# 009 # Chapter 1 Chapter 1 Endocrinolog & Metabolism Pharmacotherapy for painful diabetic neuropathy: Relevant comorbidities for drug selection Drug class Comorbidities favoring use Comorbidities favoring avoidance Serotonin-norepinephrine • Depression reuptake inhibitors (SNRIs) • Anxiety Duloxetine Venlafaxine Tricyclic antidepressants • Depression (TCAs) • Anxiety • Insomnia • Amitriptyline • Nortriptyline • Desipramine Gabapentinoid anticonvulsants • Restless legs syndrome • Essential tremor • Pregabalin • Insomnia • Gabapentin disease Peripheral neuropathy with H/O glaucoma and on tramadol for chronic back pain, what is the best treatment? • Pregabalin Acute painful neuropathy of rapid improvement of blood glucose control • rapid improvement of blood glucose control → Acute painful neuropathy (self-limiting) → Simple analgesics (paracetamol, aspirin) and local measures (bed cradles) are recommended as a first step • Duloxetine is the standard first line therapy for neuropathy • Amitriptyline is an alternative option to duloxetine if it is contraindicated; (e.g. presence of glaucoma) • Pregabalin is recommended either as a second line agent or in combination with amitriptyline. MRCPUK-part-1-September 2009 exam: H/O type 2 DM and benign prostatic hypertrophy (BPH) presents with burning pain in his feet. He tried duloxetine but no benefit. What is the most suitable initial management? • Pregabalin • Amitriptyline is first choice but given H/O BPH, it is better to avoid amitriptyline due to the risk of urinary retention. Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad • Restless legs syndrome • Sexual dysfunction (for venlafaxine) • Angle-closure glaucoma • Cardiac disease • Prolonged QTc • Orthostatic hypotension • Sexual dysfunction • Urinary retention • Angle-closure glaucoma • Substance abuse • Peripheral edema • Chronic obstructive pulmonary Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad ____________________________________________________ Diabetic autonomic neuropathy Features Urogenital system • Erectile dysfunction (most common) • Bladder dysfunction: urinary retention, incomplete bladder emptying, bladder distention, overflow incontinence, poor urinary stream Cardiovascular system • Silent myocardial infarction • Decreased heart variability or fixed rhythm  Heart rate variability during breathing of < 10 beats per minute  Heart rate increase on standing of < 15 beats per minute • Orthostatic hypotension • Persistent sinus tachycardia • Ventricular arrhythmia Gastrointestinal system • Gastroparesis  Delayed gastric emptying due to nonmechanical obstruction  Mostly idiopathic but also associated with diabetes mellitus and upper GI surgery  Manifested with nausea, abdominal bloating, early satiety  Increased risk of postprandial hypoglycemia  Treatment involves prokinetic agents, e.g., metoclopramide (first-line), erythromycin, domperidone. • Diarrhea, constipation, incontinence Other manifestations • Sweat gland dysfunction associated with heat intolerance • Pupillary dysfunction • Risk of hypoglycemia due to absence of hormonal counter-regulation (secretion of cortisol, glucagon, and catecholamines) Type 2 diabetes with erratic blood glucose control or unexplained gastric bloating or vomiting → Think about a diagnosis of gastroparesis. __________________________________________________________ Diabetic amyotrophy Leg pain, weakness and reduced knee reflexes with an impaired fasting glucose concentration suggests a diagnosis of diabetic amyotrophy →should be confirmed with OGTT. Definition • Diabetic amyotrophy is a type of diabetic neuropathy which affects the lumbosacral plexus, nerve roots and peripheral nerves, therefore known as proximal diabetic neuropathy and diabetic lumbosacral plexopathy. It is a mixed motor and sensory proximal neuropathy that can cause severe pain. Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism Epidemiology • Relatively uncommon, affect 1% of patients • Typically occurs in patients with type 2 diabetes mellitus that has been recently diagnosed or has been under fairly good control. Pathophysiology • The most likely mechanism is ischemic injury from microvasculitis leading to axonal degeneration (e.g. occlusion of the vasa nervorum of the proximal lumbar plexus and/or femoral nerve). Differences from other types of diabetic neuropathy • Patients usually have not had diabetes for a long time, and glycaemic dysregulation is often not severe.  A diagnosis of diabetic amyotrophy leads to the discovery of underlying diabetes mellitus in one quarter to one third of cases.  Long-term diabetic complications such as diabetic retinopathy and nephropathy are often absent at the time of diagnosis. Features • Pain is usually the first symptom, often in the thigh, hips or buttocks • Often asymmetrical (although it can be bilateral). • Wasting and weakness of proximal muscles (e.g. difficulty getting out of a chair) • Weight loss • Loss of knee reflexes • There is often little sensory loss. • Autonomic failure Investigations • EMG shows multifocal denervation in paraspinous & leg muscles. • MRI is useful to rule out other causes of neurologic impairment, such as structural lesions of the lumbosacral plexus, brachial plexus, or spinal cord. Prognosis • Often self-improvement with time • Most patients will not recover completely. Treatment • No treatments are proven to be effective. • Neuropathic pain treatments include amitriptyline, gabapentin, pregabalin, or duloxetine. • May improve with good control (the mainstay of treatment is supportive care and transference to insulin therapy). Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Diabetic foot Epidemiology • 2% of patients with diabetes in the community develop new foot ulcers each year Pathophysiology • It occurs secondary to two main factors:  neuropathy: resulting in loss of protective sensation (e.g. not noticing a stone in the shoe), Charcot's arthropathy, dry skin  peripheral arterial disease: diabetes is a risk factor for both macro and microvascular ischaemia Presentations • Neuropathy: loss of sensation • Ischaemia: absent foot pulses, reduced ankle-brachial pressure index (ABPI), intermittent claudication • Complications: calluses, ulceration, Charcot's arthropathy, cellulitis, osteomyelitis, gangrene Screening • All diabetic patients should be screened for diabetic foot at least annually. • screening for ischaemia: done by palpating for both the dorsalis pedis pulse and posterior tibial artery pulse • screening for neuropathy: a 10 g monofilament is used on various parts of the sole of the foot. Differential diagnosis • Venous stasis ulcers  Mechanism: Venous reflux → congestion and dilated veins, which impair the transport of fresh blood to the area.  Sites: Typically present in the area around the ankle  Treatment:  Multi-layer bandaging is most useful in reducing lower limb oedema and improving the chances of healing of venous ulcers.  An ankle brachial pressure index (ABPI) measurement is essential before beginning bandaging, as if there is significant arterial insufficiency, blood supply to the lower limb may be threatened. Features Neuropathic foot Ischaemic foot often warm Cold foot Painless or abnormal neuropathic pain. causes rest pain bounding pulses nearly pulseless foot ulceration tends to occur on the plantar surface Ulceration tends to be painful and often presents in the heal area It can be high arched, with toe clawing. there is often gravity-dependent reddening of the foot, which disappears on elevation of the foot. In about one third of patients with diabetic foot, the underlying cause is both ischemic and neuropathic. Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism This is a typical neuropathic ulcer, with callus forming the edge and a clean base. __________________________________________________________ Diabetic neuropathic arthropathy (Charcot foot) In patients with long-standing diabetes and peripheral neuropathy, a red, hot swollen foot should raise suspicion of Charcot neuroarthropathy after exclude infection. Definition • Disrupted and damaged joint (mid-foot collapse) secondary to a loss of sensation. Causes • Diabetes mellitus (The most common cause) Pathophysiology • Multifactorial, due to a combination of mechanical, neuropathic and vascular  Peripheral neuropathy (lack of pain sensation) → ↑ stress injuries to foot joints (commonly the midfoot) → Charcot process.  Autonomic neuropathy →↑ blood flow to the joint→ ↑ osteoclast activity and bone turnover "washing out" of bone substance → ↑foot susceptibility to minor trauma → destructive changes → Charcot’s • The commonest affected joints are tarso-metatarsal joint and metatarsophalangeal joint. Features • The foot and ankle are typically swollen, red and warm • Midfoot arch collapse can lead to bony prominences on the plantar aspect with later pressure ulceration • Typically, less painful than would be expected given the degree of joint disruption due to the sensory neuropathy. However, 75% of patients report some degree of pain Diagnosis • Infection such as osteomyelitis is important to exclude.  Normal C-reactive protein and white blood cell count → make osteomyelitis unlikely  Although not widely available, an indium-labelled white cell scan is the best way to differentiate between infective causes of this clinical presentation and Charcot’s arthropathy. Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad • X-ray: plain radiographs can be normal in the early stages. later on, they show joint destruction, osteolysis, joint reorganisation and subluxation. • MRI: in acute Charcot's arthropathy shows midfoot subchondral bone marrow edema Management • Immobilisation in a plaster cast for 3–6 months is the treatment of choice. • Bisphosphonates : bisphosphonates → reduction in bone reabsorption → accelerate healing. • Surgery: reserved for severe deformities ____________________________________________________ Necrobiosis lipoidica diabeticorum Definition • A disorder of collagen degeneration with a granulomatous response, thickening of blood vessel walls, and fat deposition. Causes • Occurs in patients with type 1 diabetes, • It is usually related to diabetes, but can also occur in patients with rheumatoid arthritis • May precede symptoms and signs of diabetes by several months. Epidemiology • More common in females • Presents in young adults or in early middle life. Features • Typically, painless. • Beginning as a patch of erythema that spreads across the shin, begins to yellow and can then ulcerate. Diagnosis • Biopsy reveals granuloma formation with infiltration of lymphocytes, plasma cells and eosinophils. Treatment • Topical steroids is the most appropriate treatment to the non-atrophied areas. the areas of already atrophied skin respond poorly to steroid therapy. • Support bandaging Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism Necrobiosis lipoidica diabeticorum __________________________________________________________ Diabetes mellitus: DVLA Type 1 vehicles (cars, motorcycles) • If on insulin then patient can drive a car as long as they:  have hypoglycaemic awareness,  not more than one episode of hypoglycaemia requiring the assistance of another person within the preceding 12 months  no relevant visual impairment.  Drivers are normally contacted by DVLA • If on diet controlled alone, tablets or exenatide no need to notify DVLA. Type 2 vehicles (lorries, HGV) • HGV drivers can retain their license even if taking insulin, providing they are able to meet a set of criteria. • Criteria regarding driving for patient on insulin (and also apply to patients using other hypoglycaemic inducing drugs such as sulfonylureas): If a patient has two or more episodes of severe hypoglycaemia (i.e. patient needs help to correct the hypoglycaemic episode) then they need to inform the DVLA and not drive. 1) having no episodes of hypoglycaemia requiring the assistance of another person within the preceding 12 months 2) evidence of good glycemic control - demonstrated by review of 3months of BM readings on insulin 3) close BM monitoring (at least BD) 4) full hypoglycaemia awareness 5) the ability to manage hypoglycaemia independently 6) no other complications of diabetes (e.g. visual field impairments.) Hypoglycaemia (DVLA regulations) • Group 1 drivers who have had more than one episode of severe hypoglycaemia (requiring the assistance of another person) while awake in the last 12 months  Must not drive and must notify the DVLA.  DVLA will then carry out medical enquiries before a licensing decision is made. • Group 2 drivers who have had more than one episode of severe hypoglycaemia  Must not drive and must notify the DVLA following all episodes of severe hypoglycaemia including asleep episodes. • Severe hypoglycaemia whilst driving  All Group 1 and Group 2 drivers must not drive and must notify the DVLA. Impaired awareness of hypoglycaemia – ‘hypoglycaemia unawareness’ Group 1 (Car and motorcycle) Group 2 (Bus and lorry) • Must not drive and must notify the DVLA. • Driving may resume after a clinical report by a GP or consultant diabetes specialist confirms that hypoglycaemia awareness has been regained. • Who will inform the DVLA?  the patient should be advised to inform the DVLA themselves rather than breaking patient confidentiality,  if the patient repeatedly fails to follow this advice, then the doctor should inform the DVLA after telling the patient that he or she is doing so. • What advice should be given to a patient on insulin therapy, who developed hypoglycaemia requiring the assistance of another person in the preceding twelve months, with respect to his driving?→Discontinue driving for 1 year A guide for drivers with insulin treated diabetes who wish to apply for Group 2 (bus and lorry) • No hypoglycaemic event requiring the help of another person in the last 12 months. • must have full awareness of the symptoms of hypoglycaemia. • must be able to show an understanding of the risks of hypoglycaemia. • must check blood sugar levels at least twice daily, even on non-driving days and no more than 2 hours before the start of the first journey and every 2 hours while driving. This must be done using a blood glucose (sugar) meter with a memory function to measure and record blood glucose levels. Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad • Must not drive and must notify the DVLA. • The licence will be refused or revoked. Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism • must attend an examination every 12 months with an independent consultant specialising in the treatment of diabetes. • must have at least 3 continuous months of readings available on the memory of the blood glucose meter(s) for the consultant/GP to inspect. Drivers with insulin treated diabetes are advised by DVLA to: • should check glucose less than 2 hours before the start of the first journey and every 2 hours after driving has started. • A maximum of 2 hours should pass between the pre-driving glucose check and the first glucose check after driving has started. • In each case if glucose is 5.0mmol/L or less, eat a snack. If it is less than 4.0mmol/L or feel hypoglycaemic do not drive. DVLA advice on developing hypoglycaemia at times relevant to driving • In each case if your glucose is 5.0mmol/L or less, eat a snack. • If it is less than 4.0mmol/L or you feel hypoglycaemic do not drive. • If hypoglycaemia develops while driving stop the vehicle safely as soon as possible. • You should switch off the engine, remove the keys from the ignition and move from the driver’s seat. • You should not start driving again until 45 minutes after finger prick glucose has returned to normal (at least 5.0mmol/L). It takes up to 45 minutes for the brain to recover fully. • Your finger prick glucose level must be at least 5.0mmol/L before returning to driving. Jobs that not allowed to subjects with insulin dependent diabetes • Armed forces • Working offshore or aboard ships • Air pilot • Police, Fire or driving in the post office (Traffic police driver) • Driving emergency vehicles • Offshore work If a patient has two or more episodes of severe hypoglycaemia (needs help to correct the hypoglycaemic episode) then they need to inform the DVLA and not drive. (needs to surrender their driving licence) Insulinoma Definition • Insulinoma is a neuroendocrine tumor arise from beta cells of the pancreas Overview • Most common pancreatic endocrine tumour • incidence of 4 cases per million/year • commoner in women • 10% malignant. 90% are benign. • 10% have multiple tumours. ∼ 90% occur as solitary tumors Insulinoma is diagnosed with supervised prolonged fasting Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad • 10% may be associated with the MEN-1 syndrome (50% of patients with multiple tumours, have MEN-1) • 90% are less than 2 cm in size. • < 1% occur at ectopic sites (e.g., spleen). Features • Features of hypoglycaemia: typically fasting hypoglycemia (early in morning or just before meal). e.g. hunger, diplopia, sweating, palpitations, memory loss, seizures. • Rapid weight gain: Patients eat in an attempt to avoid hypoglycaemia Diagnosis • Insulin + C-peptide levels during a hypoglycaemic episode  hypoglycemia with inappropriately high insulin levels (hyperinsulinism)  high C-peptide  raised proinsulin: insulin ratio • Supervised, prolonged fasting (up to 72 hours)  If the patient develops symptoms, then a plasma glucose is measured and if low, insulin and C-peptide is then collected and the fast terminated.  Positive if serum glucose levels remain low (< 40 mg/dL) and insulin levels remain high even after fasting for 72 hours.  After a 15 h fast, the cut-off normal limits for glucose are 2.5 mmol/l and 5 mU/l for insulin.  By 24 h, fasting leads to a detection rate of 78% for insulinoma. If the fast is extended to 72 h, this detection rate increases to 98%. • Sulphonylurea screen to exclude possible drug administration • Images to localize the tumor. abdominal CT with contrast. Elevated C-peptide and proinsulin levels may also be the result of sulfonylurea use! This can be ruled out by screening serum samples for sulfonylureas. Management • Surgery is treatment of choice • If surgery is not possible (unfit , refusal, inoperable tumor ) → inhibitors of insulin release → Diazoxide (potassium channel activator) Whipple triad is required before further investigations for insulinoma: 1. hypoglycemic symptoms, 2. low blood glucose level 3. resolution of symptoms after correcting the blood glucose levels. Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism Glucagonoma Glucagon physiology • Made by α cells of pancreas. • Secreted in response to hypoglycemia. • Inhibited by insulin, amylin, somatostatin, hyperglycemia. • Functions (catabolic effects)  ↑↑ gluconeogenesis from amino acid substrates.  ↑↑ glycogenolysis  ↑↑ lipolysis, ↑↑ amino acid oxidation , ↑↑ ketogenesis  ↑↑ blood glucose  ↑↑ catecholamine secretion  Delays gastric emptying  ↓↓ glycolysis  ↓↓ pancreatic exocrine secretions. Overview • A neuroendocrine tumor that secrete glucagon. • Very rare, with an annual incidence of 1 in 20 million. • Usually solitary, and the majority are located in the distal pancreas. • Frequently malignant. • 50 - 80% are metastatic at presentation, so prognosis is poor. Features • Glucose intolerance , secondary diabetes mellitus • Weight loss due to protein catabolism • Chronic diarrhea • Neuropsychiatric features • Venous thrombo-embolism • Necrolytic migratory erythema  The most common symptoms (found in 75% of cases)  Red, blistering rash, starts as an indurated erythema, within a few days blisters will cover the surface of the skin, which then crust and heal, leaving hyperpigmented skin.  Located predominantly on the face, perineum, and lower extremities, with lesions developing in one area while others are resolving. Glucagonoma → 6 Ds 1. Decreasing weight 2. Diabetes 3. Dermatitis 4. Diarrhea 5. DVT 6. Depression. Diagnosis • Measure plasma glucagon levels → Elevated • Image: CT scan Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad • Somatostatin analogs (eg, octreotide) → improves the skin rash and diarrhoea • Surgical cure rate is only 5% because these tumours have often metastasized on presentation. __________________________________________________ Monogenic diabetes: Maturity-onset diabetes of the young ( MODY) Definition • Different forms of autosomal dominant inherited diabetes mellitus characterized by onset of diabetes at a young age (<25 years) and lack of autoantibodies. Epidemiology • It is thought that around 1-2% of patients with diabetes mellitus have MODY, and around 90% are misclassified as having either type 1 or type 2 diabetes mellitus. General features • Subacute presentation (ketosis is not a feature at presentation). • Mild to moderate hyperglycaemia (typically 7-14 mM). • Absence of obesity → Absence of insulin resistance → low insulin requirement (e.g. less than 0.5 u/kg/day). • Strong family history of early onset diabetes. • Absence of autoimmune markers. Diagnosis • High index of suspicion (familial diabetes with autosomal dominant pattern of inheritance [≥3 generations], onset <25 years, nonobese, negative islet autoantibodies) • Genetic testing: the most common mutations:  hepatocyte nuclear factor-1-alpha (HNF1A) → MODY type 3  glucokinase (GCK) → MODY type 2  hepatocyte nuclear factor-4-alpha (HNF4A) → MODY type1 Subtypes • MODY 3 (HNF1A-MODY)  the commonest form of MODY, 60% of cases  due to a defect in the HNF-1 alpha gene (hepatic nuclear factor-1)  characterised by:  ↑HDL cholesterol levels  Preserved insulin sensitivity  Low renal threshold for glucose (glycosuria)  Sulphonylureas is the initial drug of choice  MODY3 is particularly important to diagnose as many patients initially treated with insulin can in fact be managed with sulphonylurea. • MODY 2 (GCK-MODY)  Prevalence: 20% of cases (The second commonest MODY variant after MODY3)  Mechanism: due to a defect in the glucokinase gene (GCK gene)  Glucokinase is found in the liver and in beta cells in the pancreas. acts as a sensor, recognizing when the level of glucose in the blood rises and helping stimulate the release of insulin from beta cells to control it. In the liver, Management Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism glucokinase helps determine when excess glucose should be taken in and converted to glycogen.  When this gene isn’t working properly the body allows the level of blood glucose to be higher than it should be.  Features: Mild hyperglycaemia (slightly higher than normal, generally between 5.58mmol/l). Often picked up through routine testing (eg during pregnancy).  Treatment: 90% of MODY2 patients are controlled on diet therapy alone.  Prognosis: In contrast to all other subtypes, MODY II is not associated with an increased risk of microvascular disease and can be managed with diet alone, despite stable hyperglycemia and chronically elevated HbA1C levels. • MODY type 1 (HNF4A -MODY)  Defect in HNF-4 Alpha gene.  The third commonest MODY (<10%)  Beta cell defect: Reduced insulin secretory response to glucose  Normal renal threshold for glucose  Treatment : Sulfonylureas • MODY 5 (HNF1B-MODY)  Defect in HNF-1 beta gene.  Rare  Renal cysts  Hypomagnesemia  Treatment: insulin is usually necessary Bilateral renal cysts + ↑ glucose → MODY related cyst formation __________________________________________________________ Latent autoimmune diabetes of adulthood (LADA) Definition • a variant of diabetes characterized by a late onset of type 1 (autoimmune) diabetes that is often mistaken for type 2 diabetes. Epidemiology • constitutes approximately 10% of patients incorrectly labelled as type 2 diabetic. Feature • Features consistent with type 1 diabetes (eg: weight loss) • In contrast to type 2 diabetes, patients are typically younger and without an increased body habitus. • In contrast to type 1 diabetes, insulin is not usually required in the early stages of the disease. the progression of autoimmune -cell failure is slow. Diagnosis • Glutamic Acid Decarboxylase (GAD) Autoantibodies test Management • early use of insulin may prolong beta-cell function • a recent Cochrane review concluded that a sulphonylurea should not be the first line treatment since it may be associated with a more rapid progression to insulin dependence Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad __________________________________________________________ Mitochondrial diabetes Definition • A rare variant of diabetes occurred due to mutation in the mitochondrial DNA. Features • Can present as type 1 or type 2 depending on the severity of insulinopenia. • Strong familial clustering of diabetes. Although this is also seen in MODY, mitochondrial diabetes can be discriminated from MODY by:  Presence of maternal transmission  Bilateral hearing impairment (usually precede the development of diabetes) →do audiometry. Diagnosis • Mitochondrial diabetes is suspected in female patients with a strong familial clustering of diabetes, with predominantly maternal transmission of disease and the presence of sensorineural deafness. • Genetic analysis → A3243G mutation in the tRNA gene Treatment • with type 2 DM presentation: due to an underlying mitochondrial mutation can be with sulfonylureas is the initial treatment of choice • Metformin is contraindicated due to risk of development of lactic acidosis.  A mitochondrial dysfunction in muscle is expected to lead to a higher lactate  The A3243G mutation was originally detected in patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome) Mitochondrial diseases follow a maternal inheritance pattern • All children of affected females will inherit it. • All children of affected males will not inherit the disease. High glucose + sensorineural deafness → think of mitochondrial diabetes __________________________________________________________ Diabetes in pregnancy Classification of diabetes in pregnancy • Gestational diabetes (GDM) (developed during pregnancy): most common → 87.5% of all diabetic pregnancies. • Pre-existing type 1 or type 2 diabetes Epidemiology • The prevalence of diabetes in pregnancy is 2–5% in the UK of both gestational diabetes and pre-existing diabetes. Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism Definition • GDM refers to diagnosis of diabetes at 24 to 28 weeks of gestation. • Diagnosis of diabetes in early pregnancy is more consistent with previously undiagnosed type 2 diabetes. Gestational diabetes mellitus (GDM) Risk factors for GDM • BMI of > 30 kg/m • previous macrosomic baby weighing 4.5 kg or above • previous gestational diabetes • first-degree relative with diabetes • family origin with a high prevalence of diabetes (South Asian, black Caribbean and Middle Eastern) Screening for GDM • Women who’ve previously had gestational diabetes:  Oral glucose tolerance test (OGTT) should be performed as soon as possible after booking and at 24-28 weeks if the first test is normal.  NICE also recommend that early self-monitoring of blood glucose is an alternative to the OGTTs. • Women with any of the other risk factors → OGTT at 24-28 weeks Diagnosis: GDM is diagnosed if either: • Fasting glucose is ≥ 5.6 mmol/l • 2-hour glucose is ≥ 7.8 mmol/l • If fasting blood glucose between 5.5 and 7.0 mmol/l then proceed to → 75-g oral glucose tolerance test The oral glucose tolerance test remains the investigation of choice for gestational diabetes Complications • Macrosomia (the commonest complications)  defined by a birth weight > 4.5Kg  affects up to 45% of babies  shoulder dystocia is a common delivery problem occurring in up to 15 – 20% of cases. • Neonatal hypoglycaemia • Maternal complications are hypertension, preeclampsia, increased risk of developing diabetes mellitus and increased risk of cesarean delivery. Management • Advice about diet (including eating foods with a low glycaemic index) and exercise should be given • Aspirin should also be considered given the increased risk of pre-eclampsia. • If the fasting plasma glucose level is < 7 mmol//l  Trial of diet and exercise should be offered  If glucose targets are not met within 1-2 weeks of altering diet/exercise metformin should be started  If glucose targets are still not met insulin should be added to diet/exercise/metformin Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad • If at the time of diagnosis, the fasting glucose level is ≥ 7 mmol/l  insulin should be started • If the plasma glucose level is between 6-6.9 mmol/l, and there is evidence of complications such as macrosomia or hydramnios:  insulin should be offered • Fasting blood glucose should be checked 6 -13 weeks postpartum Prognosis • the incidence of type 2 diabetes in women with a history of gestational diabetes is 16% Pre-existing diabetes in pregnancy Complications • the risk of severe congenital malformation increased by two-fold in infants born to mother with pre-existing diabetes (pregestational diabetes) Management • Planning pregnancy  Patients should achieve good diabetic control prior to planning for pregnancy.  If this has not been achieved, then NICE advises contraception and to offer termination if pregnancy does occur due to increased risks in pregnancy.  Control will reduce the risk of miscarriage, congenital malformation, stillbirth, and neonatal death. • Stop oral hypoglycaemic agents, apart from metformin, and commence insulin • Folic acid 5 mg/day from pre-conception to 12 weeks gestation • Aspirin 75mg/day from 12 weeks until the birth of the baby, to reduce the risk of preeclampsia • Detailed anomaly scan at 20 weeks including four-chamber view of the heart and outflow tracts • Tight glycaemic control reduces complication rates • Treat retinopathy as can worsen during pregnancy  It is advised, however, if the patient has not had retinal screening within the last six months to offer this urgently as there can be rapid development of diabetic retinopathy in pregnancy. • Continuous glucose monitoring (CGM) improves glucose control Patients with diabetes should have increased frequency of retinal screening during pregnancy due to increased risk of retinopathy Targets for self-monitoring of pregnant women (pre-existing and gestational diabetes) Time Target Fasting 5.3 mmol/l 1 hour after meals 7.8 mmol/l, or 2 hour after meals 6.4 mmol/l Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism __________________________________________________________ Lipids and obesity problems __________________________________________________________ Obesity: overview Classification Classification Body Mass Index (BMI) kg/m2 Healthy weight 18.5-24.9 Overweight 25-29.9 Obesity I 30-34.9 Obesity II 35-39.9 Obesity III (Morbid obesity) 40 or more Associated conditions • Metabolic syndrome (hypertension, hyperglycaemia, hyperlipidaemia) • GI conditions: cholelithiasis, nonalcoholic fatty liver disease, GERD, colonic diverticulosis • Respiratory: Obstructive sleep apnea (OSA), obesity hypoventilation syndrome (Pickwickian syndrome) • Polycystic ovary syndrome • Mental health issues: e.g., depression , anxiety, eating disorders • Gout Hormonal alterations in obesity • Increased in obesity  Testosterone (female): due to insulin resistance (PCOS) ↓ SHBG  LH in (female): due to insulin resistance  Insulin: due to ↑ insulin resistance  Renin: due to ↑ Sympathetic tone  Aldosterone: due to ↑ Adipokines, renin- angiotensin, leptin  Leptin : due to increased adipose mass, Leptin resistance • Decreased in obesity  Testosterone (male): due to ↓ SHBG ↑ aromatase ↓GnRH  LH/FSH (male): due to ↑ oestrogens/androgens  Glucagon-like peptide-1 (GLP-1): due to ↑ FFA  25-OH vitamin D: due to trapping in adipose tissue, ↓ sun exposure, ↓ 25OH vitamin D binding protein ↓ liver synthesis.  Ghrelin Appetite regulation (ghrelin and leptin) Leptin (the satiety hormone) • Produced by adipose tissue. • Acts on ventromedial area of hypothalamus (satiety center) to ↓↓ appetite. • Obese people have ↑↑leptin due to ↑↑adipose tissue but are tolerant or resistant to leptin’s anorexigenic effect. • Mutation of leptin gene → severe obesity. • Factors → ↓↓ leptin  Starvation  Sleep deprivation  Stretched stomach Ghrelin makes you ghrow hunghry (the hunger hormone). Leptin keeps you thin (the satiety hormone). __________________________________________________________ _Obesity: management (step-wise approach) Lifestyle modifications • Reduce fat intake  The current UK recommendations: total fat intake should be restricted to less than 30% of dietary energy (the average daily energy consumption of a male is 2500 kcal and 2000 kcal for a female.) • Physical activity: at least 30 minutes of moderate aerobic activity 5–7 times per week. Pharmacological management: Anti-obesity drugs • Indications:  body mass index (BMI) ≥ 30 kg/m2 in whom at least three months of managed care involving supervised diet, exercise and behaviour modification fails.  BMI ≥ 28 kg/m2 + risk factors (eg: diabetes mellitus, coronary heart disease, hypertension and obstructive sleep apnoea) • Discontinuation: Anti-obesity drug treatment should be discontinued :  If weight loss is less than 5% after the first 12 weeks.  If the individual regains weight at any time whilst receiving drug treatment • Contraindications:  Combination drug therapy is contraindicated Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Ghrelin (the hunger hormone) • Produced by stomach • Acts on hypothalamus to ↑↑ hunger, ↑↑gastric acid secretion and ↑↑GIT motility. Acts synergistically with GnRH to stimulate growth hormone release • Regulate appetite → stimulates hunger • Factors → ↑↑ghrelin  Empty stomach (fasting)  Sleep deprivation  Prader-Willi syndrome • Factors → ↓↓ghrelin Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism  Drugs should never be used as the sole element of treatment (should only be prescribed as part of an overall plan for managing obesity). • Orlistat  Action : pancreatic lipase inhibitor, blocks the breakdown and hence the absorption of dietary fat.  Normally used for < 1 year  Adverse effects: faecal urgency/incontinence and flatulence. Surgical management: bariatric surgery • Benefits  Reduces cardiovascular mortality (the risks of long-term obesity outweigh those of surgery.) • Indications as third line option after failure of lifestyle modifications and anti-obesity drugs to achieve or maintain adequate weight loss for at least 6 months + the patient is fit for surgery + commit to the need for long-term follow-up:  BMI ≥ 40 kg/m^2  BMI ≥ 35 kg/m^2 and other significant disease (eg: type 2 DM, hypertension, sleep apnea) • Indications as first-line option  BMI > 50 kg/m2 (consider orlistat before surgery if the waiting time is long) • Which procedures?  Laparoscopic-adjustable gastric banding (LAGB) is the first-line intervention in patients with a BMI of 30-39kg/m^2 (produces less weight loss than malabsorptive or mixed procedures but as it has fewer complications)  Sleeve gastrectomy (most common form of bariatric surgery) may be considered for patients with a BMI > 40 kg/m^2  Primarily malabsorptive procedures (e.g. biliopancreatic diversion with duodenal switch) are usually reserved for very obese patients (e.g. BMI > 60 kg/m^2) __________________________________________________________ Lipid disorders: Overview Causes • Acquired (more common)  Obesity  Diabetes mellitus  Heavy consumption of alcohol  Hypothyroidism  Nephrotic syndrome  Cholestatic liver disease  Cushing disease  Drugs: antipsychotics, beta blockers (e.g., metoprolol), oral contraceptive pill, highdose diuretic use • Inherited (less common) Pathophysiology • Elevated LDL and reduced HDL → promote atherosclerosis → increased risk of cardiovascular events Classification: WHO/Fredrickson classification Classification Aetiology Lipid profile Notes Type 1 Familial HyperChylomicronaemia Deficiency of Apo Cll or LPL (lipoprotein lipase) typically presents with eruptive xanthoma, abdominal colic. acute pancreatitis Type 11A Familial hypercholesterolaemia Heterozygous type is Common Associated with tendon xanthoma Type 11B Familial Combined Hyperlipidaemia LDL-receptor deficiency The commonest type (two thirds). Associated with glucose intolerance. Type 111 Remnant hyperlipidaemia (dysbetalipoproteinaemia) overproduction of apo B-100 &(VLDL) by the liver Abnormal ApoE ↑ IDL palmar xanthoma is diagnostic fibrates are first line treatment Type 1V Familial hypertriglyceridaemia Overproduction or↓catabolism of VLDL ( due to ↓ LPL) often “polygenic”. Common abdominal pain, eruptive xanthoma and strong family history = think of Chylomicronaemia Lipoproteins • High density lipoprotein (HDL)  Secreted by intestinal epithelium and liver  Composition: Mostly proteins and phospholipids  Function: Transport cholesterol from peripheral tissues (e.g., atherosclerotic arteries) to the liver (reverse cholesterol transport), where it is excreted (e.g., via bile)  Often referred to as “good cholesterol.”  Low levels of HDL are associated with an increased risk of ischaemic heart disease  Among other apoproteins, HDL contains Apo A-1, which is found only in HDL.  Causes of ↑HDL  Exercise  modest alcohol consumption.  ↑oestrogen levels (e.g. contraceptive pill). Women have naturally higher HDL levels compared to men, due to higher oestrogen levels.  Causes of ↓HDL  Diabetes causes low HDL • Low-density lipoprotein (LDL)  Arise from IDL that is modified by hepatic lipases in peripheral tissue and the liver  Composition: Mostly cholesterol  Function: Transport cholesterol from the liver to peripheral tissues and arteries Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad ↑ chylomicrons ↑TC > 7.5 ↑LDL-C > 4.9 ↑ LDL ↑VLDL ↑TG ↑TG ↑VLDL Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism  Often referred to as “bad cholesterol”  they carry only one apolipoprotein, Apo B-100 which binds tissue LDL receptors to facilitate receptor-mediated uptake of cholesterol. • Intermediate-density lipoprotein (IDL)  Formed from VLDL degradation  Function : Transport triglycerides and cholesterol to the liver • Very low-density lipoprotein (VLDL)  Secreted by the liver  Composition: Mostly triglycerides  Function: Transport hepatic triglycerides from the liver to peripheral tissues • Chylomicron  Composition: Mostly triglycerides  Secreted by the intestinal epithelial cells into lymphatics  The nascent (early) chylomicron contains only one apoprotein, Apo B-48.  Function:  Transport dietary triglycerides from the intestine to peripheral tissues  Transport dietary cholesterol to the liver in the form of triglyceride-depleted chylomicron remnants  Lipoprotein lipase (LPL) hydrolyses the chylomicron into glycerol, fatty acids, and chylomicron remnant using Apo C-2 as a co-factor. Deficiencies of LPL or Apo C-2 cause familial hyperchylomicronemia.  Apo E mediates Endocytosis of chylomicron remnants Apolipoproteins • The following table shows the apolipoproteins present on the surface of various lipoproteins: Lipoproteins apolipoproteins Chylomicron Apo CII & Apo B48 Chylomicron remnant Apo E VLDL Apo CII & Apo B100 LDL Apo B100 IDL Apo E & Apo B100 HDL Apo A1 ____________________________________________________ Familial Combined Hyperlipidaemia (type IIB) Overview • Type IIB in Frederickson classification of inherited hyperlipoproteinemia • Commonest type (two thirds) • Prevalence → 1% • Autosomal dominant • polygenic disorder • Pathogenesis: Defective LDL receptors or ApoB-100 • Hepatic overproduction of apoB-100-containing lipoprotein particles (ie, VLDL and LDL), →↑total cholesterol, triglycerides, and apoB levels Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad • Associated with: Obesity, glucose intolerance, and hyperuricaemia Features • Xanthelasma • premature cardiovascular disease • ↑ LDL, ↑VLDL, ↑TG Treatment • Statins ( e.g. atorvastatin) Which feature suggests a diagnosis of familial combined hyperlipidaemia (FCHL) rather than heterozygous familial hypercholesterolaemia (FH)?  Presence of glucose intolerance ____________________________________________________ Remnant hyperlipidaemia (type III) Overview • Type III in Frederickson classification of inherited hyperlipoproteinemia • Autosomal recessive • Pathogenesis: Defective ApoE → accumulation of IDL and chylomicron remnants Features • Premature atherosclerosis • Palmar and tuberoeruptive xanthomas • ↑Total cholesterol , ↑triglycerides, ↑Chylomicrons, ↑VLDL Diagnosis • Definitive diagnosis can be made by lipoprotein electrophoresis or genotyping of apoprotein E. Management • fibrates are first line treatment  mode of action → Increased lipoprotein lipase activity via PPAR-alpha (PPARalpha agonist) Palmar xanthomas are pathognomonic of dysbetalipoproteinaemia (type III hyperlipoproteinemia). ____________________________________________________ Familial hypertriglyceridaemia Overview • Type IV in Frederickson classification of inherited hyperlipoproteinemia • Autosomal dominant condition • Usually due to polygenic factors • Affects 1 in 300 people. • Can be exacerbated by:  alcohol  glucocorticoids  thiazide diuretics Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism Pathogenesis • Hepatic over production of VLDL • ↓lipoprotein lipase (a potent metabolizer of triglycerides within VLDL) → accumulation of VLDL molecules and triglycerides. Features • Premature atherosclerosis • Acute pancreatitis if triglyceride levels is very high (>11 mmol/l), likely due to pancreatic capillary obstruction. • Features of hyperglycemia (due to abnormal glucose tolerance and insulin resistance) • Eruptive xanthomas (yellow papules usually seen on the back, chest, and proximal extremities). • Lipaemia retinalis (pale pink milky appearance to the retinal vessels or even to the retina itself). • Retinal vein thrombosis Diagnosis • Lipid profile  raised very-low-density lipoprotein (VLDL) and triglyceride levels.  total cholesterol and LDL levels are typically normal Management • first-line →fibrates • statins if there is mixed hyperlipidaemia Tendon xanthomata are diagnostic hallmarks of heterozygous familial hypercholesterolaemia (FH) Eruptive xanthomata Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Familial hypercholesterolaemia (FH) Overview • Type II in Frederickson classification of inherited hyperlipoproteinemia • Autosomal dominant condition • Caused by mutations in the gene which encodes the LDL-receptor protein. • Heterozygous FH occur in about 1 in 300. Homozygous patients are rare • Affect around 1 in 500 people. Pathogenesis • Defective LDL receptors or ApoB-100, missing LDL receptors Features • early cardiovascular disease (CVD) • Tuberous/tendon xanthomas (especially the Achilles tendon) • Xanthelasma • High levels of LDL-cholesterol which, if untreated, may cause Suspected diagnosis: NICE advice to suspect diagnosis of FH if: • total cholesterol level ˃7.5 mmol/l • premature coronary heart disease (˂60 years) in an index individual or first-degree relative. • children of affected parents:  if one parent is affected, arrange testing in children by age 10  if both parents are affected, arrange testing in children by age 5 Clinical diagnosis is now based on the Simon Broome criteria: • Total cholesterol (TC) > 7.5 mmol/l and LDL-C > 4.9 mmol/l plus:  For definite FH: tendon xanthoma in patients or 1st or 2nd degree relatives or DNAbased evidence of FH  For possible FH: family history of myocardial infarction below age 50 years in 2nd degree relative, below age 60 in 1st degree relative, or a family history of raised cholesterol levels • If LDL-C ˃13 mmol/l → Consider a clinical diagnosis of homozygous FH • Two measurements of LDL-C are required to confirm the diagnosis. The presence of tendon xanthomata and ↑LDL, ↑T.chol → familial hypercholesterolemia. Management • First-line: high-dose statins  statins should be discontinued in women 3 months before conception due to the risk of congenital defects  aim for at least a 50% reduction in LDL C concentration from the baseline measurement • Second-line (if statin therapy is not tolerated or contraindicated) or if lipid not controlled by statin alone → Ezetimibe • Third-line: (If statins or ezetimibe are not tolerated or contraindicated) → either a bile acid sequestrant (resin) or a fibrate • Fourth-line: LDL apheresis: for homozygous or heterozygous FH who did not respond to drugs Notes & Notes for MRCP By Dr. Yousif Abdallah Hamad Chapter 1 Endocrinolog & Metabolism  ACE inhibitors should not be used in people who are being treated with LDL apheresis. Instead, angiotensin-receptor blocking agents should be used.  warfarin should be discontinued 4 days before LDL apheresis and substituted with low molecular weight heparin. • Fifth-line: Liver transplantation • Screening for first-degree relatives (they have a 50% chance of having the disorder). This includes children who should be screened by the age of 10 years if there is one affected parent. • Lifestyle interventions: Diet  total fat intake is 30% or less of total energy intake  saturated fats are 10% or less of total energy intake  intake of dietary cholesterol is less than 300 mg/day Lipid-lowering therapy in patients with ACS: (2019 ESC/EAS Guidelines for the management of dyslipidaemias) • For patients who present with an ACS, and whose LDL-C levels are not at goal despite already taking a maximally tolerated statin dose and ezetimibe, adding a PCSK9 inhibitor early after the event (if possible, during hospitalization for the ACS event) should be considered. ____________________________________________________ Secondary hypertriglyceridaemia The commonest cause of a mild hypertriglyceridaemia is obesity secondary to a reduced efficacy of lipoprotein lipase activity and overproduction of VLDL. Causes of predominantly hypertriglyceridaemia • Obesity  The commonest cause of a mild hypertriglyceridaemia is obesity secondary to a reduced efficacy of lipoprotein lipase activity and overproduction of VLDL.  hypertriglyceridaemia and raised transaminases are suggestive of increased hepatic fat → associated with Non-alcoholic steatohepatitis (NASH) • Type 2 diabetes mellitus  Bad diabetic control (↑↑ HbA1c) →↓ activity of lipoprotein lipase (LPL) (because LPL requires insulin for full activity) → hypertriglyceridaemia and low highdensity lipoprotein (HDL) • Alcohol • Chronic renal failure • Drugs: thiazides, non-selective beta-blockers, unopposed oestrogen • Liver disease Causes of predominantly hypercholesterolaemia • Nephrotic syndrome • Cholestasis • Hypothyroidism  Frank hypothyroidism is said to occur in 4% of patients with dyslipidaemias;  a raised thyroid-stimulating hormone (TSH) & normal free T4 occur in 10% of patients with dyslipidaemia  Total cholesterol often improves to some degree with thyroxine therapy but statins might be required as well.