Preya J. Patel

Underappreciation of non-alcoholic fatty liver disease by primary care clinicians: limited awareness of surrogate markers of fibrosis

Non‐alcoholic fatty liver disease (NAFLD) is a common cause of incidental liver test abnormalities. General practitioners (GP) have a key role in identifying people with NAFLD at risk of significant liver disease. Recent specialist guidelines emphasise the use of fibrosis algorithms or serum biomarkers rather than routine liver tests, to assess advanced fibrosis.

Multimorbidity and polypharmacy in diabetic patients with Nafld: Implications for disease severity and management

Abstract An observational study describing the number and type of chronic conditions and medications taken by diabetic patients with NAFLD and identifying characteristics that may impact liver disease severity or clinical management. Adults with type 2 diabetes have a high prevalence of nonalcoholic fatty liver disease (NAFLD) and increased risk of developing advanced liver disease. Appropriate management should consider the characteristics of the diabetic NAFLD population, as comorbid conditions and medications may increase the complexity of treatment strategies. Diabetic patients with NAFLD at risk of clinically significant liver disease (as assessed by the FIB-4 or NAFLD fibrosis scores) were recruited consecutively from the Endocrine clinic or primary care. Medical conditions, medication history, anthropometric measurements, and laboratory tests were obtained during assessment. NAFLD severity was classified by transient elastography and liver ultrasound into “no advanced disease” (LSM < 8.2 kPa) or “clinically significant liver disease” (LSM ≥ 8.2 kPa). The most common coexistent chronic conditions were metabolic syndrome (94%), self-reported “depression” (44%), ischaemic heart disease (32%), and obstructive sleep apnoea (32%). Polypharmacy or hyperpolypharmacy was present in 59% and 31% of patients respectively. Elevated LSM (≥ 8.2 kPa) suggesting significant liver disease was present in 37% of this at-risk cohort. Increasing obesity and abdominal girth were both independently associated with likelihood of having significant liver disease. There is a high burden of multimorbidity and polypharmacy in diabetic NAFLD patients, highlighting the importance of multidisciplinary management to address their complex health care needs and ensure optimal medical treatment.

Alcohol Consumption in Diabetic Patients with Nonalcoholic Fatty Liver Disease

Aim To examine the association between lifetime alcohol consumption and significant liver disease in type 2 diabetic patients with NAFLD. Methods A cross-sectional study assessing 151 patients with NAFLD at risk of clinically significant liver disease. NAFLD fibrosis severity was classified by transient elastography; liver stiffness measurements ≥8.2 kPa defined significant fibrosis. Lifetime drinking history classified patients into nondrinkers, light drinkers (always ≤20 g/day), and moderate drinkers (any period with intake >20 g/day). Result Compared with lifetime nondrinkers, light and moderate drinkers were more likely to be male (p = 0.008) and to be Caucasian (p = 0.007) and to have a history of cigarette smoking (p = 0.000), obstructive sleep apnea (p = 0.003), and self-reported depression (p = 0.003). Moderate drinkers required ≥3 hypoglycemic agents to maintain diabetic control (p = 0.041) and fibrate medication to lower blood triglyceride levels (p = 0.044). Compared to lifetime nondrinkers, light drinkers had 1.79 (95% CI: 0.67–4.82; p = 0.247) and moderate drinkers had 0.91 (95% CI: 0.27–3.10; p = 0.881) times the odds of having liver stiffness measurements ≥8.2 kPa (adjusted for age, gender, and body mass index). Conclusions In diabetic patients with NAFLD, light or moderate lifetime alcohol consumption was not significantly associated with liver fibrosis. The impact of lifetime alcohol intake on fibrosis progression and diabetic comorbidities, in particular obstructive sleep apnea and hypertriglyceridemia, requires further investigation.

Altered Peripheral Blood Monocyte Phenotype and Function in Chronic Liver Disease: Implications for Hepatic Recruitment and Systemic Inflammation

Background and Aims Liver and systemic inflammatory factors influence monocyte phenotype and function, which has implications for hepatic recruitment and subsequent inflammatory and fibrogenic responses, as well as host defence. Methods Peripheral blood monocyte surface marker (CD14, CD16, CD163, CSF1R, CCR2, CCR4, CCR5, CXCR3, CXCR4, CX3CR1, HLA-DR, CD62L, SIGLEC-1) expression and capacity for phagocytosis, oxidative burst and LPS-stimulated TNF production were assessed in patients with hepatitis C (HCV) (n = 39) or non-alcoholic fatty liver disease (NAFLD) (n = 34) (classified as non-advanced disease, compensated cirrhosis and decompensated cirrhosis) and healthy controls (n = 11) by flow cytometry. Results The selected markers exhibited similar monocyte-subset-specific expression patterns between patients and controls. Monocyte phenotypic signatures differed between NAFLD and HCV patients, with an increased proportion of CD16+ non-classical monocytes in NAFLD, but increased expression of CXCR3 and CXCR4 in HCV. In both cohorts, monocyte CCR2 expression was reduced and CCR4 elevated over controls. CD62L expression was specifically elevated in patients with decompensated cirrhosis and positively correlated with the model-for-end-stage-liver-disease score. Functionally, monocytes from patients with decompensated cirrhosis had equal phagocytic capacity, but displayed features of dysfunction, characterised by lower HLA-DR expression and blunted oxidative responses. Lower monocyte TNF production in response to LPS stimulation correlated with time to death in 7 (46%) of the decompensated patients who died within 8 months of recruitment. Conclusions Chronic HCV and NAFLD differentially affect circulating monocyte phenotype, suggesting specific injury-induced signals may contribute to hepatic monocyte recruitment and systemic activation state. Monocyte function, however, was similarly impaired in patients with both HCV and NAFLD, particularly in advanced disease, which likely contributes to the increased susceptibility to infection in these patients.

Hepatic expression profiling identifies steatosis-independent and steatosis-driven advanced fibrosis genes

Chronic liver disease (CLD) is associated with tissue-destructive fibrosis. Considering that common mechanisms drive fibrosis across etiologies, and that steatosis is an important cofactor for pathology, we performed RNA sequencing on liver biopsies of patients with different fibrosis stages, resulting from infection with hepatitis C virus (HCV) (with or without steatosis) or fatty liver disease. In combination with enhanced liver fibrosis score correlation analysis, we reveal a common set of genes associated with advanced fibrosis, as exemplified by those encoding the transcription factor ETS-homologous factor (EHF) and the extracellular matrix protein versican (VCAN). We identified 17 fibrosis-associated genes as candidate EHF targets and demonstrated that EHF regulates multiple fibrosis-associated genes, including VCAN, in hepatic stellate cells. Serum VCAN levels were also elevated in advanced fibrosis patients. Comparing biopsies from patients with HCV with or without steatosis, we identified a steatosis-enriched gene set associated with advanced fibrosis, validating follistatin-like protein 1 (FSTL1) as an exemplar of this profile. In patients with advanced fibrosis, serum FSTL1 levels were elevated in those with steatosis (versus those without). Liver Fstl1 mRNA levels were also elevated in murine CLD models. We thus reveal a common gene signature for CLD-associated liver fibrosis and potential biomarkers and/or targets for steatosis-associated liver fibrosis.

Medication beliefs predict medication adherence in ambulatory patients with decompensated cirrhosis

AIM To investigate the impact of medication beliefs, illness perceptions and quality of life on medication adherence in people with decompensated cirrhosis. METHODS One hundred adults with decompensated cirrhosis completed a structured questionnaire when they attended for routine outpatient hepatology review. Measures of self-reported medication adherence (Morisky Medication Adherence Scale), beliefs surrounding medications (Beliefs about Medicines Questionnaire), perceptions of illness and medicines (Brief Illness Perception Questionnaire), and quality of life (Chronic Liver Disease Questionnaire) were examined. Clinical data were obtained via patient history and review of medical records. Least absolute shrinkage and selection operator and stepwise backwards regression techniques were used to construct the multivariable logistic regression model. Statistical significance was set at alpha = 0.05. RESULTS Medication adherence was “High” in 42% of participants, “Medium” in 37%, and “Low” in 21%. Compared to patients with “High” adherence, those with “Medium” or “Low” adherence were more likely to report difficulty affording their medications (P < 0.001), lower perception of treatment helpfulness (P = 0.003) and stronger medication concerns relative to medication necessity beliefs (P = 0.003). People with “Low” adherence also experienced greater symptom burden and poorer quality of life, including more frequent abdominal pain (P = 0.023), shortness of breath (P = 0.030), and emotional disturbances (P = 0.050). Multivariable analysis identified having stronger medication concerns relative to necessity beliefs (Necessity-Concerns Differential ≤ 5, OR = 3.66, 95%CI: 1.18-11.40) and more frequent shortness of breath (shortness of breath score ≤ 3, OR = 3.87, 95%CI: 1.22-12.25) as independent predictors of “Low”adherence. CONCLUSION The association between “Low” adherence and patients having strong concerns or doubting the necessity or helpfulness of their medications should be explored further given the clinical relevance.

Controlled attenuation parameter in NAFLD identifies risk of suboptimal glycaemic and metabolic control

AIMS To examine the relationship between steatosis quantified by controlled attenuation parameter (CAP) values and glycaemic/metabolic control. METHODS 230 patients, recruited from an Endocrine clinic or primary care underwent routine Hepatology assessment, with liver stiffness measurements and simultaneous CAP. Multivariable logistic regression was performed to identify potential predictors of Metabolic Syndrome (MetS), HbA1c ≥ 7%, use of insulin, hypertriglyceridaemia and CAP ≥ 300 dB/m. RESULTS Patients were 56.7 ± 12.3 years of age with a high prevalence of MetS (83.5%), T2DM (81.3%), and BMI ≥ 40 kg/m2 (18%). Median CAP score was 344 dB/m, ranging from 128 to 400 dB/m. BMI (aOR 1.140 95% CI 1.068-1.216), requirement for insulin (aOR 2.599 95% CI 1.212-5.575), and serum ALT (aOR 1.018 95% CI 1.004-1.033) were independently associated with CAP ≥ 300 dB/m. Patients with CAP interquartile range < 40 (68%) had a higher median serum ALT level (p = 0.029), greater prevalence of BMI ≥ 40 kg/m2 (p = 0.020) and higher median CAP score (p < 0.001). Patients with higher CAP scores were more likely to have MetS (aOR 1.011 95% CI 1.003-1.019), HBA1c ≥ 7 (aOR 1.010 95% CI 1.003-1.016), requirement for insulin (aOR 1.007 95% CI 1.002-1.013) and hypertriglyceridemia (aOR 1.007 95% CI 1.002-1.013). CONCLUSIONS Our data demonstrate that an elevated CAP reflects suboptimal metabolic control. In diabetic patients with NAFLD, CAP may be a useful point-of-care test to identify patients at risk of poorly controlled metabolic comorbidities or advanced diabetes.

Medication adherence in outpatients with decompensated cirrhosis

Background: Interferon gamma release assay (IGRA) is the most widely used test for screening of latent tuberculosis (TB). However, indeterminate IGRA tests may occur, reducing the utility of the test, and have been associated with impaired immune status. The performance of the IGRA in patients with end stage liver disease, a disease state with known, multifaceted immune dysfunction, has not been well studied. The aim of this study was therefore to evaluate the prevalence and predictors of indeterminate IGRAs in patients with end stage liver disease being assessed for liver transplantation. Methods: Prospective study of 49 consecutive patients undergoing liver transplantation assessment who underwent IGRA (Quantiferon-TB Gold) to exclude latent TB. Groups (indeterminate versus determinate) were compared and tested for association with clinically relevant variables (age, aetiology of liver disease, MELD score, Child–Pugh score and absolute lymphocyte count). Groups were compared using the Mann–Whitney U-test. Testing for independent associations with an indeterminate test was performed using multivariate logistic regression. An ROC curve was also created to define the optimum probability cut off. Results: Of the 49 IGRAs performed, 12 (24%) were indeterminate and 37 (76%) were determinate. Of the determinate IGRAs, three (6 %) were positive and 34 (70%) were negative. Patients who had an indeterminate test were significantly older than those with determinate tests (57.3 vs. 50.5, p = 0.03). There were no other statistically significant differences between the indeterminate versus determinate group: mean MELD score (16.1 vs. 15.8, p = 0.43), mean Child–Pugh score (9.8 vs. 8.8, p = 0.21), mean absolute lymphocyte count (1.03 vs. 0.95, p = 0.30). Multivariate logistic regression testing for independent associations with an indeterminate test, together with changes in the area under the ROC curve, are shown in Table 1. The combination of these variables could provide a high degree of accuracy for predicting an indeterminate test with a c statistic of 0.80 for the ROC curve (Fig. 1). Conclusions: Patients with advanced liver disease had a high rate of indeterminate IGRA in this study relative to other groups described in the literature, which may limit the utility of this test in this population. Indeterminate tests could be predicted with moderate to high accuracy using five routinely collected clinical variables. The reason for the high prevalence of indeterminate tests may relate to immune dysfunction associated with advanced liver disease but results require validation in larger studies.

Non-invasive markers indicate a high prevalence of advanced fibrosis in adults with type 2 diabetes

Background: Interferon gamma release assay (IGRA) is the most widely used test for screening of latent tuberculosis (TB). However, indeterminate IGRA tests may occur, reducing the utility of the test, and have been associated with impaired immune status. The performance of the IGRA in patients with end stage liver disease, a disease state with known, multifaceted immune dysfunction, has not been well studied. The aim of this study was therefore to evaluate the prevalence and predictors of indeterminate IGRAs in patients with end stage liver disease being assessed for liver transplantation. Methods: Prospective study of 49 consecutive patients undergoing liver transplantation assessment who underwent IGRA (Quantiferon-TB Gold) to exclude latent TB. Groups (indeterminate versus determinate) were compared and tested for association with clinically relevant variables (age, aetiology of liver disease, MELD score, Child–Pugh score and absolute lymphocyte count). Groups were compared using the Mann–Whitney U-test. Testing for independent associations with an indeterminate test was performed using multivariate logistic regression. An ROC curve was also created to define the optimum probability cut off. Results: Of the 49 IGRAs performed, 12 (24%) were indeterminate and 37 (76%) were determinate. Of the determinate IGRAs, three (6 %) were positive and 34 (70%) were negative. Patients who had an indeterminate test were significantly older than those with determinate tests (57.3 vs. 50.5, p = 0.03). There were no other statistically significant differences between the indeterminate versus determinate group: mean MELD score (16.1 vs. 15.8, p = 0.43), mean Child–Pugh score (9.8 vs. 8.8, p = 0.21), mean absolute lymphocyte count (1.03 vs. 0.95, p = 0.30). Multivariate logistic regression testing for independent associations with an indeterminate test, together with changes in the area under the ROC curve, are shown in Table 1. The combination of these variables could provide a high degree of accuracy for predicting an indeterminate test with a c statistic of 0.80 for the ROC curve (Fig. 1). Conclusions: Patients with advanced liver disease had a high rate of indeterminate IGRA in this study relative to other groups described in the literature, which may limit the utility of this test in this population. Indeterminate tests could be predicted with moderate to high accuracy using five routinely collected clinical variables. The reason for the high prevalence of indeterminate tests may relate to immune dysfunction associated with advanced liver disease but results require validation in larger studies.