PL Plenary Lecture (1-4

PL-1

GENETIC DETERMINANTS OF CARDIOMETABOLIC DISEASE

PHILIP S. TSAO, PH.D.

Professor of Medicine (Cardiovascular Medicine); Stanford University School of Medicine Associate Chief of Staff for Precision Medicine; VA Palo Alto Health Care System Director; VA Palo Alto Epidemiology Research and Information Center (ERIC) for Genomics Co-Principal Investigator; Million Veteran Program

While obesity, type 2 diabetes (T2D) and dyslipidemia are known heritable risk factors for cardiovascular disease, it has only been recently that breakthroughs in measuring genetic variability associated with different traits. For many of these loci, the causal variants and the mechanisms of cardiometabolic disease from the largest US-based genetic cohort, the Million Veteran Program.

PL-2

AN UPDATE IN PARATHYROID DISEASE MANAGEMENT AND PATHOGENESIS

DOLORES M. SHOBACK, M.D.

Professor of Medicine in Residence University of California, San Francisco

Considerable progress has been made in understanding the pathogenesis and management of states of hyperparathyroidism and hypoparathyroidism that impacts the current practice of endocrinology. Primary hyperparathyroidism (PHPT) is most commonly due to a solitary adenoma (~80%) in adults with the disorder, with the remainder due to multigland hyperplasia (15-20%) or to parathyroid cancer (< 1% of cases). In more and more countries, including those in Asia, patients with PHPT present more frequently in an asymptomatic manner. In the past decades, patients presented predominantly with symptomatic disease (bone pain, fractures, renal stones, and gastrointestinal and psychiatric manifestations). Their tumors were larger, and urgent surgery was needed to effect a cure. More commonly today, asymptomatic PHPT comes to medical attention after patients with low bone mass or fractures are evaluated biochemically, and they are essentially being screened for the disease. Cohorts of patients with sporadic PHPT are composed mainly of postmenopausal women. Hereditary forms of the disease are more prevalent in younger patients with PHPT (age < 40-45). The following genetic conditions must be carefully considered in all patients with PHPT, but especially in younger ones, so that an accurate diagnosis is made: multiple endocrine neoplasia (MEN) 1, 2a and 4; the HPT of the extracellular calcium-sensing receptor (CaSR) signaling pathway [familial hypocalciuric hypercalcemia (FHH) types 1, 2, and 3]. The clinical and biochemical features of PHPT due to these genetic conditions will be reviewed as well as the diagnostic testing that is needed to support the diagnosis of PHPT, especially in its asymptomatic form. Guidelines for the management of PHPT have been established by the 4th International Workshop on PHPT(2014) and will be reviewed. Newer more sensitive localization techniques have developed that can be applied to the evaluation of patients for minimally invasive parathyroidectomy. Minimally invasive surgery can be combined with intraoperative parathyroid hormone (PTH) monitoring to ensure correction of the hyperparathyroid state. In cases of recurrent PHPT or in especially symptomatic patients, for whom surgery is indicated and appropriate, choline/PET-MRI scanning and 4-D computed tomography have emerged as superior sestamibi scanning. Results of studies establishing this approach and, in addition, newer trials looking of the disease abnormalities in patients indicated for surgery who are unable to undergo it.

In a similar manner, there has been considerable progress in understanding the effects of a

lack of PTH on bone, kidney and quality of life in patients. Although this disorder is rare, it is a not infrequent complication of thyroidectomy done for cancer or goiter, with about 75% of cases of hypoparathyroidism in adults being post-surgical and the remaining 25% being of genetic or other etiologies. Over the last 5-10 years, data have emerged that PTH replacement therapy may be an excellent option for patients with hypoparathyroidism whose disease is not well-controlled on standard therapy with calcium supplements and activated vitamin D analogues (calcitriol or 1-alpha calcidol) or vitamin D2 or D3. Trials have shown reductions in both calcium and vitamin D analogue intake, stabilization of disease-relevant biochemical endpoints, and improved quality of life in certain domains with initiation of PTH(1-84) therapy. Long-term outcomes of ongoing PTH(1-84) therapy are being reported, and additional approaches engineering PTH(1-34) into slowly released forms are being readied for testing in this patient population. Of special interest will be the effects of chronic PTH replacement on skeletal endpoints including bone mass, turnover, and fractures to ensure ongoing safe hormonal replacement.

Thus, considerable progress has ensued relevant to the management of states of both PTH

PL-3

DIABETIC FOOT: THE GLOBAL STATE OF PLAY

DAVID G. ARMSTRONG, DPM, M.D., PH.D.

Professor of Surgery, Keck School of Medicine USC; Department of Surgery

Foot wounds are now the most common diabetes-related cause of hospitalization and are a frequent precursor to amputation. Persons with diabetes have a 30-fold higher life-time risk of undergoing a lower extremity amputation compared to those without diabetes. An infected foot wound precedes about two-thirds of lower extremity amputations. and infection is surpassed only by gangrene as an indication for diabetic lower extremity amputation. Persons with diabetes have at least a 10 fold greater risk of being hospitalized for soft tissue and bone infections of the foot than persons without diabetes.

With these data as a backdrop, we will review the current state of play regarding treatment of the diabetic foot and wounds in the developed and developing world. We will explore policy factors associated with the team approach to amputation prevention as well as tips for the structure of successful teams, both at SALSA and worldwide. The concept of the “Toe and Flow” philosophy of and perhaps a way forward toward extending ulcer-free-days in remission. We also explore the use of novel new technology merging consumer electronics with medical devices in an effort to prevent problems before they start. Further information regarding this lecture including video, manuscripts and blog available at: www.diabeticfootonline.com

PL-4

HISTORY OF ENDOCRINOLOGY--THE NOBEL LAUREATES

HONG DA LIN, M.D

Active Emeritus, Division of Endocrinology and Metabolism, Taipei Veterans General Hospital; Clinical Professor, Department of Medicine, Taipei Medical University Visiting Professor, Endocrine Division, Shin Kong Medical Center Hospital

Evidences of endocrine disorders and treatment exist in the ancient Chinese, Egyptians, Hindus, Biblical, Greek, Roman and other cultural antiquity. Goiters were known in China in the era of 1600BC. People used burnt sponge and seaweed in the form of powder, pills or dissolved in wine for the treatment of this disorder. “Diabetes mellitus” had already studied by Chang Chung-Ching (160219 AD), the Chinese Hippocrates. The effects of castration and infertility were well known. Eunuchs played an important role at the Court, for the service of emperors and their queens. The use of fresh semen from young men for treatment of sexual weakness was a true organotheray. The Pen-Ts’ao Ching(Great Herbal of the Chinese Pharmacopoeia) dates back to Emperor Shen Nung (2737 BC?) and the Huang-Ti Neiching (Canon of Medicine) to the Emperor Huang-Ti (2697 BC?). The original text of Pen-Ts’ao Ching was lost and known only through an annotated edition. The Great Herbal remedies contained not only of plant origin but also from animal origin. For example, toad’s skin for dropsy, hen’s gizzard for indigestion and gastric ulcer. Mice were used not infrequently both in ancient Chinese and Egyptian remedies.

The modern endocrinology developed in the 20th century. The history of endocrinology seemed synonymous with the history of endocrine glands and with that of internal secretions. This needs some date. Claude Bernard Stated in 1855 that the liver had an external secretion in the form of bile and an internal one of sugar which passes directly into the general circulation. In 1902, Ernest Henry Starling and his closest collaborator also brother in law, William Maddock Bayliss, discovered secretin. They produced in some organ, carried by the blood to other parts of body where excited reactions. In 1905, professor starling used the world “hormone” for the first time in his Croonian lecture at the Royal College of Physicians and subsequently in two addresses given in Germany. The word “hormone” was suggested by Sir William B Hardy and his classical colleague W.T. Vesey in Cambridge. It was derived from a Greek Verb “hormone” meaning to put into quick motion, to excite or arouse. The in endocrinology followed the “four stages principle”. 1. Recognition of the gland or organ which producing hormones 2. Methods to detect hormones

3. Extraction of hormones 4. Isolation of pure hormones, determination of its structure and then its synthesis.

During the past fifty years the impacts of physiology, biochemistry, immunology, medical technology, pharmacology and molecular biology make endocrinology expand rapidly and considerably at the rate of an atomic explosion. In this address, I will highlight the great achievement