Lipid clinic experience with bempedoic acid in three UK centres.

OBJECTIVE: Novel lipid-lowering therapies are being introduced. Few studies exist of the real-world effectiveness of adenosine-tri-phosphate citrate lyase inhibition with bempedoic acid. METHODS: This study audited bempedoic acid therapy in 216 consecutive patients from three hospital centres - a university hospital (n = 77) and two district general hospitals (n = 106 and 33). Cardiovascular disease (CVD) risk factors, prescription qualification criteria, efficacy and adverse effects were assessed. RESULTS: The population was aged 65.9 ± 11.0 years, 42% were male, 25% had type 2 diabetes, and 31% had familial hypercholesterolaemia. CVD was present in 19% and multibed vascular disease in 8%. Statin intolerance was reported in 92%. Bempedoic acid reduced total cholesterol by 1.58 ± 1.44 mmol/L (20%), LDL-C by 1.37 ± 1.31 mmol/L (27%), triglycerides by 0.22 mmol/L (2%) with an 0.06 mmol/L (1%) increase in HDL-C after 22 ± 9 months follow-up. An LDL-C <2.5 mmol/L was achieved in 40% and <2 mmol/L in 20%. Efficacy (r2 = .33) was predicted by baseline LDL-C (ß = .54; p <.001). No significant changes were seen in transaminases, creatinine, creatine kinase, urate or HbA1c. Treatment was discontinued by 33% of patients and occurred due to myalgia (43%), lack of efficacy (16%) and gastrointestinal adverse effects (15%). No cases of gout were observed. In a logistic regression only the number of previous drug classes not tolerated (ß = 1.60; p = .009) was a contributing factor to discontinuation. CONCLUSION: This audit suggests that bempedoic acid therapy is effective but that adverse effects and discontinuation are common. This suggests nocebo effects might be generalizable to all lipid-lowering drug therapies in susceptible individuals.

Age- and ethnicity-related reference intervals for serum vitamin B12.

BACKGROUND: Age and ethnicity are known to influence serum vitamin B12 (B12) concentration, yet universal reference intervals (RIs) are typically applied by laboratories. Both lower and upper RI limits for B12 are clinically relevant. Low values suggest deficiency leading to anemia and/or neurological impairment, while high values are not always an innocuous consequence of high B12 intake but are associated with some cancers, autoimmune, liver, and renal diseases. This work aimed to establish age- and ethnicity-related RIs for B12 using a modified indirect method based on Hoffmann's approach. METHODS: A total of 72,091 anonymized B12 results (Jan 2018-Nov 2019) were analyzed from an ethnically-diverse South-East London general practice patient population. Patients belonged to five ethnic groups: Asian, Black, White, Mixed, or Other. Multiple records for the same patient and results with missing ethnicity were excluded from the analysis of adult RIs. B12 analyses were performed using ARCHITECT® (Abbott Diagnostics). RESULTS: B12 was significantly higher in Black compared with Asian and White adults. There were no differences in B12 between Asian and White adults. Children (all ethnicities) between 2 and 5 years old had the highest B12. Because of the small number of children (up to the age of 13) in each ethnic-related age category, all ethnic groups were combined to obtain age-related RIs. The children's RIs ranged from 159 to 1025 pmol/L for 0-1-year-olds to 276-1102 pmol/L for 2-5-year-olds. The RIs for Black and White/Asian people >13 years of age were 166-805 pmol/L and 134-511 pmol/L respectively. CONCLUSIONS: The application of age- and ethnicity-appropriate RIs into diagnostic practice will provide a more accurate evaluation of B12 status when using the B12 test alone or in combination with other markers.

Ethnicity influences total serum vitamin B12 concentration: a study of Black, Asian and White patients in a primary care setting.

AIMS: A growing body of evidence suggests that ethnicity and race influence vitamin B12 metabolism and status yet clinical awareness of this is poor, causing doubts regarding diagnosis and treatment. Moreover, deficiency and insufficiency cut-offs are universally applied for this test in most diagnostic settings. The objective of this study was to assess serum vitamin B12 concentrations in Black, Asian and White primary care patients in London, UK, particularly in patients of Black or Black British ethnic origin and establish if there is a need for specific reference ranges. METHODS: Serum B12 results from 49 414 patients were processed between January 2018 and November 2019 using the Architect assay (Abbott Diagnostics) at St. Thomas' Hospital, London, UK. Age, sex and ethnicity data were collected from the laboratory Health Informatics Team. RESULTS: Black patients (n=13 806) were found to have significantly higher serum vitamin B12 concentration across all age groups and both sexes, especially Nigerian patients (median B12 505 pmol/L,IQR: 362-727, n=891), compared with Asian and White ethnic groups (p<0.001). Binary logistic regression analysis revealed that the Black or Black British ethnic group had the strongest association with elevated serum B12 (>652 pmol/L) (adjusted OR 3.38, 95% CI 3.17 to 3.61, p<0.0001). CONCLUSIONS: It is likely that a combination of genetic and acquired/environmental factors are responsible for the ethnic differences in serum B12. This suggests that there is a need for ethnic-specific reference ranges with indications for the incorporation of age and sex too.

The Association between Metabolic Syndrome and Multiple Myeloma.

Multiple myeloma (MM) is a haematological malignancy arising from monoclonal proliferation of plasma cells in the bone marrow, resulting in the presence of paraproteins or M-protein in serum. The involvement of paraproteins produced by malignant plasma cells in the development of hyperlipidaemia and low-HDL cholesterol has been described, as has an association with MM and obesity, hypertension, and type 2 diabetes mellitus, and insulin resistance, that is, features of the metabolic syndrome (MS). There is an association between MS components, inflammatory cytokines, and the development of MM, and some drugs used in the treatment of MS such as statins and metformin may improve outcomes in MM.

Hypertriglyceridaemia as a risk factor for critical care admission in acute pancreatitis: A prospective study.

BACKGROUND AND AIMS: Hypertriglyceridaemia is both a primary cause of acute pancreatitis and an epiphenomenon. This study aimed to define the associations between hypertriglyceridaemia and clinical outcomes in patients admitted with acute pancreatitis. METHODS: This single-centre prospective observational study included patients with a confirmed clinical, biochemical or radiological diagnosis of acute pancreatitis from August 2017 to September 2018. Baseline demographics, aetiology of pancreatitis, and fasting triglyceride concentrations were recorded and assessed against the surrogate markers of severity: admission to critical care, length of stay (LOS), readmission to hospital, and mortality. RESULTS: In total, 304 patients with a mean ± SD age of 56.1 ± 19.7 years met the inclusion criteria. There were 217 (71.4%) patients with normotriglyceridaemia (<150 mg/dL or <1.7 mmol/L), 47 (15.5%) with mild hypertriglyceridaemia (150-199 mg/dL or 1.7-2.25 mmol/L) and 40 (13.2%) with moderate-to-severe hypertriglyceridaemia (≥200 mg/dL or >2.25 mmol/L). The underlying aetiologies of acute pancreatitis were gallstones (55%), alcohol (18%), idiopathic (15%), hypertriglyceridaemia (9%), iatrogenic (2%) and bile duct abnormalities (1%). Patients with hypertriglyceridaemia were younger than those with normotriglyceridaemia (p < 0.05). On multivariate regression, moderate-to-severe hypertriglyceridaemia (OR 5.66, 95% CI: 1.87 to 17.19, p = 0.002) and an elevated C-reactive protein concentration ≥120 mg/L (OR 1.00, 95% CI: 1.00-1.01, p = 0.040) were associated with admission to critical care. Moderate-to-severe hypertriglyceridaemia was also associated with an increased LOS (p = 0.002) but not readmission (p = 0.752) or mortality (p = 0.069). CONCLUSION: Moderate-to-severe hypertriglyceridaemia in all aetiological causes of acute pancreatitis was predictive of admission to critical care and prolonged LOS but not readmission or mortality.

Disorders of phosphate metabolism.

Phosphate in both inorganic and organic form is essential for several functions in the body. Plasma phosphate level is maintained by a complex interaction between intestinal absorption, renal tubular reabsorption, and the transcellular movement of phosphate between intracellular fluid and bone storage pools. This homeostasis is regulated by several hormones, principally the parathyroid hormone, 1,25-dihydroxyvitamin D and fibroblast growth factor 23. Abnormalities in phosphate regulation can lead to serious and fatal complications. In this review phosphate homeostasis and the aetiology, pathophysiology, clinical features, investigation and management of hypophosphataemia and hyperphosphataemia will be discussed.

Prevalence of Advanced Liver Fibrosis in Patients With Severe Psoriasis.

IMPORTANCE: Advanced liver fibrosis is a precursor to cirrhosis, a leading cause of mortality. People with severe psoriasis are at risk for liver disease, but our understanding of advanced fibrosis in individuals with psoriasis is limited. OBJECTIVES: To describe the prevalence of and evaluate the clinical factors associated with advanced liver fibrosis in people with severe psoriasis. DESIGN, SETTING, AND PARTICIPANTS: The Co-morbidities in Severe Psoriasis study, a prospective observational cohort study in a large center serving London and Southeast England, was conducted from October 18, 2012, to April 2, 2015; 400 adults with severe psoriasis (Psoriasis Area Severity Index score, ≥10) were recruited from outpatient clinics. Statistical analysis was conducted from October 2, 2016, to March 3, 2017. MAIN OUTCOMES AND MEASURES: The primary outcome was a diagnosis of advanced liver fibrosis determined by transient elastography, a noninvasive criterion standard test. Clinical factors evaluated included psoriasis-specific and metabolic indices, alcohol use, and methotrexate exposure. RESULTS: Of 400 patients recruited (108 women and 289 men; mean [SD] age, 49.5 [13] years), 333 had a successful transient elastography scan and were included in final analysis. Forty-seven patients (14.1%; 95% CI, 10.4%-17.9%) had advanced liver fibrosis as diagnosed by transient elastography. The clinical factors that produced the best-fit model for advanced fibrosis were central obesity (waist circumference), insulin resistance, aspartate aminotransferase level, platelet count, psoriasis disease severity, and reduced alcohol use (R2 = 0.54). CONCLUSIONS AND RELEVANCE: Findings from this study suggest that advanced fibrosis is common in severe psoriasis. Abdominal obesity (by waist circumference) and insulin resistance were associated with the presence of advanced fibrosis. Longitudinal work to characterize the hepatic sequelae of central obesity, insulin resistance, and inflammation as well as the influence of systemic drugs (methotrexate and biologics) will inform future personalized therapeutic decision-making. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02174367.

The clinical importance of recognizing capecitabine-induced hypertriglyceridemia: A case report and review of the literature.

This case report describes a patient who developed a mixed hyperlipidemia and severe hypertriglyceridemia (>20 mmol/L or 1772 mg/dL) while receiving capecitabine chemotherapy. After lipid-lowering treatment (statin and omega-3 acid ethyl esters) and completion of chemotherapy, her lipid levels had been significantly reduced. Other secondary causes of hyperlipidemia were also investigated. In view of the abnormal lipid results worsened by capecitabine, we suggest that careful lipid monitoring and thorough lipid management are important in such patients to avoid acute pancreatitis.

Undetectable high-density lipoprotein cholesterol in acute malaria.

We report the case of a 39-year-old West African man in whom high-density lipoprotein cholesterol (HDL-C) was identified as undetectable at <0.08 mmol/L. Total cholesterol in the same sample was 2.85 mmol/L; triglycerides were only mildly elevated at 2.32 mmol/L. He was admitted with a 2-week history of polydipsia, polyuria, weight loss and hyperpyrexia. Dual malarial infection with Plasmodium ovale and falciparum was identified and attributed to a recent trip to Nigeria without chemoprophylaxis. Also, he was diagnosed with diabetes mellitus with random hyperglycemia of 39 mmol/L but no ketonemia. Subsequent investigation revealed a low apolipoprotein A1 of 0.38 g/L (1.04-2.02), confirming a true HDL-C deficit. On clinical examination, he had neither orange tonsils consistent with Tangier disease nor corneal opacification consistent with lecithin-cholesterol acyltransferase deficiency. The patient was an avid gym goer but denied anabolic steroid abuse, a fact supported by a transient primary testosterone deficiency at presentation (testosterone 6.56 nmol/L, RR 8.6-29; follicle-stimulating hormone high at 9.2 mU/L, luteinising hormone high at 11.9 mU/L). He was treated for malaria and started on metformin for diabetes. At 8-week follow-up, his HDL-C was entirely normal at 1.38 mmol/L. We believe this severe drop in HDL-C level to be due to acute inflammation caused by malaria. As extreme drops in HDL-C have been found to be associated with the poorest prognosis, prospective identification of HDL-C and prompt clinical liaison may be of benefit.

Management and prevention of refeeding syndrome in medical inpatients: An evidence-based and consensus-supported algorithm.

OBJECTIVES: Refeeding syndrome (RFS) can be a life-threatening metabolic condition after nutritional replenishment if not recognized early and treated adequately. There is a lack of evidence-based treatment and monitoring algorithm for daily clinical practice. The aim of the study was to propose an expert consensus guideline for RFS for the medical inpatient (not including anorexic patients) regarding risk factors, diagnostic criteria, and preventive and therapeutic measures based on a previous systematic literature search. METHODS: Based on a recent qualitative systematic review on the topic, we developed clinically relevant recommendations as well as a treatment and monitoring algorithm for the clinical management of inpatients regarding RFS. With international experts, these recommendations were discussed and agreement with the recommendation was rated. RESULTS: Upon hospital admission, we recommend the use of specific screening criteria (i.e., low body mass index, large unintentional weight loss, little or no nutritional intake, history of alcohol or drug abuse) for risk assessment regarding the occurrence of RFS. According to the patient's individual risk for RFS, a careful start of nutritional therapy with a stepwise increase in energy and fluids goals and supplementation of electrolyte and vitamins, as well as close clinical monitoring, is recommended. We also propose criteria for the diagnosis of imminent and manifest RFS with practical treatment recommendations with adoption of the nutritional therapy. CONCLUSION: Based on the available evidence, we developed a practical algorithm for risk assessment, treatment, and monitoring of RFS in medical inpatients. In daily routine clinical care, this may help to optimize and standardize the management of this vulnerable patient population. We encourage future quality studies to further refine these recommendations.

Review of referral criteria to lipid clinics and outcomes of treatment in four UK centres.

BACKGROUND: Little data exist on the referral patterns and effectiveness of lipid clinics. METHODS: An audit was conducted in four clinics of 100 consecutive referrals each. Data were recorded on referral criteria, cardiovascular disease (CVD) risk factors, drug history, investigations, diagnoses, therapies, results and referrals. RESULTS: Patients were aged 56 ± 14 years, 47% were male and 87% were primary prevention. Risk factors included smoking (16%), type 2 diabetes (13%) and hypertension (13%). Referrals were made for hypercholesterolaemia (68%), diagnosis of FH (31%), statin intolerance (23%) and hypertriglyceridaemia (23%). Initial total cholesterol (TC) was 7.65 ± 2.64 mmol/L, triglycerides (TG) 2.17 (0.41-76.9 mmol/L) mmol/L, HDL-C 1.53 ± 0.71 mmol/L, LDL-C 4.57 ± 1.66 mmol/L with non-HDL-C 5.90 ± 2.09 mmol/L. Criteria for FH were met in 21% with genetic testing in 13% and lipid cascade testing in 30% of index cases. Triglycerides >20 mmol/L were present in 4%. The diagnosis was changed in 21%: hypercholesterolaemia (7%), mixed hyperlipidaemia (7%) and hypertriglyceridaemia (7%). Hepatic steatosis was identified in 14.5%. Lipoprotein(a) levels >125 nmol/L occurred in 41% in one clinic. Therapy changes included altered statins (40%), addition of a fibrate (11%) or ezetimibe (8%). These reduced TC by 1.92 mmol/L (19%; P = 0.0001), LDL-C 1.07 mmol/L (15%; P = 0.02), non-HDL-C 1.50 mmol/L (16%; P < 0.001), and TG 2.3 (-4 to 38) mmol/L (16%; P < 0.001) with 11% extra achieving TG <5 mmol/L while HDL-C increased by 7% (P = 0.37). CONCLUSIONS: Lipid clinics have diverse functions including diagnosis of FH, managing severe hypercholesterolaemia, mixed hyperlipidaemia and statin intolerance. Effectiveness criteria of average reductions of 1.5 mmol/L in TC or non-HDL-C, 1 mmol/L in LDL-C and 2 mmol/L in TG would be reasonable for newly referred patients.

A systematic review of the epidemiology, pathophysiology and current management of hyperlipidaemic pancreatitis.

BACKGROUND & AIMS: The aims of this systematic review were to define the epidemiology and pathophysiology of hyperlipidaemic pancreatitis, establish its association with clinical outcome and define management strategies. METHODS: The Cochrane, Embase and Medline databases were searched, limited to the last decade, for articles on hyperlipidaemic pancreatitis. All randomised controlled trials, observational studies and case series (with a minimum of 10 patients) on hyperlipidaemic pancreatitis were included. RESULTS: Thirty-eight studies with 1979 patients were included. The median admission triglyceride concentration was 42.8 mmol/L (range 13.6-108.6 mmol/L) [3785 mg/dL (range 1205-9612 mg/dL)]. Severe hypertriglyceridaemia (>1000 mg/dL, 11.0 mmol/L) was present in 1.7% of the adult population, and about 15-20% of these developed hyperlipidaemic acute pancreatitis. Medical management of severe hyperlipidaemia at onset of acute pancreatitis has not been investigated fully. However, tight regulation of triglyceride concentration after presentation with acute pancreatitis was found to reduce the risk of recurrence. Plasmapheresis reduced concentrations of triglycerides by up to 85%, but this did not impact morbidity or mortality. All studies included defined hyperlipidaemia as a more severe form of pancreatitis. CONCLUSION: The available evidence suggests an increasing risk of acute pancreatitis in patients with hyperlipidaemia and a more severe form of pancreatitis. There is some evidence to suggest biochemical benefit of using novel techniques like plasmapheresis without the desired physiological benefit. However, there is a need for an international consensus on the management of hyperlipidaemic pancreatitis. More rigorous and methodologically robust studies are required to inform such consensus guidelines.

Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres.

BACKGROUND: Prescribing criteria have been suggested for proprotein convertase subtilisin kexin-9 (PCSK-9) inhibitors but few studies exist of their real-world effectiveness. METHODS: This study audited PCSK-9 inhibitor therapy in 105 consecutive patients from two hospital centres-a university hospital (UH; n = 70) and a district general hospital (DGH; n = 35). Baseline characteristics including cardiovascular disease risk factors, NICE qualification criteria, efficacy and side effects were assessed. RESULTS: Baseline LDL-C levels were similar in both centres. NICE criteria were met for 2.05 items in the whole study (UH patients 1.7 and DGH patients 2.7). District general hospital patients were more likely to have familial hypercholesterolaemia (89 vs 69%; P = .02); intolerance to statins (94 vs 52%; P < .001) and polyvascular disease (42% vs 17%; P = .005). Prescriptions (evolocumab 73%; alirocumab 23%) were collected by 76% of patients (UH 64% vs DGH 100%). Therapy was discontinued by time of review in 15% of patients (UH 7% vs DGH 25%; P = .02). In adherent patients PCSK-9 inhibitor treatment reduced TC by 28% (2.24 ± 2.39 mmol/L; P < .001) and LDL-C by 49% (2.10 ± 1.33 mmol/L; P < .001). A LDL-C < 2.5 mmol/L was achieved in 30% of patients and <2.0 mmol/L in 20%. PCSK-9 therapy was effective and safe in patients with increased lipoprotein (a), diagnosed muscle diseases (including myopathies and muscular dystrophy) or poststatin rhabdomyolysis, nephrotic syndrome or HIV disease. Mixed results were obtained in patients with significant mixed hyperlipidaemia. CONCLUSIONS: This study suggests that PCSK-9 inhibitors are effective but that prescriptions should not be changed to long-term delivery until patients have been reviewed and shown to be adherent.

Metabolic Syndrome in Long-Term Survivors of Hematopoietic Stem-Cell Transplantation.

Since its introduction more than 50 years ago, hematopoietic stem-cell transplantation (HSCT) has transformed from an inescapably fatal procedure to one where cure from malignant and other nonmalignant hematologic diseases is becoming increasingly common. Nevertheless, longevity is not entirely restored. New causes of mortality have emerged; of particular importance is that of increased cardiovascular disease (CVD), related to metabolic syndrome and its components. Controversy exists over whether the metabolic abnormalities induced are a direct effect of HSCT itself or a consequence of other therapies involved. Analysis of the mechanisms that promote the changes in metabolic components will give insight into future HSCT therapy as well as CVD pathogenesis and prevention.