The Health Service Executive has confirmed that a child who was being treated for an acute form of hepatitis has died.
A second child who was also being treated for the same illness has received a liver transplant.
Both cases are being linked to an unexplained type of hepatitis that is being reported in children worldwide.
The European Centre for Disease Prevention and Control has said the total number of cases reported worldwide is approximately 450.
An alert about this disease in children was first raised by the UK in early April. It has since been identified in dozens of countries, including Ireland.
The HSE said that over the last two months, six probable cases of children with hepatitis of unknown cause have been detected in Ireland.
The six children were aged between one and 12 years of age. All were hospitalised.
In addition, a small number of other cases are being assessed to see if they are linked to this acute hepatitis of unknown origin or if they have another cause for their illness.
Tánaiste Leo Varadkar told the Dáil that the Government is concerned about the unexplained form of hepatitis, adding that the Government was "plugged into it and are aware of it."
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The HSE said the cause of acute hepatitis in these children has not yet been found and all possibilities are being investigated at present.
One area being explored is whether the hepatitis cases are linked to an increase in infections caused by adenovirus, a common cause of childhood illness.
Other possible causes such as another infection, including Covid-19, or something in the environment, are also being investigated.
In Ireland, as in other countries, investigations are under way to determine if current or prior Covid-19 infection may increase the risk of this disease in some children.
None of the Irish cases who were tested on admission to hospital had evidence of Covid-19 infection at that time. The majority of the cases had not received Covid-19 vaccination.
Ireland is liaising closely with ECDC, UK and WHO colleagues in efforts to identify the cause of this illness.
Since March, six probable cases of children with hepatitis of unknown cause have been identified in Ireland and a small number of children are under investigation. https://t.co/e8Vj2E1ap4 https://t.co/rbOtNeUebV— HSE Health Protection Surveillance Centre (HPSC) (@hpscireland) May 12, 2022
The HSE's National Clinical Lead for Children and Young People has said a lot of work is being done to find a cause and to be able to support those affected.
Speaking on RTÉ's Today with Claire Byrne, Dr Ciara Martin, who is also a consultant in pediatric emergency medicine at Children's Health Ireland, said it is a difficult situation because they are asking parents to look out for something, while also trying to reassure them that doctors manage hepatitis on a regular basis.
"For parents ... if you're looking for signs of hepatitis, the general signs would be temperature, muscle pain, aches and pains - but you see that with a lot of viruses.
"The difference here is if the [child's] poop is paler, grey coloured … or if the urine is a darker colour than usual, or if you think that your child looks a little yellow around the eyes and skin, they're certainly signs that your liver is inflamed.
"In those cases, we're asking you to contact your GP or local emergency department."
Meanwhile, Dr Suzanne Cotter, Specialist in Public Health Medicine with the HPSC said that while the cases are "relatively rare" the situation is of "serious concern".
Speaking on RTÉ's News at One, Dr Cotter said: "Unfortunately, we did have one fatality associated with the disease in Ireland, but this is very rare both at a European level and internationally."
She described the research into the matter as a "serious investigation".
Dr Cotter said that it is possible that this investigation might "artificially inflate" the level of the problem.
More than 170 cases in UK, no fatalities
More than 170 children with sudden onset hepatitis have now been identified in the UK.
An update from the UK Health Security Agency (UKHSA) shows an extra 13 cases, bringing the total number of cases in the UK to 176 as of Tuesday 10 May.
None of the children have died.
Of the confirmed cases, 128 are resident in England, 26 are in Scotland, 13 are in Wales and nine are in Northern Ireland.
Health officials are continuing to investigate cases of sudden onset hepatitis in children aged 10 and under that have been identified since January 2022.
The usual viruses that cause infectious hepatitis (hepatitis A to E) have not been detected.
The cases are predominantly in children under five years old who showed initial symptoms of gastroenteritis illness (diarrhoea and nausea) followed by the onset of jaundice.
As part of the investigation, a small number of children over the age of 10 are also being investigated, the UKHSA said.