Free T4 levels or the free T4 index is usually elevated, as is the free T3 level or free T3 index
– Assays for thyrotropin-receptor antibodies (particularly TSIs) almost always are positive.
– Detection of TSIs is diagnostic for Graves disease.
– Other markers of thyroid autoimmunity, such as antithyroglobulin antibodies or antithyroid peroxidase antibodies, are usually present.
– Other autoantibodies that may be present include thyrotropin receptor-blocking antibodies and anti–sodium-iodide symporter antibody.
The presence of these antibodies supports the diagnosis of autoimmune thyroid disease.
– The radioactive iodine uptake is increased and the uptake is diffusely distributed over the entire gland.

11-beta hydroxylase is stimulated by ACTH and responsible for conversion of 11-deoxycortisol to cortisol and deoxycorticosterone to corticosterone.

In 11-beta hydroxylase deficiency, the previously mentioned conversions are partially blocked, leading to:
– Increased levels of ACTH
– Accumulation of 11-deoxycortisol (which has limited biological activity) and deoxycorticosterone (which has mineralocorticoid activity)
– Overproduction of adrenal androgens (DHEA, androstenedione, and testosterone)

Elevated TSH (usually 4.5-10.0 mIU/L) with normal free T4 is considered mild or subclinical hypothyroidism.
Hypothyroidism commonly manifests as a slowing in physical and mental activity but may be asymptomatic. Symptoms and signs are often subtle and neither sensitive nor specific.
The following are symptoms of hypothyroidism:
– Fatigue, loss of energy, lethargy
– Weight gain
– Decreased appetite
– Cold intolerance
– Dry skin
– Hair loss
– Sleepiness
– Muscle pain, joint pain, weakness in the extremities
– Depression
– Emotional lability, mental impairment
– Forgetfulness, impaired memory, inability to concentrate
– Constipation
– Menstrual disturbances, impaired fertility
– Decreased perspiration
– Paraesthesia and nerve entrapment syndromes
– Blurred vision
– Decreased hearing
– Fullness in the throat, hoarseness
Physical signs of hypothyroidism include the following:
– Weight gain
– Slowed speech and movements
– Dry skin
– Jaundice
– Pallor
– Coarse, brittle, straw-like hair
– Loss of scalp hair, axillary hair, pubic hair, or a combination
– Dull facial expression
– Coarse facial features
– Periorbital puffiness
– Macroglossia
– Goitre (simple or nodular)
– Hoarseness
– Decreased systolic blood pressure and increased diastolic blood pressure
– Bradycardia
– Pericardial effusion
– Abdominal distention, ascites (uncommon)
– Hypothermia (only in severe hypothyroid states)
– Nonpitting oedema (myxoedema)
– Pitting oedema of lower extremities
– Hyporeflexia with delayed relaxation, ataxia, or both.

Intensive physical training and participation in competitive sports during childhood and early adolescence may affect athletes’ pubertal development.
Female athletes who do not begin secondary sexual development by the age of 14 or menstruation by the age of 16 warrant a comprehensive evaluation and treatment.
Since she is still 14, adequate diet and observation are enough.

The empty boxes indicate that the patient has run out of his medication.
Chronic administration of high doses of glucocorticoids (GCs) (e.g., prednisone or prednisolone) and also other hormones such as oestrogens, progestins, androgens and growth hormone induce varying degrees of tolerance, resulting in a progressively decreased response to the effect of the drug, followed by dependence and rarely addiction.
The glucocorticoid withdrawal syndrome (GWS) has been considered a withdrawal reaction due to established physical dependence on supraphysiological GC levels.
The severity of GWS depends on the genetics and developmental history of the patient, on his environment, and on the phase and degree of dependence the patient has reached. Its management should include a temporary increase in the dose of GCs followed by gradual, slow tapering to a maintenance dose.

This patient has polycystic ovarian syndrome (PCOS). Medical management of PCOS is aimed at the treatment of metabolic derangements, anovulation, hirsutism, and menstrual irregularity.
First-line medical therapy usually consists of an oral contraceptive to induce regular menses. The contraceptive not only inhibits ovarian androgen production but also increases sex hormone-binding globulin (SHBG) production. The American College of Obstetricians and Gynaecologists (ACOG) recommends the use of combination low-dose hormonal contraceptive agents for long-term management of menstrual dysfunction.
If symptoms such as hirsutism are not sufficiently alleviated, an androgen-blocking agent may be added. Pregnancy should be excluded before therapy with oral contraceptives or androgen-blocking agents are started.
First-line treatment for ovulation induction when fertility is desired is clomiphene citrate. Second-line strategies may be equally effective in infertile women with clomiphene citrate–resistant PCOS.

Sitagliptin-induced pancreatitis can occur at any time after the initiation of therapy, even after several years. Patients taking sitagliptin who present with signs and symptoms of mild or severe pancreatitis should immediately discontinue sitagliptin and use an alternate medication regimen for control of type 2 diabetes.
In response to pancreatitis reported in post-marketing surveillance through the Adverse Event Reporting System (AERS), the FDA has issued revised prescribing information for sitagliptin stating that cases of acute pancreatitis have been reported with use, to monitor closely for signs and symptoms of pancreatitis, and to use sitagliptin with caution in patients with a history of pancreatitis.

Classically, pheochromocytoma manifests with the following 4 characteristics:
– Headaches
– Palpitations
– Sweating
– Severe hypertension

The Endocrine Society, the American Association for Clinical Chemistry, and the European Society of Endocrinology have released clinical practice guidelines for the diagnosis and management of pheochromocytoma.
Biochemical testing via measurement of plasma free metanephrines or urinary fractionated metanephrines should be performed in patients suspected of having pheochromocytoma.

Catecholamines produced by pheochromocytomas are metabolized within chromaffin cells. Norepinephrine is metabolized to normetanephrine and epinephrine is metabolized to metanephrine. Because this process occurs within the tumour, independently of catecholamine release, pheochromocytomas are best diagnosed by measurement of these metabolites rather than by measurement of the parent catecholamines.

Three classes of medications are appropriate for the management of major triglyceride elevations: fibric acid derivatives, niacin, and omega-3 fatty acids.

Fibrate is used as a first-line agent for reduction of triglycerides in patients at risk for triglyceride-induced pancreatitis.

High-dose niacin (vitamin B-3) (1500 or more mg/d) decreases triglyceride levels by at least 40% and can raise HDL cholesterol levels by 40% or more. Niacin also reliably and significantly lowers LDL cholesterol levels, which the other major triglyceride-lowering medications do not.

Omega-3 fatty acids are attractive because of their low risk of major adverse effects or interaction with other medications. At high doses (>4 g/d), triglycerides are reduced.

Cabergoline, an ergot derivative, is a long-acting dopamine agonist. It is usually better tolerated than Bromocriptine (BEC), and its efficacy profiles are somewhat superior to those of BEC. It offers the convenience of twice-a-week administration, with a usual starting dose of 0.25 mg biweekly to a maximum dose of 1 mg biweekly. Some studies have shown efficacy even with once-a-week dosing. Cabergoline appears to be more effective in lowering prolactin levels and restoring ovulation. Up to 70% of patients who do not respond to BEC respond to cabergoline.

The clinical manifestations of Small cell lung cancer (SCLC) can result from local tumour growth, intrathoracic spread, distant spread, and/or paraneoplastic syndromes.
Hypertrophic pulmonary osteoarthropathy (HPO) is a rare paraneoplastic syndrome that is frequently associated with lung cancer; however, the incidence of clinically apparent HPO is not well known.
SIADH is present in 15% of cases and most commonly seen.
Although hypercalcaemia is frequently associated with malignancy, it is very rare in small cell lung cancer despite the high incidence of lytic bone metastases.
Ectopic Cushing’s syndrome in SCLC does not usually exhibit the classic signs of Cushing’s syndrome and Cushing’s syndrome could also appear during effective chemotherapy.
Chemotherapy is the treatment of choice in SCLC.

Primary aldosteronism now is considered one of the more common causes of secondary hypertension (HTN).
Individuals with primary aldosteronism may present with hypokalaemia metabolic alkalosis; however, as many as 38% of patients with primary aldosteronism may be normokalaemia at presentation.
Routine laboratory studies can show hypernatremia, hypokalaemia, and metabolic alkalosis resulting from the action of aldosterone on the renal distal convoluted tubule (DCT) (i.e., enhancing sodium reabsorption and potassium and hydrogen ion excretion).
Plasma aldosterone/plasma renin activity ratio is used for screening because it is fairly constant over many physiologic conditions.

The patient is clinically free, so Cushing diseases can be exclude.

Charcot arthropathy is a progressive condition of the musculoskeletal system that is characterized by joint dislocations, pathologic fractures, and debilitating deformities. It results in progressive destruction of bone and soft tissues at weight-bearing joints. In its most severe form, it may cause significant disruption of the bony architecture.
Charcot arthropathy can occur at any joint; however, it occurs most commonly in the lower extremity, at the foot and ankle. Diabetes is now considered to be the most common aetiology of Charcot arthropathy.

The patient is most likely to have Bulimia nervosa. A young girl with a low body mass contributes to the low urea. Hypokalaemia and hyponatraemia are due to vomiting. Her urine sodium is also low.
– In Addison’s diseases, there are low levels of sodium and high levels of potassium in the blood. In acute adrenal crisis: The most consistent finding is elevated blood urea nitrogen (BUN) and creatinine. Urinary and sweat sodium also may be elevated.
– In Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) there is hyponatremia with corresponding hypo-osmolality, continued renal excretion of sodium, urine less than maximally dilute and absence of clinical evidence of volume depletion.

The patient has hyperthyroidism and its most common cause is Grave’s Disease.
Grave’s Disease is an autoimmune disease due to circulating autoantibodies known as TSH receptor stimulating autoantibodies or Thyroid-stimulating immunoglobulins (TSIs) that bind to and activate thyrotropin receptors, causing the thyroid gland to grow and the thyroid follicles to increase the synthesis of thyroid hormone.

During pregnancy, profound changes in thyroid physiology occur to provide sufficient thyroid hormone (TH) to both the mother and foetus. This is particularly important during early pregnancy because the fetal thyroid starts to produce considerable amounts of TH only from approximately 20 weeks of gestation, until which time the foetus heavily depends on the maternal supply of TH. This supply of TH to the foetus, as well as increased concentrations of TH binding proteins (thyroxine-binding globulin) and degradation of TH by placental type 3 iodothyronine deiodinase, necessitate an increased production of maternal TH. This requires an intact thyroid gland and adequate availability of dietary iodine and is in part mediated by the pregnancy hormone human chorionic gonadotropin, which is a weak agonist of the thyroid-stimulating hormone (TSH) receptor. As a consequence, serum-free thyroxine (FT4) concentrations increase and TSH concentrations decrease from approximately the eighth week throughout the first half of pregnancy, resulting in different reference intervals for TSH and FT4 compared to the non-pregnant state.

Paget disease is a localized disorder of bone remodelling that typically begins with excessive bone resorption followed by an increase in bone formation. This osteoclastic over activity followed by compensatory osteoblastic activity leads to a structurally disorganized mosaic of bone (woven bone), which is mechanically weaker, larger, less compact, more vascular, and more susceptible to fracture than normal adult lamellar bone.
Approximately 70-90% of persons with Paget disease are asymptomatic; however, a minority of affected individuals experience various symptoms, including the following:
– Bone pain (the most common symptom)
– Secondary osteoarthritis (when Paget disease occurs around a joint)
– Bony deformity (most commonly bowing of an extremity)
– Excessive warmth (due to hypervascularity)
– Neurologic complications (caused by the compression of neural tissues)
Measurement of serum alkaline phosphatase—in some cases, bone-specific alkaline phosphatase (BSAP)—can be useful in the diagnosis of Paget disease. Elevated levels of urinary markers, including hydroxyproline, deoxypyridinoline, C-telopeptide, and N -telopeptide, may help identify patients with Paget disease.
Serum calcium and phosphate levels should be within the reference range in patients with Paget disease.

Treatment with fibrates, a widely used class of lipid-modifying agents, results in a substantial decrease in plasma triglycerides and is usually associated with a moderate decrease in LDL cholesterol and an increase in HDL cholesterol concentrations.
Evidence from studies is available to implicate 5 major mechanisms underlying the above-mentioned modulation of lipoprotein phenotypes by fibrates:
1. Induction of lipoprotein lipolysis.
2. Induction of hepatic fatty acid (FA) uptake and reduction of hepatic triglyceride production.
3. Increased removal of LDL particles. Fibrate treatment results in the formation of LDL with a higher affinity for the LDL receptor, which is thus catabolized more rapidly.
4. Reduction in neutral lipid (cholesteryl ester and triglyceride) exchange between VLDL and HDL may result from decreased plasma levels of TRL.
5. Increase in HDL production and stimulation of reverse cholesterol transport. Fibrates increase the production of apoA-I and apoA-II in the liver, which may contribute to the increase of plasma HDL concentrations and a more efficient reverse cholesterol transport.

Graves’ disease is the most common cause of thyrotoxicosis in pregnancy.

– Poor control of thyrotoxicosis is associated with pregnancy loss, pregnancy-induced hypertension, prematurity, low birth weight, intrauterine growth restriction, stillbirth, thyroid storm, and maternal congestive heart failure.

– Antithyroid drugs are the treatment of choice of hyperthyroidism during pregnancy. The lowest dose of ATD needed to maintain TT4 1.5× the upper limit of the non-pregnant reference range or FT4 at the upper limit of the reference range should be used.
Two different antithyroid drug (ATD) regimens are in common use for Grave’s disease: i) Titration method and ii) Block-and-replace method.
In the titration method, the usual starting dose is 15–30 mg/day methimazole (or equivalent doses of other thionamides); further to periodic thyroid status assessment, daily dose is tapered down to the lowest effective dose (avoiding both hyper- and hypothyroidism).
The block-and-replace method uses persistently high ATD doses in association with L-thyroxine replacement to avoid hypothyroidism; treatment lasts 6 months. This method has advantages and disadvantages over the titration method. Higher doses of ATDs may have a greater immunosuppressive action useful for a permanent remission of hyperthyroidism, but this effect remains to be demonstrated.
Avoidance of hypothyroidism or ‘escape’ of hyperthyroidism seems easier than with the titration method; treatment is shorter, and the number of visits lower. On the other hand, the much higher number of tablets taken every day may create problems of poor compliance. The block-and-replace method should not be used during pregnancy.

– Breastfeeding has been shown to be safe in mothers taking ATDs in appropriate doses.

The patient is most likely to have Addison’s disease as he has a history of autoimmune disease, hyperkalaemia and hypotension.
It is important to keep an Addisonian crisis on the differential in cases of shock, especially since adrenal crisis can be the patient’s first presentation of adrenal insufficiency.
Patients with Addison’s disease are prone to developing hypoglycaemia due to loss of the glucogenic effect of glucocorticoids. Given the sudden deterioration, a glucose level must be checked.

The patient has Cushing syndrome suggested by the elevated 24hr urine free cortisol. Hence, the mass is most probably a cortisol secreting adenoma.

Approximately one third of patients treated with radioiodine therapy develop transient hypothyroidism. Unless a patient is highly symptomatic, thyroxine replacement may be withheld if hypothyroidism occurs within the first 2 months of therapy. If it persists for longer than 2 months, permanent hypothyroidism is likely and replacement with T4 should be initiated.

Raloxifene is a selective oestrogen-receptor modulator (SERM) that has been approved for use in the prevention and treatment of osteoporosis in postmenopausal women.
A SERM interacts with oestrogen receptors, functioning as an agonist in some tissues and an antagonist in other tissues. Because of their unique pharmacologic properties, these agents can achieve the desired effects of oestrogen without the possible stimulatory effects on the breasts or uterus.

RET (rearranged during transfection) is a receptor tyrosine kinase involved in the development of neural crest derived cell lineages, kidney, and male germ cells. Different human cancers, including papillary and medullary thyroid carcinomas, lung adenocarcinomas, and myeloproliferative disorders display gain-of-function mutations in RET.
In over 90% of cases, MEN2 syndromes are due to germline missense mutations of the RET gene.
Multiple endocrine neoplasias type 2 (MEN2) is an inherited disorder characterized by the development of medullary thyroid cancer (MTC), parathyroid tumours, and pheochromocytoma.

Achondroplasia is the most common type of short-limb disproportionate dwarfism. A single gene mapped to the short arm of chromosome 4 (band 4p16.3) is responsible for achondroplasia and is transmitted as an autosomal dominant trait. All people with achondroplasia have a short stature.
Characteristic features of achondroplasia include an average-size trunk, short arms and legs with particularly short upper arms and thighs, limited range of motion at the elbows, and an enlarged head (macrocephaly) with a prominent forehead. Fingers are typically short and the ring finger and middle finger may diverge, giving the hand a three-pronged (trident) appearance. People with achondroplasia are generally of normal intelligence.
Examination of the infant after birth shows increased front-to-back head size. There may be signs of hydrocephalus. It may be diagnosed radiographically at birth, or becomes obvious within the first year with disparity between a large skull, normal trunk length and short limbs.

The use of hormone replacement therapy (HRT) based on unopposed oestrogen increases the risk of endometrial cancer, and uterine hyperplasia or cancer.
Evidence from randomized controlled studies showed a definite association between HRT and uterine hyperplasia and cancer. HRT based on unopposed oestrogen is associated with this observed risk, which is unlike the increased risk of breast cancer linked with combined rather than unopposed HRT.

Pregnancies affected by T1DM are at increased risk for preterm delivery, preeclampsia, macrosomia, shoulder dystocia, intrauterine fetal demise, fetal growth restriction, cardiac and renal malformations, in addition to rare neural conditions such as sacral agenesis.
Successful management of pregnancy in a T1DM patient begins before conception. Research indicates that the implementation of preconception counselling, emphasizing strict glycaemic control before and throughout pregnancy, reduces the rate of perinatal mortality and malformations.
The 2008 bulletin from the National Institute for Health and Clinical Excellence recommends that preconception counselling be offered to all patients with diabetes. Physicians are advised to guide patients on achieving personalized glycaemic control goals, increasing the frequency of glucose monitoring, reducing their HbA1C levels, and recommend avoiding pregnancy if the said level is > 10%.
Other sources suggest deferring pregnancy until HbA1C levels are > 8%, as this margin is associated with better outcomes.

Biguanides (Metformin):
People who take metformin alone should be able to fast safely given that the possibility of hypoglycaemia is minimal. However, patients should modify its dose and administration timing to provide two-thirds of the total daily dose, which should be taken immediately with the sunset meal, while the other third is taken before the predawn meal.

Thiazolidinediones: No change needed.

Sulfonylurea:
Once-daily sulfonylurea (such as glimepiride or gliclazide MR): the total daily dose should be taken with the sunset meal.
Shorter-acting sulfonylurea (such as gliclazide twice daily): the same daily dose remains unchanged, and one dose should be taken at the sunset meal and the other at the predawn meal.
Long-acting sulfonylurea (such as glibenclamide): these agents should be avoided.

It is important that diabetic patients to eat a healthy balanced diet and choose foods with a low glycaemic index (such as complex carbohydrates), which can help to maintain blood glucose levels during fasting. Moreover, it is crucial to consume adequate fluids to prevent dehydration. Physical activity is encouraged, especially during non-fasting periods.

The patient has hyperprolactinaemia with otherwise normal oestradiol, FSH and LH. This is highly suggestive of Prolactinoma rather than a non functioning tumour.
In polycystic ovaries, there is increase in the level of LH while FSH is normal or low.

Autonomic Neuropathy may involve the cardiovascular, gastrointestinal, genitourinary systems and the sweat glands.
Patients with generalized autonomic neuropathies may report ataxia, gait instability, or near syncope/syncope. In addition, autonomic neuropathies have further symptoms that relate to the anatomic site of nerve damage—gastrointestinal, cardiovascular, bladder, or sudomotor.
– Gastrointestinal autonomic neuropathy may produce the following symptoms:
Dysphagia, abdominal pain, nausea/vomiting, malabsorption, faecal incontinence, diarrhoea, constipation.
– Cardiovascular autonomic neuropathy may produce the following symptoms :
Persistent sinus tachycardia, orthostatic hypotension, sinus arrhythmia, decreased heart variability in response to deep breathing, near syncope upon changing positions from recumbent to standing.
– Bladder neuropathy (which must be differentiated from prostate or spine disorders) may produce the following symptoms:
Poor urinary stream
Feeling of incomplete bladder emptying
Straining to void
– Sudomotor neuropathy may produce the following symptoms:
Heat intolerance
Heavy sweating of head, neck, and trunk with anhidrosis of lower trunk and extremities
Gustatory sweating