Inflammatory bowel disease increases the risk of liver cirrhosis: a retrospective population-based study

Abstract

Introduction:

Inflammatory bowel disease (IBD) incidence continues to increase in many parts of the world, especially in Asia, while the highest rates are still seen in Northern America and Europe. Data on the influence of IBD on the occurrence of liver cirrhosis are scarce.

Objectives:

This study investigated the impact of IBD on the incidence of liver cirrhosis in a large German primary care cohort over a 20-year timeframe.

Design:

Patients with IBD were matched to non-IBD individuals based on age, sex, index year, and co-diagnoses of obesity, diabetes mellitus, and alcohol addiction in a 1:5 ratio, while IBD subgroup Crohn’s disease contained 10,264 and ulcerative colitis 13,228 patients. The primary outcome of the study was the incidence of cirrhosis.

Methods:

The relationship between IBD and cirrhosis was investigated using univariable Cox regression analysis.

Results:

We compared 23,492 patients with IBD with 117,460 matched individuals without IBD. After up to 20 years of follow-up, 1.68% of patients with IBD and 0.68% of matched non-IBD patients were diagnosed with liver cirrhosis (p = 0.001).

In the total cohort, IBD was associated with an increased risk of cirrhosis (HR: 1.51; 95% CI: 1.18–1.93), while in sensitivity analyses, there was a significant association between ulcerative colitis and development of liver cirrhosis (HR: 1.59; 95% CI: 1.16–2.18), while there was no significant association between Crohn’s disease and liver cirrhosis. The association was stronger and statistically significant in individuals aged ⩾ 50 years (HR: 1.56; 95% CI: 1.19–2.04), but not in younger individuals. A more pronounced risk was observed in women (HR: 1.83; 95% CI: 1.28–2.62) compared to men (HR: 1.29; not significant).

Conclusion:

In conclusion, IBD is associated with an increased risk of a cirrhosis diagnosis, with older patients appearing to be particularly vulnerable.

Plain language summary

People with inflammatory bowel disease have a higher risk of developing liver cirrhosis

This study looked at whether people with inflammatory bowel disease (IBD) are more likely to develop liver cirrhosis. Researchers analyzed data from a large group of patients in Germany over a 20-year period. They compared more than 23,000 people with IBD (including Crohn’s disease and ulcerative colitis) to over 117,000 similar individuals without IBD. They found that people with IBD were more likely to be diagnosed with liver cirrhosis than those without IBD - about 1.7% of IBD patients developed cirrhosis, compared to 0.7% of people without IBD. The increased risk was especially clear in people with ulcerative colitis, women, and those aged 50 or older. Crohns disease, on the other hand, was not clearly linked to cirrhosis. In summary, having IBD - particularly ulcerative colitis -may increase the risk of liver cirrhosis, especially for older adults and women.

Keywords

chronic liver disease Crohn’s disease ulcerative colitis liver gut axis large primary care cohort

Introduction

Inflammatory bowel disease (IBD), encompassing Crohn’s disease (CD) and ulcerative colitis (UC), is characterized by chronic, idiopathic inflammation of the gastrointestinal tract, manifesting clinically with symptoms such as diarrhea, abdominal pain, and weight loss.¹ The global prevalence of inflammatory bowel disease is substantial, with an estimated 6.8 million individuals affected worldwide, and incidence rates are rising, especially in Asia.²

Hepatobiliary manifestations are common in patients with IBD, with up to 30% displaying abnormalities in hepatic biochemical markers.³ For instance, there is a well-established association between primary sclerosing cholangitis (PSC) and IBD, with a particularly strong link to UC.⁴ By contrast, autoimmune diseases such as autoimmune hepatitis or primary biliary cholangitis are less common among patients with IBD, but their prevalence is still higher than in the general population.⁴ Other chronic liver diseases in patients with IBD include liver amyloidosis, granulomatous hepatitis, and metabolic dysfunction-associated steatotic liver disease (MASLD), previously referred to as non-alcoholic fatty liver disease (NAFLD).^5,6 Notably, MASLD is prevalent in approximately one-third of patients with IBD, with a twofold increased risk compared to healthy controls.⁷ In general, MASLD is associated with metabolic comorbidities, including obesity, type 2 diabetes mellitus, hypertension, and hyperlipidemia, and can result in liver cirrhosis with a high risk for hepatocellular carcinoma (HCC), a difficult-to-treat primary liver cancer.⁸ Furthermore, patients with MASLD have an elevated risk of cardiovascular disease events and all-cause mortality.⁹ In patients with IBD, older age and higher body mass index have been identified as factors significantly associated with an increased risk of MASLD.⁷ Concerning the prognosis of IBD patients, a meta-analysis has found that patients with IBD have higher rates of all-cause mortality as well as mortality related to nonalcoholic liver disease, although the underlying causality remains unclear.¹⁰

Liver cirrhosis is the end-stage of every chronic liver disease and an important cause of morbidity and mortality worldwide, with both the prevalence of cirrhosis and the number of deaths associated with cirrhosis increasing.^11,12 While many studies have investigated the prevalence of liver disease in patients with IBD, large patient data evidence regarding the progression to liver cirrhosis in this population remains limited.^7,13–16 A recent registry-based cohort study has identified an increased risk of liver cirrhosis among patients with IBD compared to those without IBD, with CD patients exhibiting a higher risk than UC patients.¹⁷

Consequently, current data are insufficient to adequately define the risk of progression to liver cirrhosis in patients with IBD, limiting the understanding of the disease burden and the need for liver monitoring in this patient population. Therefore, the aim of this study was to assess whether IBD is associated with an increased risk of liver cirrhosis using a primary care cohort in Germany.

Methods

Database

This retrospective cohort study utilized data from the Disease Analyzer database (IQVIA), which includes anonymized information on drug prescriptions, diagnoses, and basic medical and demographic variables recorded directly from the computer systems of general practitioners and specialists. The database comprises approximately 3000 office-based physicians across Germany and has been demonstrated to be representative of both general and specialty practices in the country.¹⁸ It has also been used in previous research focusing on IBD and liver cirrhosis.^19,20

Study population

This study included adult patients (⩾18 years) with an initial diagnosis documentation of Crohn’s disease (ICD-10: K50) or ulcerative colitis (ICD-10: C51) in 1293 general practices in Germany between January 2005 and December 2023 (index date; Figure 1). Only patients with an observation time of at least 12 months prior to the index date were included to assess the co-diagnoses documented within 12 months prior to the index date. Patients with diagnoses of liver diseases (ICD-10: B18, K70-K77, K83.0) prior to the index date or on the index date were excluded. The FIB-4 score, a well-established laboratory marker for estimating liver fibrosis, was calculated in both cohorts. The median FIB-4 score was below 1.3, indicating a low risk of advanced liver fibrosis.²¹ Laboratory data were available for 3390 individuals (14% of the IBD cohort) and 9971 individuals (9% of the non-IBD cohort; Table 1).

Table 1.

Median FIB-4 scores and the number of available laboratory values in the matched cohorts.

Cohort	Median	IQR	N
IBD	0.92	0.58–1.40	3390
No IBD	1.03	0.69–1.51	9971

IQR, interquartile range; N, numbers.

After applying analogous inclusion criteria, individuals without IBD were matched to IBD patients using nearest-neighbor propensity score matching (5:1) based on age, sex, index year, and co-diagnoses of obesity (ICD-10: E66), diabetes mellitus (ICD-10: E10–E14), and alcohol addiction (ICD-10: F10) documented within 12 months before or on the index date. For the non-IBD cohort, the index date corresponded to a randomly selected visit between January 2005 and December 2023 (Figure 1). Covariate balance between cohorts was assessed using the standardized mean difference (SMD), with an SMD < 0.1 indicating acceptable balance.

Study outcomes

The outcomes of the study were the initial diagnoses of liver cirrhosis (ICD-10: K70.2, K70.3, K74) and MASLD (ICD-10: K75.8, K76.0) as secondary outcomes in the up to 20 years following the index date as a function of IBD.

Statistical analyses

Kaplan–Meier curves were used to analyze the 20-year cumulative incidence of liver cirrhosis. Univariable Cox regression models assessed the association between IBD and liver cirrhosis, with analyses stratified by disease subtype (CD and UC), age group (⩽50 vs >50 years), and sex. Results from the Cox regression model are presented as hazard ratios (HRs) and 95% confidence intervals (CIs). p Value of <0.05 was considered statistically significant. Analyses were conducted using SAS version 9.4 (SAS Institute, Cary, USA).

STROBE statement

The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement (Supplemental File).

Results

Basic characteristics of the study sample

The present study included 23,492 individuals with IBD, comprising 10,264 with Crohn’s disease CD and 13,228 with UC, as well as 117,480 matched individuals without IBD. The mean age was 50.0 years (SD: 18.6), and men (45%) and women (55%) were mostly equally balanced. However, the proportion of alcoholic liver cirrhosis was 29.4% in the IBD cohort and 42.0% in the non-IBD cohort (p = 0.034).

After matching for IBD-relevant risk factors – including age, sex, index year, and co-diagnoses such as obesity, diabetes mellitus, and alcohol dependence – no significant differences were observed between the IBD and non-IBD cohorts. Basic characteristics of the study population are summarized in Table 2.

Table 2.

Baseline characteristics of the study sample (after 1:5 propensity score matching by age, sex, index year, and co-diagnoses of obesity, diabetes mellitus, and alcohol addiction).

Variable	Proportion affected among patients with IBD (%)	Proportion affected among patients without IBD (%)	SMD
n	23,492	117,460
Mean age (years, SD)	50 (18.6)	50 (18.6)	0.001
Age < 50 years (n, %)	11,520 (49)	57,563 (49)
Age 50 ⩾ years (n, %)	11,972 (51)	59.897 (51)
Female (n, %)	12,986 (55.3)	64,889 (55.2)	0.000
Male (n, %)	10.506 (44.7)	52,571 (44.8)	0.000
Crohn’s disease (n, %)	10,264 (43.7)
Ulcerative colitis (n, %)	13,228 (56.3)
Year of study inclusion
2005–2008 (n, %)	2092 (8.9)	10,462 (8.9)	−0.001
2009–2012 (n, %)	3558 (15.1)	17,808 (15.2)
2013–2016 (n, %)	5491 (23.4)	27,370 (23.3)
2017–2020 (n, %)	6813 (29.0)	34,050 (24.0)
2021–2023 (n, %)	5538 (23.6)	27,770 (23.6)
Obesity (n, %)	1767 (7.5)	8.739 (7.4)	−0.001
Diabetes mellitus (n, %)	2713 (11.5)	13,507 (11.5)	0.000
Alcohol addiction (n, %)	1046 (4.5)	4915 (4.2)	−0.003

Number of patients in N, % given, unless otherwise indicated.

SD, standard deviation; SMD, standardized mean difference.

Cumulative incidence of liver cirrhosis and MASLD

After up to 20 years of follow-up, 1.68% of patients with IBD and 0.68% of matched non-IBD patients were diagnosed with liver cirrhosis, resulting in 71.6 liver cirrhosis patients per 100,000 person-years in the IBD and 47.5 cases per 100,000 person-years in the non-IBD cohort (p = 0.001, Figure 2). The incidence was higher in the UC cohort (76.2 cases per 100,000 person-years) than in the CD cohort (65.5 cases per 100,000 person-years).

As IBD is an acknowledged risk factor for MASLD, the incidence of MASLD was assessed in both cohorts (7, 19). During the follow-up period, significantly more patients were diagnosed with MASLD in the IBD cohort compared to the non-IBD cohort (p < 0.001), corresponding to 618.3 versus 458 cases per 100,000 person-years (Figure 3).

Association of IBD with subsequent liver cirrhosis

IBD was significantly associated with an increased risk of liver cirrhosis (HR: 1.51; 95% CI: 1.18–1.93). This association was statistically significant for UC (HR: 1.59; 95% CI: 1.16–2.18), but not for CD (HR: 1.40; 95% CI: 0.95–2.06).

When stratified by age, the association between IBD and liver cirrhosis was stronger and statistically significant in individuals aged ⩾ 50 years (HR: 1.56; 95% CI: 1.19–2.04), while it was not significant in those under 50 years. The association was also more pronounced in women (HR: 1.83; 95% CI: 1.28–2.62) than in men (HR: 1.29; not significant).

Similarly, the association between UC and liver cirrhosis was significant in patients aged ⩾50 years (HR: 1.78; 95% CI: 1.26–2.52) and in women (HR: 2.00; 95% CI: 1.27–3.16), but not in those under 50 years (HR: 1.03) or in men (HR: 1.29).

By contrast, the association between CD and liver cirrhosis did not reach statistical significance in any age or sex subgroup. However, the strongest effect was observed in patients younger than 50 years (HR: 2.33; 95% CI: 0.98–5.56), with a borderline significant p-value of 0.056 (Table 3).

Table 3.

Association between IBD and subsequent liver cirrhosis diagnoses in patients followed in general practices in Germany (univariable Cox regression models).

	IBD		Crohn’s disease		Ulcerative colitis
Patient subgroup	HR (95% CI)	p Value	HR (95% CI)	p Value	HR (95% CI)	p Value
Total	1.51 (1.18–1.93)	0.001	1.40 (0.95–2.06)	0.093	1.59 (1.16–2.18)	0.004
Age < 50 years	1.47 (0.82–2.62)	0.195	2.33 (0.98–5.56)	0.056	1.03 (0.46–2.31)	0.936
Age 50 ⩾ years	1.56 (1.19–2.04)	0.001	1.28 (0.82–1.98)	0.278	1.78 (1.26–2.52)	0.001
Female	1.83 (1.28–2.62)	<0.001	1.61 (0.90–2.85)	0.106	2.00 (1.27–3.16)	0.003
Male	1.27 (0.90–1.78)	0.172	1.23 (0.73–2.09)	0.437	1.29 (0.83–2.02)	0.256

CI, confidence interval; HR, hazard ratio; IBD, inflammatory bowel disease.

Discussion

In this large cohort study comparing matched patients with and without IBD, we found that IBD was significantly associated with a higher risk of receiving a diagnosis of liver cirrhosis over a follow-up period of 20 years. However, when analyzing CD and UC separately, this association was significant only in patients with UC, whereas no significant association was observed for CD. However, incidence rates of MASLD were also higher in the IBD cohort as observed before by other studies.^7,22

Importantly, no relevant differences in FIB-4 scores were observed between the cohorts, suggesting that the FIB-4 score did not influence the associations analyzed in this study.

The association between UC and cirrhosis is unlikely to be biased by underreporting of primary sclerosing cholangitis (PSC) within the IBD cohort, considering that 7% of UC patients also have PSC. PSC is an autoimmune-driven progressive disease causing destruction of the intra- and extrahepatic bile ducts, which leads to cirrhosis in the majority of affected patients. Importantly, patients with pre-existing liver disease, including PSC, at the index date were excluded from our study.²³ It is also unlikely that PSC remained undiagnosed at baseline, given that the condition is typically associated with abnormal laboratory parameters detectable during routine clinical monitoring, and the mean age at PSC diagnosis is typically in the thirties, while the mean age in our cohort was 50.²⁴

The association between IBD and liver cirrhosis was more pronounced in patients over 50 years of age (HR 1.56, 95% CI 1.19–2.04) compared to younger patients, which is consistent with age being a well-recognized risk factor for cirrhosis across all underlying etiologies.^25,26

Moreover, a potential sex-specific susceptibility was observed, with a stronger association in women (HR 1.83, 95% CI 1.28–2.62) than in men (HR 1.27, 95% CI 0.90–1.78), the latter not reaching statistical significance.

It is well recognized that women exhibit greater susceptibility to liver cirrhosis compared to men, particularly in the context of alcohol-related cirrhosis.²⁷ While global epidemiological data consistently show higher overall cirrhosis prevalence among men, the incidence rate between 2010 and 2019 has increased more rapidly in women.²⁸

The mechanistic link between UC and cirrhosis remains incompletely understood. One hypothesis is that disruptions in tight junction integrity and epithelial barrier dysfunction have been observed in patients with UC.^17,29 A potential underlying mechanism of gut barrier dysfunction has been uncovered through metabolomic analysis of plasma from patients with cirrhosis, which demonstrates that liver injury reduces nicotinamide availability, thereby impairing intestinal NAD⁺ biosynthesis. Further investigations identify intestinal group 2 innate lymphoid cells (ILC2s) as key mediators of colitis exacerbated by liver injury. In experimental models of dextran sulfate sodium (DSS)-induced colitis, both ILC2 reconstitution and restoration of NAD⁺ metabolism significantly alleviate disease severity. Mechanistically, the NAD⁺ salvage pathway supports ILC2 function in a cell-intrinsic manner by facilitating succinate production, which fuels the electron transport chain and is essential for maintaining ILC2 activity.³⁰

As with UC, the exact reasons why patients with Crohn’s disease have a higher risk of developing cirrhosis are still not fully understood. One possible explanation is the “leaky gut hypothesis,” which might help explain why MAFLD-related cirrhosis and higher rates of MAFLD are more common in people with IBD, as seen in our study.^17,31,32 According to this hypothesis, hepatic steatosis may develop as a consequence of chronic intestinal inflammation, gut microbiota dysbiosis, increased intestinal permeability, translocation of microbial products, and the systemic release of proinflammatory cytokines. Notably, impaired intestinal barrier function has been associated with both the progression to cirrhosis and the early, preclinical stages of CD pathogenesis.³³ However, this was an observational study, which cannot fully control for confounding factors, making it difficult to determine whether the observed association is truly causal.

In a large Danish cohort study including 495,220 patients with IBD matched to 450,200 non-IBD controls, an increased risk of incident cirrhosis was observed over the study period from 1998 to 2018. To date, the study is available only as a preprint server and has not yet been indexed in a freely accessible public database.¹⁷ Notably, key differences emerged when comparing their findings to ours. The Danish study identified a particularly elevated risk of cirrhosis among patients diagnosed with IBD at or before the age of 40. The authors proposed that the chronic inflammatory and destructive processes associated with IBD may require prolonged exposure to cause hepatic damage, thereby placing younger patients at greater long-term risk. Furthermore, when analyzing IBD subtypes, CD showed a stronger association with liver cirrhosis compared to UC, which contrasts with our findings, where the association between CD and cirrhosis did not reach statistical significance. Although we included a large group of patients, this might be explained by a lack of power in this special subgroup. The major difference between the Danish study and our own is that patients with chronic liver disease were not excluded in the Danish one, with alcohol-related and steatotic liver disease representing the predominant etiologies throughout all years of cohort inclusion in the Danish study. The minor difference is that in the Danish cohort, the distribution of IBD subtypes was different. In our study, UC and CD were equally distributed; however, UC was with 70% overrepresented in the Danish cohort. Furthermore, the Danish cohort was 10 years younger in median age than ours. One possible explanation for the higher median age in our cohort is a delayed entry of the diagnosis code by general practitioners.

Predictive biomarkers that identify IBD patients at risk for chronic liver disease could support earlier referral for hepatologic evaluation. Abenavoli et al. investigated non-invasive biomarkers for predicting MASLD in patients with IBD. Among the evaluated markers, the metabolic score for insulin resistance (METS-IR; AUC = 0.754) and waist circumference (AUC = 0.754) showed the highest predictive accuracy, followed by the lipid accumulation product (LAP; AUC = 0.737). By contrast, the LDL/HDL ratio demonstrated only moderate discriminative ability (AUC = 0.656), whereas the fibrosis-4 index (FIB-4; AUC = 0.562) exhibited the weakest diagnostic performance.³⁴ In another study, gene-based biomarkers were identified through a machine-learning–powered in silico analysis of curated datasets. MMP2, COL1A2, CXCL1, and STAT1 emerged as shared biomarkers for IBD and liver fibrosis, providing a molecular basis for early diagnosis and precision medicine approaches.³⁵

This study has several strengths. In addition to the previously reported Danish cohort, it represents the first large German population-based cohort to investigate the association between inflammatory bowel disease (IBD) and cirrhosis. The cohort includes 23,492 patients with IBD and 117,460 matched controls, reinforcing prior evidence of a potential link between IBD and cirrhosis. The use of extensive matching helped reduce potential bias from comorbid conditions unrelated to IBD. Moreover, the data were derived from the German Disease Analyzer database, which has been validated in numerous medical studies, thereby enhancing the reliability of our findings. Furthermore, all quality criteria of STROBE have been applied in this study (Supplemental File).

However, several limitations must be acknowledged. Due to the relatively low incidence of cirrhosis in our cohort, we were unable to perform a time-to-event analysis, which would have yielded unstable results, and therefore could not account for the timing of cirrhosis diagnosis. In addition, the database contains information on therapeutic interventions or medications only if they were prescribed by general practitioners. However, costly advanced therapies such as biologicals used in IBD therapy are typically prescribed by gastroenterologists in Germany and are therefore not captured, potentially limiting the assessment of their influence on the development of cirrhosis or MASLD. Furthermore, the database does not include information on IBD severity or disease duration, which may have influenced the analysis. ICD-10 coding does not capture key lifestyle factors such as alcohol consumption, smoking habits, or physical activity, limiting our ability to adjust for these important confounders. The association between UC and cirrhosis is an observation, and the underlying biological mechanisms remain hypothetical and require further investigation. Finally, because fewer than 1% of patients in the cirrhosis cohort were coded as having autoimmune liver disease, subgroup analyses were not feasible. This diagnosis is rarely documented or coded by general practitioners, as affected patients are typically referred directly to specialists (e.g., hepatologists).

Our findings, demonstrating an altered incidence of cirrhosis with IBD, support the need for higher awareness for chronic parenchymal liver disease in all IBD patients – particularly among older adults with UC and female patients. Early identification of liver involvement would allow timely referral to a hepatologist, with the potential to prevent progression to cirrhosis.

Supplemental Material

sj-doc-1-taj-10.1177_27558428261421720 – Supplemental material for Inflammatory bowel disease increases the risk of liver cirrhosis: a retrospective population-based study

Supplemental material, sj-doc-1-taj-10.1177_27558428261421720 for Inflammatory bowel disease increases the risk of liver cirrhosis: a retrospective population-based study by Alexander Barton, Christian Labenz, Stephan Grabbe, Jörn M. Schattenberg, Leonard Kaps and Karel Kostev in Sage Open Chronic Disease

Footnotes

Acknowledgements

None.

ORCID iDs

Alexander Barton

Leonard Kaps

Ethical considerations

The database used in this study contains only anonymized data and complies with all applicable data protection regulations. Under German law (Federal Data Protection Act, BDSG, web page: ), anonymized electronic medical records may be used for research without requiring patient consent or ethics committee approval. Because all patient information was analyzed in aggregate form and no protected health information was accessible, Institutional Review Board approval was not required for the use of this database or the conduct of this study.

Consent to participate

The database used in this study contains only anonymized data and complies with all applicable data protection regulations. Because all patient information was analyzed in aggregate form and no protected health information was accessible, the need for informed consent was not required.

Consent for publication

Not applicable (see ethics approval and consent to participate, compare also Federal Data Protection Act, BDSG, web page: )).

Author contributions

Alexander Barton: Conceptualization; Investigation; Methodology; Writing – original draft.

Christian Labenz: Conceptualization; Investigation; Methodology; Supervision; Writing – review & editing.

Stephan Grabbe: Formal analysis; Writing – review & editing.

Jörn M. Schattenberg: Formal analysis; Investigation; Resources; Writing – review & editing.

Leonard Kaps: Conceptualization; Investigation; Methodology; Writing – original draft.

Karel Kostev: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Resources; Software; Validation; Visualization; Writing –review & editing.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: The authors have no project-related conflicts of interest to declare. LK declares receiving travel expenses and speaker honoraria from AbbVie, Gilead Science, and Takeda. JMS declares consultant honorary from Akero, Alentis, Alexion, Altimmune, Astra Zeneca, 89Bio, Bionorica, Boehringer Ingelheim, Boston Pharmaceuticals, Gilead Sciences, GSK, HistoIndex, Ipsen, Inventiva Pharma, Madrigal Pharmaceuticals, Kríya Therapeutics, Lilly, MSD Sharp & Dohme GmbH, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi, Siemens Healthineers; speaker honorarium from AbbVie, Boehringer Ingelheim, Gilead Sciences, Ipsen, Lilly, Novo Nordisk, Madrigal Pharmaceuticals, Stockholder options: Hepta Bio.

Data availability statement

The data that support the findings of this study are available from K.K. and IQVIA. Restrictions apply to the availability of these data, which were used under license for this study. Data are available from K.K. with the permission of IQVIA.

Supplemental material

Supplemental material for this article is available online.

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