Hepatitis E and Pregnancy: An Unholy Alliance Unmasked from Kashmir, India

Mohammad Sultan Khuroo, Mohammad Sultan Khuroo

Abstract

The adverse relationship between viral hepatitis and pregnancy in developing countries had been interpreted as a reflection of retrospectively biased hospital-based data collection by the West. However, the discovery of hepatitis E virus (HEV) as the etiological agent of an epidemic of non-A, non-B hepatitis in Kashmir, and the documenting of the increased incidence and severity of hepatitis E in pregnancy via a house-to-house survey, unmasked this unholy alliance. In the Hepeviridae family, HEV-genotype (gt)1 from genus Orthohepevirus A has a unique open reading frame (ORF)4-encoded protein which enhances viral polymerase activity and viral replication. The epidemics caused by HEV-gt1, but not any other Orthohepevirus A genotype, show an adverse relationship with pregnancy in humans. The pathogenesis of the association is complex and at present not well understood. Possibly multiple factors play a role in causing severe liver disease in the pregnant women including infection and damage to the maternal-fetal interface by HEV-gt1; vertical transmission of HEV to fetus causing severe fetal/neonatal hepatitis; and combined viral and hormone related immune dysfunction of diverse nature in the pregnant women, promoting viral replication. Management is multidisciplinary and needs a close watch for the development and management of acute liver failure. (ALF). Preliminary data suggest beneficial maternal outcomes by early termination of pregnancy in patients with lower grades of encephalopathy.

Keywords: acute liver failure; delivery; epidemic hepatitis; fetus; genotypes; hepatitis E; hepatitis E vaccine; hepatitis E virus; neonate; pregnancy; sporadic hepatitis.

Conflict of interest statement

The author declares no conflict of interest.

Figures

Figure 1
Figure 1
Gulmarg Kashmir Epidemic, 1978–1979. (A) Upper panel. The epidemic curve with the weekly occurrence of hepatitis E cases. The region had an open-source water supply from a canal (Ningli Nallah) which originates from the Alpather Lake situated at the foot of Apharwat Peaks, Gulmarg. After passing through mountains as the world-famous Sharanz waterfall, the stream crosses the valley to join the Wular lake. The canal along its route is used for multiple purposes including drinking water, linen washing, swimming, fishing, and sewage and garbage disposal, and thus stays highly polluted. Lower panel. The data on incidence and severity of viral hepatitis in men (15–45 years), NPF (nonpregnant females; 15–45 years) and PF (pregnant females) were collected by four door-to-door surveys done at 4 to 6 week intervals during the epidemic. (B) Kashmir strain of HEV (Pinglina epidemic, 1993–94, Kashmir, India [20].). Unrooted phylogenetic tree generated by Maximum Likelihood method using MEGA software (version 10.1.8), on the basis of 326 bp sequences of HEV ORF1 genomic. Reference sequences of different HEV genotypes from GenBank are shown in gray filled circles, while country specific HEV sequences are shown in color filled circles. Kashmir strain of HEV was of genotype 1 with 94.6% homology with the Burmese isolates of HEV (Courtesy Saleem Kamili & Xia, Guo-Liang, both at CDC, Atlanta, Georgia). α = 6 pregnant women died.
Figure 2
Figure 2
Hepatitis E virus Genotype 1. Genomic organization. (a) The hepatitis E virus genome; (b) Genomic RNA and bicistronic sub-genomic RNA; (c) Four Open reading frames (ORFs) and (d) Four encoded proteins (pORF1, pORF2, pORF3, and pORF4). ORF4, spanning nt2835-3308 and overlapping ORF1 in present in HEV genotype 1 alone, and its protein expression is regulated via an IRES-like RNA element (nt2701-2787). ORF4 encodes a protein (pORF4) of 124 aa, which functions to enhance viral polymerase activity and promote viral replication and is indispensable for the HEV genotype 1 life cycle.
Figure 3
Figure 3
Pathogenesis of hepatitis E virus-related acute liver failure in pregnancy. IAVH = icteric acute viral hepatitis, AIAVH = Anicteric acute viral hepatitis, HEV-ALF = Hepatitis E virus related acute liver failure.
Figure 4
Figure 4
Fetal-neonatal hepatitis E virus infection recorded in fetuses and neonates from 72 pregnant women with hepatitis E virus infection seen at Sher-I-Kashmir Institute of Medical Sciences, Srinagar Kashmir, India from Dec 1993 onwards [140,174,175]. ALF = acute liver failure, RNA = HEV RNA, IgM = IgM anti-HEV.
Figure 5
Figure 5
Spontaneous Vaginal Delivery in pregnancy with HEV-ALF and the outcome on maternal disease. A 30-year-old pregnant woman presented with features of icteric hepatitis E virus infection. On the 24th day of her illness, she had rapid deterioration with encephalopathy, cerebral edema, and laboratory features of DIC. She delivered a live baby vaginally with icteric hepatitis E four days after the onset of encephalopathy. Serial follow-up showed rapid clinical improvement in encephalopathy, cerebral edema, and DIC. PSE = portosystemic encephalopathy, CE = cerebral edema, DIC = disseminated intravascular coagulation, RNA = HEV RNA, IgM = IgM anti-HEV, IgG = IgG anti-HEV.

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