In a large national cohort of more than 68,000 non-Veterans with dementia enrolled across the US, we found an elevated FIB-4 index and potentially undiagnosed advanced liver disease in 7-13% of patients. This was associated with alcohol use disorder, viral hepatitis, and chronic metabolic diseases and was consistent across both FIB-4 thresholds
Reversible causes of cognitive impairment are sought in patients with dementia to ensure a correct diagnosis and improve outcomes. With the aging population, including those with cirrhosis, the potential for overlap between HE and dementia has risen and should be considered in the differential diagnosis. Within the VA system, there was 5% rate of FIB-4>3.25 and 10% rate of FIB-4>2.67 in patients with dementia who were not diagnosed with cirrhosis a priori8. Patients with a high FIB-4 had a higher AUD and viral hepatitis rates despite controlling for major co-morbid conditions, including PTSD, traumatic brain injury, and homelessness. While the data in the VA represent the national breadth of that specific population, a similar analysis is needed in the non-Veterans.
There are substantial differences between the VA and non-VA populations9. The VA population has more men, is less diverse (lower Hispanic ethnicity and minority races), and more likely to be older than the non-Veteran population. Moreover, cardiovascular, metabolic, and cancer-related as well as mental-health-related (PTSD, AUD, and substance abuse) comorbidities are higher in Veterans compared to the non-Veteran population. Therefore, despite these differences, similarities across the rates and determinants of a high FIB-4 are striking, including a greater proportion of patients who were not White in the high FIB-4 group. While we did not study the specific factors behind these disparities, a lack of access to therapy or medical care in both dementia care and comorbidity care could contribute12,13.
Recognizing the rate of undiagnosed cirrhosis is critical because treatment for potential HE could reverse or improve symptoms enough for functional improvement. When the reverse, i.e., rate of dementia in Veterans with cirrhosis was studied, this again resulted in an 8% prevalence, which only overlapped with HE7. Moreover, in patients above the age of 65 with cirrhosis who were tested for both HE and MCI/dementia, almost half had HE and a quarter had HE+MCI overlap, which resulted in poor quality of life6.
Our study is limited by the selected centers in our TriNetX population, lack of chart review to confirm these diagnoses in individual cases, the need for the components of FIB-4 to be collected, and the use of a modified FIB-4 with age capped at 65 years. However, the codes used are validated, the rate of high FIB-4 and determinants are largely similar to that found in a separate large population, and the higher AUD and viral hepatitis rate in the high FIB-4 population lend biological plausibility. Furthermore, prior studies have used FIB-4 in the TriNetX cohort14. Whether these patients have underlying HE in addition to cirrhosis also needs to be determined. However, even if these patients have cirrhosis but not HE, they can be followed for important outcomes such as variceal bleeding and hepatocellular cancer that would have been ignored otherwise.
We conclude that an elevated FIB-4 suggestive of undiagnosed cirrhosis and potential hepatic encephalopathy is found in 7-13% of patients with dementia without previous diagnoses of cirrhosis in a multicenter cohort. This rate and determinants of undiagnosed cirrhosis parallel that found in a Veteran population despite differing demographic characteristics. Undiagnosed cirrhosis and potential hepatic encephalopathy can be a reversible cause of or contributor towards cognitive impairment. With the rapidly rising aging population, providers should use the FIB-4 index as a screening tool to detect cirrhosis in patients with dementia.