Endocrinology

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An article on Thyroid Disorders Submitted by Dr.Tariq Azeez President Pakistan Society of Family Physicians

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Endocrinology

  1. 1. Hypothyroidism: Panhypopituitarism Normal Thyroid State: Isolated TSH deficiency Synthesis and release of thyroid Hypothalamic: hormone is controlled by TSH Neoplastic released from the anterior pituitary Infilterative (sarcoidosis) TSH is controlled by the release of Congenital defects thyroid releasing hormone (TRH) Infection (encephalitis) from the hypothalamus and a negative Causes of Hypothyroidism: feedback loop to the pituitary Self-limiting Thyroid hormone production is Following withdrawal of suppressive dependent on adequate iodine intake thyroid therapy Normal Thyroid State: Subacute and chronic thyroiditis with Thyroid hormone is reversibly transient hypothyroidism bound to various proteins including Postpartum thyroiditis thyroxin-binding globulin (TBG) Symptoms and Signs: Free unbound portions are Non-specific. biologically active May be confused with other T4 is the predominant circulating conditions especially in postpartum hormone depression and elderly. T4 is deiodinated to T3 Maintain high index of suspicion. T3 is biologically more active than In older patients, hypothyroidism T4 but has a shorter half-life may be confused with Alzheimer’s Hypothyroidism: and depression. 1.8% of total population. Patient may end up getting treated Second only to DM as most common for depression. endocrine disorder. Clinical Features – Adult: Incidence increases with age. Insidious, non specific onset More common in females. Fatigue, lethargy, constipation 2-3% of older women. Cold intolerance Causes of Hypothyroidism: Muscle stiffness, cramps, carpel Non-Goitrous Causes: tunnel syndrome Post-ablative (radio-iodine, surgery) Menstrual irregularities Congenital developmental defect Slowing of intellectual and motor Atrophic thyroiditis activities Post radiation (e.g., for lymphoma) Decreasing appetite and weight gain Causes of Hypothyroidism: Clinical Features – Adult: Goitrous Dry skin, hair loss Chronic thyroiditis (Hashimotos Deep hoarse voice thyroiditis) Decreasing visual acuity Iodine deficiency Obstructive sleep apnoea Drugs (amiodarone, ASA, iodides, Clinical Features – Myxoedema: lithium, IFN) Dull expressionless face, sparse hair Heritable biosynthetic defects Periorbital puffiness, Maternally transmitted antithyroid macroglossiaPale cool skin that feels agents, iodides rough and doughy Pituitary Enlarged heart
  2. 2. Megacolon / intestinal obstruction Thyroxin can cause increases in Psychiatric symptoms e.g resting heart rate and blood pressure Depression, psychosis So replacement should start at low Clinical Features – Myxoedema: doses in older and patients at risk for Cerebellar ataxia cardiovascular compromise Prolonged relaxation phase of deep Treatment of Hypothyroidism: tendon reflexes Need for replacement Peripheral neuropathy Patients >50 or high risk of Cardiac Encephalopathy Disease Common signs and symptoms: Monitor TSH - Primary S/S % pt’s affected: hyperthyroidism or Weakness 99 Free T4 - Secondary hypothyroidism, Skin changes 97 every 6-8 Weeks and adjust doses Slow speech 91 Monitoring thyroid function: Eyelid edema 90 Most patients can be followed by Cold sensation 89 serial TSH measurements. Decreased sweating 89 Changes in TSH levels lag behind Cold skin 83 serum thyroid levels. Thick tongue 82 So TSH should not be checked Facial edema 79 sooner than four weeks after adjusting Coarse hair 76 doses. Skin pallor 67 Full effect of replacement on TSH Forgetfulness 66 may not become apparent until eight Constipation 61 weeks. Diagnosis: Patients with pituitary insufficiency, In Primary Hypothyroidism; T3 and T4 can be followed. TSH is high. Goal is to keep thyroid hormone Free thyroid hormone are depressed. level in middle to upper range of In Secondary Hypothyroidism: normal. Both TSH and free thyroid Frequency: hormones are low. TSH or Free T4 monitored yearly. Anti bodies in hypothyroidism: No data supports the practice. Anti bodies: Usually once stable dosage is Anti thyroid peroxidase [ anti established, it remains stable until microsomal] antibodies 60-70 years. Anti thyroglobulin antibodies. In elderly serum albumin levels may Anti TSH receptor (blocking) decrease, so dosage may have to be antibody decreased by 20%. In primary hypothyroidism; Less frequent monitoring in young - up to 12 % pts do have anti gastric patients and annually in elderly. parietal cell Increased thyroxin Requirements: antibodies. Pregnancy - these pts can develop pernicious Gastrointestinal Disorders anemia. - Mucosal diseases of the small bowel Thyroid Hormone Replacement: (e.g.,sprue)
  3. 3. - After jejunoileal bypass and small- bowel resection - Diabetic diarrhoea Conditions That May Block Deiodinase Synthesis - Selenium deficiency - Cirrhosis Increased thyroxin Requirements: Drugs That Interfere with Thyroxin Absorption Cholestyramine,Sucralfate,Aluminum hydroxide,Calcium carbonate, Ferrous sulphate Drugs That Increase the Cytochrome P450 Enzyme (CYP3A4) Rifampicin, Carbamazepine, Estrogen Phenytoin, Sertraline, ? Statins Drugs That Block T4 to T3 Conversion Amiodarone Decreased thyroxin Requirements: Aging (65 years and older) Androgen therapy in women Subclinical Hypothyroidism: TSH > 10 Antithyroid antibody positive Previous treatment of Grave’s disease Symptomatic Six to 12 monthly TSH measurement.
  4. 4. Management of Diabetes Mellitus Prevalence: India 6%, Pakistan: and Role of analogues By Dr Bilal bin 8.3% Younis (MRCP)UK: In SEAR, WPR: Pakistan stands 160 10th place in prevalence million 140 120 100 80 60 40 20 0 N. America S America Europe Australasia Africa Middle East Asia Disease burden of DM per hour: Ave Age of onset: New Cases – 4,100 Deaths – 810 50 40 Amputations – 230 30 20 Kidney Failure – 120 10 Females 39 yrs Males 42 yrs Blindness - 55 0 Females Males age of age of Onset Onset Natural History of Type 2 Diabetes: 350 300 Post Meal Glucose 250 200 (11.1 mmol/L) 150 (7.0 mmol/L) 100 50 % of Normal Function 250 200 Insulin Resistance 150 100 Developing Insulin Level 50 Diabetes sa f Beta cell failure 0 0 5 10 15 20 25 30 It’ r o -10 -5 Years of Diabetes Defined glycaemic targets in T2DM: atte e! Glucose control Healthy ADA1 AACE2 JD m m HbA1c (%) <6 <7 ≤ 6.5 5.8 ti The Rise of the Diabetes in Asia: Mean FPG mmol/l (mg/dl) <5.6 (<100) 5―7.2 <6 (90―130) (<110) 5.6 (10 Percentage increase in T2DM would be highest (170%) in India in next 20 Mean postprandial <7.8 <10* <7.8** ― years PG mmol/l (mg/dl) (<140) (<180) (<140) Our multi-site Indo-US collaborative study: 1/10 in Delhi and 1/5 Indian in US is a diabetic. In 2007: India-40 million DM, Pakistan: 7 million DM
  5. 5. Nateglinide Acarbose Repaglinie Rosiglitazoe Pioglitazoe Glimepiride Glipizide GITS Metformin 0 -0.5 -1. -1. -2. 0 5 0 Reduction in A1C (%) Reduction in A1C (%) Proposed Algorithm of Efficacy of OHAs Declines with Time: Therapy for Type 2 Diabetes: A1C rises at ~0.2% to 0.3% yearly Inadequate stable therapy nonpharmacologic therapy This rate is the same as for diet alone, sulfonylureas, and metformin β-Cell function declines at the same Severe symptoms Severe hyperglycae Oral 2 Oral 3 Oral mia Ketosis Pregnancy agent agents agents rate with all these treatments Combination treatments are routinely needed Add Insulin Earlier in the Algorithm Selected Clinical Trials Showing Tier 1: Well-validated core therapies: Benefits of Intensive Glycemic Life Style +Metformin + + Control: At diagnosis: Life Style Basal Insulin Intensive Insulin Trial Total + Metformin Life Style +Metformin Subjects + Sulfonylurea DCCT 1441 Step 1 Tier 2: Less Well-validated core therapies Step 2 Step 3 (type 1) Life Style +Metformin Life Style +Metformin Kumamoto Study 110 + + Pioglitazone No Hyperglycemia Oedema Pioglitazone + (type 2) UKPDS 5102 /CHF Nausea/Vomiting Sulfonylurea (type 2) Life Style +Metformin + Life Style +Metformin GLP-1 agonist Summary of Intervention Studies: + No Hyperglycemia Weight loss Basal Insulin Nausea/Vomiting Type 2 Clinical Pathway: Risk Reduction With Treatment: Entry Criteria Therapies Lowers Blood pressure treatment 20%–40% HbA1c Insulin Deficiency: Symptomatic, Lean Insulin Resistance: HTN, Dyslipidemia, Obesity 20%–50% Fasting < 200 mg/dL (11.1 mmol/L) Casual < 250 mg/dL (13.9 mmol/L) HbA1c <8% Medical Nutrition Stage ~1% Lipid treatment – 25%–55 Fasting 200–300 mg/dL (11.1 – 16.7 mmol/L) Oral Agent Stage Insulin Deficiency Insulin Resistance ~2% Glucose treatment 12%–35%* Secretagogues Sensitizers Casual 250–350 mg/dL (13.9 – 19.4 mmol/L) HbA1c 8-11% 10%–20%* Combination Oral Agent Stage Secretagogue + Sensitizer Correlation of A1c and ~2-4% Note: Each stage requires a pre- set BG target: and a timeline to Combination Oral Agent/Insulin Stage Oral Agent + Insulin Complication Risk: UKPDS: reach that goal Risk reduction in complications per Fasting > 300 mg/dL (16.7 mmol/ L) Physiologic Insulin Stage 4 Basal/Bolus Insulin > 4% each 1% reduction in mean A1c Casual > 350 mg/dL (19.4 RA - RA - RA - G mmol/L) HbA1c > 11% International Diabetes Center 50 Oral Antihyperglycemic Monotherapy - Maximum Therapeutic Effect on 40 A1C: 30 20 10 0
  6. 6. Glycemic Responses in the UKPDS: 9 10-Year Cohort 8 10-year median 7.9% 7 10-year median 7.0% 6 0 0 3 6 9 1 2 Year UKPDS Group. Lancet. 1998;352:837-853 s 50% of sulphonylurea-treated patients with T2DM required insulin after 6 years to achieve glycaemic target Normal Insulin Secretion: Insulin added when FPG >6 mmol/l 50 (>108 mg/dl) 40 30 20 10 50 requiring additional insulin n=826 HbA1c <7% 0 0 2 4 6 8 10 12 14 16 18 20 22 24 at 6 years SU-treated patients 47 Time (Hours) (%) 25 35 25 Insulin Action: 20 comparison of new Insulin Analogs Insulin levels (U/ml) 140 e in on 0 ul 0 Rapid(Lispro, Aspart) al s 120 in 1 2 3 4 5 6 lin ± su SU In Time since randomisation (years) 100 80 Regular Percentages of patients on different 60 glucose lowering therapy 40 Intremediate (NPH) 20 1 OAD 37% 0 Long (UL,HOE) 12 15 3 6 9 2 OAD 34% Hours 3 OAD 3% Insulin Alone 18% Insulin + OAD 8% From Orals to Insulin:
  7. 7. Diabetes Care: R/N – 0 –R/N – 0 or LP/N –0 – LP/N – 0 Dose Calculation and Adjustment If BG < 80 mg/dl 140-250 mg/dl > 250 mg/dl Begin modestly with 0.3 to 0.5 U/kg/ A.M. Pm N 1-2 u (a.b.) pm N 1-2 u (a) Pm N 1-2 u (a.b.) day insulin (total) am R or LP 1-2 u. am R or LP MIDDAY am N 1-2 U (f.h) 2/3 of this dose in the morning and (c.e.) 2-4 U (f.g) am N 2-4 U 1/3 in the evening P.M. am N 1-2U (d.e) am N 1-2 U (f.h) (f.h)  2/3 of the insulin should be NPH If BG < 100 mg/dl 160-250 mg/dl >250 mg/dl and 1/3 should be regular or simply BEDTIME pm R or LP 1-2 U (e) pm R or LP 1-2 U (f) pm R or LP 2-4 U (f) use 70/30 combination Control of Blood sugar Insulin vs non  Begin with loose control and tighten insulin: with experience  Tight control is dependant on the 350 stage of the disease 300 250 Type 2: Insulin Adjustment 200 150 Guidelines: 100 50 253.5mg 312mg Insulin Pattern Adjustments 0 insulin(alone Adjust insulin from 3- days pattern or combination) Determine which insulin is Controlled vs Uncontrolled: responsible for pattern Adjust by 2-4 units 100% Adjust only one dose at a time 90% 80% Correct hypoglycemia first. 70% If total dose >1.5 U/Kg. Consider 60% 50% controlled (200mg%and over insulization 40% 30% less) If hyperglycemia throughout the 20% 10% Uncontrolled( More than day, correct highest SMBG first; if all 0% 200mg%) 14 %Controlled within 50 mg/dl, correct AM first. Type 2: Insulin Start (cont): R/N – 0 –R/N –0 LP/N – 0 –LP/N – 0 At Diagnosis or from Oral Therapy Calculate total dose at 0.3 U/kg based on current weight AM MIDDAY PM BT Distribution2/3 0 1/3 0 R/N or LP/N ratio 1:2 1:1 - Pre-mixed insulin, 70/30 AM and 50/50 PM,may be used for patients Normal Insulin Secretion: unable to draw insulin correctly Refer patient for nutrition and diabetes education 50 40 30 20 10 0 Conventional Insulin Stage 2 0 2 4 6 8 10 12 14 16 18 20 22 24 R/N-0-R/N-0 or RA/N-0-RA/N-0:
  8. 8. 50 40 n = patient numbers in each BMI category NPH insulin 3.5 36 37 39 30 3.0 50 76 2.5 35 Mean weight change (kg) 20 2.0 34 1.5 55 10 1.0 69 42 0.5 0 0.0 0 2 4 6 8 10 12 14 16 18 20 22 24 -0.5 ≤25 >25-27 >27-29 >29-31 >31 Baseline BMI Management of Hyperglycemia Common Oral + Insulin Hermansen treat-to-target trial: Combinations: Overall hypoglycaemia Insulin detemir (n=237) 2000 ** A1C 1 or 2 Oral Agents NPH insulin (n=238) % + 1688 9.7 9.7 Glargine Baseline 1600 9 monotherapy ** 8.6 1200 923 908 ** Combination 800 755 8 therapy 519 7.6 387 400 7.2 1 8 7 7.0 0 All Major Minor confirmed Symptomatic unconfirmed ** p<0.001 Met Glim Oral Duration of action in type 2 diabetes: Hermansen treat-to-target trial: 0.4 U/kg 0.8 U/kg 1.4 U/kg weight change 86 Detemir 12.0 (8.5) 16.8 (6.8) 22.1 (2.6) 85 Glargine 10.2 (7.4) 19.4 (6.9) 24.0 (0) Weight (kg) 84 Objectives and design of Hermansen treat-to-target study: 83 Insulin detemir twice-daily 82 n=237 81 80 NPH twice-daily -2 1 3 5 7 9 11 13 15 17 19 21 23 n=238 Weeks Existing OADs continued (both groups) 24 weeks Philis-Tsimikas study: Weight change Insulin titrated to target: at 20 weeks detemir pm vs. NPH pm fasting and pre-dinner PG ≤6 mmol/l p=0.005 2.0 Weight change Hermansen treat-to-target study: 1.5 HbA1c and FPG : (kg) 1.6 1.0 Hermansen treat-to-target trial: Change in weight by baseline BMI 0.5 0.7 Insulin detemir pm NPH insulin pm Clean switch’ type 2 diabetes patients: change in HbA1c
  9. 9. Comparable glycaemic control Mean HbA1c (%) Mean HbA1c (%) NPH insulin 8.2 * 8.2 † Significantly fewer minor – 8.1 8.1 8.1 8.1 –0.6% hypoglycaemic events: 53% reduction 8.0 8.0 7.9 7.9 7.9 Significantly fewer minor nocturnal 7.8 7.7 7.8 7.7 hypoglycaemic events: 65% reduction 7.6 7.6 7.5 Significantly less weight gain: (0.7 7.5 7.5 7.4 Baseline Three 7.4 vs. 1.6 kg) Baseline Three months (n=152) months (n=97) No significant differences between PREDICTIVE detemir am and pm regarding HbA1c, TM data on file Clean switch’ type 2 diabetes patients: hypoglycaemia and weight change change in nocturnal hypoglycaemia Summary cont: * In randomised clinical trials in 8 8 Events per patient-year 7 6.9 7 NPH insulin insulin naïve T2DM patients: 6 5 -81% 6 5 Insulin detemir is equally effective in Events per patient-year 4 4 † achieving glycaemic control in 3 3 2 1.3 2 1.6 -75% comparison to NPH 1 0 1 0 0.4 Insulin detemir exerts significantly Baseline Three months Baseline Three months lower risk of overall and nocturnal n=175 n=118 *p<0.001 †p<0.05 hypoglycaemia in comparison to NPH Insulin detemir once-daily results in Clean switch’ type 2 diabetes patients: Detemi significantly less weight gain than NPH r 90 * 86 insulin NPH Mean weight (kg) Mean weight (kg) 85.5 89.3 -0.7 * 89 85 -0.5 OCD Spectrum disorders 88.6 84.5 84.6 and their treatment: 84.1 88 84 Baseline Three months Baseline Three months n=160 n=101 Insulin-naïve type 2 diabetes patients: change in HbA1c: Mean HbA1c (%) 8.9 8. 8. 8. -1.3% 8. 8. 7. 7. 7.6 7. 7. Baselin Three (n=1799) Change in HbA1c and weight in three comparable treat-to-target trials: Summary: Obsessive-Compulsive Disorder: Detemir vs. NPH in basal + OAD Affects Almost 3% Of World’s Therapy: Population
  10. 10. Start Anytime From Preschool To 18th century finally considered Adulthood Typically Between 20-24 medical issue Many Different Forms Of OCD – 20th century began treating with Differ From Person To Person behavioral techniques Cause Of OCD Is Still Unknown Theories: Better When Diagnosed Early Scientist split into 2 groups Psychological disorder where people Definition: are responsible for feelings they have Specific criteria to be clinically Abnormalities in the brain diagnosed Causes: Anxiety disorder with presence of Serotonin is involved in regulating obsessions or compulsions anxiety ego dystonic – realize thoughts and Abnormality in the neurotransmitter actions are irrational or excessive serotonin Must take up more than 1 hour a __In order to send chemical messages day serotonin must bind to the receptor Must disrupt daily routine sites located on the neighboring nerve Symptoms can’t result from effects cells of other medical conditions or __OCD suffers may have blocked or substances damaged receptor sites preventing Obsessions serotonin from functioning to full Repetitive And Constants Thoughts, potential Images, Or Impulses That Cause Possible genetic mutation Anxiety Or Distress __Some people suffering have Thoughts, Images, Or Impulses Not mutation in the human serotonin About Real-life Problems transporter gene Try To Ignore Or Counter Act Thoughts, Images, Or Impulse Thoughts, Images, Or Impulses “Recognized As A Product Of One’s Own Mind And Not Imposed From Without” Compulsions: Repetitive behaviors or mental acts person does in reaction to obsessions behaviors or mental acts done to avoid or decrease distress behaviors or mental acts are clearly excessive or not realistic History: 14th & 15th century thought people were possessed by the devil and treated by exorcism 17th century thought people were cleansing their guilt OCD and the Brain:
  11. 11. PET scans show people with OCD --- Medication have different brain activity from Cognitive-Behavioral Therapy: others Cognitive: change the way they Another theory: miscommunication think to deal with their fears between the orbital frontal cortex, the Behavioral: change the way they caudate nucleus, and the thalamus react to “anxiety-provoking” Caudate nucleus doesn’t function situations properly and causes thalamus to Exposure and Response Prevention become hyperactive and sends “never- --- Slowly learning to tolerate anxiety ending” worry signals between OFC associated with not performing ritual and thalamus ◊ OFC responds by behavior increasing anxiety Psychotherapy --- Talking with therapist to discover what causes the anxiety and how to deal with symptoms --- Systematic Desensitization --- Learning cognitive strategies to deal with anxiety then gradual exposure to feared object Medication: Antidepressants because of common depression Selective Serotonin Reuptake Comorbidity : Inhibitors (SSRIs): alter the levels of Has excessive comorbidity with neurotransmitter serotonin in the other diseases brain which helps brain cells Common diseases: Depression, communicate with one another Schizophrenia, Tourette Syndrome ---- Prevents excess serotonin from Depression is the most common being pumped back into original Many people with OCD suffered neuron that released it from depression first ---- Then can bind to receptor sites of 2/3 of OCD patients develop nearby neurons and send chemical depression ◊ makes OCD symptoms message that can help regulate anxiety worse and more difficult to treat and obsessive compulsive thoughts People with OCD common ---- Most effective drug treatment diagnosed as Schizophrenic ◊ hard to helping about 60% of patients separate obsessions from delusions Conclusion: Treatment: OCD is a complicated issue Only completely curable in rare Most cases are incurable cases Best form of treatment is CBT in Most people have some symptom combination with medication relief with treatment Most important thing that can be Treatment choices depend on the done to discover more about OCD and problem and patients preferences its treatments is to research the brain Most common treatments: ---Behavioral Therap --- Cognitive Therapy
  12. 12. The WHO predicts that by 2020, Major Depressive Disorder is expected to move from 4th to 2nd place in terms of greater global disease burden.” Mean overall prevalence of anxiety and depressive disorders in the community population was 34% (range 29-66% for women and 10-33% for men).”

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