Publications by authors named "Stephen Fava"

46 Publications

Adrenal insufficiency in HIV/AIDS: a review.

Expert Rev Endocrinol Metab 2021 Sep 14:1-12. Epub 2021 Sep 14.

Department of Diabetes, Endocrinology and General Medicine, Mater Dei Hospital, Msida, Malta.

Introduction: Adrenal insufficiency (AI) is one of the most common potentially life-threatening endocrine complications in people living with human immunodeficiency virus (PLHIV) infection and acquired immunodeficiency syndrome (AIDS).

Areas Covered: In this review, the authors explore the definitions of relative AI, primary AI, secondary AI and peripheral glucocorticoid resistance in PLHIV. It also focuses on the pathophysiology, etiology, diagnosis and management of this endocrinopathy in PLHIV. A literature review was conducted through Medline and Google Scholar search on the subject.

Expert Opinion: Physicians need to be aware of the endocrinological implications of HIV infection and its treatment, especially CYP3A4 enzyme inhibitors. A high index of clinical suspicion is needed in the detection of AI, especially in PLHIV, as it may present insidiously with nonspecific signs and symptoms and may be potentially life threatening if left untreated. Patients with overt primary and secondary AI require glucocorticoid replacement therapy. Overt primary AI also necessitates mineralocorticoid replacement. On the other hand, the management of relative AI remains controversial. In order to reduce the risk of adrenal crisis during periods of stress, the short-term use of glucocorticoids may be necessary in relative AI.
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http://dx.doi.org/10.1080/17446651.2021.1979393DOI Listing
September 2021

Para-adrenal schwannoma mimicking a giant adrenal lesion.

BMJ Case Rep 2021 Jul 20;14(7). Epub 2021 Jul 20.

Diabetes and Endocrinology, Mater Dei Hospital, Msida, Malta.

A 57-year-old man was incidentally diagnosed with a 7 cm left-sided retroperitoneal mass. The mass was presumed to be arising from the left adrenal gland on a CT scan of the adrenal glands. Thus, a thorough workup ensued, looking into the possible functionality of the lesion. All investigations resulted in the negative. Subsequently, the patient was referred for surgery to fully characterise the tumour. Histology proved that the lesion was a benign retroperitoneal schwannoma with no relation to the adrenal gland.
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http://dx.doi.org/10.1136/bcr-2021-243652DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292798PMC
July 2021

Pseudohyperkalaemia in essential thrombocytosis: an important clinical reminder.

Endocrinol Diabetes Metab Case Rep 2021 Apr 1;2021. Epub 2021 Apr 1.

Mater Dei Hospital of Malta, Department of Medicine, Msida, Malta.

Summary: An 82-year-old female was admitted to a general hospital due to progressive bilateral lower limb weakness. A T8-T9 extramedullary meningioma was diagnosed by MRI, and the patient was referred for excision of the tumour. During the patient's admission, she was noted to have persistent hyperkalaemia which was refractory to treatment. Following a review by an endocrinology team, a diagnosis of pseudohyperkalaemia secondary to thrombocytosis was made. This case demonstrates the importance of promptly identifying patients who are susceptible to pseudohyperkalaemia, in order to prevent its potentially serious consequences.

Learning Points: Pseudohyperkalaemia should be considered in patients with unexplained or asymptomatic hyperkalaemia. It should also be considered in those patients who are resistant to the classical treatment of hyperkalaemia. A diagnosis of pseudohyperkalaemia is considered when there is a difference of >0.4 mmol/L of potassium between serum and plasma potassium in the absence of symptoms and ECG changes. In patients who are presenting with consistently elevated serum potassium levels, it may be beneficial to take venous blood gas and/ or plasma potassium levels to rule out pseudohyperkalaemia. Pseudohyperkalaemia may subject patients to iatrogenic hypokalaemia which can be potentially fatal. Pseudohyperkalaemia can occur secondary to thrombocytosis, red cell haemolysis due to improper blood letting techniques, leukaemia and lymphoma.
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http://dx.doi.org/10.1530/EDM-21-0013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115417PMC
April 2021

Why is the Incidence of Type 1 Diabetes Increasing?

Curr Diabetes Rev 2021 ;17(8):3-15

Department of Medicine, University of Malta & Mater Dei Hospital, Tal-Qroqq, Msida, Malta.

Type 1 diabetes is a condition that can lead to serious long-term complications and can have significant psychological and quality of life implications. Its incidence is increasing in all parts of the world, but the reasons for this are incompletely understood. Genetic factors alone cannot explain such a rapid increase in incidence; therefore, environmental factors must be implicated. Lifestyle factors have been classically associated with type 2 diabetes. However, there are data implicating obesity and insulin resistance to type 1 diabetes as well (accelerator hypothesis). Cholesterol has also been shown to be correlated with the incidence of type 1 diabetes; this may be mediated by immunomodulatory effects of cholesterol. There is considerable interest in early life factors, including maternal diet, mode of delivery, infant feeding, childhood diet, microbial exposure (hygiene hypothesis), and use of anti-microbials in early childhood. Distance from the sea has recently been shown to be negatively correlated with the incidence of type 1 diabetes. This may contribute to the increasing incidence of type 1 diabetes since people are increasingly living closer to the sea. Postulated mediating mechanisms include hours of sunshine (and possibly vitamin D levels), mean temperature, dietary habits, and pollution. Ozone, polychlorinated biphenyls, phthalates, trichloroethylene, dioxin, heavy metals, bisphenol, nitrates/nitrites, and mercury are amongst the chemicals which may increase the risk of type 1 diabetes. Another area of research concerns the role of the skin and gut microbiome. The microbiome is affected by many of the factors mentioned above, including the mode of delivery, infant feeding, exposure to microbes, antibiotic use, and dietary habits. Research on the reasons why the incidence of type 1 diabetes is increasing not only sheds light on its pathogenesis but also offers insights into ways we can prevent type 1 diabetes.
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http://dx.doi.org/10.2174/1573399817666210503133747DOI Listing
September 2021

Amiodarone-induced type 2 thyrotoxicosis.

BMJ Case Rep 2021 Jan 8;14(1). Epub 2021 Jan 8.

Department of Diabetes and Endocrinology, Mater Dei Hospital, Msida, Malta.

The authors present a case of a 55-year-old gentleman with a medical history of atrial fibrillation on amiodarone who presented with weight loss, palpitations and exertional dyspnoea. Thyroid function tests revealed thyrotoxicosis with a free thyroxine (T4) of 117 pmol/L and a thyroid-stimulating hormone (TSH) of <0.008 mIU/L. Interleukin-6 level was low. The negative TSH-receptor antibody status, the presence of a small thyroid gland with heterogeneous echotexture and decreased internal vascularity on ultrasound together with the relatively quick drop in free T4 and free tri-iodothyronine (T3) levels once prednisolone therapy was added to carbimazole suggested that this was typical of amiodarone-induced thyrotoxicosis (AIT) type 2. Subsequently, carbimazole was discontinued and treatment with prednisolone was continued. This case highlights that AIT management may be challenging and it is of paramount importance to establish the type of AIT present as this will guide management and is key to improving prognosis.
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http://dx.doi.org/10.1136/bcr-2020-238145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798414PMC
January 2021

A case of severe relapsing sulphonylurea-induced hypoglycaemia.

BMJ Case Rep 2019 Dec 2;12(12). Epub 2019 Dec 2.

Department of Diabetes and Endocrinology, Mater Dei Hospital, Msida, Malta.

The authors report a case of a 64-year-old woman who was diagnosed with severe relapsing sulphonylurea-induced hypoglycaemia. Sulphonylureas are frequently used in patients with type 2 diabetes mellitus. They promote insulin secretion independent of the prevailing glucose level and thus are associated with an increased risk of hypoglycaemia. In patients with adequate renal function, gliclazide's effect lasts 10-24 hours and it is usually completely eliminated within 144 hours postdose. Since our patient suffered from chronic kidney disease, gliclazide's effect was prolonged and she was experiencing spontaneous hypoglycaemic episodes up to 21 days postomission of gliclazide. This case highlights two important aspects. Primarily, the prolonged effect of sulphonylureas in patients with impaired renal function, hence highlighting the need to be cautious prior to prescribing sulphonylureas in such patients. Secondly, the importance of prolonged observation of patients on sulphonylureas even after the initial hypoglycaemic event is corrected, due to the extended effects of such drugs.
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http://dx.doi.org/10.1136/bcr-2019-231368DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7001685PMC
December 2019

Obesity and cardio-metabolic health.

Br J Hosp Med (Lond) 2019 08;80(8):466-471

Professor, Department of Medicine, University of Malta and Mater Dei Hospital, Msida, MSD2090, Malta.

Obesity is a major and growing global health problem. It is associated with increased mortality as a result of an increasing number of complications, including type 2 diabetes, dyslipidaemia, hypertension, non-alcoholic hepatic steatosis, cardiovascular disease, sleep apnoea, gallbladder disease, obesity-related renal disease, increased risk of falls and injuries, and mental health problems as well as increased risk of certain malignancies. This article discusses the metabolic derangements associated with obesity. These include insulin resistance, dysglycaemia, low and dysfunctional high-density lipoprotein, formation of small dense and oxidised low-density lipoprotein, and high circulating levels of free fatty acids. This article reviews the aetiology of these derangements and their relationship to cardiovascular disease, and discusses the concept of metabolic health.
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http://dx.doi.org/10.12968/hmed.2019.80.8.466DOI Listing
August 2019

Gestational Glycemic Parameters and Future Cardiometabolic Risk at Medium-Term Follow Up.

Can J Diabetes 2019 Dec 27;43(8):621-626. Epub 2019 Mar 27.

Mater Dei Hospital, Msida, Malta; University of Malta Medical School, Msida, Malta. Electronic address:

Objectives: Gestational diabetes is known to be associated with increased risk for future maternal cardiovascular disease. However, it is not known which gestational glycemic parameters mediate this risk. The study's aim was to assess the relationship between gestational glycemic parameters and gestational diabetes with future cardiometabolic status.

Methods: This cohort study comprised subjects who underwent assessment for gestational diabetes by means of a 75 g oral glucose tolerance test at Mater Dei Hospital, Malta, during 2009. These patients were consequently followed up through January 2018. Carotid intima-media thickness was assessed as a marker of subclinical atherosclerosis in both common carotid arteries.

Results: The mean age of the study population was 38.3±5.4 years. Of the 203 participants, 43 (21.2%) had gestational diabetes. Gestational diabetes and individual glycemic parameters of intrapregnancy oral glucose tolerance tests were associated with higher glycated hemoglobin, fasting plasma glucose, low-density-cholesterol and lower high-density-cholesterol levels and with the presence of the metabolic syndrome in both univariate and multivariate analyses after a median follow up of 8 years. Neither gestational diabetes nor individual glycemic parameters of intrapregnancy oral glucose tolerance tests was associated with current carotid intima-media thickness.

Conclusions: Our results suggest that there is no threshold of glycemic parameters for predicting future cardiometabolic status. Our data also suggest that the known association between gestational diabetes and cardiovascular disease is mediated, at least in part, by higher postpregnancy glycemia and worse lipid profiles, even though these metabolic parameters often remain within the normal range.
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http://dx.doi.org/10.1016/j.jcjd.2019.03.007DOI Listing
December 2019

Identification of an p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family.

Clin Med Insights Case Rep 2019 20;12:1179547619831034. Epub 2019 Feb 20.

Department of Medicine, Mater Dei Hospital, Msida, Malta.

The diagnosis of maturity onset diabetes of the young (MODY) is a challenging process in view of the extensive clinical and genetic heterogeneity of the disease. Mutations in the gene encoding hepatocyte nuclear factor 1α () are responsible for most forms of monogenic diabetes in Northern European populations. Genetic analysis through a combination of whole exome sequencing and Sanger sequencing in three Maltese siblings and their father identified a rare duplication/frameshift mutation in exon 4 of that lies within a known mutational hotspot in this gene. In this report, we provide the first description of an -MODY3 phenotype in a Maltese family. The findings reported are relevant and new to a regional population, where the epidemiology of atypical diabetes has never been studied before. This report is of clinical interest as it highlights how monogenic diabetes can be misdiagnosed as either type 1, type 2, or gestational diabetes. It also reinforces the need for a better characterisation of monogenic diabetes in Mediterranean countries, particularly in island populations such as Malta with a high prevalence of diabetes.
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http://dx.doi.org/10.1177/1179547619831034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6383084PMC
February 2019

Benefits and risks of testosterone therapy in older men.

Minerva Urol Nefrol 2019 Jun 28;71(3):217-229. Epub 2019 Jan 28.

Diabetes and Endocrine Center, Mater Dei Hospital, Msida, Malta -

Adult-onset hypogonadism is used to define androgen deficiency and its associated symptoms commonly occurring in middle-aged and elderly men, who are unable to mount an adequate compensatory gonadotropin response but may also have an element of testicular failure. It often occurs in relation with chronic metabolic conditions such as diabetes and the metabolic syndrome. There is a growing demand from elderly men for testosterone therapy. The physician should therefore be well-informed so as the patient can make an informed decision. Indeed, testosterone therapy in older men has been a matter of debate, especially with regard to its impact on cardiovascular events and mortality. Not all studies have reported consistent results regarding its effect on diabetes, obesity and the metabolic syndrome. In contrast, it appears to improve sexual, physical function and bone density and it does not appear to increase the risk of prostate cancer; however, it increases hematocrit and hemoglobin levels. Therefore, testosterone therapy might provide significant beneficial effects in older symptomatic hypogonadal men; treatment should be individualized, and comorbidities addressed. Further research is required into its long-term effects.
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http://dx.doi.org/10.23736/S0393-2249.19.03301-0DOI Listing
June 2019

Food consumption and the risk of childhood allergy.

Asia Pac Allergy 2018 Oct 16;8(4):e35. Epub 2018 Oct 16.

Department of Medicine, Mater Dei Hospital, Msida, Malta.

Background: The prevalence of allergic conditions is increasing in most countries. One possible explanation may be childhood nutrition.

Objective: The aim of the study was to investigate the relationship between consumption of pre-specified types of food in school-aged children and presence of respiratory and allergic symptoms.

Methods: A total of 191 students aged 9-11 years were recruited from 5 schools to geographically cover all of Malta. Data was collected between October 2011 and February 2012. This was part of a bigger study which included clinical and environmental tests besides standardized health questionnaires. For the purposes of this part of the study only the health questionnaires were used. These standardized health questionnaires based on the International Study of Asthma and Allergies in Childhood (ISAAC) were used to identify the presence of respiratory and allergic symptoms and to identify the types of foods and the frequency of consumption of various types of foods.

Results: We found that milk, meat, butter, olive oil, and yoghurt consumption had a negative association with allergic symptoms in children, whilst fish consumption had a detrimental effect. These relationships remained significant after correction for paternal level of education.

Conclusion: The study highlights the fact that nutrition in early childhood may have a significant effect on the risk of allergic conditions. Our results, taken together with data in the literature, suggest that different types of fish might have had different effects. This is probably related to their different fatty acid constitution thus warranting further studies.
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http://dx.doi.org/10.5415/apallergy.2018.8.e35DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209597PMC
October 2018

All-cause mortality in patients on sulphonylurea monotherapy compared to metformin monotherapy in a nation-wide cohort.

Diabetes Res Clin Pract 2019 Jan 30;147:62-66. Epub 2018 Oct 30.

Diabetes & Endocrine Centre, Mater Dei Hospital, Malta; University of Malta, Malta. Electronic address:

Background: Type 2 diabetes is associated with increased mortality. There is some data that sulphonylurea therapy may contribute to this.

Aims: To compare all-cause 3-year mortality of patients on sulphonylurea monotherapy to that of patients on metformin monotherapy after adjusting for potential confounders.

Methods: We searched the Maltese national electronic database for diabetes treatment in April 2014. This is an electronic database of all treatment that patients are prescribed through the local National Health Service. We identified patients on metformin or sulphonylurea monotherapy and linked this to the national mortality database and the laboratory information system.

Results: There were 25,792 persons who were on treatment for diabetes in April 2014. Of these, 9977 were on metformin monotherapy and 1717 on sulphonylurea monotherapy. This cohort was followed up until April 2017. There were 2518 deaths (9.76%) during this period, giving an average of 32.5 deaths per 1000 persons with diabetes. Logistic regression showed that persons on sulphonylurea monotherapy were 2.03 (95% CI 1.68-2.44, p < .001) times more likely to die within 3 years than persons on metformin monotherapy, after adjusting for age, eGFR and HbA1c. The logistic regression model was statistically significant, p < .001. Additional adjustment for LDL-cholesterol, HDL-cholesterol and urinary albumin-creatinine ratio did not alter the results.

Conclusion: Our data shows that sulphonylurea monotherapy is associated with higher all-cause mortality when compared to metformin monotherapy after adjusting for potential confounders.
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http://dx.doi.org/10.1016/j.diabres.2018.10.014DOI Listing
January 2019

Incidence of type 1 diabetes and distance from the sea: A descriptive epidemiological study.

J Diabetes 2019 May 4;11(5):345-347. Epub 2018 Nov 4.

University of Malta, Msida, Malta.

Background: Increasingly, environmental factors are being shown to play a role in the etiology of type 1 diabetes (T1D). One geographical feature that exerts a major effect on climate but whose relationship with T1D incidence has not been studied is distance from the sea. This study investigated any possible relationship between distance from the sea and the incidence of T1D.

Methods: Spearman correlation analysis was performed to investigate the relationship between the incidence of T1D (determined using data from the DiaMond Project) and distance from the sea. This was followed by multivariate analyses to adjust for potential cofounders.

Results: A significant negative association was found between T1D incidence and shortest distance from sea (r = -0.251, P = 0.01235), mean hours of sunshine (r = -0.325, P = 0.002), and mean temperature (r = -0.224, P = 0.046), and a positive association was found between T1D incidence and latitude (r = 0.434, P = 0.0001). Multivariate analysis (generalized linear model) showed that both distance from the sea and latitude were independently associated with the incidence of T1D. The association of distance from sea and the incidence of T1D remained significant even after adjusting for mean temperature (P = 0.002) and mean hours of sunshine (P = 0.005).

Conclusions: The data show that there is a negative correlation between distance from the sea and the incidence of T1D, which was independent of latitude, mean temperature, and mean hours of sunshine. This suggests that environmental factors associated with climatic conditions may influence the risk of T1D.
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http://dx.doi.org/10.1111/1753-0407.12862DOI Listing
May 2019

Relationship of Hyperglycaemia, Hypoglycaemia, and Glucose Variability to Atherosclerotic Disease in Type 2 Diabetes.

J Diabetes Res 2018 22;2018:7464320. Epub 2018 Jul 22.

Mater Dei Hospital and University of Malta, Msida, Malta.

Objective: Type 2 diabetes mellitus (T2DM) is known to be associated with increased cardiovascular risk. The aim of this study was therefore to investigate the independent effects of hyperglycaemia, hypoglycaemia, and glucose variability on microvascular and macrovascular disease in T2DM.

Methods: Subjects with T2DM of <10 years duration and on stable antiglycaemic treatment underwent carotid intima-media thickness (CIMT), ankle-brachial index (ABI), albumin-creatinine ratio (ACR), and HbA measurement, as well as 72-hour continuous glucose monitoring. Macrovascular disease was defined as one or more of the following: history of ischaemic heart disease (IHD), cerebrovascular accident (CVA), ABI < 0.9, or abnormal CIMT.

Results: The study population comprised 121 subjects with T2DM (89 males : 32 females). The mean age was 62.6 years, and the mean DM duration was 3.7 years. Macrovascular disease was present in 71 patients (58.7%). In multivariate logistic regression analysis, body surface area (BSA) (OR 18.88 (95% CI 2.20-156.69), = 0.006) and duration of blood glucose (BG) < 3.9 mmol/L (OR 1.12 (95% CI 1.014-1.228), = 0.024) were independent predictors of macrovascular disease. BSA (OR 12.6 (95% CI 1.70-93.54), = 0.013) and duration of BG < 3.9 mmol/L (OR 1.09 (95% CI 1.003-1.187), = 0.041) were independent predictors of abnormal CIMT. Area under the curve for BG > 7.8 mmol/L ( = 15.83, = 0.005) was the sole independent predictor of albuminuria in generalised linear regression.

Conclusions: This study demonstrates that hypoglycaemia is associated with the occurrence of atherosclerotic disease while hyperglycaemia is associated with microvascular disease in a Caucasian population with T2DM of recent duration.
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http://dx.doi.org/10.1155/2018/7464320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081537PMC
December 2018

Predictors and generation of risk equations for albuminuria progression in type 2 diabetes.

Clin Nephrol 2017 Jul;88(1):33-39

Diabetes & Endocrine Centre, Mater Dei Hospital, and University of Malta, Msida, Malta.

Background: Diabetes is the most common cause of end-stage renal disease and is associated with increased mortality. Although only a proportion of type 2 diabetic subjects develop albuminuria or progress, it is not currently possible to identify those patients who will develop this complication or who will progress.

Aim: The aim of the study was to identify baseline risk factors for the development and progression of albuminuria in a cohort with type 2 diabetes and use this data to generate risk equations.

Patients And Methods: Type 2 diabetic subjects who had albumin-creatinine ratio (ACR) measurement in 2007 - 2008 were recruited and followed-up for 8 years.

Results: 260 patients were included in the study. Of all the normoalbuminuric and microalbuminuric patients, 24.3% progressed. Baseline HbA1c, white cell count (WCC), smoking, and duration of diabetes were associated with progression of albuminuria stage in univariate analysis. Duration of diabetes (p = 0.034) was independently associated with progression in binary logistic regression. Baseline HbA1c (p = 0.002), age (p = 0.01), serum creatinine (p = 0.02), serum potassium (p = 0.04), serum urea (p = 0.0004), WCC (p = 0.02), serum triglycerides (p = 0.02), systolic blood pressure (p = 0.02), and duration of diabetes (p = 0.003) were positively correlated with percentage change (% change) in ACR, whilst baseline estimated glomerular filtration rate (eGFR) (p = 0.03), serum sodium (p = 0.04), hemoglobin (p = 0.0006), and hematocrit (p = 0.0002) were negatively correlated in Spearman correlation. Duration of diabetes (p = 0.025) and baseline HbA1c (p = 0.02) were independently associated with % change in ACR in multivariate analysis. Based on these results, novel risk equations were generated.

Conclusions: We have identified baseline characteristics associated with progression of renal disease in type 2 diabetic subjects and generated equations to estimate the risk of progression. If validated in other populations, these equations might be useful in predicting risk of progression in clinical practice.
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http://dx.doi.org/10.5414/CN109010DOI Listing
July 2017

Red blood cell distribution width and myocardial scar burden in coronary artery disease.

Postgrad Med J 2017 Oct 10;93(1104):607-612. Epub 2017 May 10.

University of Malta Medical School, University of Malta, Tal-Qroqq, Msida, Malta.

Introduction: Red blood cell distribution width (RDW) is a novel independent marker of cardiovascular disease including heart failure, coronary artery disease and myocardial ischaemia. The aim of the study was to investigate a possible relationship between RDW and myocardial scar burden, as assessed by a MIBI viability scan. A secondary objective was to assess whether there is an association between RDW and left ventricular ejection fraction (LVEF).

Methods: The study comprised 123 subjects with ischaemic heart disease who underwent a myocardial viability scan between June 2008 and July 2014. Haemoglobin, mean corpuscular volume, RDW, platelet count, mean platelet volume (MPV), estimated glomerular filtration rate, fasting blood glucose, liver and lipid profiles were evaluated for all patients. The extent of myocardial scarring and LVEF were noted. Data were analysed using IBM SPSS Statistics 22.0. Univariate followed by multivariate analyses were performed to assess for independent predictors of myocardial scarring and LVEF, respectively.

Results: The mean age of the study population was 63.5 years; most of the subjects were men. The median LVEF was 31% and median percentage of myocardial scarring was 8.7%. Multivariate analyses revealed that RDW, HDL-cholesterol and alanine transaminase were independent predictors of myocardial scarring while RDW, MPV, LDL-cholesterol and gamma-glutamyl transpeptidase were independent predictors of LVEF.

Conclusions: Increased RDW is an independent predictor both of myocardial scar burden and of impaired left ventricular function in subjects with coronary artery disease.
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http://dx.doi.org/10.1136/postgradmedj-2016-134781DOI Listing
October 2017

Seasonal Variation in the Peritoneal Dialysis-Related Infections: A Single Center Experience in the Mediterranean.

Ther Apher Dial 2016 Oct 15;20(5):501-506. Epub 2016 Sep 15.

Department of Medicine, Mater Dei Hospital, Malta.

Seasonal variation in the incidence of peritoneal dialysis-related infections (PDRI) has been sparingly investigated, especially in the Mediterranean. Our aim was to explore this association in Malta. All PDRI occurring between Jan-2008 and Dec-2012 were retrospectively studied.A total of 137 patients were followed-up for a median time of 32.5 months (range: 2-81). During this time, 19% never had PDRI, 11.7% transferred permanently to hemodialysis and 6.6% received a kidney transplant. A total of 279 PDRI were identified, equating to 145 catheter-related infections (CRI) and 144 peritonitis episodes (including 10 catheter related peritonitis). A spring peak in the overall gram positive PDRI (0.61 vs. 0.34/patient-year-at-risk, P=0.05), together with a peak in gram negative peritonitis in the warm period (0.13 vs. 0.07/patient-year at risk, P=0.04) was identified. The incidence rate ratios (Confidence Interval) involving the overall gram positive PDRI, gram positive peritonitis, coagulase-negative Streptococci (CoNS) and Streptococci were 1.82 (1.18-2.82, P=0.007), 2.20 (1.16-4.16, P=0.02), 2.65 (1.17-6.02, P=0.02] and 3.18 (1.03-9.98, P=0.04) in spring when compared to winter. No significant difference in the overall PDRI, peritonitis or CRI rates between seasons or warm/cold period was identified.To our knowledge, this is the first study which examines the effect of seasons on the incidence of PDRI in the Mediterranean basin. Findings suggest that spring confers a higher risk for gram positive PDRIs, gram positive peritonitis, CoNS and Streptococcus, whilst the warm period was associated with a peak in the gram negative peritonitis.
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http://dx.doi.org/10.1111/1744-9987.12416DOI Listing
October 2016

Association of cholesterol and lifestyle markers with type 1 diabetes incidence rates at a population level.

J Public Health (Oxf) 2017 09;39(3):542-548

Diabetes and Endocrine Centre, Mater Dei Hospital, Msida, MSD 2090, Malta.

Background: We investigated the hypotheses that mean population body mass index (BMI), systolic blood pressure (SBP), fasting plasma glucose (FPG), total cholesterol (TC) and the prevalence of type 2 diabetes (T2DM) are correlated with type 1 diabetes (T1DM) incidence rates.

Methods: Population-based mean incidence rates for T1DM in children aged ≤14 years participating in the World Health Organization Diabetes Mondial (DiaMond) project were compared with population mean values for BMI, SBP, TC and FPG, as well as prevalence rates for T2DM as reported by The Global Burden of Metabolic Risk Factors Chronic Diseases Collaborating Group, using Spearman's rank correlation and multiple regression analysis.

Results: The mean incidence rate for T1DM in boys was significantly correlated with country mean BMI, SBP and TC in men and mean TC in women, and negatively correlated with the country incidence of T2DM in either gender. We also found significant correlations between mean incidence rates of T1DM in girls and mean BMI, SBP and TC in men and mean TC in women. In multiple regression analyses, mean TC emerged as the sole significant predictor for T1DM in both boys (P < 0.001, adjusted R2 = 0.393) and girls (P < 0.001, adjusted R2 = 0.372).

Conclusion: Population mean total cholesterol is a significant predictor for country incidence of type 1 diabetes in both boys and girls. This association may fuel the rising incidence rates of type 1 diabetes reported in many countries.
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http://dx.doi.org/10.1093/pubmed/fdw081DOI Listing
September 2017

Prognostic indicators and generation of novel risk equations for estimation of 10-year and 20-year mortality following acute coronary syndrome.

Postgrad Med J 2017 May 19;93(1099):245-249. Epub 2016 Aug 19.

University of Malta Medical School, Mater Dei Hospital, Msida, Malta.

Objectives: Although risk assessment is an integral part of management, there are currently no risk calculators of long-term mortality after acute coronary syndrome (ACS). The aim was to provide risk equations for 10-year and 20-year mortality following ACS.

Methods: Patients hospitalised with ACS from December 1990 to June 1994 were recruited and followed up through 31 December 2012.

Results: The study followed 881 patients for 10 years and 712 patients for 20 years. Using Cox regression analysis, 20-year all-cause mortality was associated with myocardial infarction (MI) in the index admission, age and diabetes mellitus (DM). Twenty-year cardiovascular disease (CVD) and cardiac mortality were both associated with MI in the index admission, age, DM and female gender. 10-year all-cause mortality was associated with age and total cholesterol levels; age, DM and total cholesterol levels were found to be independent predictors of 10-year CVD and cardiac mortality. Risk equations were consequently generated for 10-year and 20-year cardiac, cardiovascular and all-cause mortality, with age and DM emerging as the strongest and most consistent predictors of all outcomes studied.

Conclusions: Novel risk equations for all-cause, cardiovascular and cardiac mortality at 10 and 20 years were generated using follow-up data in a large patient population.
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http://dx.doi.org/10.1136/postgradmedj-2016-134129DOI Listing
May 2017

Nephrolithiasis, stone composition, meteorology, and seasons in Malta: Is there any connection?

Urol Ann 2016 Jul-Sep;8(3):325-32

Department of Medicine, Mater Dei Hospital, L-Imsida, Malta.

Context: The effect of seasons and meteorology on the incidence of nephrolithiasis has been studied in various regions around the globe, but seldom in the Mediterranean.

Aims: This retrospective analysis aims at investigating these putative effects in the Maltese Islands, whose climate is typically Mediterranean, followed by a systematic review of the literature.

Materials And Methods: Submission rate and chemical composition of all kidney stones after spontaneous passage or surgical removal between January 2009 and December 2011 were analyzed according to seasons and corresponding meteorology.

Results: A total of 389 stones were analyzed. A higher stone submission rate was observed in summer compared to winter (31.6% vs. 20.8%, P = 0.0008) and in the warm period compared to the cold period (57.1% vs. 42.9%, P = 0.0001). Significant correlation was established between the monthly number of stones and mean monthly maximum temperature (r = 0.50, P = 0.002), mean monthly temperature (r = 0.49, P = 0.003) and mean monthly Humidex (r = 0.49, P = 0.007). Humidex was found to be an independent predictor for stone submission (β = 0.49, P = 0.007). The majority of stones contained calcium (83.3%), combined with oxalate (77.6%), phosphate (14.7%), and carbonate (2.8%). Some stones (11.8%) contained a mixture of >1 negatively charged molecules. Urate (11.6%), cysteine (4.6%), and ammonium-magnesium-phosphate (0.5%) constituted the rest. There was no association between chemical composition and seasons. Literature review included 25 articles. Higher ambient temperature and warm seasons were the most commonly encountered risk factors for both presentation and etiology of nephrolithiasis.

Conclusions: A significant positive correlation was noted between ambient temperature and stone submission rate, which was significantly higher during the warm months in Malta.
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http://dx.doi.org/10.4103/0974-7796.184892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4944626PMC
July 2016

Prediction of insulin resistance in type 2 diabetes mellitus using routinely available clinical parameters.

Diabetes Metab Syndr 2016 Apr-Jun;10(2 Suppl 1):S96-S101. Epub 2016 Mar 28.

University of Malta Medical School, University of Malta, Tal-Qroqq, Msida MSD 2090, Malta; Department of Cardiac Services, Mater Dei Hospital, Tal-Qroqq, Msida MSD 2090, Malta.

Aims: To determine if insulin resistance (IR), an important predictor of cardiovascular risk in the general population and in type 2 diabetes mellitus, can be assessed using simple parameters which are readily available in clinical practice.

Methods: This cross-sectional study included 194 patients with type 2 diabetes. Body mass index, waist index (WI), triglyceride levels, 1/HDL, triglyceride/HDL, uric acid and urine albumin:creatinine ratio were investigated as possible predictors of IR.

Results: WI correlated more strongly than any other parameter with log insulin levels, log fasting glucose to insulin ratio (FGIR), log fasting glucose to insulin product (FGIP), homeostatic model assessment (HOMA-IR) and quantitative insulin check index (QUICKI). WI also emerged as the strongest independent predictor of IR indices studied in regression as well as in ROC analyses. At a cut-off of 1.115, WI had a 78% sensitivity and 65% specificity for predicting IR when HOMA-IR was used as indicator of IR, and 74% sensitivity and specificity when QUICKI was used as indicator of IR. Combining WI with other variables did not improve performance significantly.

Conclusions: In our cohort of patients with type 2 diabetes, WI was the parameter with the strongest association with, and the best predictor of, IR.
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http://dx.doi.org/10.1016/j.dsx.2016.03.002DOI Listing
February 2017

Bone mineral density and intervertebral disc height in type 2 diabetes.

J Diabetes Complications 2016 May-Jun;30(4):644-50. Epub 2016 Jan 29.

Diabetes and Endocrine Centre, Mater Dei Hospital, Msida, Malta. Electronic address:

Background: Studies of the effect of type 2 diabetes (T2D) on bone mineral density (BMD have produced conflicting results, possibly due to failure to adjust for potential confounding factors. Nonetheless, T2D has consistently been associated with increased fracture risk, suggesting that other factors might play a role.

Objective: This study assesses the relationship between T2D and BMD at the femoral neck and spine in diabetic and non-diabetic subjects, after adjusting for multiple covariates which may affect BMD. Intervertebral disc height was also investigated in view of its possible relation to fracture risk.

Methods: A cross-sectional study of 100 patients with T2DM of at least 5 years duration and 86 non-diabetic subjects was carried out.

Results: There were no significant differences in T scores in either the spine or femoral neck after adjustment for potential confounding variables between T2D subjects and controls. Diabetic patients had a statistically lower intervertebral disc height between the 2nd and 3rd lumbar vertebrae (D3) after adjustment for potential confounders (p=0.004). Urinary albumin:creatinine ratio, total cholesterol, LDL-cholesterol and cigarette smoking were independently associated with lower height of D3 in diabetic subjects.

Conclusions: There is no significant independent association between T2D and BMD. However we found a novel association of significantly lower disc height in patients with T2D. This may contribute to the increased vertebral fracture risk in subjects with T2D. Further studies are needed to investigate the relationship of disc height, T2D and fracture risk.
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http://dx.doi.org/10.1016/j.jdiacomp.2016.01.021DOI Listing
January 2017

Chronic kidney disease referral practices among non-nephrology specialists: A single-centre experience.

Eur J Intern Med 2016 Apr 19;29:93-7. Epub 2016 Jan 19.

Diabetes and Endocrine Department, Mater Dei Hospital, Msida, Malta. Electronic address:

Background: Early referral of CKD patients to nephrology teams (NT) is vital to identify patients most likely to progress, delay decline of excretory function, and provide planned RRT. Unfortunately, many are still being referred late.

Methods: We conducted a retrospective analysis to investigate referral rates, predictors of non-referral, and performed urine investigations in hospitalised CKD patients.

Results: Out of 388 patients studied, 5.6%, 11.4%, and 16.4% in CKD3A, 3B, and 4+5, respectively, were referred to an NT upon discharge (CKD3A vs. CKD4+5, p=0.016). For every additional year of age, the odds of being referred decreased by 5% (OR: 0.95, CI: 0.92-0.98, p=0.003). Patients were more likely to be referred to an NT if they were males (OR: 2.31, CI: 1.09-4.90, p=0.029) and having reached CKD 4+5 (OR: 3.99, CI: 1.58-10.10, p=0.003). Only 28.8%, 43.9%, and 50.7% of patients with CKD3A, 3B, and 4+5 were followed up with urine investigations after discharge (p=0.001). CKD stage 3B (OR: 3.54, CI: 1.23-10.19, p=0.019), CKD stage 4+5 (OR: 6.06, CI: 1.69-21.67, p=0.006), DM (OR: 6.28, CI: 2.38-16.58, p<0.0001), and having been referred to a NT (OR: 20.95, CI: 3.54-123.92, p=0.001) were independent predictors for having urine investigations.

Conclusion: The highest rate of referral was achieved in males, younger age group, and those who have reached CKD stage 4+5. Urine tests remain largely underutilised and only a minority (16.4%) of patients with an eGFR <30mL/min/1.73m(2) were referred to a NT.
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http://dx.doi.org/10.1016/j.ejim.2016.01.010DOI Listing
April 2016

Primary Bilateral Non-Hodgkin's Lymphoma of the Adrenal Gland Presenting as Incidental Adrenal Masses.

Case Rep Med 2015 22;2015:620381. Epub 2015 Nov 22.

Diabetes and Endocrine Centre, Mater Dei Hospital, Msida MSD 2090, Malta ; Department of Medicine, University of Malta Medical School, Msida MSD 2080, Malta.

Although lymphoma may occasionally involve the adrenal glands as part of a generalized disease process, primary adrenal lymphoma (PAL) is a rare disease. We present a case of a 62-year-old woman with a history of mild/moderate hereditary spherocytosis with a well-compensated baseline haemoglobin, who presented with rapidly progressive symptomatic anaemia. During the diagnostic workup, imaging revealed bilateral large adrenal masses and she was later diagnosed with diffuse large B-cell non-Hodgkin's lymphoma (DLBCL), with the adrenal glands being the dominant site of the disease. The patient was started on systemic chemotherapy, but her disease progressed with neurological involvement which responded to second-line therapy. Her adrenal disease however was refractory to further therapy.
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http://dx.doi.org/10.1155/2015/620381DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4670633PMC
December 2015

Association of prevalence of rhinitis, atopic eczema, rhinoconjunctivitis and wheezing with mortality from infectious diseases and with antibiotic susceptibility at a country level.

Asia Pac Allergy 2015 Jul 29;5(3):145-55. Epub 2015 Jul 29.

Department of Medicine, Mater Dei Hospital, Msida, MSD 2090, Malta. ; Faculty of Medicine and Surgery, University of Malta, Msida, MSD 2090, Malta.

Background: It was previously reported that there is a positive correlation between incidence of type 1 diabetes and prevalence of asthma and atopic eczema. A negative correlation between the prevalence of type 1 diabetes and mortality from infectious diseases as well as a positive correlation with antibiotic susceptibility at a country level have also been reported.

Objective: The aim of this study was to investigate the association between country prevalence of rhinitis, atopic eczema, rhinoconjunctivitis, and wheezing with mortality from infectious diseases and also with antibiotic susceptibility at a country level.

Methods: Data for prevalence of rhinitis, eczema, rhinoconjunctivitis, and wheezing was obtained from the International Study of Asthma and Allergies in Childhood study (ISAAC). ISAAC Phase one was a multicentre multicountry cross sectional study involving over 700,000 children in 2 age groups of school children, 13-14 years old (adolescents) and 6-7 years old (children) in 156 centres from 56 countries. Mortality from infectious diseases was taken from World Health Organisation data. The Alexander project was used to identify antibiotic susceptibilities to common bacteria.

Results: There were significant positive correlations between atopic eczema and mortality from all infectious diseases studied, diarrhoeal illness, tropical infections, and childhood infections. A negative correlation exists between the prevalence of rhinitis and Streptococcus pneumoniae susceptibility to penicillin and to erythromycin, rhinitis and Haemophilus influenzae susceptibility to ampicillin and between rhinoconjunctivitis and H. influenzae susceptibility to ampicillin.

Conclusion: Th1/Th2 responses might influence the pathogenesis of infectious disease mortality, while antibiotic overprescription could explain the negative association between atopy and antibiotic susceptibility.
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http://dx.doi.org/10.5415/apallergy.2015.5.3.145DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4521163PMC
July 2015

Peripartum cardiomyopathy.

Br J Hosp Med (Lond) 2015 Feb;76(2):95-100

Foundation Year Doctor in the Department of Internal Medicine, Mater Dei Hospital, Tal-Qroqq, Msida MSD 2090, Malta.

Peripartum cardiomyopathy is a form of dilated cardiomyopathy of indeterminate aetiology occurring in late pregnancy or the months following delivery. This article reviews current knowledge of its pathophysiology, therapeutic strategies and prognosis, as well as new treatments and future directions.
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http://dx.doi.org/10.12968/hmed.2015.76.2.95DOI Listing
February 2015

Glucagon-like peptide 1 and the cardiovascular system.

Authors:
Stephen Fava

Curr Diabetes Rev 2014 ;10(5):302-10

Head, Diabetes & Endocrine Centre, Mater Dei, University of Malta, Malta.

Glucagon-like peptide 1 (GLP1) is a major incretin hormone. This means that it is secreted by the gut in response to food and helps in reducing post-prandial glucose exertion. It achieves this through a number of mechanisms, including stimulating insulin release by pancreatic β-cells in a glucose-dependent manner; inhibition of glucagon release by pancreatic α-cells (also in a glucose-dependent manner); induction of central appetite suppression and by delaying gastric empting thereby inducing satiety and also reducing the rate of absorption of nutrients. However, GLP1 receptors have been described in a number of extra-pancreatic tissues, including the endothelium and the myocardium. This suggests that the physiological effects of GLP1 extend beyond post-prandial glucose control and raises the possibility that GLP1 might have cardiovascular effects. This is of importance in our understanding of incretin hormone physiology and especially because of the possible implications that it might have with regard to cardiovascular effects of incretin-based therapies, namely DPP-IV inhibitors (gliptins) and GLP1 analogues. This review analyzes the animal and human data on the effects of GLP1 on the cardiovascular system in health and in disease and the currently available data on cardiovascular effects of incretin-based therapies. It is the author's view that the physiological role of GLP1 is not only to minimize postprandial hypoglycaemia, but also protect against it.
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http://dx.doi.org/10.2174/1573399810666141030125830DOI Listing
August 2015

Non-dipping heart rate and microalbuminuria in type 2 diabetes mellitus.

Cardiology 2014 25;129(1):28-35. Epub 2014 Jun 25.

Department of Cardiac Services, Mater Dei Hospital, Msida, Malta.

Objectives: The aim of this study was to identify factors which are independently associated with non-dipping heart rate (HR) in a type 2 diabetic population at high risk of cardiovascular disease.

Methods: The study recruited 179 type 2 diabetic subjects with a mean diabetes duration of 18.3 years and with proliferative retinopathy. All underwent 24-hour blood pressure and HR monitoring, and were assessed for markers of inflammation, insulin resistance, albuminuria, presence of peripheral neuropathy and peripheral vascular disease. Subjects whose night-time HR did not decrease by more than 10% as compared to daytime readings were classified as non-dippers.

Results: Univariate analysis revealed that non-dippers had significantly higher logarithmic albumin-creatinine ratio (ACR; p = 0.001) and higher platelet count (p = 0.014). Also, non-dippers were more likely to be on β-blockers (p = 0.037). Binary logistic regression analysis showed that logarithmic ACR (p = 0.001) and platelet count (p = 0.026) were independent predictors of non-dipping HR, even when correcting for β-blocker use.

Conclusions: In this high-risk type 2 diabetic population, non-dipping HR was independently associated with ACR and platelet count, suggesting that non-dipping HR might give an indication of underlying generalised atherosclerosis in diabetic patients. Also, non-dipping HR may represent a novel mechanism explaining the association of nephropathy with cardiovascular events. This merits further study.
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http://dx.doi.org/10.1159/000362714DOI Listing
May 2015

Diabetic renal disease.

Int J Endocrinol 2014 7;2014:598015. Epub 2014 Apr 7.

NHS Lothian, University of Edinburgh, Scotland, UK.

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http://dx.doi.org/10.1155/2014/598015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3997849PMC
May 2014

Glycaemic control: a balancing act or a different approach?

Authors:
Stephen Fava

Curr Diabetes Rev 2014 Mar;10(2):124-30

Diabetes & Endocrine Centre, Mater Dei Hospital, Msida MSD2090, Malta.

The prevalence of diabetes is increasing world-wide. Tight glycaemic control has been shown to reduce diabetes complications in a number of landmark trials. Apart from increasing the risk of microvascular and macrovascular disease, poor glycaemic control is also associated with cognitive and memory impairment as well as with mood disturbance. However, tighter glycaemic control with conventional anti-hyperglycaemic medication is also associated with increased risk of hypoglycaemia. There is increasing evidence that hypoglycaemia is much more than a troublesome inconvenience. Indeed it is associated with acute cognitive impairment, dementia, increased risk of falls, rebound hyperglycaemia with consequent loss of glycaemic control, acute coronary syndrome and increased mortality. Hence, a very difficult balance needs to be achieved so as to achieve the best glycaemic control possible, whilst avoiding hypoglycaemia. This paper will briefly discuss the potential benefits of tight glycemic control and reviews the risks associated with hypoglycaemia. A paradigm shift in diabetes care may be needed; use of newer anti-hyperglycemic agents with low hypoglycaemia risk may allow us to achieve good control in most patients whilst avoiding the serious consequences of hypoglycaemia. This may be especially important in those at significant risk of hypoglycaemia (e.g. those with brittle diabetes) or of its consequences such as elderly patients, those in certain occupations or those with cardiovascular disease or epilepsy.
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http://dx.doi.org/10.2174/1573399810666140421124051DOI Listing
March 2014
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