Medical alert: Six out of 10 pregnant women who catch HEV don?t survive

At the facility where Dr Ajay Singh works, as in clinics elsewhere, a pregnant woman turning up with jaundice portends a ?medical red alert?, demanding rapid investigations to pinpoint its cause. The concern intensifies even more if tests reveal that she?s infected with the hepatitis E virus (HEV), a germ that usually makes its way into the human body through contaminated drinking water or food.

This subtype of the hepatitis virus can damage the liver and cause jaundice in any child or adult, but it can have particularly devastating effects in pregnant women. In the three years that he?s been in New Delhi?s Lok Nayak Jai Prakash (LNJP) Hospital, Singh estimates that six out of every 10 pregnant women brought into the facility with severe liver damage caused by HEV did not survive. The fatality rate of HEV infection, according to the US Food and Drug Administration, is less than one per cent in the general population. But why HEV is so lethal to pregnant women has been a medical mystery.

Now, a team of doctors and virologists in New Delhi may have solved a part of the puzzle. The researchers from the LNJP and the Institute of Cytology and Preventive Oncology (ICPO) have shown how pregnancy-related hormones, the natural immunity of pregnant women, and a missing protein may explain the high fatality rates of HEV during pregnancy. Their study is among the first to explore the genetic mechanisms at work during HEV infection during pregnancy.

The researchers specifically focused on proteins in the body that are known to play a role in the regeneration of a liver under attack by infection.

?An HEV infection in pregnancy is a serious condition,? says Singh, who was in the four-member LNJP-ICPO team that studied liver damage in pregnant women with HEV.

Singh cites a typical case: a woman in her mid-20s visiting the hospital with a two-week history of jaundice. She was found infected with HEV. In the week that she was in hospital, she progressively showed other symptoms of irreversible liver failure ? persistent vomiting, altered states of consciousness and, eventually, deep coma followed by death, sometimes within weeks of the start of infection.

?We find the liver has shrunk dramatically ? indicating massive death of liver cells,? says Dr Premashish Kar, a senior doctor at the LNJP and another team member.

The study that Kar and his colleagues conducted was aimed at understanding why HEV destroys the liver so efficiently and so fast during pregnancy. The researchers collected blood from 25 patients with acute liver failure ? 20 pregnant women and five non-pregnant women. All the 20 pregnant women were in the third trimester of pregnancy.

Fifteen out of the 20 were infected with HEV and five had hepatitis B and hepatitis C viruses, both of which are acquired through contaminated blood. Eighteen out of the 20 women infected died.

The researchers conducted liver biopsies to examine the tissues of all patients. In the liver tissues of the women who died, they found that a protein called P65 was either negligible or altogether missing.

The P65 is a component of a larger and more complex protein called NF Kappa B that plays a key role in the regeneration of the liver, says Bhupesh Prusty, a researcher at the ICPO. The liver has a tremendous capacity to regenerate. Even when a chunk of the liver has been sliced off, the residual portion can grow back in weeks.

Ten years ago, a landmark study by biologist David Baltimore and his colleagues in the US had shown that mice that lack the P65 component of NF Kappa B die during embryonic development because of widespread death of liver cells. ?The binding of P65 to the genetic material inside liver cells is a crucial process for regeneration,? says Prusty. The LNJP-ICPO researchers discovered that P65 was completely absent in all liver tissues form the pregnant women who died.

The researchers say they have no idea what makes the P65 go missing in these women. That, says Mr Bhudev Das, director ICPO, is a subject for future research. But it isn?t the missing P65 alone that influences the high fatality rate of HEV during pregnancy.

The researchers say natural immunity is altered during pregnancy. The studies showed that the immunity of non-pregnant women with liver disease was much better than the immunity in pregnant women. The reduction in an appropriate immune response during pregnancy may contribute further to the loss of liver cells due to the infection.

A third factor influencing mortality from HEV in pregnancy, according to the researchers, are the sex hormones progesterone and oestrogen that are known to increase during the second half of pregnancy. These hormones can make a virus multiply faster in a pregnant woman who already has lower immunity.

The researchers say that understanding such molecular mechanisms underlying the high fatality rate may lead to the development of novel treatment strategies. Das concedes that the picture isn?t complete yet, but the missing P65, low immunity and the sex hormones may be three key pieces of the puzzle.