Undiagnosed Liver Disease May Be Common in Patients With Dementia


Significant numbers of patients with dementia may have undiagnosed liver disease, and hepatic encephalopathy may be contributing to their cognitive impairment, said authors of a national cohort study.

In 177,422 U.S. veterans diagnosed with dementia from 2009 to 2019, more than 10% had a Fibrosis-4 (FIB-4) score greater than 2.67, which is suggestive of advanced fibrosis, and more than 5% had a FIB-4 score greater than 3.25, which suggests cirrhosis, reported researchers led by Jasmohan Bajaj, MD, of the Richmond VA Medical Center in Virginia. None of the study participants had a prior cirrhosis diagnosis.

“The combination of high FIB-4 scores and other risk factors for liver disease in patients with dementia raises the possibility that reversible HE [hepatic encephalopathy] could be a factor associated with cognitive impairment,” Bajaj and colleagues wrote in JAMA Network Open.

“These findings highlight the potential to enhance cognitive function and quality of life by increasing awareness of risk factors and diagnostic indicators of advanced liver disease that may be associated with HE as a factor or as a differential diagnosis of dementia among clinicians other than liver specialists,” they added.

Prevalence of scores suggesting potentially undiagnosed cirrhosis were significantly lower among white versus non-white and Hispanic patients and in rural versus urban residents, and were higher among patients with more comorbidities, alcohol use disorder (AUD), and viral hepatitis, the study found.

For example, white patients were 21% less likely to have a FIB-4 score greater than 3.25 (OR 0.79, 95% CI 0.73-0.85). Patients living in rural areas had an overall 8% reduction for this risk (OR 0.92, 95% CI 0.87-0.97). Patients with AUD had a more than 50% higher risk (OR 1.56, 95% CI 1.44-1.68), the researchers reported.

“The disparity in potential undiagnosed cirrhosis in veterans with dementia who lived in urban areas, were of Hispanic ethnicity, and were not white, is an important issue,” the study authors said. Dementia disproportionately affects Black and Hispanic veterans, and it is diagnosed later in the disease course in these populations, which has been attributed to lack of high-quality healthcare access, they added.

“A lack of access to healthcare services could also explain potentially underdiagnosed cirrhosis, which reiterates the need for focus on these subpopulations to accurately diagnose cirrhosis and potentially HE,” wrote Bajaj and co-authors.

High FIB-4 scores are only a marker of potential liver disease, the researchers acknowledged. And while it is not a perfect index, FIB-4 is commonly used to exclude the presence of advanced liver disease in the general population due to its ease of calculation and interpretation. “The FIB-4 score also adds specificity to the alternative of using aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels alone, since patients with even advanced liver disease often have laboratory values within the reference ranges,” they added.

“In conclusion, FIB-4 should be considered as a screening tool to detect cirrhosis and potential HE in older veterans with dementia. Those with high scores (e.g., >2.67) should be considered for further evaluation and treatment,” Bajaj’s group recommended.

The research team analyzed data from the Veteran’s Health Administration Corporate Data Warehouse. Eligible study participants had a diagnosis of dementia at two or more clinic visits, no diagnosis of cirrhosis, and sufficient laboratory test results to calculate the FIB-4 score. The majority of the participants were male (97%) and white (81%). Their mean age was 78. Multivariable logistic regression analysis was used to identify demographic and clinical characteristics associated with FIB-4 scores.

To validate their findings, the researchers extracted data on 89 patients from the cohort to determine reasons for high FIB-4 scores. Two clinicians reviewed each medical record. They found evidence of advanced liver disease in the majority of patients, including hypoalbuminemia, liver stiffness, and AST to ALT ratios greater than 1. Ten patients had cirrhosis confirmed by imaging. Only four patients had other reasons for the high scores: two had myelodysplastic syndrome and two had a liver biopsy.

For further validation, the researchers examined data from another cohort of patients with dementia seen by the geriatrics clinic at the Richmond VA Medical Center. Of these 80 patients, nine (11.2%) had a FIB-4 score greater than 2.67, which was similar to the findings from the main cohort, they said.

Limitations of the study included its reliance on International Classification of Diseases (ICD) codes to determine a diagnosis of dementia, Bajaj and colleagues noted. Furthermore, the study did not identify the proportion of patients with undiagnosed liver disease who actually had hepatic encephalopathy.

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    Jeff Minerd is a freelance medical and science writer based in Rochester, NY.


The study was partly funded by VA Merit Review.

Bajaj reported receiving grants from Bausch, Grifols, Sequana, and Mallinckrodt outside the submitted work. One co-author reported being an employee of the Department of Veterans Affairs and another reported receiving personal fees from Mallinckrodt Pharmaceuticals outside the submitted work.

Primary Source

JAMA Network Open

Source Reference: Bajaj JS, et al “Undiagnosed cirrhosis and hepatic encephalopathy in a national cohort of veterans with dementia” JAMA Netw Open 2024; DOI: 10.1001/jamanetworkopen.2023.53965.


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