GI & Liver case studies

The Gastrointestinal & Liver Disorder theme have been working with a family in the Midlands affected by liver diseases. In the space of two months, one sibling was diagnosed with cirrhosis and a second diagnosed and treated for hepatocellular carcinoma. The family had questions about why this was happening. When they weren't able to get the answers they needed from their healthcare team, they turned to research for the answers.

Our GI&Liver experts agreed it was unusual to have two cases in family, at which point a 3rd sibling was diagnosed with cirrhosis.

The family were referred to their local NHS Genetics service for further investigations whilst the research team worked with the family to understand the clinical characteristics. They identified previous cases of progressive liver disease (cancer, cirrhosis, hepatitis & steatosis), with an average age of onset between 48 – 60 years.

The initial inbestigations developed into a research study which compared DNA samples from the family, with common genetic variations and a South Asian reference genome.

ResDNA exome sequencing was conducted for 24 family members; 1 ‘variant’ was found to be present in all 12 people diagnosed with steatotic liver disease that was not identified in unaffected family members. It was also found that siblings with two copies of the mutation were the ones with the most severe disease.

Family members were offered closer monitoring both pre and post cirrhosis diagnosis. An outcome of this closer monitoring meant a liver tumour was identified in one of the siblings, who then received a liver transplant: “Because we were being closely monitored and aware my liver cancer was picked-up early. The outcomes of my siblings made me request a transplant rather than resection, as we knew the replacement liver has normal MTTP gene.”

Since these initial findings, the GI&Liver theme and the family have continued to co-produce research questions:

1. Does the ‘T’ variant have reduced MTP functionality?

2. Does the genetic variant affect fat processing in vivo?

3. Does it lead to liver fat build up?

4. Will this cause disease progression?

In April 2023, this work was published in Innovation in Hepatology:

Publication: Identification and characterisation of a rare MTTP variant underlying hereditary non-alcoholic fatty liver disease - JHEP Reports (jhep-reports.eu)

Conclusions

• We have identified and characterised a rare causal variant in MTTP, and homozygosity for MTTP is associated with progressive NAFLD without any other manifestations of abetalipoproteinaemia.
• Our findings provide insights into mechanisms driving progressive NAFLD.

Impact and Implications

• A cell line created harbouring this variant gene was characterised to understand how this genetic variation leads to a defect in liver cells, which results in accumulation of fat and processes that promote disease.
• This is now a useful model for studying the disease pathways and to discover new ways to treat common types of fatty liver disease.