Hayden Flume, BS¹; Ryan Johnson, MS²; Javier Tello, BS¹; Julieanne P. Sees, DO MBA^3
1Texas College of Osteopathic Medicine at UNT Health, Fort Worth, TX
²Capitol Technology University, Laurel, MD
³Saint Joseph’s University Haub School of Business, Philadelphia, PA

DOI: http://doi.org/10.70709/1zdlygtdjbapfd

Abstract

Background
Non-alcoholic fatty liver disease (NAFLD) is defined as a condition where fat accumulates in the liver secondary to conditions other than heavy alcohol use. The altered liver function ultimately affects the postoperative outcomes of total knee arthroplasty (TKA). While cirrhosis is known to influence postoperative outcomes, the independent impact of NAFLD remains unclear. This study aims to assess postoperative complications following TKA in patients with NAFLD. 

Methods
A retrospective cohort study using the TriNetX database identified patients with NAFLD who underwent primary TKA between 2005 and 2025 (n = 20,663) and were propensity-matched to non-NAFLD controls. Patients were matched based on age, gender, race, and multiple systemic comorbidities. Outcomes included 30-day, 90-day, and 1-year postoperative systemic and local complications and mortality.   

Results
At 30 days postoperatively, NAFLD patients had significantly increased odds of pneumonia (OR 1.35, 95% CI 1.07-1.70), emergency room visits (OR 1.30, 95% CI 1.21-1.41), urinary tract infections (OR 1.20, 95% CI 1.03-1.42), stiffness (OR 1.09, 95% CI 1.00-1.19), and dislocation of knee (OR 1.85, 95% CI 1.41-2.44) versus controls. At 90 days postoperatively, increased odds persisted for pneumonia (OR 1.35), urinary tract infection (OR 1.18), knee dislocation (OR 1.39), and emergency visits (OR 1.32), with an additional increased odds of pulmonary embolism (OR 1.20, 95% CI 1.01-1.42) and sepsis (OR 1.26, 95% CI 1.01-1.58). At 1 year, NAFLD remained associated with increased odds of pneumonia (OR 1.29), pulmonary embolism (OR 1.15), sepsis (OR 1.23), acute kidney failure (OR 1.18), urinary tract infection (OR 1.21), knee dislocation (OR 1.17) and emergency visits (OR 1.39), with an additional increased odds of acute kidney failure (OR 1.18, 95% 1.08-1.29)

Conclusion
NAFLD is associated with increased odds of postoperative medical and surgical complications following TKA and should be considered a clinically relevant risk factor during preoperative evaluation. These findings support the incorporation of NAFLD into perioperative risk stratification and optimization to improve patient outcomes.

Keywords: Total Knee Arthroplasty; Non-Alcoholic Fatty Liver Disease; Propensity Score Matching; Postoperative Complications; Sepsis; Pneumonia

Abbreviations:

• NAFLD – nonalcoholic fatty liver disease
• TKA – total knee arthroplasty
• OR – odds ratio
• ICD – International Classification of Diseases
• CPT – Current Procedural Terminology
• HIPAA – Health Insurance Portability and Accountability Act
• IRB – Institutional Review Board
• CI – confidence interval
• MELD – Model for End-Stage Liver Disease
• PAI-1 – plasminogen activator inhibitor -1

Introduction
Total knee arthroplasty (TKA) is a surgical procedure designed to treat primary, end-stage, and tricompartmental osteoarthritis by replacing the damaged surfaces of the knee with a prosthesis, thereby alleviating pain and restoring function¹. Patients typically elect to pursue TKA surgery after failed conservative management that consisted of a combination of medication, physical therapy, or injections¹. Patients with osteoarthritis often present with multiple comorbidities. Individuals with osteoarthritis are almost two times more likely to have multi-morbidity (>=2 comorbidities) compared with patients of the same age who are not diagnosed with osteoarthritis². Outcome studies have demonstrated that liver cirrhosis and obesity are associated with increased perioperative morbidity³. Non-alcoholic fatty liver disease (NAFLD) is understood to be among the leading causes of cirrhosis⁴.

NAFLD has been previously demonstrated to be associated with an increased rate of mortality and morbidity⁵. A study assessing the impact of NAFLD on perioperative mortality concluded that patients who underwent surgery while diagnosed with a comorbidity of NAFLD had a statistically significant longer hospital stay and readmission rates within 30 days following operations⁵. The literature confirms that cirrhosis is a significant risk factor for postoperative complications, prolonged lengths of stay, and consequently, higher overall medical costs in patients undergoing TKA⁵. However, the independent impact of NAFLD on TKA postoperative outcomes is unclear. NAFLD, even prior to progressing into cirrhosis, likely propagates the systemic inflammation and metabolic dysfunction that contribute to overall operative risk factors and negatively impact a patient’s overall surgical candidacy⁶. The primary study objective was to assess the association between a pre-existing diagnosis of NAFLD and the incidence of adverse postoperative outcomes following TKA.

Materials and methods

Data Collection
The data were collected from the TriNetX Global Collaborative Network, which provided deidentified electronic medical records from approximately 155 million patients from 154 healthcare organizations. Patient data were obtained from August 2005 to 2025 and consisted of demographic, International Classification of Diseases 10th edition diagnosis codes (ICD-10)⁷, Current Procedural Terminology codes (CPT)⁸, postoperative complications, and healthcare outcomes, such as mortality, useful for a retrospective cohort analysis. All analyses were conducted using de-identified data, rendering the study compliant with the Health Insurance Portability and Accountability Act (HIPAA) regulations and exempt from Institutional Review Board (IRB) approval.

Inclusion and Exclusion Criteria
Patients older than 18 years of age and diagnosed with NAFLD or Nonalcoholic Steatohepatitis prior to receiving a TKA were included in this study. The control group consisted of adult patients who underwent TKA without a prior history of NAFLD. Exclusion criteria comprised data prior to 2005, revision or bilateral TKA, and missing demographic and primary outcome data.

Propensity Score Matching
The experimental cohort, TKA with a past medical history of NAFLD or Nonalcoholic Steatohepatitis, consisted of 20,795 patients, and the control cohort contained 352,987 patients. The sample size was determined by the number of patients who met the inclusion and exclusion criteria within the TriNetX database based on predefined ICD-10 and CPT codes; therefore, no formal sample size calculation was performed. To reduce confounding and selection bias, experimental and control subjects were paired on a one-to-one basis using propensity scores derived from preoperative characteristics and comorbidities. The matching characteristics included age, sex, race, ischemic heart disease, hypertension, hyperlipidemia, diabetes, obesity, tobacco use, and alcohol abuse. The matched data were summarized, and chi-square tests were conducted to evaluate the propensity matching.

Statistical Analysis
Statistical analysis was conducted using Microsoft Excel (2025)⁹ and TriNetX Analytics. Two cohorts were classified as NAFLD, consisting of patients with NAFLD or Nonalcoholic steatohepatitis, and Control, which underwent a 1:1 Propensity matching. A total of twenty-two postoperative complications and outcomes were evaluated. These included acute kidney injury (N17), acute myocardial infarction (I21), atrial fibrillation (I48), blood loss anemia (D62), cardiac arrest (I46), deep vein thrombosis (I82.40), pneumonia (J18), pulmonary embolism (I26), sepsis (A41), stroke (I63), transfusion (CPT1012085), urinary tract infection (N39), dislocation of knee (S83), disruption of wound (T81.3), manipulation under anesthesia (CPT27570), periprosthetic fracture (M97), septic arthritis of knee (M00.869), stiffness of knee (M25.66), emergency visit, mortality, revision (CPT-27486), and readmissions. The outcomes were summarized using t-tests for continuous variables and chi-square tests for categorical variables. Postoperative outcomes were evaluated at 30 days, 90 days, and 1 year following TKA. Multivariate logistic regression comparing the outcomes of the NAFLD cohort to the control calculated odds ratios (ORs) with 95% confidence intervals, and the significance was set at P < 0.05. The primary outcome of this study was the incidence of overall postoperative complications within 30 days following TKA. Secondary outcomes included individual postoperative complications, complications assessed at 90 days and 1 year, and healthcare utilization measures, including emergency department visits, readmissions, and mortality.

Missing-Data Handling
The TriNetX database does not provide detailed information regarding missing data; therefore, missing-data handling could not be assessed, and no imputation methods were applied.

Results

Baseline Patient Characteristics
Table 1 presents the baseline characteristics of the patients who underwent TKA following a 1:1 propensity score matching. A total of 20,663 patients with NAFLD were compared to 20,663 matched controls without NAFLD. Matching achieved covariant balance across demographic variables and systemic comorbidities with no statistically significant differences between groups (Table 1). In the NAFLD group, the mean age was 65.55 ± 8.77 and 65.53 ± 8.84 in the control, with a predominance of females (61%) in both cohorts. The prevalence of hypertension (83%), hyperlipidemia (68%), ischemic heart disease (30%), diabetes (45%), obesity (67% & 68%), and tobacco use (6% & 5%) was statistically similar between groups, thus confirming adequate adjustment for baseline risk factors. Although a statistically significant difference was observed in alcohol abuse (6.5% vs 5.9%, p = 0.02), the standardized mean difference was negligible (SMD = 0.023), indicating excellent covariate balance between the two cohorts. 

Table 1: Baseline Patient Characteristics After Matching

Outcomes in NAFLD Patients at 30 days
Table 2 presents the relationship between NAFLD and postoperative complications within 30 days following TKA. At 30 days postoperatively, patients with NAFLD demonstrated significantly higher rates of several systemic and local complications compared with controls. Specifically, NAFLD was associated with increased odds of pneumonia (OR 1.35, 95% CI 1.07-1.70, p=0.01), urinary tract infection (OR 1.21, 95% CI 1.03-1.42, p=0.02), knee dislocation (OR 1.85, 95% CI 1.41-2.44, p<0.001), stiffness (OR 1.09, 95% CI 1.00-1.19, p=0.04), and emergency department visits (OR 1.30, 95% CI 1.21-1.41, p<0.001). No significant differences were observed in mortality, revision rates, readmissions within 30 days, or other systemic and local complications (Table 2).

Table 2: Effect of NAFLD on 30-Day Outcomes following TKA

Outcomes in NAFLD Patients at 90 days
Table 3 outlines the impact of NAFLD on 90-day postoperative complications after TKA. By 90 days, the NAFLD cohort continued to demonstrate elevated risks of both systemic and local surgical complications. Rates of pneumonia remained significantly higher (OR 1.35, 95% CI 1.11-1.62, p=0.0002), as did urinary tract infection (OR 1.18, 95% CI 1.06-1.32, p=0.004), and knee dislocation (OR 1.39, 95% CI 1.14-1.69, p=0.001). The frequency of knee stiffness no longer remained significantly elevated at 90 days postoperative as well. Within 90 days, however, NAFLD patients demonstrated increased odds of pulmonary embolism (OR 1.20, 95% CI 1.01-1.42, p=0.04) and sepsis (OR 1.26, 95% CI 1.01-1.58, p=0.04). Health care utilization remained higher in the NAFLD cohort, as reflected by increased emergency visits (OR 1.32, 95% CI 1.25-1.41, p<0.0001). Mortality, revision, and readmission rates remained comparable (Table 3).

Table 3: Effect of NAFLD on 90-Day Outcomes following TKA

Outcomes in NAFLD Patients at 1 year
Table 4 details postoperative complications at 1 year in patients with and without NAFLD undergoing TKA. At 1-year post-TKA, the NAFLD cohort demonstrated persistent elevation in adverse outcomes. They remained to have increased odds of pneumonia (OR 1.29, 95% CI 1.14-1.46, p<0.0001), pulmonary embolism (OR 1.15, 95% CI 1.00-1.32, p=0.046), sepsis (OR 1.23, 95% CI 1.00-1.32, p=0.008), urinary tract infection (OR 1.21, 95% CI 1.12-1.31, p<0.0001), and knee dislocation (OR 1.17, 95% CI 1.02-1.34, p<0.0001). Interestingly, the rate of stiffness remained insignificant at 1 year, as it did at 90 days. Although not previously elevated, the rate of acute kidney failure (OR 1.18, 95% CI 1.08-1.29, p=0.0004) was significantly higher in the NAFLD cohort 1 year after TKA. Health care utilization continued to be elevated, with a markedly higher rate of emergency department visits (OR 1.39, 95% CI 1.32-1.46, p<0.0001) as compared to the control group. Mortality, revision, and readmission rates remained not significantly different between groups (Table 4).

Table 4: Effect of NAFLD on 1-year Outcomes following TKA

Summary of Findings
Overall, NAFLD was independently associated with higher rates of postoperative systemic complications (pneumonia, sepsis, pulmonary embolism, acute kidney injury, urinary tract infection) and local complications (knee dislocation, stiffness) following TKA. These differences were present in the first 90 days as well and persisted through 1 year, accompanied by increased emergency department visits. Mortality, revision, and readmission rates did not significantly differ between groups at any time.

Discussion
This study evaluates the association between NAFLD and postoperative outcomes following TKA, demonstrating an elevated risk of complications at 30 days, 90 days, and 1 year, including infections, thromboembolic events, and mechanical complications. Patients with NAFLD also exhibited increased healthcare utilization, as reflected by emergency visit rates. Collectively, these observations underscore NAFLD as a significant determinant of postoperative risk in patients undergoing TKA.

Although NAFLD has not been extensively studied in the context of TKA, broader research on hepatic disease indicates a heightened risk of postoperative complications. Lan et al. found that patients with moderate-to-severe cirrhosis (MELD score ≥ 10) had significantly higher rates of intrahospital, 30-day, and 90-day overall complications compared to patients with mild cirrhosis and noncirrhotic patients³. Some of the complications in their study included deep vein thrombosis, pulmonary embolism, fever, or death. Tiberi III et al. examined the effect of liver cirrhosis on TKA. They noted that in patients with cirrhosis, there were increased rates of urinary tract infections, dislocations, infections, renal failure, and readmission in 90 days. Furthermore, they saw a three times increased likelihood of each complication when a MELD score was 10 or greater¹⁰. In a separate analysis, Shih et al. similarly identified a greater incidence of postoperative complications among cirrhosis patients, with infections occurring most frequently¹¹. While reinforcing the observations from earlier work, our study underscores NAFLD as a unique etiology of liver disease impacting postoperative outcomes, rather than cirrhosis in general.

Other hepatic etiologies have also been evaluated in the context of TKA outcomes. Luo et al. found that patients with established Alcohol Use Disorder were at an increased odds of venous thrombosis within 90 days and 1 year post TKA¹². A subgroup analysis conducted by Bell et al. showed that cirrhotic patients, specifically alcoholic, viral, and other etiologies, were at an increased risk of developing complications, including disseminated intravascular coagulation, encephalopathy, and periprosthetic infection following TKA¹³. Pour et al. reported that patients seropositive for hepatitis C who underwent TKA had higher rates of mechanical complications, including loosening and periprosthetic fracture requiring revision¹⁴. Consistent with these findings across diverse causes of liver dysfunction, our results demonstrate that NAFLD was independently associated with systemic complications after TKA, including higher rates of pneumonia, sepsis, pulmonary embolism, acute kidney injury, and urinary tract infection.

Previous studies have also reported mechanical complications following TKA in patients with underlying liver disease. Pour et al. found that hepatitis C-infected patients were associated with an increased rate of surgical complications necessitating mechanical revision following joint arthroplasty. In their TKA subgroup, patients experienced mechanical complications, including loosening and periprosthetic fracture¹⁴. Similarly, Metikala et al. found cirrhotic patients had an increased likelihood of developing periprosthetic fracture and periprosthetic infection following TKA, displaying higher rates of perioperative complications than non-cirrhotic patients¹⁵. In congruence with these studies, our results show increased rates of local complications, including knee dislocation and knee stiffness, following TKA in patients with established NAFLD.

Thromboembolic risk in patients with NAFLD has been abundantly documented in non-orthopedic populations, suggesting a biologic basis for our observation of an increased odds of pulmonary embolism. Scheres et al. demonstrated that higher fatty liver index scores were associated with increased incidences of venous thromboembolism in a large population-based cohort¹⁶. Several other studies suggest that patients with NAFLD have a hypercoagulable state that may increase their risk of thromboembolic events. Verrijken et al. reported that increasing hepatic steatosis correlates with elevated levels of plasminogen activator inhibitor-1 (PAI-1), an important inhibitor of fibrinolysis¹⁷. Additionally, Tripodi et al. found that patients with NAFLD have increased levels of factor VIII and reduced protein C, reflecting a procoagulant imbalance¹⁸. Although these studies were not conducted in orthopedic populations, they support the biologic plausibility of our observed finding that patients with NAFLD undergoing TKA have higher rates of pulmonary embolism.

The risk of infection following TKA in patients with liver dysfunction has also previously been analyzed. Kinnard et al. found patients with liver disease undergoing revision total knee arthroplasty had an increased risk of wound complications, septic complications, and other major complications requiring readmission compared to those without liver disease¹⁹. Similarly, Bendich et al. reported that hepatitis C patients who received antiviral treatment had significantly lower implant infection rates at 90 days and 1 year than untreated controls, underscoring that unmanaged hepatic disease confers greater postoperative infection risk²⁰. In line with these studies, our results showed patients with NAFLD demonstrated increased rates of postoperative sepsis, pneumonia, and urinary tract infection at 30-day, 90-day, and 1-year follow-up following TKA. Multiple mechanisms have been implicated in the heightened infection risk observed in liver disease, including cirrhosis-associated immune dysregulation, portosystemic shunting, alterations in gut microbiota, and increased bacterial translocation²¹. Overall, poor liver function, as in hepatitis C and NAFLD, poses a significant risk for infection.

The limitations of this study are typical of retrospective database research, particularly those dependent on ICD and CPT coding for data extraction. While the use of these codes allows for access to extensive patient information, it carries the inherent risk of inaccuracies and inconsistencies in provider coding of diagnoses, procedures, and complications. This can lead to data misclassification or omission. Specific coding practice may also vary between institutions, which can further contribute to over-coding or underreporting. Although propensity score matching was performed across ten preoperative variables, residual confounding may persist due to unmeasured or unavailable variables within the database, including, but not limited to, NAFLD disease severity and fibrosis stage, liver function indices, BMI granularity, frailty and functional status, socioeconomic status, surgeon volume and experience. These unaccounted variables may influence the observed associations and should be considered when interpreting the results. Furthermore, ICD and CPT coding provide limited insight into detailed clinical characteristics, such as full medical history, lab and imaging findings, clinical manifestation, and functional outcomes, while also omitting variability in surgical methods and institutional care patterns. Selection bias may also be introduced through the structure of TriNetX network, which draws from participating healthcare organizations and may underrepresent uninsured, rural, or socioeconomically disadvantaged populations, thus limiting the generalizability to those groups. Nonetheless, given the large, matched cohort size of 20,663 patients, the findings of this study are likely representative of the broader U.S. population.

Prospective research could explore patterns of postoperative adverse events in patients with nonalcoholic steatohepatitis. Additional studies could also stratify NALFD patients based on MELD scores as well as comorbidities, such as type 2 diabetes. Lastly, future initiatives could investigate the effects NAFLD has on length of stay, cost of care, and readmission rates, as they were not analyzed in this study.

Conclusions
In this large propensity-matched cohort, NAFLD was associated with increased odds of postoperative complications following TKA, such as pneumonia, pulmonary embolism, stiffness, and sepsis. These findings suggest the consideration of NAFLD as a clinically relevant risk factor in patients undergoing TKA and highlight the importance of incorporating liver disease into surgical decision-making and optimization protocols. Recognition of this association may improve patient counseling and enhance postoperative outcomes. 

Explicit Ethics/Institutional Review Board (IRB) Statement
This study was conducted using de-identified data obtained from a national database and thus did not require institutional review board approval or informed consent. All procedures adhered to HIPAA regulations and were consistent with the ethical standards of the Helsinki Declaration.

Consent-to-Participate Statement
Informed consent was waived due to the retrospective nature of this study and the use of de-identified data.

Consent for Publication
Consent for publication was not applicable as no identifiable patient information was included.

Conflict-of-Interest Statement
The authors have no financial or personal conflicts of interest to disclose.

Funding Statement
No funding was received for this work.

Sponsor Statement
The authors declare that there was no sponsor involvement in the design, conduct, analysis, interpretation, or writing of this study.

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