Current and Emerging Biomarkers and Imaging Modalities for Nonalcoholic Fatty Liver Disease: Clinical and Research Applications.

PURPOSE: Nonalcoholic fatty liver disease (NAFLD) is a metabolic disorder that frequently coexists with obesity, metabolic syndrome, and type 2 diabetes. The NAFLD spectrum, ranging from hepatic steatosis to nonalcoholic steatohepatitis, fibrosis, and cirrhosis, can be associated with long-term hepatic (hepatic decompensation and hepatocellular carcinoma) and extrahepatic complications. Diagnosis of NAFLD requires detection of liver steatosis with exclusion of other causes of chronic liver disease. Screening for NAFLD and identification of individuals at risk of end-stage liver disease represent substantial challenges that have yet to be met. NAFLD affects up to 25% of adults, yet only a small proportion will progress beyond steatosis to develop advanced disease (steatohepatitis and fibrosis) associated with increased morbidity and mortality. Identification of this cohort has required the gold standard liver biopsy, which is both invasive and expensive. The use of serum biomarkers and noninvasive imaging techniques is an area of significant clinical relevance. This narrative review outlines current and emerging technologies for the diagnosis of NAFLD, nonalcoholic steatohepatitis, and hepatic fibrosis. METHODS: We reviewed the literature using PubMed and reviewed national and international guidelines and conference proceedings to provide a comprehensive overview of the evidence. FINDINGS: Significant advances have been made during the past 2 decades that have enhanced noninvasive assessment of NAFLD without the need for liver biopsy. For the detection of steatosis, abdominal ultrasonography remains the first-line investigation, although a controlled attenuation parameter using transient elastography is more sensitive. For detecting fibrosis, noninvasive serum markers of fibrosis and algorithms based on routine biochemistry are available, in addition to transient elastography. These techniques are well validated and have been incorporated into national and international screening guidelines. These approaches have facilitated more judicious use of liver biopsy but are yet to entirely replace it. Although serum biomarkers present a pragmatic and widely available screening approach for NAFLD in large population-based studies, magnetic resonance imaging techniques offer the benefit of achieving high degrees of accuracy in disease grading, tumor staging, and assessing therapeutic response. IMPLICATIONS: This diagnostic clinical and research field is rapidly evolving; increasingly combined applications of biomarkers and transient elastography or imaging of selective (intermediate or high risk) cases are being used for clinical and research purposes. Liver biopsy remains the gold standard investigation, particularly in the context of clinical trials, but noninvasive options are emerging, using multimodality assessment, that are quicker, more tolerable, more widely available and have greater patient acceptability.

Emerging and Established Therapeutic Approaches for Nonalcoholic Fatty Liver Disease.

PURPOSE: Nonalcoholic fatty liver disease (NAFLD), more recently referred to as metabolic-associated fatty liver disease, refers to a disease spectrum ranging from hepatic steatosis to nonalcoholic steatohepatitis (NASH), fibrosis, and cirrhosis, associated with hepatic complications (including liver fibrosis, cirrhosis, and hepatocellular carcinoma) and extrahepatic complications (particularly cardiometabolic complications, including type 2 diabetes and cardiovascular disease). Treatment options include lifestyle interventions (dietary modification and physical activity programs) and pharmacologic interventions. Treatment aims should be broad, with a hepatic focus (to improve/reverse hepatic inflammation, fibrosis, and steatohepatitis), ideally with additional extrahepatic effects affecting metabolic co-morbidities (eg, insulin resistance, glucose dysregulation, dyslipidemia), causing weight loss and affording cardiovascular protection. NASH and fibrosis represent the main histopathological features that warrant treatment to prevent disease progression. Despite a paucity of established treatments, the array of potential molecular targets, pathways, and potential treatments is continually evolving. The goal of this article was to provide a narrative review summarizing the emerging and more established therapeutic options considering the complex pathophysiology of NAFLD and the important long-term sequelae of this condition. METHODS: The literature was reviewed by using PubMed, conference abstracts, and press releases from early-phase clinical studies to provide an overview of the evidence. FINDINGS: As understanding of the pathophysiology of NASH/NAFLD evolves, drugs with different mechanisms of action, targeting different molecular targets and aberrant pathways that mediate hepatic steatosis, inflammation, and fibrosis, have been developed and are being tested in clinical trials. Pharmacologic therapies fall into 4 main categories according to the molecular targets/pathways they disrupt: (1) meta-bolic targets, targeting insulin resistance, hepatic de novo lipogenesis, or substrate utilization; (2) inflam-matory pathways, inhibiting inflammatory cell recruitment/signaling, reduce oxidative/endoplasmic reticulum stress or are antiapoptotic; (3) the liver-gut axis, which modulates bile acid enterohepatic circulation/signaling or alters gut microbiota; and (4) antifibrotic targets, targeting hepatic stellate cells, decrease collagen deposition or increase fibrinolysis. IMPLICATIONS: Lifestyle modification must remain the cornerstone of treatment. Pharmacologic treatment is reserved for NASH or fibrosis, the presence of which requires histopathological confirmation. The disease complexity provides a strong rationale for combination therapies targeting multiple pathways simultaneously.

Mechanisms, screening modalities and treatment options for individuals with non-alcoholic fatty liver disease and type 2 diabetes.

Non-alcoholic fatty liver disease (NAFLD) exists as a spectrum of disease ranging from excessive accumulation of fat within the liver (simple steatosis), inflammation (non-alcoholic steatohepatitis) through to fibrosis, cirrhosis and end-stage liver disease. There is also an increased risk of hepatocellular carcinoma. The principal risk factor for NAFLD is overweight or obesity, along with type 2 diabetes, and NAFLD itself is also a risk factor for incident type 2 diabetes. Overweight/obesity is synergistic with alcohol consumption in causing progressive and insidious liver damage. Recent consensus advocates a change in nomenclature from NAFLD to 'metabolic associated fatty liver disease' (MAFLD), reflective of the associated metabolic abnormalities (insulin resistance/type 2 diabetes and metabolic syndrome components). Additional extra-hepatic manifestations of NAFLD include cardiovascular disease, chronic kidney disease and certain cancers. Unlike other micro- and macrovascular complications of type 2 diabetes, systematic screening or surveillance protocols have not been widely adopted in routine diabetes care to assess for presence/severity of NAFLD. Various screening tools are available (non-invasive tests and biochemical indices) combined with imaging techniques (e.g. transient elastography) to detect steatosis and more importantly advanced fibrosis/cirrhosis to facilitate appropriate surveillance. Liver biopsy may be sometimes necessary. Treatment options for type 2 diabetes, including lifestyle interventions (dietary change and physical activity), glucose-lowering therapies and metabolic surgery, can modulate hepatic steatosis and to a lesser extent fibrosis. Awareness of the impact of liver disease on the choice of glucose-lowering medications in individuals with type 2 diabetes is also critical.

Variation in Cardiac Screening and Management of Carcinoid Heart Disease in the UK and Republic of Ireland.

AIMS: Screening for carcinoid heart disease is an important, yet frequently neglected aspect of the management of patients with neuroendocrine tumours (NETs). Screening is advocated in international guidelines, although recommendations on the modality and frequency are poorly defined. We mapped current practice for the screening and management of carcinoid heart disease in specialist NET centres throughout the UK and Republic of Ireland. MATERIALS AND METHODS: Thirty-five NET centres were invited to complete an online questionnaire outlining the size of NET service, patient selection criteria for carcinoid heart disease screening and the modality and frequency of screening. RESULTS: Twenty-eight centres responded (80%), representing over 5500 patients. Eleven per cent of centres screen all patients with any NET, 14% screen only patients with midgut NETs, 32% screen all patients with liver metastases and/or carcinoid syndrome and 43% screen all patients with evidence of syndrome or raised urinary/serum/plasma 5-hydroxyindoleacetic acid (5HIAA). The mode of screening included clinical examination, echocardiography and biomarker measurement: 89% of centres carry out echocardiography, ranging from at initial presentation only (24%), periodically without clearly defined intervals (28%), annually (36%) or less than annually (12%); three centres use a scoring system to report their echocardiograms. Fifty per cent of centres utilise biomarkers for screening (chromogranins, plasma/urinary 5HIAA or most commonly N-terminal pro-brain natriuretic peptide) at varying time intervals. CONCLUSION: There is considerable heterogeneity across the UK and Ireland in multiple aspects of screening and management of carcinoid heart disease.

Cerebral activations during viewing of food stimuli in adult patients with acquired structural hypothalamic damage: a functional neuroimaging study.

BACKGROUND/OBJECTIVES: Obesity is common following hypothalamic damage due to tumours. Homeostatic and non-homeostatic brain centres control appetite and energy balance but their interaction in the presence of hypothalamic damage remains unknown. We hypothesized that abnormal appetite in obese patients with hypothalamic damage results from aberrant brain processing of food stimuli. We sought to establish differences in activation of brain food motivation and reward neurocircuitry in patients with hypothalamic obesity (HO) compared with patients with hypothalamic damage whose weight had remained stable. SUBJECTS/METHODS: In a cross-sectional study at a University Clinical Research Centre, we studied 9 patients with HO, 10 age-matched obese controls, 7 patients who remained weight-stable following hypothalamic insult (HWS) and 10 non-obese controls. Functional magnetic resonance imaging was performed in the fasted state, 1 h and 3 h after a test meal, while subjects were presented with images of high-calorie foods, low-calorie foods and non-food objects. Insulin, glucagon-like peptide-1, Peptide YY and ghrelin were measured throughout the experiment, and appetite ratings were recorded. RESULTS: Mean neural activation in the posterior insula and lingual gyrus (brain areas linked to food motivation and reward value of food) in HWS were significantly lower than in the other three groups (P=0.001). A significant negative correlation was found between insulin levels and posterior insula activation (P=0.002). CONCLUSIONS: Neural pathways associated with food motivation and reward-related behaviour, and the influence of insulin on their activation may be involved in the pathophysiology of HO.

Impact of bariatric surgery on physical functioning in obese adults.

Obesity is associated with a profound impairment in the ability to perform the basic physical activities required for everyday function. This impacts on quality of life and contributes to disability. Bariatric surgery leads to weight loss and metabolic improvements in severe obesity; however, less is known about its effect on physical functioning. This narrative review summarizes current evidence on the effect of bariatric surgery on this outcome with a consideration of the mechanisms involved. Nine longitudinal observational studies reporting objective measures of physical functioning were identified. Inclusion criteria, follow-up time and outcomes reported varied considerably between studies and sample sizes were small. They all showed a significant improvement in performance following surgery despite variations in baseline patient characteristics. Additionally, six studies were found in which subjects were subjected to exercise testing protocols. Performance of the test protocol improved in all. Where reported, peak oxygen uptake related to body weight improved; however, absolute values were either unchanged or decreased. In conclusion, observational evidence suggests that patients' physical functioning improves following bariatric surgery. More evidence is required regarding mechanisms involved; however, it may be due to improved efficiency in performing activities as opposed to absolute improvements in cardiorespiratory or muscle function.

Serial surveillance of carcinoid heart disease: factors associated with echocardiographic progression and mortality.

BACKGROUND: Carcinoid heart disease is a complication of metastatic neuroendocrine tumours (NETs). We sought to identify factors associated with echocardiographic progression of carcinoid heart disease and death in patients with metastatic NETs. METHODS: Patients with advanced non-pancreatic NETs and documented liver metastases and/or carcinoid syndrome underwent prospective serial clinical, biochemical, echocardiographic and radiological assessment. Patients were categorised as carcinoid heart disease progressors, non-progressors or deceased. Multinomial regression was used to assess the univariate association between variables and carcinoid heart disease progression. RESULTS: One hundred and thirty-seven patients were included. Thirteen patients (9%) were progressors, 95 (69%) non-progressors and 29 (21%) patients deceased. Baseline median levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in the progressors. Every 100 nmol l(-1) increase in 5-HIAA yielded a 5% greater odds of disease progression (OR 1.05, 95% CI: 1.01, 1.09; P=0.012) and a 7% greater odds of death (OR 1.07, 95% CI: 1.03, 1.10; P=0.001). A 100 ng l(-1) increase in NT-proBNP did not increase the risk of progression, but did increase the risk of death by 11%. CONCLUSIONS: The biochemical burden of disease, in particular baseline plasma 5-HIAA concentration, is independently associated with carcinoid heart disease progression and death. Clinical and radiological factors are less useful prognostic indicators of carcinoid heart disease progression and/or death.

The clinical presentation and management of carcinoid heart disease.

Carcinoid heart disease is a major cause of morbidity and mortality in patients with metastatic neuroendocrine tumours (NETs). Although cases of carcinoid syndrome and severe carcinoid heart disease requiring urgent intervention are well described, many patients with significant carcinoid heart disease may have insidious symptoms or even be asymptomatic. As haemodynamically significant carcinoid heart disease may be clinically silent, specific and individualised considerations must be made as to the most appropriate clinical criteria and time point at which surgical valve replacement should be undertaken in patients with carcinoid heart disease.

Presentation, management and outcomes in acute pituitary apoplexy: a large single-centre experience from the United Kingdom.

OBJECTIVE: To study the presentation, management and outcomes and to apply retrospectively the Pituitary Apoplexy Score (PAS) (United Kingdom (UK) guidelines for management of apoplexy) to a large, single-centre series of patients with acute pituitary apoplexy. DESIGN: Retrospective analysis of casenotes at a single neurosurgical centre in Liverpool, UK. RESULTS: Fifty-five patients [mean age, 52·4 years; median duration of follow-up, 7 years] were identified; 45 of 55 (81%) had nonfunctioning adenomas, four acromegaly and six prolactinomas. Commonest presenting features were acute headache (87%), diplopia (47·2%) and visual field (VF) defects (36%). The most frequent ocular palsy involved the 3rd nerve (81%), followed by 6th nerve (34·6%) and multiple palsies (19%). Twenty-three patients were treated conservatively, and the rest had surgery either within 7 days of presentation or delayed elective surgery. Indications for surgery were deteriorating visual acuity and persistent field defects. Patients presenting with VF defects (n = 20) were more likely to undergo surgery (75%) than to be managed expectantly (25%). There was no difference in the rates of complete/near-complete resolution of VF deficits and cranial nerve palsies between those treated conservatively and those who underwent surgery. Endocrine outcomes were also similar. We were able to calculate the PAS for 46 patients: for the group treated with early surgery mean, PAS was 3·8 and for those managed conservatively or with delayed surgery was 1·8. CONCLUSIONS: Patients without VF deficits or whose visual deficits are stable or improving can be managed expectantly without negative impact on outcomes. Clinical severity based on a PAS ≥ 4 appeared to influence management towards emergency surgical intervention.

Peptide receptor radionuclide therapy with (90)Y-DOTATATE/(90)Y-DOTATOC in patients with progressive metastatic neuroendocrine tumours: assessment of response, survival and toxicity.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is an established treatment for patients with metastatic neuroendocrine tumours (NETs), although which factors are associated with an improved overall survival (OS) remains unclear. The primary aim of this study is to determine to what extent a radiological response to (90)Y-DOTATOC/(90)Y-DOTATATE PRRT is associated with an improved OS. The association of biochemical and clinical response to OS were assessed as secondary outcome measures. METHODS: A retrospective analysis was conducted on 57 patients: radiological response was classified using RECIST criteria, biochemical response was classified using WHO criteria and clinical response was assessed subjectively. Responses were recorded as positive response (PR), stable disease (SD) or progressive disease (PD), and survival analysed. RESULTS: Radiological response was achieved in 71.5% (24.5% PR, 47% SD) and was associated with a greater OS (51 and 56 months, respectively), compared with PD (18 months). A biochemical or clinical response post PRRT were not associated with a statistically significant improvement in OS. However, when combined with radiological response a survival benefit was observed according to the number of outcomes (radiological, biochemical, clinical), in which a response was observed. Mild haematological toxicity was common, renal toxicity was rare. CONCLUSION: In patients with progressive metastatic NETs receiving (90)Y-DOTATOC/(90)Y-DOTATATE PRRT, a radiological response with either a PR or a SD post therapy confers a significant OS benefit.

Nitric oxide-mediated cutaneous microvascular function is impaired in polycystic ovary sydrome but can be improved by exercise training.

Polycystic ovary syndrome (PCOS) is associated with cardiovascular disease. The contribution of the nitric oxide (NO) dilator system to cutaneous endothelial dysfunction is currently unknown in PCOS. Our aim was to examine whether women with PCOS demonstrate impaired cutaneous microvascular NO function and whether exercise training can ameliorate any impairment. Eleven women with PCOS (age, 29 ± 7 years; body mass index, 34 ± 6 kg m(-2)) were compared with six healthy obese control women (age, 29 ± 7 years; body mass index, 34 ± 5 kg m(-2)). Six women with PCOS (30 ± 7 years; 31 ± 6 kg m(-2)) then completed 16 weeks of exercise training. Laser Doppler flowmetry, combined with intradermal microdialysis of l-N(G)-monomethyl-l-arginine, a nitric oxide antagonist, in response to incremental local heating of the forearm was assessed in women with PCOS and control women, and again in women with PCOS following exercise training. Cardiorespiratory fitness, homeostasis model assessment for insulin resistance, hormone and lipid profiles were also assessed. Differences between women with PCOS and control women and changes with exercise were analysed using Student's unpaired t tests. Differences in the contribution of NO to cutaneous blood flow [expressed as a percentage of maximal cutaneous vasodilatation (CVCmax)] were analysed using general linear models. At 42°C heating, cutaneous NO-mediated vasodilatation was attenuated by 17.5%CVCmax (95% confidence interval, 33.3, 1.7; P = 0.03) in women with PCOS vs. control women. Exercise training improved cardiorespiratory fitness by 5.0 ml kg(-1) min(-1) (95% confidence interval, 0.9, 9.2; P = 0.03) and NO-mediated cutaneous vasodilatation at 42°C heating by 19.6% CVCmax (95% confidence interval, 4.3, 34.9; P = 0.02). Cutaneous microvascular NO function is impaired in women with PCOS compared with obese matched control women but can be improved with exercise training.

Effects of chronic treatment with metformin on dipeptidyl peptidase-4 activity, glucagon-like peptide 1 and ghrelin in obese patients with Type 2 diabetes mellitus.

AIMS: Studies investigating the acute effects of metformin have demonstrated actions on the incretin system and appetite regulatory hormones. There are limited data to support that these effects are sustained in the long term. We therefore studied the effects of chronic treatment with metformin on endogenous glucagon-like peptide 1, dipeptidyl peptidase-4 activity and active ghrelin (an orexigenic hormone) in obese patients with Type 2 diabetes mellitus. METHODS: Eight subjects [six male, age 58.7 ± 2.6 years, BMI 41.1 ± 2.9 kg/m(2) , HbA(1c) 69 ± 6 mmol/mol (8.5 ± 0.5%), mean ± sem] with drug-naïve Type 2 diabetes were studied for 6 h following a standard mixed meal, before and after at least 3 months of metformin monotherapy (mean dose 1.75 g daily). RESULTS: The area under the curve (AUC(0-6 h) ) for active glucagon-like peptide 1 was significantly higher on metformin (pre-metformin 1750.8 ± 640 pmol l(-1) min(-1) vs. post-metformin 2718.8 ± 1182.3 pmol l(-1) min(-1) ; P=0.01). The areas under the curves for dipeptidyl peptidase-4 activity and ghrelin were not significantly different pre- and post-treatment with metformin. CONCLUSION: Three months or more of metformin monotherapy in obese patients with Type 2 diabetes was associated with increased postprandial active glucagon-like peptide 1 levels. The effects of metformin on the enteroinsular axis may represent yet another important mechanism underlying its glucose-lowering effects.

Hypopituitarism--a late consequence of aneurysmal subarachnoid haemorrhage?

Over the last decade subarachnoid haemorrhage (SAH) has increasingly been recognised as a cause of hypopituitarism. We report on the case of a patient with evidence of growth hormone deficiency manifesting after a period of time, with a favourable response to growth hormone replacement. This is followed by a review of the current literature.

Improvement in the care of multiple endocrine neoplasia type 1 through a regional multidisciplinary clinic.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is associated with significant morbidity and mortality. Timely detection of MEN1 kindred, together with treatment of associated tumours, results in an improved outcome. We describe how the development of a dedicated multidisciplinary MEN clinic has improved the diagnosis and treatment of MEN1-associated endocrinopathies. DESIGN AND PATIENTS: A dedicated MEN clinic was developed at Aintree University Hospital, Liverpool in 2002 for patients living in Merseyside, Cheshire and North Wales. The multidisciplinary approach adopted, aimed to improve communication and continuity of care. Patients see all clinicians involved in their care (Consultant Endocrinologist, Paediatrician, Clinical Geneticist and Endocrine Surgeon) simultaneously, allowing for a unified, clear approach and a reduction in unnecessary attendances. The clinicians adopt a proactive approach to tracing the relatives of patients, with the aim of identifying kindred with previously asymptomatic disease. RESULTS: In 2002, 16 patients from 5 families were diagnosed clinically with MEN1. Twenty MEN1-associated endocrinopathies had been diagnosed and 21 surgical procedures had been performed. By the end of 2008, 45 patients from 15 families had been identified, with 83 endocrinopathies diagnosed and 50 surgical procedures performed. Ninety-four known relatives are awaiting screening for MEN1. CONCLUSION: The successful identification of patients with MEN1 has resulted in an exponential increase in the number of patients attending the clinic. As relatives undergo screening, the diagnosis of MEN is likely to increase. The ever increasing numbers of patients requiring screening, surveillance and treatment has implications in the planning of future service provision.

Collagen synthesis in human musculoskeletal tissues and skin.

We have developed a direct method for the measurement of human musculoskeletal collagen synthesis on the basis of the incorporation of stable isotope-labeled proline or leucine into protein and have used it to measure the rate of synthesis of collagen in tendon, ligament, muscle, and skin. In postabsorptive, healthy young men (28 +/- 6 yr) synthetic rates for tendon, ligament, muscle, and skin collagen were 0.046 +/- 0.005, 0.040 +/- 0.006, 0.016 +/- 0.002, and 0.037 +/- 0.003%/h, respectively (means +/- SD). In postabsorptive, healthy elderly men (70 +/- 6 yr) the rate of skeletal muscle collagen synthesis is greater than in the young (0.023 +/- 0.002%/h, P < 0.05 vs. young). The rates of synthesis of tendon and ligament collagen are similar to those of mixed skeletal muscle protein in the postabsorptive state, whereas the rate for muscle collagen synthesis is much lower in both young and elderly men. After nutrient provision, collagen synthesis was unaltered in tendon and skeletal muscle, remaining at postabsorptive values (young: tendon, 0.045 +/- 0.008%/h; muscle, 0.016 +/- 0.003%/h; elderly: muscle, 0.024 +/- 0.003%/h). These results demonstrate that the rate of human musculoskeletal tissue collagen synthesis can be directly and robustly measured using stable isotope methodology.