (HEV) results primarily from human-to-human transmission through the fecal-oral route and is most prevalent in low-resource countries. It presents primarily as "acute viral hepatitis" syndrome, which is usually a self-limiting illness. A few cases progress to acute liver failure, a serious illness with a high mortality rate. Infection during pregnancy is associated with a higher risk of symptomatic disease, severe liver injury, and mortality. Severe disease has also been observed in persons with pre-existing chronic liver disease. Some cases have associated extrahepatic features, particularly acute pancreatitis, and neurological manifestations. Chronic infection appears to be extremely infrequent with these HEV genotypes [1].

Review Objectives
The objectives of this literature review is to discuss the extrahepatic manifestations of Hepatitis E and their complications and management plan.
ClinicalTrials.gov for studies, and ISI Web of Science. No date restrictions were placed on the search. A thorough search for controlled clinical trials and cohort studies was conducted. We used the keywords "Extrahepatic manifestations" and "Hepatitis E." Included studies were studies published in English that assessed the association between the extrahepatic manifestations of Hepatitis E. Reference lists were also screened. From the search results, articles with irrelevant titles were discounted, with the remaining abstracts examined for relevance.
The authors of this review independently determined the eligibility of studies and assessed the methodology of the included studies. In this review article, we will discuss the extrahepatic manifestations of Hepatitis E.

Extrahepatic manifestations of Hepatitis E
HEV infection appears to be strongly associated with acute pancreatitis, neurological disorders (with primarily dominant peripheral nerve involvement, most commonly manifested as Guillain-Barré syndrome, followed by neuralgic amyotrophy), hematological diseases (hemolytic anemia due to glucose phosphate dehydrogenase deficiency and severe thrombocytopenia), glomerulonephritis, and mixed cryoglobulinemia. Thirteen case reports and 4 case series were found with 55 patients meeting the inclusion criteria. All patients originated from Southern Asia or had recently traveled to that area. The mean age at diagnosis was 28 years with a male to female ratio of 18:1. The mean interval between the onset of jaundice and the onset of AP pain was 10 days. AP was mild or moderately severe in 45 patients (82%) and severe in 10 patients (18%). Mortality was reported in 2 patients (3.6%).
Two previous reports described an association between mixed cryoglobulinemia and HEV infection.  Woolson et al. [22] Extra-hepatic manifestations of autochthonous hepatitis E infection.
Autochthonous, or locally acquired, hepatitis E is increasingly recognized in developed countries, and is thought to be a porcine zoonosis. The authors conducted a retrospective review of the data in 106 cases of autochthonous hepatitis E (105 acute and 1 chronic). Eight (7.5%) cases presented with neurological syndromes, which included brachial neuritis, GBS, peripheral neuropathy, neuromyopathy, and vestibular neuritis. One patient presented with a cardiac arrhythmia, 12 patients (11.3%) presented with thrombocytopenia, 14 (13.2%) with lymphocytosis, and 8 (7.5%) with a lymphopenia, none of which had any clinical consequence.

Guillain-Barre Syndrome and HEV
It is recommended that clinicians consider the possibility of HEV infection in patients with neurological disorders and concurrent transaminase elevation, especially those with peripheral nerve involvement. The diagnosis may be suggested by HEV serology but should be confirmed with molecular testing in serum, cerebrospinal fluid (CSF), or both. The recognition of HEV infection in a patient presenting with neurological manifestations could present an opportunity to treat an active HEV infection with antivirals before chronic damage takes place, but further studies are needed to clarify their role in this setting [2].
The mechanisms of neurologic damage are unknown. Many viruses (including hepatotropic viruses) trigger neurologic signs and symptoms, especially Guillain-Barré syndrome. Such infections may elicit an immune response that cross-reacts with axolemmal or Schwann cell antigens and thereby damages peripheral nerves [13].
We recommend that clinicians strongly consider the possibility of HEV infection in patients with neurologic disorders, especially those with peripheral nerve involvement and liver abnormalities indicated by blood tests. The diagnosis may be suggested by HEV serology but should be confirmed by molecular documentation of HEV RNA in the serum, CSF, or both [13].

Neuralgic Amyotrophy and HEV
The mechanism by which HEV triggers neuralgic amyotrophy (NA) is uncertain. Direct infection of the brachial plexus cannot be excluded because HEV RNA was demonstrated in all HEV-associated patients at the start of their illness. Alternatively, HEV may trigger an immune response that damages the peripheral nervous system, similar to the pathogenesis of GBS.
At present, there is no evidence that HEV-related NA should be treated differently than any other forms of NA [20].

Acute Pancreatitis and HEV
Acute pancreatitis associated with hepatitis E usually has a good prognosis. The mechanism of pancreatitis in patients with acute viral hepatitis (nonfulminant) is unknown, and it may be multifactorial. One proposed pathogenesis of pancreatitis associated with hepatitis is the development of edema of the ampulla of Vater with obstruction to the outflow of pancreatic fluid. A more plausible mechanism for virus-associated acute pancreatitis is the direct inflammation and destruction of pancreatic acinar cells by the virus [23].
In conclusion, acute pancreatitis is not uncommon. In a patient with acute viral hepatitis and acute or disproportionate abdominal pain, acute pancreatitis should be kept as a possibility.
Conservative treatment leads to recovery in all the patients [23].

Cryoglobulinemia and HEV
Traditionally, Hepatitis C has been associated with cryoglobulinemia. In 2012, Kamar and colleagues reported eight documented cases of mixed cryoglobulinemia in French patients who had undergone an organ transplant and had chronic Hepatitis E, genotype 3. Three months after treatment with pegylated interferon or ribavirin, HEV clearance was achieved in all patients followed by the loss of cryoglobulinemia in all patients [12].
Pischke reported a case of HEV-associated cryoglobulinemia, no genotype documented, and symptoms resolved after HEV clearance [16]. Marson had earlier reported a probable case in 1995 of HEV cryoglobulenemia [14]. Del Bello reported a case of de novo membranoproliferative glomerulonephritis that occurred in a kidney transplant patient who developed a chronic HEV3 infection, which was successfully treated with ribavirin [24].
Guinault first documented a case of autochthonous HEV-induced cryoglobulinemic crescentic and membranoproliferative glomerulonephritis in an immunocompetent man with no notable medical history. He presented with edema, hypertension, increased serum creatinine level, and nephrotic syndrome. Type II cryoglobulinemia with monoclonal immunoglobulin G (IgG) κ light chain was detected. Anti-HEV IgG and IgM, as well as HEV RNA, were detected in serum and cryoprecipitate. Histologic analysis of a kidney biopsy specimen revealed features of crescentic and membranoproliferative glomerulonephritis. After HEV clearance, kidney and liver parameters improved and HEV RNA and cryoglobulinemia were undetectable [25].
There were only a few cases of Hepatitis E-associated cryoglobulenemia reported in the medical literature, all of these patients are chronic hepatitis patients, immunocompromised, all from western Europe, with genotype 3 confirmed in eight cases, with all MC type 2 or 3.
Antiviral treatment and immunosuppressive treatment are effective in all these cases and further clinical trials are needed to confirm these data.

Strengths of this literature review
The studies were done in multiple centers, which will increase the generalizability of the results within a population. The strengths of this review are in the systematic literature search with well-defined inclusion criteria, careful exclusion of redundant studies, the inclusion of goodquality studies with detailed extraction of data, and rigorous evaluation of study quality.

Limitations of this literature review
Most of the studies are retrospective and based on the small sample size and done in single centers. Therefore the risk of selection bias was unavoidable. Further, various aspects of interest are not included or not discussed in detail, such as race/ethnicity, medications, and outpatient care. The study is limited by the use of different practice patterns over the different centers and by the lack of a control group without infections. Most of the studies are done in a tertiary referral center and the intensity of liver disease from these centers may be more severe.

Conclusions
Demyelinating polyneuropathies is known to be part of the complication from Hepatitis B and Hepatitis C infection. Again, it is worth screening for HEV in those patients with neuropathy and liver function abnormality. Physicians should be aware of the extrahepatic manifestations of Hepatitis E, as these manifestations have been reported in both acute and chronic cases. Physicians should also strongly consider the possibility of Hepatitis E infection in patients with neurologic disorders, especially in peripheral nerve and liver complications. The vast majority of cases of Hepatitis E are treated conservatively; however, a small number of patients can develop extrahepatic manifestations and physicians should look for these complications, as early diagnosis and treatment improve outcomes.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the