Where Are We Now with Liver Transplantation in Neuroendocrine Neoplasms? The Place of Liver Transplantation for Grades 1 and 2 Well-Differentiated Unresectable Liver Metastatic Neuroendocrine Tumours.

PURPOSE OF REVIEW: This review outlines the role of liver transplantation in selected patients with unresectable neuroendocrine tumour liver metastases. It discusses the international consensus on eligibility criteria and outlines the efforts taking place in the UK and Ireland to develop effective national liver transplant programmes for neuroendocrine tumour patients. RECENT FINDINGS: In the early history of liver transplantation, indications included cancer metastases to the liver as well as primaries of liver origin. Often, liver transplantation was a salvage procedure. The early results were disappointing, including in patients with neuroendocrine tumours. These data discouraged the widespread adoption of liver transplantation for neuroendocrine tumour liver metastases (NET LM). A few centres persisted in performing liver transplantation for patients with NET LM and in determining parameters predictive of good outcomes. Their work has provided evidence for benefit of liver transplantation in a selected group of patients with NET LM. Liver transplantation for NET LM is now accepted as a valid indication by many professional bodies, including the European Neuroendocrine Tumour Society (ENETS) and the United Network for Organ Sharing (UNOS). It is nevertheless rarely utilised. The UK and the Republic of Ireland are commencing a pilot programme of liver transplantation in selected patients. This programme will help develop the expertise and infrastructure to make liver transplantation for NET LM a routine procedure.

Association of maternal vitamin B12 and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study).

AIMS/HYPOTHESIS: The prevalence of gestational diabetes mellitus (GDM) is increasing worldwide in all ethnic groups. Low vitamin B12 and low/high folate levels may contribute to GDM risk, but there is conflicting evidence. Our aim is to assess the relationships of early pregnancy vitamin B12 and folate levels with the risk of GDM status at 26-28 weeks of gestation. METHODS: This was a prospective, multi-centre, multi-ethnic cohort study (n = 4746) in the UK. Participants who were eligible to be selectively screened as per the National Institute for Health and Care Excellence (NICE) criteria were included in the study. RESULTS: GDM prevalence was 12.5% by NICE and 14.7% by International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria. Folate deficiency (1.3%) was rare but B12 insufficiency (42.3% at <220 pmol/l) and folate excess (36.5%) were common in early pregnancy. Early pregnancy median B12 levels were lower, and folate levels higher, in women who were diagnosed with GDM at 26-28 weeks. B12 was negatively associated with fasting plasma glucose (1 SD: -0.06 mmol/l; 95% CI -0.04, -0.08; p < 0.0001) and 2 h plasma glucose levels (-0.07 mmol/l; 95% CI -0.02, -0.12; p = 0.004). Higher B12 was associated with 14.4% lower RR of IADPSG-GDM (0.856; 95% CI 0.786, 0.933; p = 0.0004) after adjusting for key confounders (age, parity, smoking status, ethnicity, family history, household income and folate status). Approximately half of this association was mediated through BMI. Folate was positively associated with 2 h plasma glucose levels (0.08 mmol/l; 95% CI 0.04, 0.13; p = 0.0005) but its relationship with fasting plasma glucose was U-shaped (quadratic ß: 0.011; p = 0.05). Higher folate was associated with 11% higher RR of IADPSG-GDM (adjusted RR 1.11; 95% CI 1.036, 1.182; p = 0.002) (age, parity, smoking status, ethnicity, family history, household income and B12 status). Although no interactions were observed for B12 and folate (as continuous variables) with glucose levels and GDM risk, a low B12-high folate combination was associated with higher blood glucose level and risk of IADPSG-GDM (adjusted RR 1.742; 95% CI 1.226, 2.437; p = 0.003). CONCLUSIONS/INTERPRETATION: B12 insufficiency and folate excess were common in early pregnancy. Low B12 and high folate levels in early pregnancy were associated with small but statistically significant changes in maternal blood glucose level and higher RR of GDM. Our findings warrant additional studies on the role of unmetabolised folic acid in glucose metabolism and investigating the effect of optimising early pregnancy or pre-conception B12 and folate levels on subsequent hyperglycaemia. TRIAL REGISTRATION: ClinicalTrials.gov NCT03008824.

Increased fetal adiposity prior to diagnosis of gestational diabetes in South Asians: more evidence for the 'thin-fat' baby.

AIMS/HYPOTHESIS: Gestational diabetes mellitus (GDM) is associated with an increased future risk of obesity in the offspring. Increased adiposity has been observed in the newborns of women with GDM. Our aim was to examine early fetal adiposity in women with GDM. METHODS: Obstetric and sonographic data was collated for 153 women with GDM and 178 controls from a single centre in Chennai, India. Fetal head circumference (HC), abdominal circumference (AC), femur length (FL) and biparietal diameter (BPD) were recorded at 11, 20 and 32 weeks. Anterior abdominal wall thickness (AAWT) as a marker of abdominal adiposity at 20 and 32 weeks was compared between groups. Adjustments were made for maternal age, BMI, parity, gestational weight gain, fetal sex and gestational age. RESULTS: Fetuses of women with GDM had significantly higher AAWT at 20 weeks (ß 0.26 [95% CI 0.15, 0.37] mm, p < 0.0001) despite lower measures of HC, FL, BPD and AC. AAWT remained higher in the fetuses of women with GDM at 32 weeks (ß 0.48 [0.30, 0.65] mm, p < 0.0001) despite similar measures for HC, FL, BPD and AC between groups. Both groups had similar birthweights at term. There was an independent relationship between fasting plasma glucose levels and AAWT after adjustment as described above. CONCLUSIONS/INTERPRETATION: A 'thin but fat' phenotype signifying a disproportionate increase in adiposity despite smaller or similar lean body mass was observed in the fetuses of mothers with GDM, even at 20 weeks, thus pre-dating the biochemical diagnosis of GDM. Increased AAWT may serve as an early marker of GDM.

Vitamin B12 deficiency is associated with adverse lipid profile in Europeans and Indians with type 2 diabetes.

BACKGROUND: Metformin, a standard therapy in type 2 diabetes, reduces vitamin B12 levels. Studies linking low vitamin B12 levels and cardiovascular disease are equivocal and suggest improving B12 levels may help in primary prevention. The role of vitamin B12 deficiency on cardiovascular risk factors, especially in type 2 diabetes has not been explored. The aim of this study is to investigate whether vitamin B12 deficiency in type 2 diabetes patients is associated with cardiovascular risk factors in two different ethnic groups in UK and India. METHODS: Type 2 diabetes patients from two secondary care diabetic centres (Europeans - UK and Indians - India) were studied. Serum vitamin B12, folate and biochemical parameters were measured. RESULTS: The prevalence rates of vitamin B12 deficiency (<191 ng/L) were 27% and 12% in Europeans and Indians, respectively and higher in metformin treated type 2 diabetes patients. In linear regression analysis, after adjusting for all likely confounding factors, vitamin B12 independently associated with triglycerides in both the populations and cholesterol/HDL ratio in Indians. Logistic regression showed type 2 diabetes patients with vitamin B12 deficiency were at significantly higher odds of having coexisting coronary artery disease (CAD) in Europeans with similar but non-significant trend in Indians, after adjusting for all likely confounding factors. CONCLUSIONS: The prevalence of vitamin B12 deficiency is common in type 2 diabetes patients and is associated with adverse lipid parameters. Type 2 diabetes management guidelines should include the recommendation for regular testing for B12 levels, especially for those on metformin.

Surgical Correction of Carcinoid Heart Disease Improves Liver Function and 5-Hydroxyindoleacetic Acid Levels.

Introduction: Carcinoid heart disease (CHD) is a consequence of neuroendocrine tumors releasing 5-hydroxytryptamine (5-HT) into the systemic circulation, affecting right heart valves, causing fibrosis, and eventually right heart failure. The aim of this study was to determine the effect of valve-replacement on kidney function, liver function, and 5-hydroxyindoleacetic acid (5-HIAA) levels. Methods: A Retrospective study of 17 patients with CHD who had undergone heart-valve replacement surgery between 2010 and 2019, from the Queen Elizabeth Hospital Birmingham. 5-HIAA levels, liver, and kidney function were measured in addition to hepatic inferior vena cava (IVC) diameter and its relationship to carcinoid symptoms. Results: Eleven patients were male and six were female. At time of surgery, average age was 66.6 ± 8.1 years and average BMI was 25.8 ± 5.5 Kg/cm2. Three out of 17 patients had one valve replaced, 13/17 had two replaced (tricuspid and pulmonary), and 1/17 had three replaced (tricuspid, pulmonary and aortic). There was a 31% average decline in 5-HIAA [799.8 (343.6-1078.0) to 555.3 (275.8-817.9), p = 0.011], a 35% decline in bilirubin [20 (16-29) to 13 (10-19), p = < 0.001], and a 15% reduction in the short and long axes of the IVC after valve-replacement surgery [20.0 (18.0-25.0) and 36.5 (29.0-39.8) to 17.0 (14.5-19.3) and 31.0 (26.5-34.3) respectively, p = < 0.001 and 0.002 respectively]. Conclusion: Valve replacement surgery improves 5-HIAA levels alongside improved liver function and hepatic IVC diameter. These findings are consistent with resolution of congestive hepatopathy, and therefore enhanced clearance of 5-HIAA. This suggests that valve-replacement surgery can indirectly have beneficial outcomes on hepatic function and is also associated with a drop in the circulating levels of tumor derived serotonin.

The effects of somatostatin analogues on glycaemia in the treatment of neuroendocrine tumours.

Long-acting somatostatin analogues (SSAs) are the most commonly used drugs in the management of neuroendocrine tumours (NETs) because of their ability to control symptoms and prolong survival. SSA use is associated with changes in glucose metabolism. However, the impacts on glycaemic control and body mass index (BMI) caused by SSAs in NETs are largely unknown. In the present study, we evaluated the effects of SSA treatment on BMI and glycated haemoglobin (HbA1c) in our cohort of patients with NETs. We also assessed changes in glycaemic control and BMI before and after SSA treatment. In addition, we assessed the incidence of new diabetes or whether there was worsening of glycaemic control for patients with pre-existing diabetes. The study comprised a retrospective study of 279 patients with NETs who were treated with SSAs between January 2014 and January 2019. Glycaemic control was assessed by measuring changes in Hba1c. A number needed to harm analysis was used to look at new cases of diabetes within the study population. Treatment with SSAs was associated with a mean increase in HbA1c of 3.35 ± 6.30 mmol mol-1 despite a mean decrease in BMI of -1.04 ± 2.79 kg m-2 . There were 19 new cases of type 2 diabetes mellitus (T2DM) in the population of 209 with a number needed to harm of 12.5. Of the 34 patients with pre-existing T2DM, five had worsening of their mean HbA1c. Treatment with SSAs for NETs is associated with an increase in HbA1c, despite a reduction in BMI and, importantly, a risk of developing T2DM with a number needed to harm of 12.5. This project was registered with the National Health Service Clinical Audit and Registries. It has a CARMS number - 17666.

Multidisciplinary team management of carcinoid heart disease.

Carcinoid heart disease (CHD) is a consequence of valvular fibrosis triggered by vasoactive substances released from neuroendocrine tumours, classically in those with metastatic disease and resulting in tricuspid and pulmonary valve failure. CHD affects one in five patients who have carcinoid syndrome (CS). Valve leaflets become thickened, retracted and immobile, resulting most often in regurgitation that causes right ventricular dilatation and ultimately, right heart failure. The development of CHD heralds a significantly worse prognosis than those patients with CS who do not develop valvular disease. Diagnosis requires a low threshold of suspicion in all patients with CS, since symptoms occur late in the disease process and clinical signs are difficult to elicit. As a result, routine screening is recommended using the biomarker, N-terminal pro-natriuretic peptide, and regular echocardiography is then required for diagnosis and follow-up. There is no direct medical therapy for CHD, but the focus of non-surgical care is to control CS symptoms, reduce tumour load and decrease hormone levels. Valve surgery improves long-term outcome for those with severe disease compared to medical management, although peri-operative mortality remains at between 10 and 20% in experienced centres. Therefore, care needs to be multidisciplinary at all stages, with clear discussion with the patient and between teams to ensure optimum outcome for these often-complex patients.

Lesson of the month 2: Blunt abdominal trauma: atypical presentation of phaeochromocytoma.

A 26-year-old man presented following blunt abdominal trauma to a regional major trauma centre for emergency embolisation of a retroperitoneal bleed from a presumed renal laceration. Imaging had also revealed a large right suprarenal mass. Embolisation resulted in a hypertensive crisis raising the suspicion of a metabolically active adrenal tumour. The course was further complicated by the development of ischaemic bowel requiring emergency laparotomy. Intraoperatively he became haemodynamically unstable from an actively haemorrhaging lesion. Emergency laparotomy and adrenalectomy was performed as a life-saving procedure. Histology confirmed a phaeochromocytoma. The patient made a gradual recovery and was discharged home with no sequelae. Definitive management of phaeochromocytoma is surgical resection which requires prolonged preoperative optimisation with alpha receptor blockers to adequately control blood pressure and prevent hypertensive crises. Parenteral alpha receptor blockers, such as phentolamine, are optimal treatment for intraoperative hypertensive emergencies, yet they are currently not available in the UK.

Vitamin B12 status in women of childbearing age in the UK and its relationship with national nutrient intake guidelines: results from two National Diet and Nutrition Surveys.

OBJECTIVE: To assess serum B12, folate and the associated homocysteine (Hcy) levels among women of childbearing age in the UK and examine their association with dietary intake in relation to the UK Recommended Nutrient Intakes (RNIs) for B12 and folate. DESIGN: Cross-sectional study. SETTING: Data from two publicly available National Diet and Nutrition Surveys (NDNS 2000/2001 and 2008/2012) were used. These were population-based surveys of randomly selected samples of adults which were carried out in their households. PARTICIPANTS: Women of childbearing age (aged 19-39 years), representative of the UK population. Those who were pregnant or breastfeeding were excluded. OUTCOME MEASURES: The associations between micronutrient intakes and blood levels of B12, folate and Hcy were assessed by correlation and stepwise linear regression. B12 intake was divided into quintiles and plotted against blood B12 and Hcy concentrations to determine the threshold of any associations. RESULTS: 299 women from the first NDNS cohort had complete intake and biomarker data. The prevalence of serum vitamin B12 (≤150 pmol/L) and serum folate (≤10 nmol/L) deficiency and hyperhomocysteinemia (≥12 µmol/L) was 12.4%, 6.4% and 21.2%, respectively, despite seemingly adequate B12 intakes (median 3.8 µg/day, 96% consumed more than the UK RNI of 1.5 µg/day). B12 concentrations increased across all quintiles of intake with serum levels in quintiles 4 and 5 (median intake 4.9 and 7.1 µg/day, respectively) significantly higher than quintile 1. However, Hcy concentrations levelled off between quintiles 4 and 5. Comparison of micronutrient intake between the two surveys found that folate intake has reduced in the more recent cohort. CONCLUSIONS: The UK RNI for B12 intake should be increased for women of childbearing age with intakes of around 5-7 µg/day likely to be associated with stable biomarker levels. B12 levels should also be measured in women preconceptionally or in early pregnancy given the high rates of deficiency.

Vitamin B12 Status among Pregnant Women in the UK and Its Association with Obesity and Gestational Diabetes.

BACKGROUND: To evaluate vitamin B12 and folate status in pregnancy and their relationship with maternal obesity, gestational diabetes mellitus (GDM), and offspring birthweight. METHODS: A retrospective case-control study of 344 women (143 GDM, 201 no-GDM) attending a district general hospital and that had B12 and folate levels measured in the early 3rd trimester was performed. Maternal history including early pregnancy body mass index (BMI) and neonatal data (birthweight, sex, and gestational age) was recorded for all subjects. RESULTS: 26% of the cohort had B12 levels <150 pmol/L (32% vs. 22% in the two groups respectively, p < 0.05) while 1.5% were folate deficient. After adjusting for confounders, 1st trimester BMI was negatively associated with 3rd trimester B12 levels. Women with B12 insufficiency had higher odds of obesity and GDM (aOR (95% CI) 2.40 (1.31, 4.40), p = 0.004, and 2.59 (1.35, 4.98), p = 0.004, respectively), although the latter was partly mediated by BMI. In women without GDM, the lowest quartile of B12 and highest quartile of folate had significantly higher adjusted risk of fetal macrosomia (RR 5.3 (1.26, 21.91), p = 0.02 and 4.99 (1.15, 21.62), p = 0.03 respectively). CONCLUSION: This is the first study from the UK to show that maternal B12 levels are associated with BMI, risk of GDM, and additionally may have an independent effect on macrosomia. Due to the increasing burden of maternal obesity and GDM, longitudinal studies with B12 measurements in early pregnancy are needed to explore this link.