Metabolic Dysfunction-associated Fatty Liver Disease: An Urgent Call for Global Action.

There has been an exponential increase in the global prevalence of fatty liver disease in recent years in association with the obesity pandemic worldwide. 'Metabolic dysfunction-associated fatty liver disease', the new terminology adopted by an international panel of experts in 2020 to largely replace the old term 'non-alcoholic fatty liver disease', has now been accepted by most hepatologists and diabetologists across the globe. The term metabolic dysfunction-associated fatty liver disease was created to better reflect the metabolicand liver-specific manifestations and complications of fatty liver disease. It is important to disseminate our current understanding of this enigmatic disease among the global scientific fraternity. Recent publications, including articles from the latest issue of Endocrinology & Metabolism Clinics of North America, are attempting to fill this knowledge gap.

Metabolic Dysfunction-Associated Fatty Liver Disease and Chronic Viral Hepatitis: The Interlink.

Metabolic dysfunction-associated fatty liver disease (MAFLD) has now affected nearly one-third of the global population and has become the number one cause of chronic liver disease in the world because of the obesity pandemic. Chronic hepatitis resulting from hepatitis B virus (HBV) and hepatitis C virus (HCV) remain significant challenges to liver health even in the 21st century. The co-existence of MAFLD and chronic viral hepatitis can markedly alter the disease course of individual diseases and can complicate the management of each of these disorders. A thorough understanding of the pathobiological interactions between MAFLD and these two chronic viral infections is crucial for appropriately managing these patients. In this comprehensive clinical review, we discuss the various mechanisms of chronic viral hepatitis-mediated metabolic dysfunction and the impact of MAFLD on the progression of liver disease.

Endocrine Hypertension: The Urgent Need for Greater Global Awareness.

Hypertension affects about 1.28 billion adults globally, and significantly increases the risk of chronic morbidity and mortality among sufferers. About 15% of these individuals have secondary hypertension, the majority of whom have dysfunction of one or more endocrine systems as the cause of hypertension. Although adrenal disorders are often identified as the cause of endocrine hypertension, extra-adrenal disease and pituitary disorders also can cause the disease. Timely diagnosis is of paramount importance, because of the potential for a surgical cure or optimal disease control with pharmacotherapy to prevent hypertensive complications. Even with its relatively high prevalence compared with many other chronic illnesses, the diagnosis of endocrine hypertension is often delayed or never made because of poor awareness about the disease among physicians. This review attempts to provide an overview of the disease, with some practical aspects of diagnosis and management of a few of the important disorders causing endocrine hypertension.

Pregnancy and Metabolic-associated Fatty Liver Disease: A Clinical Update.

The intricate relationship between metabolic-associated fatty liver disease (MAFLD) and maternal complications has rapidly become a significant health threat in pregnant women. The presence of MAFLD in pregnancy increases the maternal risk of metabolic complications and comorbidities for both mother and baby. The preexistence or development of MAFLD in pregnancy is a complex multifactorial disorder that can lead to further complications for mother and baby. Therefore, as pregnant women are severely underrepresented in clinical research, there is a great need for a fair inclusion of this group in clinical trials. This review aims to explore the effects of MAFLD during pregnancy in the context of maternal complications and outcomes and explore the effects of pregnancy on the development and progression of MAFLD within the context of maternal obesity, altered metabolic profiles, gestational diabetes and altered hormonal profiles. We also addressed potential implications for the presence of MAFLD during pregnancy and its management in the clinical setting.

Diagnostic Test Accuracy of Urine C-peptide Creatinine Ratio for the Correct Identification of the Type of Diabetes: A Systematic Review.

Objective: To examine the accuracy of urine c-peptide creatinine ratio (UCPCR) for identifying the type of diabetes in appropriate clinical settings. Design: Systematic review of test accuracy studies on patients with different forms of diabetes. Data sources: Medline, Embase and Cochrane library databases from 1 January 2000 to 15 November 2020. Eligibility criteria: Studies reporting the use of UCPCR for diagnosing patients with type 1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM) and monogenic forms of diabetes (categorized as maturity-onset diabetes of the young [MODY]). Study selection and data synthesis: Two reviewers independently assessed articles for inclusion and assessed the methodological quality of the studies using the Quality Assessment of Diagnostic Accuracy Studies-2 tool, with input from a third reviewer to reach consensus when there was a dispute. Meta-analysis was performed with the studies reporting complete data to derive the pooled sensitivity, specificity and diagnostic odds ratio (DOR), and narrative synthesis only for those with incomplete data. Results: Nine studies with 4,488 patients were included in the qualitative synthesis, while only four of these (915 patients) had complete data and were included in the quantitative synthesis. All the studies had moderate risk of bias and applicability concerns. Meta-analysis of three studies (n=130) revealed sensitivity, specificity and DOR of 84.4% (95% confidence interval [CI] 68.1-93.2%), 91.6% (82.8-96.1%) and 59.9 (32.8-106.0), respectively, for diagnosing T1DM using a UCPCR cut-off of <0.2 nmol/mmol. For participants with T2DM (three studies; n=739), UCPCR >0.2 nmol/mmol was associated with sensitivity, specificity and DOR of 92.8% (84.2-96.9%), 81.6% (61.3-92.5%) and 56.9 (31.3-103.5), respectively. For patients with MODY in the appropriate clinical setting, a UCPCR cut-off of >0.2 nmol/mmol showed sensitivity, specificity and DOR of 85.2% (73.1-92.4%), 98.0% (92.4-99.5%) and 281.8 (57.5-1,379.7), respectively. Conclusions: Based on studies with moderate risk of bias and applicability concerns, UCPCR confers moderate to high sensitivity, specificity, and DOR for correctly identifying T1DM, T2DM and monogenic diabetes in appropriate clinical settings. Large multinational studies with multi-ethnic participation among different age groups are necessary before this test can be routinely used in clinical practice. Study registration: Protocol was registered as PROSPERO CRD42017060633.

Epidemiological link between obesity, type 2 diabetes mellitus and cancer.

There exists a complex interaction between obesity, type 2 diabetes mellitus (T2DM) and cancer, and an increase in the incidence of cancer is expected with the growing obesity-diabetes pandemic. The association of cancer with diabetes mellitus and obesity appears to be site-specific, the highest risk being for post-menopausal breast cancer, endometrial cancer, and colorectal cancer. Moreover, there is worsening of hyperglycaemia with the onset of cancer, evidencing a bi-directional link between cancer and diabetes mellitus and the need for monitoring for diabetes in cancer survivors. In this review, we look at the epidemiological evidence from observational studies and Mendelian randomization studies linking obesity, diabetes, and cancer, as well as the complex pathophysiological mechanisms involved, including insulin resistance with associated hyperinsulinaemia, the effect of chronic low-grade inflammation, and the effect of various adipokines that are associated with obesity and T2DM. Additionally, we describe the novel therapeutic strategies, based on their role on the discrete pathophysiological mechanisms involved in the tumourigenesis.

Gastroenteropancreatic neuroendocrine neoplasms: A clinical snapshot.

Our understanding about the epidemiological aspects, pathogenesis, molecular diagnosis, and targeted therapies of neuroendocrine neoplasms (NENs) have drastically advanced in the past decade. Gastroenteropancreatic (GEP) NENs originate from the enteroendocrine cells of the embryonic gut which share common endocrine and neural differentiation factors. Most NENs are well-differentiated, and slow growing. Specific neuroendocrine biomarkers that are used in the diagnosis of functional NENs include insulin, glucagon, vasoactive intestinal polypeptide, gastrin, somatostatin, adrenocorticotropin, growth hormone releasing hormone, parathyroid hormone-related peptide, serotonin, histamine, and 5-hydroxy indole acetic acid (5-HIAA). Biomarkers such as pancreatic polypeptide, human chorionic gonadotrophin subunits, neurotensin, ghrelin, and calcitonin are used in the diagnosis of non-functional NENs. 5-HIAA levels correlate with tumour burden, prognosis and development of carcinoid heart disease and mesenteric fibrosis, however several diseases, medications and edible products can falsely elevate the 5-HIAA levels. Organ-specific transcription factors are useful in the differential diagnosis of metastasis from an unknown primary of well-differentiated NENs. Emerging novel biomarkers include circulating tumour cells, circulating tumour DNA, circulating micro-RNAs, and neuroendocrine neoplasms test (NETest) (simultaneous measurement of 51 neuroendocrine-specific marker genes in the peripheral blood). NETest has high sensitivity (85%-98%) and specificity (93%-97%) for the detection of gastrointestinal NENs, and is useful for monitoring treatment response, recurrence, and prognosis. In terms of management, surgery, radiofrequency ablation, symptom control with medications, chemotherapy and molecular targeted therapies are all considered as options. Surgery is the mainstay of treatment, but depends on factors including age of the individual, location, stage, grade, functional status, and the heredity of the tumour (sporadic vs inherited). Medical management is helpful to alleviate the symptoms, manage inoperable lesions, suppress postoperative tumour growth, and manage recurrences. Several molecular-targeted therapies are considered second line to somatostatin analogues. This review is a clinical update on the pathophysiological aspects, diagnostic algorithm, and management of GEP NENs.

Organ-specific Adverse Events of Immune Checkpoint Inhibitor Therapy, with Special Reference to Endocrinopathies.

Immune checkpoint inhibitors are potent and promising immunotherapeutic agents that are increasingly used for the management of various types of advanced cancers. The widespread approval of this group of drugs simultaneously revealed immune-related adverse events as unique side-effects. Endocrinopathies are one of the most common immune-related adverse events. The precise pathogenic mechanisms for these endocrinopathies are still unclear. Though few of the endocrinopathies are reversible, calling for only symptom control, most are irreversible, requiring multiple long-term hormone replacement therapies. However, in contrast to other organ-specific immune-related adverse events, patients with endocrinopathies can continue their immune checkpoint therapy, provided the hormone replacement therapy is adequate and the symptoms are controlled. Though patients who have developed immune-related adverse events demonstrate superior antitumor activity and overall survival, due to the high morbidity associated with the immune-related adverse events, researchers are trying to uncouple the antitumour activity associated with immune checkpoint inhibitor therapy from the immune-related adverse events, to preserve antitumour activity without adverse events.

Male Obesity-related Secondary Hypogonadism - Pathophysiology, Clinical Implications and Management.

The single most significant risk factor for testosterone deficiency in men is obesity. The pathophysiological mechanisms involved in male obesity-related secondary hypogonadism are highly complex. Obesity-induced increase in levels of leptin, insulin, proinflammatory cytokines and oestrogen can cause a functional hypogonadotrophic hypogonadism with the defect present at the level of the hypothalamic gonadotrophin-releasing hormone (GnRH) neurons. The resulting hypogonadism by itself can worsen obesity, creating a self-perpetuating cycle. Obesity-induced hypogonadism is reversible with substantial weight loss. Lifestyle-measures form the cornerstone of management as they can potentially improve androgen deficiency symptoms irrespective of their effect on testosterone levels. In selected patients, bariatric surgery can reverse the obesity-induced hypogonadism. If these measures fail to relieve symptoms and to normalise testosterone levels, in appropriately selected men, testosterone replacement therapy could be started. Aromatase inhibitors and selective oestrogen receptor modulators are not recommended due to lack of consistent clinical trial-based evidence.

Diabesity and antidiabetic drugs.

The prevalence of "diabesity" - diabetes related to obesity - has increased tremendously over the past few decades because of the global obesity epidemic. Although bariatric surgery is the best treatment option for patients with diabesity, a majority of patients are managed only with antidiabetic drugs for various reasons. Diabetes control with antidiabetic agents may affect diabesity outcomes positively or negatively because of their effects on body weight and other metabolic parameters. For this reason, rational use of anti-diabetic medications is imperative to optimise long-term management of diabesity. Understanding the molecular mechanisms of antidiabetic drugs and/or drug combinations on diabesity outcomes are therefore important not only for the basic scientists but also for clinicians. This review explores the molecular signalling cascades of antidiabetic medications in the management of diabesity.