Gathering momentum for the way ahead: fifth report of the Lancet Standing Commission on Liver Disease in the UK.

This report presents further evidence on the escalating alcohol consumption in the UK and the burden of liver disease associated with this major risk factor, as well as the effects on hospital and primary care. We reiterate the need for fiscal regulation by the UK Government if overall alcohol consumption is to be reduced sufficiently to improve health outcomes. We also draw attention to the effects of drastic cuts in public services for alcohol treatment, the repeated failures of voluntary agreements with the drinks industry, and the influence of the industry through its lobbying activities. We continue to press for reintroduction of the alcohol duty escalator, which was highly effective during the 5 years it was in place, and the introduction of minimum unit pricing in England, targeted at the heaviest drinkers. Results from the introduction of minimum unit pricing in Scotland, with results from Wales to follow, are likely to seriously expose the weakness of England's position. The increasing prevalence of obesity-related liver disease, the rising number of people diagnosed with type 2 diabetes and its complications, and increasing number of cases of end-stage liver disease and primary liver cancers from non-alcoholic fatty liver disease make apparent the need for an obesity strategy for adults. We also discuss the important effects of obesity and alcohol on disease progression, and the increased risk of the ten most common cancers (including breast and colon cancers). A new in-depth analysis of the UK National Health Service (NHS) and total societal costs shows the extraordinarily large expenditures that could be saved or redeployed elsewhere in the NHS. Excellent results have been reported for new antiviral drugs for hepatitis C virus infection, making elimination of chronic infection a real possibility ahead of the WHO 2030 target. However, the extent of unidentified cases remains a problem, and will also apply when new curative drugs for hepatitis B virus become available. We also describe efforts to improve standards of hospital care for liver disease with better understanding of current service deficiencies and a new accreditation process for hospitals providing liver services. New commissioning arrangements for primary and community care represent progress, in terms of effective screening of high-risk subjects and the early detection of liver disease.

Preoperative medical treatment in Cushing's syndrome: frequency of use and its impact on postoperative assessment: data from ERCUSYN.

BACKGROUND: Surgery is the definitive treatment of Cushing's syndrome (CS) but medications may also be used as a first-line therapy. Whether preoperative medical treatment (PMT) affects postoperative outcome remains controversial. OBJECTIVE: (1) Evaluate how frequently PMT is given to CS patients across Europe; (2) examine differences in preoperative characteristics of patients who receive PMT and those who undergo primary surgery and (3) determine if PMT influences postoperative outcome in pituitary-dependent CS (PIT-CS). PATIENTS AND METHODS: 1143 CS patients entered into the ERCUSYN database from 57 centers in 26 countries. Sixty-nine percent had PIT-CS, 25% adrenal-dependent CS (ADR-CS), 5% CS from an ectopic source (ECT-CS) and 1% were classified as having CS from other causes (OTH-CS). RESULTS: Twenty per cent of patients took PMT. ECT-CS and PIT-CS were more likely to receive PMT compared to ADR-CS (P < 0.001). Most commonly used drugs were ketoconazole (62%), metyrapone (16%) and a combination of both (12%). Median (interquartile range) duration of PMT was 109 (98) days. PIT-CS patients treated with PMT had more severe clinical features at diagnosis and poorer quality of life compared to those undergoing primary surgery (SX) (P < 0.05). Within 7 days of surgery, PIT-CS patients treated with PMT were more likely to have normal cortisol (P < 0.01) and a lower remission rate (P < 0.01). Within 6 months of surgery, no differences in morbidity or remission rates were observed between SX and PMT groups. CONCLUSIONS: PMT may confound the interpretation of immediate postoperative outcome. Follow-up is recommended to definitely evaluate surgical results.

Disease burden and costs from excess alcohol consumption, obesity, and viral hepatitis: fourth report of the Lancet Standing Commission on Liver Disease in the UK.

This report contains new and follow-up metric data relating to the eight main recommendations of the Lancet Standing Commission on Liver Disease in the UK, which aim to reduce the unacceptable harmful consequences of excess alcohol consumption, obesity, and viral hepatitis. For alcohol, we provide data on alcohol dependence, damage to families, and the documented increase in alcohol consumption since removal of the above-inflation alcohol duty escalator. Alcoholic liver disease will shortly overtake ischaemic heart disease with regard to years of working life lost. The rising prevalence of overweight and obesity, affecting more than 60% of adults in the UK, is leading to an increasing liver disease burden. Favourable responses by industry to the UK Government's soft drinks industry levy have been seen, but the government cannot continue to ignore the number of adults being affected by diabetes, hypertension, and liver disease. New direct-acting antiviral drugs for the treatment of chronic hepatitis C virus infection have reduced mortality and the number of patients requiring liver transplantation, but more screening campaigns are needed for identification of infected people in high-risk migrant communities, prisons, and addiction centres. Provision of care continues to be worst in regions with the greatest socioeconomic deprivation, and deficiencies exist in training programmes in hepatology for specialist registrars. Firm guidance is needed for primary care on the use of liver blood tests in detection of early disease and the need for specialist referral. This report also brings together all the evidence on costs to the National Health Service and wider society, in addition to the loss of tax revenue, with alcohol misuse in England and Wales costing £21 billion a year (possibly up to £52 billion) and obesity costing £27 billion a year (treasury estimates are as high as £46 billion). Voluntary restraints by the food and drinks industry have had little effect on disease burden, and concerted regulatory and fiscal action by the UK Government is essential if the scale of the medical problem, with an estimated 63 000 preventable deaths over the next 5 years, is to be addressed.

NICE-Accredited Commissioning Guidance for Weight Assessment and Management Clinics: a Model for a Specialist Multidisciplinary Team Approach for People with Severe Obesity.

Despite increasing prevalence of obesity, no country has successfully implemented comprehensive pathways to provide advice to all the severely obese patients that seek treatment. We aimed to formulate pathways for referral into and out of weight assessment and management clinics (WAMCs) that include internal medicine/primary care physicians as part of a multidisciplinary team that could provide specialist advice and interventions, including referral for bariatric surgery. Using a National Institute of Health and Care Excellence (NICE)-accredited process, a Guidance Development Group conducted a literature search identifying existing WAMCs. As very few examples of effective structures and clinical pathways existed, the current evidence base for optimal assessment and management of bariatric surgery patients was used to reach a consensus. The model we describe could be adopted internationally by health services to manage severely obese patients.

Aggressive pituitary tumours: the role of temozolomide and the assessment of MGMT status.

BACKGROUND: Aggressive pituitary tumours are associated with substantial morbidity and mortality. Treatment options are often limited, and chemotherapy has been reserved as salvage therapy although historically results have often been disappointing. However, temozolomide, an oral alkylating agent, has recently demonstrated significant activity against these tumours. A DNA repair protein, 06-methylguanine-DNA methyltransferase (MGMT) has been suggested as a biomarker to predict response to temozolomide in pituitary tumours. MATERIALS AND METHODS: This paper will review the current literature on temozolomide and pituitary tumours and discuss the recent controversy surrounding the value of determining the MGMT status in this tumour group. A PubMed search was performed to retrieve articles, using the terms 'pituitary tumour' and 'temozolomide'. RESULTS: Overall, 24/40 (60%) of the published cases demonstrated a response to temozolomide therapy. The highest response rates were seen amongst prolactinomas (73%) and ACTH-secreting tumours (60%), whilst nonfunctioning pituitary tumours exhibit lower response rates (40%). Responsivity is typically evident in the first 3 months of therapy and may be dramatic and sustained. Low MGMT expression, as determined by immunohistochemistry, is associated with a high response rate (76%), whilst high MGMT expression has not been associated with responses. MGMT promoter methylation does not correlate with temozolomide response. CONCLUSIONS: Temozolomide is the first chemotherapeutic agent to show substantial response rates in aggressive pituitary tumours. MGMT immunohistochemistry, but not MGMT methylation analysis, shows promise as a predictive tool. Prospective clinical trials are now necessary to more accurately determine the efficacy of this agent in this patient group.

Assessment of p27 (cyclin-dependent kinase inhibitor 1B) and aryl hydrocarbon receptor-interacting protein (AIP) genes in multiple endocrine neoplasia (MEN1) syndrome patients without any detectable MEN1 gene mutations.

OBJECTIVE: Germline mutations in the MEN1 gene predispose to the multiple endocrine neoplasia (MEN1) syndrome; however, approximately 10-20% of patients with MEN1 do not have a detectable MEN1 mutation. A rat strain with multiple endocrine tumours, a phenotypic overlap of both MEN1 and MEN2, has been reported to have a homozygous germline p27 (CDKN1B) mutation. Recently, two MEN1 mutation-negative MEN1 syndrome patients have been identified to harbour a germline CDKN1B mutation. The recently identified gene AIP can also cause familial isolated pituitary adenoma, but no other specific tumour is associated with this syndrome. The objective of this study was to evaluate the possible contribution of CDKN1B and AIP germline mutations in a cohort of MEN1 mutation-negative MEN1 syndrome patients. PATIENTS: Eighteen sporadic and three familial cases of MEN1 mutation-negative MEN1 syndrome were studied (18 pituitary adenomas, 12 hyperparathyroidism, 10 neuroendocrine tumours including 2 ACTH-secreting lesions and one adrenal nodular hyperplasia). Clinical data and genomic DNA were analysed for mutations in the CDKN1B and AIP genes. RESULTS: There were no mutations in the coding region or exon/intron junction of the CDKN1B and AIP genes in any patient. Although we have a limited number of patients in our cohort, our data is consistent with others in the literature suggesting that CDKN1B and AIP mutations are extremely rare in MEN1 syndrome. CONCLUSION: Our results suggest that mutations in the CDKN1B and AIP genes are relatively uncommon in MEN1 mutation-negative MEN1 syndrome patients.

Impact of musculoskeletal disease on quality of life in long-standing acromegaly.

OBJECTIVE: To provide rheumatological assessment of patients with long-standing acromegaly and investigate the impact of musculoskeletal disease on quality of life. DESIGN: Cross-sectional observational study. METHODS: Fifty-eight patients diagnosed with acromegaly at least 5 years previously were interviewed and examined by a rheumatologist. Each patient completed the short form-36 (SF-36), arthritis impact measurement scales 2 (AIMS2) and acromegaly quality of life questionnaires (AcroQol). RESULTS: Fifty-two out of 58 (90%) reported musculoskeletal pain, with 29 (50%) reporting neck pain. Hip osteoarthritis was present in 49 (84%) and knee osteoarthritis in 20 (34%). Half the patients (52%) reported sleep disturbance, but only 2 (3.5%) had fibromyalgia. Ten (17.2%) had previously undergone carpal tunnel decompression. Fifty-one (88%) patients had consulted their general practioner and 31 (54%) complementary therapists. SF-36, AIMS2 and AcroQol scores were lower in patients with musculoskeletal pain. CONCLUSIONS: This study of musculoskeletal problems in patients with acromegaly reports systematic rheumatological examination, use of medical services and quality of life scores. Musculoskeletal problems should be routinely addressed in acromegaly by both endocrinologist and rheumatologist and a multidisciplinary approach taken to management.

Systematic dose-extension of octreotide LAR: the importance of individual tailoring of treatment in patients with acromegaly.

OBJECTIVE: The depot long-acting somatostatin analogue octreotide LAR (LAR) provides effective and well-tolerated treatment for acromegaly. Despite a 4-weekly recommended injection frequency, prolonged duration of GH suppression has been observed in some patients following treatment with long-acting somatostatin analogues. The aim of our study was to perform a prospective systematic study to determine whether extending the interval between doses of LAR allows maintenance of 'safe' GH in selected patients with acromegaly. PATIENTS AND METHODS: Twenty-two patients (15 men, seven women), mean age 58.9 years (35-81 years) with active acromegaly (mGH > 5 mU/l), requiring treatment were selected to receive treatment with LAR. Eleven patients had received previous treatment with both transsphenoidal surgery and radiotherapy, while six had received surgery alone. All patients were commenced on treatment with 20 mg LAR intramuscularly (i.m.) every 4 weeks. Mean GH (mGH) was measured after three consecutive injections immediately prior to the fourth injection. The dose frequency was systematically reduced after every four injections if mGH < 5 mU/l. Once mGH > 5 mU/l, the dose frequency was increased and mGH reassessed. RESULTS: The dosing interval was successfully increased to greater than 4 weeks in 20/22 patients (90.9%). Six of 22 (27.3%) were receiving injections every 8 weeks and 3/22 (13.6%) every 12 weeks. GH and IGF-I were lower on treatment compared with baseline (P < 0.01). There was no difference in individual mGH and IGF-I between the values on 4-weekly dosing and those at final dose frequency. There was no relationship between final dose frequency and either mean GH or IGF-I prior to LAR, patient age, or previous treatment. The percentage suppression following 100 micro g octreotide subcutaneously did not predict subsequent dose frequency of LAR. The drug cost if patients had continued at 4-weekly intervals would be UK pound 187 850, compared with UK pound 101 065 for the individually titrated dose frequency (P < 0.01). This represents a final cost of 53.8% of the 4-weekly injection price. CONCLUSION: Individual tailoring of LAR administration maintains control of acromegaly, with reduced injection frequency and improved cost-effectiveness.