Matthew J. Armstrong

Extrahepatic complications of nonalcoholic fatty liver disease

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease, and is strongly associated with the metabolic syndrome. In the last decade, it has become apparent that the clinical burden of NAFLD is not restricted to liver‐related morbidity or mortality, and the majority of deaths in NAFLD patients are related to cardiovascular disease (CVD) and cancer. These findings have fuelled concerns that NAFLD may be a new, and added risk factor for extrahepatic diseases such as CVD, chronic kidney disease (CKD), colorectal cancer, endocrinopathies (including type 2 diabetes mellitus [T2DM] and thyroid dysfunction), and osteoporosis. In this review we critically appraise key studies on NAFLD‐associated extrahepatic disease. There was marked heterogeneity between studies in study design (cross‐sectional versus prospective; sample size; presence/absence of well‐defined controls), population (ethnic diversity; community‐based versus hospital‐based cohorts), and method of NAFLD diagnosis (liver enzymes versus imaging versus biopsy). Taking this into account, the cumulative evidence to date suggests that individuals with NAFLD (specifically, nonalcoholic steatohepatitis) harbor an increased and independent risk of developing CVD, T2DM, CKD, and colorectal neoplasms. We propose future studies are necessary to better understand these risks, and suggest an example of a screening strategy. (Hepatology 2014;59:1174–1197)

Presence and severity of non-alcoholic fatty liver disease in a large prospective primary care cohort.

BACKGROUND & AIMS Non-alcoholic fatty liver disease (NAFLD) is a common cause of abnormal LFTs in primary care, but there are no data defining its contribution nor reporting the range of NAFLD severity in this setting. This study seeks to calculate the range of disease severity of NAFLD in a primary care setting. METHODS Adult patients with incidental abnormal LFTs, in the absence of a previous history, or current symptoms/signs of liver disease were prospectively recruited from eight primary care practices in Birmingham. NAFLD was diagnosed as fatty liver on ultrasound, negative serological liver aetiology screen, and alcohol consumption ≤30 and ≤20 g/day in males and females, respectively. The NAFLD Fibrosis Score (NFS) was calculated to determine the presence or absence of advanced liver fibrosis in subjects identified with NAFLD. RESULTS Data from 1118 adult patients were analysed. The cause of abnormal LFTs was identified in 55% (614/1118) of subjects, with NAFLD (26.4%; 295/1118) and alcohol excess (25.3%; 282/1118) accounting for the majority. A high NFS (>0.676) suggesting the presence of advanced liver fibrosis was found in 7.6% of NAFLD subjects, whereas 57.2% of NAFLD patients had a low NFS (<-1.455) allowing advanced fibrosis to be confidently excluded. CONCLUSIONS NAFLD is the commonest cause of incidental LFT abnormalities in primary care (26.4%), of whom 7.6% have advanced fibrosis as calculated by the NFS. This study is the first of its kind to highlight the burden of NAFLD in primary care and provide data on disease severity in this setting.

Glucagon-like peptide 1 decreases lipotoxicity in non-alcoholic steatohepatitis.

Graphical abstract

Mobile health use in low- and high-income countries: an overview of the peer-reviewed literature

The evolution of mobile phone technology has introduced new possibilities to the field of medicine. Combining technological advances with medical expertise has led to the use of mobile phones in all healthcare areas including diagnostics, telemedicine, research, reference libraries and interventions. This article provides an overview of the peer -reviewed literature, published between 1 August 2006 and 1 August 2011, for the application of mobile/cell phones (from basic text-messaging systems to smartphones) in healthcare in both resource-poor and high-income countries. Smartphone use is paving the way in high-income countries, while basic text-messaging systems of standard mobile phones are proving to be of value in low- and middle-income countries. Ranging from infection outbreak reporting, anti-HIV therapy adherence to gait analysis, resuscitation training and radiological imaging, the current uses and future possibilities of mobile phone technology in healthcare are endless. Multiple mobile phone based applications are available for healthcare workers and healthcare consumers; however, the absolute majority lack an evidence base. Therefore, more rigorous research is required to ensure that healthcare is not flooded with non-evidence based applications and is maximized for patient benefit.

Tobacco smoking and solid organ transplantation.

Smoking, both by donors and by recipients, has a major impact on outcomes after organ transplantation. Recipients of smokers’ organs are at greater risk of death (lungs hazard ratio [HR], 1.36; heart HR, 1.8; and liver HR, 1.25), extended intensive care stays, and greater need for ventilation. Kidney function is significantly worse at 1 year after transplantation in recipients of grafts from smokers compared with nonsmokers. Clinicians must balance the use of such higher-risk organs with the consequences on waiting list mortality if the donor pool is reduced further by exclusion of such donors. Smoking by kidney transplant recipients significantly increases the risk of cardiovascular events (29.2% vs. 15.4%), renal fibrosis, rejection, and malignancy (HR, 2.56). Furthermore, liver recipients who smoke have higher rates of hepatic artery thrombosis, biliary complications, and malignancy (13% vs. 2%). Heart recipients with a smoking history have increased risk of developing coronary atherosclerosis (21.2% vs. 12.3%), graft dysfunction, and loss after transplantation. Self-reporting of smoking is commonplace but unreliable, which limits its use as a tool for selection of transplant candidates. Despite effective counseling and pharmacotherapy, recidivism rates after transplantation remain high (10–40%). Transplant services need to be more proactive in educating and implementing effective smoking cessation strategies to reduce rates of recidivism and the posttransplantation complications associated with smoking. The adverse impact of smoking by the recipient supports the requirement for a 6-month period of abstinence in lung recipients and cessation before other solid organs.

Renal function in patients undergoing transplantation for nonalcoholic steatohepatitis cirrhosis: Time to reconsider immunosuppression regimens?

Nonalcoholic fatty liver disease is an independent risk factor for chronic kidney injury (CKI), yet the impact of liver transplantation (LT) on renal function in this at‐risk group is not known. We compared the post‐LT renal function of patients with nonalcoholic steatohepatitis (NASH) and a matched comparison group. Forty‐eight consecutive patients who underwent transplantation for NASH between 2000 and 2008 in a single UK center were compared to non‐NASH patients who were matched by age, sex, Model for End‐Stage Liver Disease score, and estimated glomerular filtration rate (eGFR; calculated with the Modification of Diet in Renal Disease formula). In comparison with non‐NASH patients, NASH patients had a significantly lower eGFR 3 months after LT (eGFR difference = 8.85 mL/minute/1.73 m2, 95% confidence interval = 2.93‐14.77). After adjustments for the effects of the body mass index, tacrolimus levels, diabetes mellitus, hypertension, and hepatocellular carcinoma, the difference between the groups remained significant 3 months after LT (P = 0.001). These data were then analyzed at numerous time points after LT (6, 12, and 24 months), and the time did not significantly affect the difference between the groups (P = 0.17). Within 2 years, 31.2% of the NASH patients (15/48) had developed stage IIIb CKI, whereas only 8.3% of the non‐NASH patients (4/48) did (P = 0.009). In conclusion, this study has identified NASH as an independent risk factor for renal dysfunction after LT. Renal‐sparing immunosuppression regimens should be considered at the time of LT to reduce the development of kidney injury in NASH patients. The optimization of such regimens requires a prospective study. Liver Transpl 17:1292–1298, 2011.

Development of Hepatocellular Carcinoma in a Murine Model of Nonalcoholic Steatohepatitis Induced by Use of a High-Fat/Fructose Diet and Sedentary Lifestyle

Obesity is increasingly prevalent, strongly associated with nonalcoholic liver disease, and a risk factor for numerous cancers. Here, we describe the liver-related consequences of long-term diet-induced obesity. Mice were exposed to an extended obesity model comprising a diet high in trans-fats and fructose corn syrup concurrent with a sedentary lifestyle. Livers were assessed histologically using the nonalcoholic fatty liver disease (NAFLD) activity score (Kleiner system). Mice in the American Lifestyle-Induced Obesity Syndrome (ALIOS) model developed features of early nonalcoholic steatohepatitis at 6 months (mean NAFLD activity score = 2.4) and features of more advanced nonalcoholic steatohepatitis at 12 months, including liver inflammation and bridging fibrosis (mean NAFLD activity score = 5.0). Hepatic expression of lipid metabolism and insulin signaling genes were increased in ALIOS mice compared with normal chow-fed mice. Progressive activation of the mouse hepatic stem cell niche in response to ALIOS correlated with steatosis, fibrosis, and inflammation. Hepatocellular neoplasms were observed in 6 of 10 ALIOS mice after 12 months. Tumors displayed cytological atypia, absence of biliary epithelia, loss of reticulin, alteration of normal perivenular glutamine synthetase staining (absent or diffuse), and variable α-fetoprotein expression. Notably, perivascular tumor cells expressed hepatic stem cell markers. These studies indicate an adipogenic lifestyle alone is sufficient for the development of nonalcoholic steatohepatitis, hepatic stem cell activation, and hepatocarcinogenesis in wild-type mice.

Mental health disorders and solid-organ transplant recipients.

Depression affects up to 60% of solid-organ recipients and is independently associated with both mortality (hazard ratio for death of ∼2) and de novo malignancy after transplantation, although the mechanism is not clear. Both pretransplantation psychosis and depression occurring more than 2 years after transplantation are associated with increased noncompliance and graft loss. It remains to be shown that effective treatment of depression is associated with improved outcomes and quality of life. Immunosuppressive drugs (especially corticosteroids and calcineurin inhibitors) and physiologic challenges can precipitate deterioration in mental health. All potential transplant candidates should be assessed for mental health problems and preexisting medical conditions that can mimic mental health problems, such as uremic, hepatic, or hypoxic encephalopathy, should be identified and treated appropriately. Expert mental health review of those with identified risk factors (such as previous suicide attempts, history of mental illness or noncompliance with medications) is advisable early in the transplant assessment process to mitigate risk and support the patient. Patients with mental health disorders, when adequately controlled and socially supported, have outcomes similar to the general transplant population. Therefore, exclusion from transplantation based on the diagnosis alone is neither ethically nor medically justified. However, it is ethically and clinically justifiable to deny access to transplantation to those who, despite full support, would have a quality of life that is unacceptable to the candidate or are likely to be noncompliant with treatment or follow-up, which would lead to graft loss.

Glucocorticoids Fail to Cause Insulin Resistance in Human Subcutaneous Adipose Tissue In Vivo

CONTEXT It is widely believed that glucocorticoids cause insulin resistance in all tissues. We have previously demonstrated that glucocorticoids cause insulin sensitization in human adipose tissue in vitro and induce insulin resistance in skeletal muscle. OBJECTIVE Our aim was to determine whether glucocorticoids have tissue-specific effects on insulin sensitivity in vivo. DESIGN Fifteen healthy volunteers were recruited into a double-blind, randomized, placebo-controlled, crossover study, receiving both an overnight hydrocortisone and saline infusion. The tissue-specific actions of insulin were determined using paired 2-step hyperinsulinemic euglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis. SETTING The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom. MAIN OUTCOME MEASURES The sensitivity of sc adipose tissue to insulin action was measured. RESULTS Hydrocortisone induced systemic insulin resistance but failed to cause sc adipose tissue insulin resistance as measured by suppression of adipose tissue lipolysis and enhanced insulin-stimulated pyruvate generation. In primary cultures of human hepatocytes, glucocorticoids increased insulin-stimulated p-ser473akt/protein kinase B. Similarly, glucocorticoids enhanced insulin-stimulated p-ser473akt/protein kinase B and increased Insulin receptor substrate 2 mRNA expression in sc, but not omental, intact human adipocytes, suggesting a depot-specificity of action. CONCLUSIONS This study represents the first description of sc adipose insulin sensitization by glucocorticoids in vivo and demonstrates tissue-specific actions of glucocorticoids to modify insulin action. It defines an important advance in our understanding of the actions of both endogenous and exogenous glucocorticoids and may have implications for the development and targeting of future glucocorticoid therapies.

Loss of 5α-Reductase Type 1 Accelerates the Development of Hepatic Steatosis but Protects Against Hepatocellular Carcinoma in Male Mice

Nonalcoholic fatty liver disease (NAFLD) has been associated with glucocorticoid excess and androgen deficiency, yet in the majority of patients with steatohepatitis, circulating cortisol and androgen levels are normal. The enzyme 5α-reductase (5αR) has a critical role in androgen and glucocorticoid action. We hypothesize that 5αR has an important role in the pathogenesis of steatohepatitis through regulation of intracrine/paracrine hormone availability. Human liver samples from patients with NAFLD and normal donor tissue were used for gene expression and immunohistochemical analysis. NAFLD samples were scored using the Kleiner classification. In addition, 5αR1−/−, 5αR2−/−, and wild-type (WT) mice were fed normal chow or American lifestyle-induced obesity syndrome (ALIOS) diet for 6 or 12 months. Liver histology was graded and staged. Hepatic and circulating free fatty acid and triglyceride levels were quantified, and gene and protein expression was measured by real-time PCR and immunohistochemistry. 5αR1 and -2 were highly expressed in human liver, and 5αR1 protein expression increased with severity of NAFLD. 5αR1−/− (but not 5αR2−/−) mice fed an ALIOS diet developed greater hepatic steatosis than WT mice, and hepatic mRNA expression of genes involved in insulin signaling was decreased. Furthermore, 60% of WT mice developed focal hepatocellular lesions consistent with hepatocellular carcinoma after 12 months of the ALIOS diet, compared with 20% of 5αR2−/− and 0% of 5αR1−/− mice (P < .05). 5αR1 deletion accelerates the development of hepatic steatosis but may protect against the development of NAFLD-related hepatocellular neoplasia and therefore has potential as a therapeutic target.