Considerations in the Diagnoses and Management of Hepatic Disease in Older Adults

Multiple changes occur during healthy aging in older people. This review will focus on considerations of diagnosing and managing liver disease in individuals 60 years and older. In people over 75 years, total hepatic blood flow declines by about 30%, with the most major reductions occurring in the portal vein flow along with shrinkage of the liver volume by 20%–40% (1,2). With age, the number of hepatocytes decreases, while the levels of apoptosis, polyploidy, and senescence increase (2). The smooth endoplasmic reticulum, which plays a crucial role in drug metabolism, reduces in surface area, and there is a decline in the number of mitochondria (Table 11). There are significant changes in the liver structure which result in impaired blood flow and disrupt the exchange of substances between the blood and liver cells (2).Table 11.: Summary of effect of aging on liver and drug metabolismThese age-related changes in liver structure and function contribute to significant alterations in liver physiology. A reduction in portal blood flow results in diminished first-pass metabolism of many medications, which can lead to higher plasma concentrations of these drugs (3). As hepatocyte function declines, so does the liver's ability to produce proteins, including albumin, which is responsible for transporting substances like bilirubin, fatty acids, and medications (4,5). Consequently, albumin levels decrease with age, which may impact the liver's ability to regulate and distribute these compounds efficiently (5). Overall, the liver's regenerative capacity declines significantly with age, which limits its ability to recover from injury and maintain normal function (6). These changes make older adults more susceptible to pathologic changes resulting in chronic liver disease. This review will discuss the clinical implications of impaired hepatic functioning with aging that may impact development, consequences and management of common chronic liver diseases in older adults. METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE (MASLD) The rapidly increasing incidence and prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) over the last 3 decades has led to its emergence as the most common etiology of chronic liver disease (7,8). MASLD has the highest incidence in individuals 61–65 years of age (9) and MASLD-related cirrhosis is the leading indication for liver transplantation for individuals older than 65 years of age (10). As the older adult population expands, an increasing number of people will live with and manage the complications of MASLD. Unfortunately, many individuals with MASLD are undiagnosed (11). This underdiagnosis leads to significant rates of MASLD presenting with advanced fibrosis and associated complications in older adults living with undiagnosed disease for many years, exacerbating the negative impact of this disease in the older adult population (12). The high burden of MASLD makes it imperative for providers to recognize at-risk individuals and adopt effective strategies for screening and identification at earlier stages of the disease. MASLD typically presents with mild, asymptomatic liver enzyme abnormalities (13). Some individuals will have liver enzymes within the normal range (14). Therefore, risk factor identification is key in screening for MASLD. In addition to traditional metabolic risk factors including insulin resistance, dyslipidemia, hypertension and central obesity; the presence of polycystic ovarian syndrome and obstructive sleep apnea should prompt providers to consider screening (15,16). At-risk populations recommended for screening of MASLD include individuals with type 2 diabetes mellitus (17), individuals with obesity and any additional metabolic risk factors (18), patients with family history of cirrhosis (19) and individuals with significant alcohol use (20). Limited abdominal ultrasound is a cost-effective and accessible means for screening for the presence of moderate to severe hepatic steatosis, although less sensitive to steatosis detection than other modalities due to variability of results based on operator experience (21). Vibration controlled transient elastography (VCTE) and MRI-proton density fat fraction are alternative modalities for steatosis detection that provide greater accuracy than ultrasound when available (22). Individuals with positive screening or incidentally identified hepatic steatosis should undergo non-invasive fibrosis staging with the Fibrosis-4 Index (FIB-4) (23). If FIB-4 is low risk, then periodic screening every 1–2 years should be continued for patients with increased risk for MASLD (24). If FIB-4 is indeterminate, secondary testing with the Enhanced liver fibrosis test (ELF), VCTE or ultrasound elastography is recommended (25). Individuals with abnormal secondary risk assessment or high-risk FIB-4 score should be managed in gastroenterology or hepatology clinic. Given the overwhelming presence of MASLD, it is not feasible for this population to be exclusively diagnosed and managed in gastroenterology and hepatology clinic. Empowerment of primary care and endocrine providers to increase identification and perform evidence-based screening algorithms for low-risk individuals is necessary. Appropriate referral of high-risk individuals for interdisciplinary, subspecialty care including gastroenterology and hepatology should be prioritized (25). There are important considerations when managing MASLD in an older adult population. The mainstay of management is lifestyle modifications that achieve and maintain a healthy weight (26). Older adults with liver disease are susceptible to functional decline and decreased mobility that may challenge their ability to incorporate standard recommendations for > 150 minutes of weekly vigorous physical activity into their routines (27). Older adults may also have challenges in accessing gyms or expensive exercise equipment as they are more likely to have a limited, fixed income (28). Healthcare providers can mitigate these concerns by providing evidence-based recommendations for exercise programs ideally combining resistance and endurance activities (29). Providers managing this population may benefit by compiling resources that support increased physical activity for older adults with limited physical capacity and finances. Activities such as walking (30), chair aerobics (31), water aerobics (32), and Tai Chi (33) have been studied in various settings and older adult populations with improved mobility and overall health when consistently maintained in an exercise program. Utilizing exercise physiologists or physical therapists can also be beneficial for individuals with coverage (34). Lastly, social workers and case managers may aid in identifying insurance benefits and community services such as senior centers that can support increased physical activities in older adults. Additionally, when managing older adults with MASLD there should be consideration of multimorbidity with associated polypharmacy. Polypharmacy is much more common in older adults (35). It is important that gastroenterologists and hepatologists managing patients with MASLD carefully review medication lists routinely. As discussed in the introduction, physiologic changes in the liver may result in reduced medication metabolism and increased risk for adverse effects of these medications. These risks are compounded with the presence of polypharmacy when older adults routinely use medications to control risk factors for MASLD including statins for hyperlipidemia, hypoglycemics for blood glucose control and antihypertensives for blood pressure management (36). Older adults typically have modified goals for blood pressure, cholesterol and diabetes management compared to younger adults to balance the potential clinical harms of tight control (37). Specific considerations are working with primary care and specialists to ensure proper risk-benefit analysis for hypoglycemic therapies (including removal of metformin with advanced liver disease) and antihypertensives (utilizing carvedilol for variceal prophylaxis in MASLD with clinically significant portal hypertension). Statin use should be encouraged in patients with MASLD when there is an indication for use. The side effect of elevated transaminases is not associated with clinically significant liver disease and typically resolves spontaneously without interruption of the medication. Reassessment of medications and encouragement to remove unnecessary or ineffective medications should be iteratively performed. Resmetirom has emerged as the first FDA approved medication for treatment of MASLD, adding the potential for pharmacotherapy in addition to lifestyle modification for management of this condition. Resmetirom is a thyroid hormone receptor beta agonist that remains in phase III clinical trial but has demonstrated significant results in reducing steatosis and fibrosis for patients with stage 2 and 3 metabolic dysfunction-associated steatohepatitis (MASH), prompting its accelerated approval in March 2024 (38). Older adults were appropriately included in clinical testing and the medication had equivalent but more adverse effects when compared to younger adults (38). Additionally, receptor and receptor are in phase 3 clinical their ability to fibrosis associated with of these are patients with to fibrosis but with the for effective strategies of MASLD in high-risk older adults. Lastly, while be in for in older it has been demonstrated that weight has been in managing MASLD without significant in complications or for older adults with obesity As the management for MASLD to consideration of these should be to their in the burden of MASLD in the older adult population. dysfunction-associated steatotic liver disease (MASLD) MASLD is the most common etiology of chronic liver disease in older adults. MASLD remains and individuals with type 2 obesity with any additional metabolic risk family history of cirrhosis and alcohol use should be with hepatic steatosis should be for fibrosis staging Fibrosis-4 exercise programs may be for older adults with functional decline and decreased to adverse effects of polypharmacy with to hypoglycemic and use is necessary. Resmetirom is the first FDA approved medication for treatment of MASLD. 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