Undiagnosed Cases of Cirrhosis Common in Veterans With Dementia, Potentially Leading to Cognitive Impairment

A newly published national cohort study in JAMA Network Open showed that 5% to 10% of veterans with dementia had high Fibrosis-4 scores suggestive of advanced liver fibrosis to cirrhosis, despite previously not receiving a formal diagnosis of cirrhosis. These findings suggest that clinicians should screen for cirrhosis in patients with dementia to uncover reversible factors associated with cognitive impairment, such as hepatic encephalopathy (HE), to enhance outcomes.^1,2

Among 177,422 veterans with a diagnosis of dementia (97.1% men; White, 80.7%; mean age, 78.35; SD, 10.97 years) 5.3% of the cohort who previously did not have a diagnosis of cirrhosis had a Fibrosis-4 (FIB-4) score greater than 3.25 (n = 9373), suggestive of cirrhosis. Notably, investigators observed that 10.3% of the total cohort had an FIB-4 score greater than 2.67 (n = 18,390), suggestive of advanced fibrosis, and also did not have a prior diagnosis of cirrhosis.

“We focused on this because patients with cirrhosis are growing older and are increasingly being diagnosed with cirrhosis de novo at a later age. In addition, patients with HE (covert and overt) form nearly 50% of patients with cirrhosis and several risk factors such as alcohol, obesity, diabetes etc predispose to both cirrhosis and dementia,” lead author Jasmohan Bajaj, MD, associate professor of medicine, Division of Gastroenterology, Hepatology, and Nutrition at Virginia Commonwealth University and gastroenterologist at Richmond VA Medical Center, told NeurologyLive®.

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Investigators conducted a retrospective cohort study between 2009 and 2019 using data from the Veterans Health Administration and 2 separate validation cohorts from the Richmond Veterans Affairs Medical Center. Participants included in the analysis had a diagnosis of dementia at 2 or more clinic visits, no prior diagnosis of cirrhosis, and with sufficient laboratory test results to calculate the FIB-4 score. Because higher age can lead to erroneous scores on FIB-4, the investigators entered 65 years as an input variable (rather than their actual age) to calculate the FIB-4 scre.

On the multivariable logistic regression models, investigators observed that a FIB-4 greater than 3.25 was associated with older age (OR, 1.07; 95% CI, 1.06-1.09), male gender (OR, 1.43; 95% CI, 1.26-1.61), congestive heart failure (OR, 1.48; 95% CI, 1.43-1.54), viral hepatitis (OR, 1.79; 95% CI, 1.66-1.91), Alcohol Use Disorders Identification Test score (OR, 1.56; 95% CI, 1.44-1.68), and chronic kidney disease (OR, 1.11; 95% CI, 1.04-1.17). Authors noted that patients who had a FIB-4 greater than 3.25 were inversely associated with being White (OR, 0.79; 95% CI, 0.73-0.85), having diabetes (OR, 0.78; 95% CI, 0.73-0.84), hyperlipidemia (OR, 0.84; 95% CI, 0.79-0.89), stroke (OR, 0.85; 95% CI, 0.79-0.91), tobacco use disorder (OR, 0.78; 95% CI, 0.70-0.87), and living in a rural residence (OR, 0.92; 95% CI, 0.87-0.97).All told, similar findings were found when using a FIB-4 score greater than 2.67.

In local validation cohort of patients with dementia, investigators observed a similar percentage of high FIB-4 scores (4.4%-11.2%). Of these 9 patients, 4 had diabetes, 3 had prior AUD, none were obsese, 5 were checked for hepatits C virus antibodies (1 was positive), a 1 had already been diagnosed with cirrhosis and was monitored by the hepatology department. Upon further evaluation, potential cirrhosis was possibly present in 7 patients (8.7) of the validation cohort.

“In a prior study of veterans with cirrhosis, the only decompensating event that had an overlap with dementia was HE. This study, as you know, is the reverse where we wanted to see the rate of undiagnosed cirrhosis in dementia where we did not diagnose HE or decompensation but focused on cirrhosis diagnosis only,” Bajaj added. “While we found a diagnosis of cirrhosis, the assumption is that some or most of them may have either covert or prior overt HE as contributors. We found the alcohol and viral hepatitis were related but other factors such as diabetes, hyperlipidemia were actually not associated with undiagnosed cirrhosis most likely because of the population only consisting of patients with dementia.”

A previous study conducted by Baja and colleagues published in The American Journal of Gastroenterology showed dementia was associated with HE among US veterans.³ Using the VA Corporate Data Warehouse, investigators identified veterans with cirrhosis through the International Classification of Diseases -10 codes between October 1, 2019, and September 30, 2021. The characteristics at baseline were compared between the cohorts based on the presence versus the absence of dementia. The factors associated with a diagnosis of dementia were assessed using multivariate logistic regression models where authors adjusted for demographics, comorbid illnesses, cirrhosis etiology, and cirrhosis complications.

Among 71,552 veterans with cirrhosis, 5,647 (7.89%) had a diagnosis of dementia. Authors observed that the patients with dementia were older, more frequently White, urban located, and had a diagnosis of alcohol-related cirrhosis. Notably, these patients also had metabolic syndrome, brain trauma, and cerebrovascular disease more frequently. In multivariable analysis, the presence of any decompensating event was associated with dementia and individual decompensating events revealed HE associated with dementia, but not ascites, independent of other risk factors.

“These should increase awareness among providers and families of patients with dementia to see if there is undiagnosed cirrhosis and therefore potential for HE as a contributing factor towards the mental dysfunction. These could be using FIB-4, deeper history taking for risk factors for cirrhosis, and referral to GI/hepatology as needed,” Baja told. “We need to validate this in other populations and discuss strategies within the healthcare systems to define strategies such as using FIB-4 and other lab-related evaluations to rule out those with cirrhosis.”

REFERENCES
1. Bajaj JS, Silvey SG, Rogal S, et al. Undiagnosed Cirrhosis and Hepatic Encephalopathy in a National Cohort of Veterans With Dementia. JAMA Netw Open. 2024;7(1):e2353965. Published 2024 Jan 2. doi:10.1001/jamanetworkopen.2023.53965
2. Hostetler AJ. 1 of 10 veterans diagnosed with dementia may instead have cognitive decline from cirrhosis. News Release. Virginia Commonwealth University. Published January 31, 2023. Accessed Febraury 8, 2024. https://www.vcuhealth.org/news/1-of-10-veterans-diagnosed-with-dementia-may-instead-have-cognitive-decline-from-cirrhosis
3. Adejumo A, Noll A, Rogal SS, et al. Dementia Frequently Coexists With Hepatic Encephalopathy but Not Other Cirrhosis Complications in US Veterans. Am J Gastroenterol. 2023;118(3):475-480. doi:10.14309/ajg.0000000000002189