Introduction

Osteoarthritis causes pain, stiffness, and reduced physical activity and quality of life [1]. Secondary osteoarthritis has a well-known etiology such as sequelae to trauma, congenital abnormalities, infection, or rheumatoid arthritis, whereas primary osteoarthritis is defined by absence of such previous pathology. Like old age and biomechanical stress, localized joint inflammation is a risk factor for primary osteoarthritis [2], and we hypothesized that also chronic systemic inflammation increases the risk of primary osteoarthritis [3]. This possibility is supported by studies linking raised serum markers for inflammation with radiographic changes, symptoms, and symptom progression in primary osteoarthritis [4, 5]. Cirrhosis is the end-stage of all chronic liver diseases and characterized by chronic systemic inflammation [6]. Thus, cirrhosis patients offer an opportunity to study chronic systemic inflammation as a risk factor for primary osteoarthritis, and this has not been examined before. Given this background, our objective was to examine cirrhosis as a risk factor for primary osteoarthritis of the hip or knee.

Patients and methods

Results

We included 10,049 cirrhosis patients and 44,370 matched reference persons. Their median age was 67 years, 65% were male, 66% had alcoholic cirrhosis, and 33% had ascites; 10.5% of the cirrhosis patients and 4.5% of the reference persons had chronic obstructive pulmonary disease. A total of 208 cirrhosis patients and 2,490 reference persons were diagnosed with primary osteoarthritis of the hip or knee during the follow-up. Among the cirrhosis patients the crude incidence rate of primary osteoarthritis was 8.40 (95% CI: 7.30–9.63) per 1000 person-years compared with 8.76 (95% CI: 8.43–9.12) per 1000 person-years among the reference persons; the incidence rates were similar in cirrhosis patients and reference persons in all age groups (Table 1).

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Table 1. Incidence rate (IR) of primary osteoarthritis of the hip or knee in Danish cirrhosis patients and age- and gender-matched reference persons from the general population.

https://doi.org/10.1371/journal.pone.0167134.t001

As we anticipated, chronic obstructive pulmonary disease was associated with a reduced rate of primary osteoarthritis (HR for persons with and without chronic obstructive pulmonary disease = 0.69, 95% CI: 0.53–0.90), but even when we adjusted the osteoarthritis rates for chronic obstructive pulmonary disease’s confounding effect, cirrhosis remained unassociated with primary osteoarthritis (HR ratio for cirrhosis vs. reference persons = 0.99, 95% CI: 0.85–1.16). This HR was similar across gender and age groups; similar for cirrhosis patients with or without ascites; similar for patients with alcoholic cirrhosis or unspecified cirrhosis; and similar for primary osteoarthritis of the hip or the knee (Table 2).

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Table 2. Hazard ratio (HR) for primary osteoarthritis for cirrhosis patients vs. reference persons by gender, age on index date, ascites, cirrhosis etiology, and site.

https://doi.org/10.1371/journal.pone.0167134.t002

However, the HR for the composite outcome for cirrhosis patients vs. reference persons was 0.78 (95% CI: 0.60–1.01), which may indicate that even though cirrhosis patients and reference persons have a similar rate of osteoarthritis, cirrhosis patients are less likely to undergo THA/TKA for primary osteoarthritis.

Discussion

In this nationwide cohort study we found that cirrhosis was not a risk factor for primary osteoarthritis, and the narrow confidence interval ranging from 0.85 to 1.16 essentially rules out a clinically relevant association. Moreover, we found a similar effect of cirrhosis on the risk for primary osteoarthritis in subgroups defined by age, gender, alcoholic vs. unspecified cirrhosis, and for cirrhosis patients with and without ascites.

The strength of our study is its foundation in the Danish healthcare data which enables precise estimates, complete follow-up, and a population-based design. The study population was based on hospitalized patients with cirrhosis. Consequently, persons with cirrhosis that for various reasons were treated outside hospitals were not included. Moreover, 6% of patients with biopsy-verified cirrhosis did not have a discharge diagnosis for cirrhosis [14]. Altogether, our study might overlook an unknown proportion of Danish residents with cirrhosis, but these patients probably have less severe cirrhosis compared with hospitalized cirrhosis patients. Therefore, we find it unlikely that their risk of primary osteoarthritis is different from hospitalized cirrhosis patients.

Cirrhosis diagnoses recorded in the NPR were confirmed by biopsy or clinical evaluation in 85% of cases [14], and we find it unlikely that the 15% without cirrhosis in our patient cohort caused us to miss an existing association; that could only happen if all those 15% possessed a factor that confers a greatly reduced (or increased) risk of primary osteoarthritis. The NPR diagnoses for primary osteoarthritis have never been validated, but we corroborated our results by combining diagnoses for primary osteoarthritis in the NPR with data on the indication for arthroplasty from the DHR/DKR. The validity of the indication ‘primary osteoarthritis’ in the DHR is 85% [9], and we assume that the validity of this indication is similar in the DKR. We expect the validity to be the same for cirrhosis patients and reference persons. So, we do not believe that inadequacies of our data sources impaired the reliability of our results.

The most important risk factor for primary osteoarthritis is old age, and this potential confounder was eliminated by the matching. The use of hospital diagnosis codes for chronic obstructive pulmonary disease as an indicator for smoking will underestimate its prevalence. So if cirrhosis patients’ higher prevalence of smoking decreases their risk of primary osteoarthritis, we may underestimate the hazard ratio slightly. Danish cirrhosis patients have a low employment rate [15], and socioeconomic deprivation increases the risk the risk for primary osteoarthritis [16]. Thus, the lack of adjustment for socioeconomic factors will probably cause to overestimate the hazard ratio. Mechanical stress is also a potential confounder. We had no data on body mass index (BMI), and cirrhosis patients’ fluctuating volume of ascites makes their BMI a poor marker of mechanical stress; and notably, ascites did not alter the association between cirrhosis and primary osteoarthritis. Ethnicity is an unlikely confounder because the Danish population is 95% Caucasian [17]. Alcohol consumption is a possible confounder, but we found a similar association when we divided our analyses into patients with alcoholic cirrhosis and patients with unspecified cirrhosis. So, although we cannot exclude uncontrolled confounding from smoking, BMI, socioeconomic factors, ethnicity and alcohol completely, we do not believe that it explained our results.

From a clinical point of view, the lack of an increased risk for osteoarthritis in cirrhosis is valuable information, because we have shown that hip- and knee arthroplasty in such patients carry an increased risk for postoperative complications [18–20]. The increased risk of complications may imply that orthopedic surgeons hesitate to perform arthroplasty in cirrhosis patients, and that is the best explanation to the slightly lower rate of arthroplasty for osteoarthritis in the cirrhosis patients than in the reference persons.

The increased risk of complications also raises the possibility that cirrhosis patients are less likely to be referred to work-up for primary osteoarthritis than reference patients without cirrhosis, because they are deemed unfit for arthroplasty surgery. This scenario might produce a referral bias that would cause us to underestimate the true association between cirrhosis and primary osteoarthritis. However, physiotherapy offers an alternative to surgery and is not contraindicated in cirrhosis patients, so it is always clinically meaningful to refer cirrhosis patients to work-up for joint pain. Moreover, we find it unlikely that the effect of a referral bias nullifies a true association between cirrhosis and primary osteoarthritis in the main analysis and in all strata defined by age and gender. All in all, we acknowledge that a referral bias might exist, but we maintain our conclusion that cirrhosis not is a risk factor for primary osteoarthritis.

There is strong evidence that cirrhosis patients suffer from chronic systemic inflammation [6], so the absence of an association between cirrhosis and primary osteoarthritis refutes our hypothesis that chronic systemic inflammation causes primary osteoarthritis. Previous studies have found that biomarkers for inflammation (Interleukin-6 and Tumor Necrosis Factor α) are elevated in alcoholic cirrhosis patients and predict increasing knee pain in patients with primary osteoarthritis [4, 5, 21]. One way to unite those findings with ours is to posit that it takes decades of systemic inflammation to develop primary osteoarthritis. Cirrhosis patients do not survive long enough to settle that possibility [22], but patients with less life-threatening chronic inflammatory diseases, such as asthma or inflammatory bowel disease, are not good models, either; their systemic inflammation is only active during exacerbations.

In conclusion, cirrhosis was not associated with primary osteoarthritis of the hip and knee, and this null association was also present when we analyzed subgroups defined by age, gender, alcohol vs. unspecified cirrhosis, and with vs. without ascites. This result suggests that chronic systemic inflammation does not have an important role in primary osteoarthritis.

Supporting Information