Jonathan Hazlehurst

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

Graphical abstract

Non-alcoholic fatty liver disease and diabetes

Non-alcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2DM) are common conditions that regularly co-exist and can act synergistically to drive adverse outcomes. The presence of both NAFLD and T2DM increases the likelihood of the development of complications of diabetes (including both macro- and micro- vascular complications) as well as augmenting the risk of more severe NAFLD, including cirrhosis, hepatocellular carcinoma and death. The mainstay of NAFLD management is currently to reduce modifiable metabolic risk. Achieving good glycaemic control and optimising weight loss are pivotal to restricting disease progression. Once cirrhosis has developed, it is necessary to screen for complications and minimise the risk of hepatic decompensation. Therapeutic disease modifying options for patients with NAFLD are currently limited. When diabetes and NAFLD co-exist, there are published data that can help inform the clinician as to the most appropriate oral hypoglycaemic agent or injectable therapy that may improve NAFLD, however most of these data are drawn from observations in retrospective series and there is a paucity of well-designed randomised double blind placebo controlled studies with gold-standard end-points. Furthermore, given the heterogeneity of inclusion criteria and primary outcomes, as well as duration of follow-up, it is difficult to draw robust conclusions that are applicable across the entire spectrum of NAFLD and diabetes. In this review, we have summarised and critically evaluated the available data, with the aim of helping to inform the reader as to the most pertinent issues when managing patients with co-existent NAFLD and T2DM.

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.

Non-alcoholic fatty liver disease in common endocrine disorders

Non-alcoholic fatty liver disease (NAFLD) is a spectrum of disease spanning from simple benign steatosis to steatohepatitis with fibrosis and scarring that can eventually lead to cirrhosis. Its prevalence is rising rapidly and is developing into the leading indication for liver transplantation worldwide. Abnormalities in endocrine axes have been associated with NALFD, including hypogonadism, hypothyroidism, GH deficiency and hypercortisolaemia. In some instances, correction of the endocrine defects has been shown to have a beneficial impact. While in patients with type 2 diabetes the association with NAFLD is well established and recognised, there is a more limited appreciation of the condition among common endocrine diseases presenting with hormonal excess or deficiency. In this review, we examine the published data that have suggested a mechanistic link between endocrine abnormalities and NAFLD and summarise the clinical data endorsing these observations.

Abdominal subcutaneous adipose tissue insulin resistance and lipolysis in patients with non-alcoholic steatohepatitis

Systemic insulin resistance (IR) is a primary feature in non‐alcoholic steatohepatitis (NASH), however, there remain limited data on tissue‐specific insulin sensitivity in vivo.

A comparative quality assessment of evidence-based clinical guidelines in endocrinology.

Evidence‐based clinical guidelines in endocrinology attempt to improve and standardize patient care. There has been an expansion in guideline production although some of the heterogeneous methods used to assess the quality of the underlying evidence base might limit interpretation and implementation.

Dual-5α-Reductase Inhibition Promotes Hepatic Lipid Accumulation in Man

Context: 5α-Reductase 1 and 2 (SRD5A1, SRD5A2) inactivate cortisol to 5α-dihydrocortisol in addition to their role in the generation of DHT. Dutasteride (dual SRD5A1 and SRD5A2 inhibitor) and finasteride (selective SRD5A2 inhibitor) are commonly prescribed, but their potential metabolic effects have only recently been identified. Objective: Our objective was to provide a detailed assessment of the metabolic effects of SRD5A inhibition and in particular the impact on hepatic lipid metabolism. Design: We conducted a randomized study in 12 healthy male volunteers with detailed metabolic phenotyping performed before and after a 3-week treatment with finasteride (5 mg od) or dutasteride (0.5 mg od). Hepatic magnetic resonance spectroscopy (MRS) and two-step hyperinsulinemic euglycemic clamps incorporating stable isotopes with concomitant adipose tissue microdialysis were used to evaluate carbohydrate and lipid flux. Analysis of the serum metabolome was performed using ultra-HPLC-mass spectrometry. Setting: The study was performed in the Wellcome Trust Clinical Research Facility, Queen Elizabeth Hospital, Birmingham, United Kingdom. Main Outcome Measure: Incorporation of hepatic lipid was measured with MRS. Results: Dutasteride, not finasteride, increased hepatic insulin resistance. Intrahepatic lipid increased on MRS after dutasteride treatment and was associated with increased rates of de novo lipogenesis. Adipose tissue lipid mobilization was decreased by dutasteride. Analysis of the serum metabolome demonstrated that in the fasted state, dutasteride had a significant effect on lipid metabolism. Conclusions: Dual-SRD5A inhibition with dutasteride is associated with increased intrahepatic lipid accumulation.

Operator training requirements and diagnostic accuracy of Fibroscan in routine clinical practice

Background Fibroscan is a quick, non-invasive technique used to measure liver stiffness (kPa), which correlates with fibrosis. To achieve a valid liver stiffness evaluation (LSE) the operator must obtain all the following three criteria: (1) ≥10 successful liver stiffness measurements; (2) IQR/median ratio <0.30 and (3) ≥60% measurement success rate. Objectives To assess the operator training requirements and the importance of adhering to the LSE validity criteria in routine clinical practice. Methods We retrospectively analysed the LSE validity rates of 2311 Fibroscans performed (1 August 2008 to 31 July 2011) in our tertiary liver outpatients department at the University Hospital Birmingham, UK. The diagnostic accuracy of Fibroscan was assessed in 153 patients, by comparing LSE (valid and invalid) with the modified Ishak fibrosis stage on liver biopsy. Results Learning curve analysis highlighted that the greatest improvement in validity of LSE rates occurs in the operator’s first 10 Fibroscans, reaching 64.7% validity by the 50th Fibroscan. The correlation between LSE and the fibrosis stage on liver biopsy was superior in patients with a valid LSE (n=97) compared with those with an invalid LSE (n=56) (rs 0.577 vs 0.259; p=0.022). Area under receiving operating characteristics for significant fibrosis was greater when LSE was valid (0.83 vs 0.66; p=0.048). Using an LSE cut-off of 8 kPa, the negative predictive value of valid LSE was superior to invalid LSE for the detection of significant (84% vs 71%) and advanced fibrosis (100% vs 93%). Conclusions Fibroscan requires minimal operator training (≥10 observed on patients), and when a valid LSE is obtained, it is an accurate tool for excluding advanced liver fibrosis. To ensure the diagnostic accuracy of Fibroscan it is essential that the recommended LSE validity criteria are adhered to in routine clinical practice.

Severe asymptomatic non-alcoholic fatty liver disease in routine diabetes care; a multi-disciplinary team approach to diagnosis and management

OBJECTIVES To prospectively use a non-invasive algorithm to identify asymptomatic, advanced non-alcoholic fatty liver disease (NAFLD) in a secondary care diabetes clinic and to determine the short-term effect of a multi-disciplinary team (MDT) approach in a liver clinic. RESEARCH DESIGN AND METHODS NAFLD Fibrosis Score (NFS) was calculated in 64 asymptomatic patients with type 2 diabetes. Advanced fibrosis was identified using transient elastography and confirmed with liver biopsy. In a subsequent retrospective study, 95 patients newly referred to the NAFLD MDT clinic were investigated and the impact of the MDT approach assessed. RESULTS 25/64 (39.0%) of patients with diabetes had a low NFS (<-1.455). 39/64 (61.0%) patients had a high or indeterminate NFS and were referred for review in the NAFLD MDT clinic, of which 23/39 attended for assessment. 19/23 (82.6%) were diagnosed with NAFLD, of which 6/19 (31.6%) patients had a positive transient elastography (≥8 kPa). Liver biopsy confirmed advanced fibrosis in 5/6 cases, with moderate fibrosis in 1 case. In the retrospective study, 65/95 (68.4%) new referrals to the NAFLD MDT clinic had a diagnosis of NAFLD. Over a median 98 days (IQR 70-182) follow-up, there was a significant improvement in weight (-0.8 kg; P = 0.024), total cholesterol (-0.2 mmol/L; P = 0.044), ALT (alanine transmaminase, -12.5 IU/L; P < 0.001) and GGT (gammu-glutamyl transferase, -13.0 IU/L; P < 0.0001). 7/28 (25%) of patients with diabetes achieved >5% weight loss. CONCLUSIONS A significant proportion of asymptomatic patients attending type 2 diabetes clinics have undiagnosed advanced NAFLD fibrosis. An MDT approach to NAFLD results in short-term improvements in metabolic and liver parameters.

Advanced non-alcoholic fatty liver disease and adipose tissue fibrosis in patients with Alström syndrome.

Alström syndrome (AS) is a recessive monogenic syndrome characterized by obesity, extreme insulin resistance and multi‐organ fibrosis. Despite phenotypically being high risk of non‐alcoholic fatty liver disease (NAFLD), there is a lack of data on the extent of fibrosis in the liver and its close links to adipose in patients with AS. Our aim was to characterize the hepatic and adipose phenotype in patients with AS.