Risk stratification of all patients
Of the 576 patients who attended the pathway, 533 patients had a reliable TE reading, and 66 (12.4%) had a TE reading of ≥8.0 kPa consistent with clinically significant liver disease. The characteristics of these patients are outlined in Table 3, stratified by their TE reading. Fifty-six patients (84.8%) with a raised TE reading accepted an invitation to be reviewed by a hepatologist in the community. After this, 12 patients (18.2%) were diagnosed with cirrhosis based on a combination of TE, clinical acumen, radiology, and endoscopy criteria. Patients with an elevated reading were significantly older and more likely to have a raised BMI or have been diagnosed with other features of the metabolic syndrome (hypertension and hyperlipidemia). In the subset of patients (n = 504) in which the ALT was available, there was also a significant difference in the average (median) between the 2 groups and the proportion with a raised ALT (≥45 U/L). However, only 27.3% of patients with an elevated TE reading had an ALT level above the upper limit of normal.
Of the patients who had obesity as a single risk factor for chronic liver disease, 8.9% had a TE reading of ≥8.0 kPa. This proportion was similar to the patients who only had type 2 diabetes as a risk factor (10.8%). In those patients with hazardous alcohol use as a single risk factor, the proportion with a TE reading of ≥8.0 kPa was lower (4.8%), although the difference was not statistically significant in comparison with the other risk factors (Table 4). Of all the patients with a single risk factor and an elevated TE reading (≥8.0 kPa), 60.0% had obesity as their only risk factor.
The proportion of patients with a TE reading of ≥8.0 kPa increased with additional risk factors. Sixteen percent of patients with hazardous alcohol use and obesity had a TE reading of ≥8.0 kPa. The proportion was greater in patients who had type 2 diabetes and obesity (36.7%) and highest in those with all 3 risk factors (44.4%) (Table 4). Thirty-one percent of all the patients with an elevated TE reading (≥8.0 kPa) had obesity as their only risk factor.
A univariate logistic regression analysis identified an increasing BMI and age, and diagnoses of type 2 diabetes, hypertension, and hyperlipidemia as significant variables associated with a TE reading of ≥8.0 kPa. Using the dichotomized variable of obesity as a risk factor in the univariate analysis, instead of BMI as a continuous variable, we have shown that obesity is associated with a 3.13-fold increase in the odds of a raised TE reading, respectively. This is comparable with the OR for the risk of chronic liver disease between those with and without type 2 diabetes (OR = 2.99). In the multivariate analysis, only increasing BMI and having a diagnosis of type 2 diabetes remained significant variables and were therefore included within the final model. For every 1 kg/m2 increase in BMI, the odds of having an elevated TE reading (≥8.0 kPa) increased by 17% (Table 5). BMI was an independent predictor of TE ≥ 8.0 kPa both in those without a raised ALT where the multivariate OR for this outcome per unit rise in BMI was 1.16 (1.09–1.23) and in those with a raised ALT where it was 1.31 (1.10–1.55) (see Table 1a,b, Supplemental Digital Content 1, http://links.lww.com/AJG/B255).
Obesity as a single risk factor
Of the 533 people who attended the pathway and had a reliable TE reading, 235 had obesity as their only risk factor. (The characteristics of these patients are outlined in Supplementary data Table 2 [see Supplemental Digital Content 1, http://links.lww.com/AJG/B255], stratified by their TE reading.) Patients with an elevated reading were significantly more likely to have a diagnosis of hypertension. The percentage of patients with a TE reading of ≥8.0 kPa increased with increasing BMI (Figure 1). This trend was also observed in those patients with 2 risk factors (see Figure 1, Supplemental Digital Content 2, http://links.lww.com/AJG/B256). In those patients (n = 216) in which the ALT was available, there was a significant difference in the average (median) between the 2 groups and the proportion with a raised ALT (≥45 U/L), but still only 38.1% of those with a TE reading of ≥8.0 kPa also had an ALT level above the upper limit of normal.
A univariate logistic regression analysis identified an increasing BMI and a diagnosis of hypertension as significant variables associated with a TE reading of ≥8.0 kPa. In the multivariate analysis, these variables remained significant (see Table 3, Supplemental Digital Content 1, http://links.lww.com/AJG/B255). Of the 21 patients with a TE reading of ≥8.0 kPa, 57.1% had a diagnosis of hypertension and 38.1% had a diagnosis of hyperlipidemia. In 42.9% of patients, obesity was their only diagnosed metabolic risk factor (see Table 4, Supplemental Digital Content 1, http://links.lww.com/AJG/B255).
Obesity as an additional risk factor
Combining all patients who had type 2 diabetes (n = 143) or hazardous alcohol use (n = 134) as a risk factor demonstrates the increasing ORs of having a TE reading of ≥8.0 kPa across BMI categories (Figure 2). In a patient with type 2 diabetes and a BMI between 30 and 34.9 kg/m2, the odds of having a TE reading of ≥8.0 kPa increased nearly 5-fold (OR = 5.24, 95% confidence interval 1.21–22.69, P value = 0.027) in comparison to a similar patient with a BMI of <25 kg/m2. An even greater difference in ORs was seen across BMI categories in those patients with hazardous alcohol use as a risk factor. In comparison to a patient with a BMI of <25 kg/m2, the OR of having a TE reading of ≥8.0 kPa was 8.40 (95% confidence interval 0.80–88.41; P value = 0.076) in a patient with a BMI between 30 and 34.9 kg/m2.
In this study, obesity has been highlighted as a significant independent risk factor for detecting an elevated TE reading, which is consistent with significant liver disease. Almost 9% (8.9%) of patients with obesity as their only risk factor had an elevated TE reading (≥8.0 kPa), which is comparable with the subjects who had type 2 diabetes as a solitary risk factor (10.8%) and higher than those with only hazardous alcohol use (4.8%) as a risk factor. Furthermore, 31% of all the patients with an elevated TE reading (≥8.0 kPa) had obesity as their only risk factor.
The synergism of a raised BMI in combination with other risk factors was also clearly demonstrated with an increased proportion of patients identified to have an elevated TE reading (hazardous alcohol use + obesity = 16.1%; type 2 diabetes + obesity = 36.7%). For a TE reading of ≥8.0 kPa, a rise in ORs was observed across increasing BMI categories in patients who had 2 risk factors.
A multivariate logistic regression analysis of the studied cohort demonstrated that after adjusting for having a diagnosis of type 2 diabetes, a 1 kg/m2 increase in BMI resulted in the odds of a TE reading of ≥8.0 kPa, increasing by 17%.
Strengths and weaknesses
This is the first study assessing obesity as a single and additional risk factor within a community-based risk stratification pathway. To limit selection bias, we were able to identify and invite all eligible patients from a single primary care practice coded to have the relevant lifestyle-related risk factors for chronic liver disease. Use of the electronic database also allowed us to obtain detailed data regarding patient alcohol intake and their BMI; 87.7% of patients within the practice had a BMI recorded within the past 5 years. This allowed us to stratify a large well-characterized community cohort using TE. However, implementation of a stratification pathway based on risk factors potentially biases the outcomes that have been observed. We are unable to determine the risk of chronic liver disease within the general population or indeed within patients without any risk factors at all, as they were excluded from screening.
Of the patients invited to attend the pathway, a response rate of 56.3% was achieved, which is comparable with other community-based case-finding strategies for chronic liver disease (17) and better than those reported for national bowel cancer screening programs (25). However, there may still be a responder bias, and although patient uptake between the 3 different risk factors was equivalent, the patients who attended may not be representative of the whole spectrum of those within the at-risk groups. This may have been the case in particular for those identified to have hazardous alcohol use as a risk factor in which the proportion of those with an elevated TE reading was less than expected, although this was not statistically significant to the proportions observed with the other solitary risk factors. Also, identification of patients from the routine electronic primary care records is only as useful as the accuracy of the data recorded within it. If a patient has not been asked about their alcohol use or had an AUDIT questionnaire completed, there will be no documentation within the electronic records from which all patients within the study were identified.
Use of TE as a surrogate marker for clinically significant liver disease could also be viewed as a limitation. Although TE has been widely tested and validated across all etiologies and against the gold standard of a liver biopsy (22), false positives may still occur because of steatohepatitis, cholestasis, and congestive cardiac failure, particularly in those patients who continue to drink alcohol (26–28). Subsequently, this may lead to an overestimation of those who have clinically significant liver disease. However, a liver stiffness cutoff of 8.0 kPa was used to increase the sensitivity of identifying all patients with advanced fibrosis (F3 disease) and cirrhosis (F4 disease). There has also been some debate as to whether a raised BMI in itself could be a confounding factor and falsely raise the liver stiffness measurement. Although studies of healthy volunteers have previously demonstrated a higher liver stiffness measurement in subjects who were obese compared with those with a normal BMI (29,30), it must be noted that only the M probe was available in these studies. Subjects with a raised BMI are likely to have an increased skin-to-capsule distance, which could result in an overestimation of their liver stiffness measurement with this probe. In studies of cohorts with chronic liver disease, liver fibrosis has been demonstrated to be the only consistent independent variable predicting the liver stiffness measurement (24,31,32).
Owing to the ethical constraints of performing a liver biopsy in an asymptomatic community population, we were not able to compare TE readings against histological findings, although a liver biopsy in itself has its own limitations (33). However, if a liver biopsy was offered, it is unlikely that the whole cohort would have accepted this invasive test as demonstrated by previous studies in the community (17). Consequently, the results would not have been representative of the population who have been risk stratified. The only true way to determine whether these patients have been stratified correctly is to follow-up this cohort for long-term clinical outcomes. This would aid justification of future randomized control trials to determine whether implementation of a case-finding strategy as a whole (by actively identifying patients at risk and encouraging behavioral change at an earlier time point within their natural history) has a long-term effect on health outcomes or mortality.
Relevance to clinical practice
The rise of obesity as a metabolic risk factor is already having a demonstrable effect on the prevalence of chronic liver disease within our community population—12.4% of subjects had evidence of clinically significant liver disease (defined by a TE reading of ≥8.0 kPa), with nearly a third of these having obesity as their only risk factor. This study provides a forecast of the impact liver disease associated with obesity will have on our hospital wards over the next 20–30 years.
Although we recognize that replication of our results in another cohort would provide stronger evidence that isolated obesity is a significant independent risk factor and that all other confounders have been excluded, we believe that some important implications should be pointed out even now. Although we agree with the clinical practice guidelines of the European Association for the Study of Liver (16) that emphasize the importance for case finding of advanced liver disease in patients who are at high risk (age>50 years, type 2 diabetes, and metabolic syndrome), we would argue that the same importance should be afforded to patients who are obese. Omitting obesity as an independent risk factor from any proposed case-finding strategy risks missing a large proportion of patients who already have established liver disease. This is of particular significance given the increasing prevalence of obesity within the general population. Between 1980 and 2013, the worldwide prevalence of adults who were overweight (BMI ≥ 25 kg/m2) rose by 27.5%, and in Western Europe, the prevalence of obesity is reported to be one-fifth of the population (20.5% in men and 21.0% in women) (1).
Although the case for screening is far from proven case-finding strategies to actively identify these patients, this will enable clinical trials to be conducted and allow therapeutic strategies for early liver disease to be tested, whether this be a trial of pharmacotherapy (e.g., pioglitazone that has recently been recommended for patients with biopsy-proven nonalcoholic steatohepatitis (16,34)) or the effects of encouraging behavioral change.
Further work is also required to enrich the population, which is stratified, and increase the diagnostic yield of any case-finding approach. The synergistic effect of having 2 risk factors clearly increases the likelihood of having an elevated TE reading. However, for those with solitary risk factors, an algorithm that includes patient-related factors, e.g., age and gender, may be more effective for patient selection rather than being identified by a risk factor alone.
Stratifying patients at risk of liver disease will also create an opportunity for primary care physicians to identify those who would benefit from weight management and those who should be assessed for other associated health complications, e.g., hypertension, hypercholesterolemia, and type 2 diabetes. Of the patients in this study who had an elevated TE reading (≥8 kPa) and obesity as their only risk factor, 42.9% had no other recorded metabolic risk factor yet had evidence of organ damage. Improvement in these other health outcomes could ensure that a risk stratification pathway for chronic liver disease is cost effective despite the large number of individuals who would require assessment.
Obesity as a single or additional risk factor for chronic liver disease is significant and will continue to affect the hepatology landscape over the next 20–30 years. Indeed, it is already having an impact on the liver disease detectable within a community population. Population-based interventions are urgently required to address this crisis, but in the interim, implementation of case-finding strategies using a risk factor approach which includes obesity is feasible and offers an opportunity to conduct clinical trials of screening for liver disease. The study has been registered on a trials registry website (NCT02037867).
CONFLICTS OF INTEREST
Guarantor of the article: Indra N. Guha, PhD.
Specific author contributions: R.H., T.R.C., T.D., G.P.A., and I.N.G. were involved in the study design and concept, implementation of the study in primary care, interpretation of the results, and editing of the manuscript. R.H. analyzed the data set and wrote the initial manuscript draft. All authors had full access to the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. All authors approved the final version of this manuscript.
Financial support: Funding for the study was provided by i) the Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre part of the Nottingham University Hospitals NHS Trust and University of Nottingham and ii) The East Midlands Academic Health Sciences Network (EMAHSN). The study sponsor is the University of Nottingham, who are data custodians but had no role in the design, analysis, or interpretations of the data. All authors declare that they are free from other sources of external funding related to this study.
Potential competing interests: None to report.
Disclosure: This paper presents independent research funded by the National Institute for Health Research (NIHR). The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, or the Department of Health.
WHAT IS KNOWN
- ✓ Obesity as a risk factor for chronic liver disease has been independently associated with liver fibrosis.
- ✓ Guidelines do not emphasize obesity as an independent risk factor in which to have a high index of suspicion of advanced disease.
WHAT IS NEW HERE
- ✓ This is the first study which has assessed obesity as a single and additional risk factor within a community based risk stratification pathway.
- ✓ The proportion of patients with an elevated transient elastography reading was similar among those with obesity (8.9%) compared to patients with more recognized solitary risk factors (type 2 diabetes 10.8%; hazardous alcohol use 4.8%).
- ✓ Thirty-one percent of all the patients with an elevated TE reading (≥8.0 kPa) had obesity as their only risk factor.
- ✓ A multivariate logistic regression analysis of the studied cohort demonstrated that after adjusting for a diagnosis of type 2 diabetes, a 1 kg/m2 increase in BMI resulted in the odds of a TE reading of ≥8.0 kPa, increasing by 17%.
- ✓ This study provides a forecast for the impact liver disease associated with obesity will have on our hospital wards over the next 20-30 years.
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