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Showing posts with label endocrinology. Show all posts
Showing posts with label endocrinology. Show all posts

What are the Signs and Symptoms of Cushing’s Syndrome

Cushing syndrome produce changes in body fat,skin,bone,muscle,resproductive system,cardiovasular and blood.
Changes in the body fat
  •          Body fat Weight gain
  •        Central obesity
  •          Rounded face
  •          Fat pad on back of neck (“buffalo hump”)
Changes in the Skin
  •  Facial plethora
  •          Thin and brittle skin
  •          Easy bruising,
  •          Broad and purple stretch marks,
  •          Acne
  • ·        Hirsutism
Changes in Bone
  •         Osteopenia
  •          Osteoporosis (vertebral fractures),
  •         Decreased linear growth in children
Changes in muscle
  •          Muscle Weakness
  •          Proximal myopathy (prominent
  • ·        Atrophy of gluteal and upper leg muscles
Changes Metabolism
  • Glucose intolerance/diabetes
  • Dyslipidemia
  • Changes in the Cardiovascular system
  • Hypertension
  • Hypokalemia,
  • Edema
  • Atherosclerosis 
Reproductive system changes
  • Decreased libido,  amenorrhea in women
Blood and immune system changes
  • Increased susceptibility to infections
  • Increased white blood cell count
  • Eosinopenia,
  • Hypercoagulation with increased risk of deep vein thrombosis and pulmonary embolism
Central nervous system changes
  • Irritability
  • Emotional lability
  • Depression,
  • Cognitive defect and paranoid psychosis

Hormones secreted by the pituitary gland

This include hormone secreted by adenohypophysis (anterior pituitary)and neurohypophysis (posterior pituitary)
Hormone secreted by the adenohypophysis (anterior pituitary)
1.Thyroid stimulating hormone (TSH)
Triggers the release of thyroid hormones
Thyrotropin releasing hormone promotes the release of TSH
2.Adrenocorticotropic hormone (ACTH)

Stimulates the release of glucocorticoids by the adrenal gland
Corticotrophin releasing hormone causes the secretion of ACTH
3.Follicle stimulating hormone (FSH)
Stimulates follicle development and estrogen secretion in females and sperm production in males
4.Leutinizing hormone (LH)
Causes ovulation and progestin production in females and androgen production in males
Gonadotropin releasing hormone (GNRH) promotes the secretion of FSH and LH
5.Prolactin (PH)
Stimulates the development of mammary glands and milk production
6.Growth hormone (GH or somatotropin)
Stimulates cell growth and replication through release of somatomedins or IGF
Secretion is controlled by Growth-hormone releasing hormone  (GH-RH) and Growth-hormone inhibiting hormone  (GH-IH)
7.Melanocyte stimulating hormone (MSH)
May be secreted by the pars intermedia during fetal development, early childhood, pregnancy or certain diseases
Stimulates melanocytes to produce melanin
The hormones secreted by posterior lobe of the pituitary gland (neurohypophysis)
Posterior pituitary contains axons of hypothalamic nerves
Neurons of the supraoptic nucleus manufacture antidiuretic hormone (ADH) 
Decreases the amount of water lost at the kidneys
Elevates blood pressure
Neurons of the paraventricular nucleus manufacture oxytocin
Stimulates contractile cells in mammary glands
Stimulates smooth muscle cells in uterus

What is cretinism ?

Cretinism is a condition produced due to hypothyroidism since birth due to partial or complete failure of thyroid gland  (commonly it is due to thyroidal agensis).
Juvenile myxoedema is a condition with onset of hypothyroidism since childhood but develops before puberty ,this is only due to dyshormonogenesis
Myxoedema is characteried by onset of hypothyroidism after puberty (probably Hashimolo's thyroiditis is the commonest cause of myxoedema).
What are the morphologic characteristics of cretin?
 The facies in cretinism 
  • Appearance is dull and idiotic.
  • There is depressed bridge of the nose, broad flat nose with big nostrils.
  • Hypertelorism (widely set eyes) with wrinkling of eyebrows : narrow palpebral fissures.
  • Cretin has Sparse hair with dry skin.
  • Their lips are thick and everted with big, protruded tongue (macroglossia)
  • There is Delayed dentition.
The other features are
  • Short stature but they maintains the infantile proportion, ie. upper segment > lower segment.
  • These patients are lethargic and apathetic.
  • Memory is grossly impaired. Markedly retarded intelligence
  • Skin is dry. rough  and cold with sparse scalp hair.
  • Thick and short neck with presence of supraclavicular pad ot fat.
  • Pot-bellied abdomen with umbilical hernia is observed
Clinical features of hypothyroidism in neonatal period
Hypothyroididm in the neonatal period may be associated with the following
  • Prolonged physiological jaundice.
  • Somnolence.
  • Feeding problem (difficulty in sucking)
  • Constipation
  • Hoarse cry 
  • Delayed milestones of development (is observed in  later months)
How will you diagnose cretinism based on laboratory tests?
Blood investigations
  • High serum cholesterol.
  • Low protein bound iodine
  • Low radioactive I131 uptake.
  • T3 and T4 levels are low with high TSH level.
ECG - Low voltage complex is seen.
Skeletal x-ray (of long bones and pelvis) 
In cretinism there is delayed closure of epiphysis (i.e. bone age is less than that of chronological age).
Epiphyseal dysgenesis - Instead of one epiphysis, there are multiple epiphysis (This is DIAGNOSTIC of cretinism).
How will you treat Cretin?
  • Very small dosage of L-thyroxine is needed. Initial dose is 10 to 25 microgram and the dose is adjusted according to clinical improvement as well as the biochemical findings.
  • Rehabilitation.

What is pseudohypoparathyroidism ?

Pseudohypoparathyroidism  is a condition with increased  secretion of parathormone (PTH) is there but due to end organ resistance, there is no response to PTH hormone resulting in clinical features of hypoparathyroidism. This is a hereditary disorder with distinctive skeletal and developmental defects. These patients have elevated levels of serum PTH.
The common features are :
  • Short height with stocky built.
  • Round face with short neck.
  • Mental retardation.
  • Epileptic convulsions.
  • Short 4th and 5th metacarpals and metatarsals.
  • Basal ganglia calcification.

Cardinal features of addisons disease

Following are the cardinal features of Addison s disease
Commonly the patient is female and suffers from :
  • Asthenia,hypotenstion.hyperpigmentation are the major manifestations
The minor manifestations are
  • Anorexia, malaise, weight loss.
  • Decreased body hairs
  • Hyperkalaemia.
  • Hvpoglycaemia
  • Nausea, vomiting.
  • Chronic fatigue syndrome.
  • Acute adrenal crisis.
Pigmentation in addison's disease .
  • Pigmentation in addisons disease is due to increased pituitary MSH andACTH secretions
  • Initially there is tanning after exposure to the sun.
  • Later there is tanning noticed pressure points (elbow).
  • Normally  pigmented areas like areola ,knuckles palmar creases and scars become more pigmented
  • Mucous membrane pigmentation can occur (genitals and oral cavity)
  • There may be areas of vililigo
Differentiation between primary and secondary adrenocortical insufficiency
In primary (Addison s disease) cases, there are features of.
  • Absence of hypothyroidism and hypogonadism
  • High plasma ACTH level.
In secondary hypofunction, there are :
  • Absence of pigmentation.
  • Presence of hypothyroidism and hypogonadism
  • Low plasma ACTH level.

What are the cutaneous manifestation of Diabetes mellitus?

Diabetes mellitus is associated with following cutaneous manifestation
  • Necrobiosis lipoidica diabeticorum is characterised by papulonodular lesions enlarging to form brownish yellow plaques with waxy surface over the front of legs.
  • Diabetic dermopathy are  dull red, oval, flat-topped papules over both legs
  • Diabetic bullae are seen the over legs, hands and feet bilaterally and  healing with atrophic scars.
  • Diabetic rubeosis is the flushed skin of face.
  • Scleredema diabeticorum is a diffuse, waxy nonpitting induration_of skin particularly over back of the neck and upper trunk
  • Carotenoderma is the yellowish tint of skin due to deposition of carotene
  • Granuloma annulare is characterised by the papular lesion over central areas of body and flexures of neck, arm and thigh.
  • Infections like furuncle, carbuncle, candidalparonychia, balanoposthitis, intertrigo, recurrent dermatophytosis are common in diabetic patients

What are the newer hypoglycemic agents ?

The newer hypoglycemic agents act based on Incretin effect.Incretins are neuroendocrine substances that are released from GIT and increases the intestinal absorption of glucose and insulin release from pancreas.

They are of  two types
Glucagon like peptide 1(GLP1) that is degraded by dpp 
Glucose dependant insulinotropic peptide

GLP increases the glucose dependant insulin secretion only when the blood glucose >70  so, hypoglycemia not a problem with these agents.Following are the mechanism of actions of GLP
  • Supress glucagon secretion
  • Inhibit gastric emptying
  • Decrease appetite & food intake
There are incretin mimetics and incretin enhancers

Incretin mimetics 
Incretin mimeters are degradation resistant GLP 1 R agonist
They can be given through S/C injection

Incretin enhancers
The incretin enhancers act by inhibiting DPP-4 activity
They are available as oral preparations

Advantages of these newer incretin based therapy are 
This is associated with decreased risk of hypoglycemia
They help in B cell restoration upto 30%
Cytoprotective effect is also observed 
Helps to reduce weight .
Lipid friendly action is seen with incretin based therapy
They are able to combat the post prandial hyperglycemia that is produced by glucagon

Adverse effects Exenatide are 

Role of Amyelin in treatment of diabetes
Amyelin is a β cells product to supress α cells
Hence Synthetic amylin analogues are used to decreases α action 
These agents help to lower the postprandial hyperglycemia
Amyelin exerts centrally mediated anorectic action
This can be used as an adjuvant to insulin/SU/Metformin 

What are different Insulin preparations?

Various insulin preparations are available based on onset and duration of action.They can be short acting or long acting.

1. Lispro
Short acting group insulin.
28th lysine & 29th proline in B chain is reversed by recombinant DNA technology.
It has less tendency to form local aggregates.
Lispro has less incidence of hypoglycemia.
Absorption is delayed with NPH insulin, but not with ultralente.
Injected just before or after food.

2. Aspart
This is the shortest acting group of insulin.
This can be protaminated to extend the duration of action.
Aspart + protaminated aspart = Biphasic insulin.
Can be used as 30/70 insulin.
Used in pen devices.

3. Glulisine
Short acting insulin.
Not commonly available.
Asparagine @ B23 position is replaced by Lysine, lysine at B29 replaced by Glutamic acid.

4. Isophane / NPH insulin
Biphasic isophane available as pen devices.(Mixtard 30 novolet).
Most popular in 30/70 combination.
Lente available as Monotard.
Can be used once daily.
Ultara lente not available now.

5. Glargine
Asparagine at 21 replaced by Glycine.
2 Arginine residues added to c terminus of B chain.
Longest acting.
No peak in action,smooth sustained effect.
Less chance of hypoglycemia.
Not stable at room temp.
Cant mix with others.

6. Detemir
Myristic acid is bound to B29 lysine.
Long acting.
No local aggregate is formed.
Bound to albumin.
Less chance of hypoglycemia.

7. Degludec
Newer Long acting.
Effective at physiological pH.
Can be mixed with other insulins.

Regulation of insulin secretion (Chemical,Hormonal and Neural factors)

Insulin was discovered in 1921 by BANTING and BEST.  
It is a peptide hormone composed of 51 amino acid residues.
Insulin has a molecular weight of 5808.
Insulin is synthesized in the beta cells of the pancreas.
The name insulin comes from the Latin word insula for "island
Insulin is initially produced as a single polypeptide chain, preproinsulin which contain 110 amino acid residue.
1unit of insulin is secreted per hour under basal conditions.

Regulation of insulin secretion is by Chemical, hormonal and neural factors
Chemical factors

  1. Glucose, amino acids (arginine, etc.), fatty acids, and ketone bodies stimulate  the secretion of insulin. 
Hormonal factors

  1. Glucagon increase insulin release
  2. Somatostatin inhibits the insulin release
  3. Growth hormone,Thyroid hormone,cortisol produce  hyperglycemia.

Neural factors

  1. Alpha2 stimulation decreases insulin secretion.
  2. B2 stimulation increases the insulin level.
  3. Cholinergic stimulation increases insulin.

Pathogenesis of graves disease

A combination of environmental as well as genetic factors contribute to an individuals susceptility to Graves' disease.
The hyperthyroidism of Graves' disease is caused by TSI (thyroid stimulating immunoglobulin), TSI are synthesized in the 
  1. Thyroid gland
  2. Bone marrow
  3. Lymph nodes. 
Other thyroid autoimmune responses are also seen concurrently in patients with Graves' disease. Especially TPO (thyroperoxidase) antibodies occur in up to 80% of Graves disease and serve as a readily measurable marker of autoimmunity.

There is no direct correlation between the level of TSI and thyroid hormone levels in Graves' disease as the coexisting thyroiditis can also affect thyroid function.

Cytokines play major role in thyroid ophthalmopathy
There is infiltration of the extraocular muscles by activated T cells,there is  release of cytokines such as IFN-, TNF, and IL-1 which in turn  results in fibroblast activation and increased synthesis of glycosaminoglycans.These glycosaminoglycans trap water, there by leading to characteristic muscle swelling.In the later stages of the disease, there is irreversible fibrosis of the muscles.
Why there is more ocular involvement ?
Orbital fibroblasts may be more sensitive to cytokines, perhaps explaining the ophthalmic localization of the immune response. 
An additional cause of retrobulbar tissue expansion is increased fat deposition.
All these will increase the intraorbital pressure which will lead to proptosis, diplopia, and optic neuropathy.

Drug treatment of Graves'disease

The hyperthyroidism of Graves' disease is treated either by 
1.Reducing the synthesis of thyroid hormone using antithyroid drugs or   
2.Reducing the amount of thyroid tissue with radioiodine (Iodine131) treatment or by thyroidectomy
Antithyroid drugs include
Thionamides such as propylthiouracil, carbimazole and the active metabolite of the carbimazole that is methimazole. 
Effects of these drugs are following
1.Inhibit the function of TPO(thyroperoxidase) 
2.Reduce oxidation and organification of iodide. 
3.These drugs also reduce thyroid antibody levels 
4.They enhance rate of remission. 
Drug dosage
The initial dose of carbimazole or methimazole is usually 10–20 mg given every 8 or 12 h, but after euthyroidism is restored once-daily dosing is possible. 
Propylthiouracil is given at a dose of 100–200 mg every 6–8 h, this drug is given in divided doses are usually throughout the course. 
Lower doses of each drug may suffice in areas of low iodine intake as thyrotoxicosis improves.
Ttitration regimen 
In titration regimen the starting dose of antithyroid drugs can be gradually reduced once euthyroidism is achieved.The titration regimen is often preferred beause of the following
1.To minimize the dose of antithyroid drug 
2.It provides an index of treatment response
Block-replace regimen
Alternatively, high doses may be given combined with levothyroxine supplementation .
The advantage of this regimen is this will avoid drug-induced hypothyroidism. 
Monitoring treatment response
Thyroid function tests and clinical manifestations are reviewed every 3–4 weeks after starting drugs and the dose is titrated based on unbound T4 levels in blood. Most patients do not achieve euthyroidism until 6–8 weeks after initiation of treatment. 
TSH levels often remain suppressed for several months and therefore it do not provide a sensitive index of treatment response
The usual daily maintenance doses of antithyroid drugs in the titration regimen are
2.5mg –10 mg of carbimazole or methimazole
50–100 mg of propylthiouracil
Time taken for remission
Maximum remission rates are achieved by 18–24 months for the titration regimen 
6 months for the block-replace regimen. 
Patients with severe hyperthyroidism and large goiters are most likely to relapse once treatment stops, close follow up is required  in all patients for relapse during the first year after treatment and at least annually thereafter.
The common side effects of antithyroid drugs
Rash, urticaria, fever, and arthralgia (seen in 1–5% of patients).These side effect may resolve spontaneously or after substituting an alternative drug. 
Rare but major side effects include
Hepatitis, an SLE-like syndrome; and,the most important agranulocytosis (seen in <1%).
Antithyroid drug should be stopped and not to be restarted if a patient develops major side effects
Written instructions should be provided regarding the symptoms of possible agranulocytosis (sore throat, fever, mouth ulcers) and the patients should be advised to stop treatment and a complete blood count shoud be checked to confirm that agranulocytosis is not present
Propranolol (20–40 mg every 6 h) or longer-acting beta blockers such as atenolol is given  to control adrenergic symptoms, especially in the early stages of disease.
Beta blockers are especially useful in patients with thyrotoxic periodic paralysis
Anticoagulation should be considered in all patients with atrial fibrillation.Digoxin doses need to be increased in the thyrotoxic state

What are the causes of thyrotoxicosis ?

Thyrotoxicosis is defined as the state of thyroid hormone excess. 
But it is not synonymous with hyperthyroidism, which is the result of excessive thyroid function.
Following are the causes of thyrotoxicosis
  • Primary hyperthyroidism 
  • Thyrotoxicosis without hyperthyroidism
  • Secondary hyperthyroidism 
1. Primary hyperthyroidism
Graves' disease.
Toxic multinodular goiter.
Toxic adenoma.
Functioning thyroid carcinoma metastases.
Activating mutation of the TSH receptor.
Activating mutation of Gs alpha (McCune-Albright syndrome.  Struma ovarii ).
Drugs-iodine excess.
2.Thyrotoxicosis without hyperthyroidism
Subacute thyroiditis. 
Silent thyroiditis.
Other causes of thyroid destruction are amiodarone, radiation, infarction of adenoma.
Ingestion of excess thyroid hormone (thyrotoxicosis factitia) or thyroid tissue.
3.Secondary hyperthyroidism
TSH-secreting pituitary adenoma. 
Thyroid hormone resistance syndrome. 
Chorionic gonadotropin-secreting tumors.
Gestational thyrotoxicosis. 

Atypical manifestations of hypothyroidism

Thyroid hormone can directly influence every cell in the human body.Diagnostic confusion may occur when the functional derangement of one body system dominates the clinical picture.
Following are the common manifestations of hypothyroidism
Weight gain
Cold intolerance
Puffy face
Pedal edema
Atypical manifestation of hypothyroidism are not so rare.So high index of suspicion is necessary to diagnose the situation, this is very important because the disease is completely reversible and the treatment is cheap.When there is unexplained clinical conditions such as neuropsyhiatric, non responding cardiac,locomotor, gastrointestinal problems and in PUO(pyrexia of unknown origin) rule out thyroid dysfunction (can be hypothyroidism or hyperthyroidism)  including auto immune status.
Psychiatric manifestations of hypothyroidism
Psychiatric symptoms are common in both overt hypothyroidism as well as in subclinical hypothyroidism.Depression may be the first or sometimes the only clinical manifestation in hypothyroidism.Hypothyroidism may manifest as a variety of other neuropsychiatric symptoms which include
Mood disorders
Bipolar disease
Visual and auditory hallucinations
Cognitive dysfunction
Impaired concentration
Decline in intelligence
Memory disturbance
Cognitive dysfunction are more pronounced in elderly, hence it should be considered as a reversible cause of dementia.
Dermatological manifestations of hypothyroidism 
Sometimes dermatological manifestations are initial manifestation of hypothyroidism.
This may present as pruritus or urticaria .Symptoms may continue even after correction of hypothyroidism.
Muskuloskeletal manifestations of hypothyroidism
Arthralgia, arthritis
If there Is predominant small joint involvement of hands it mimick rheumatoid arthritis
Hypothyroidism can  also involve large joints producing myxedematous arthropathy is characterized by synovial thickening, ligamentous laxity and  effusion
Hyperuricemia may contribute to joint pathology.
Joint involvement is more common when the hypothyroidism is of autoimmune etiology
Other presentations are 
Association with other endocrine dysfunction.
Hyponatremia  is seen in 10 % of hypothyroid patients.Mechanism of hyponatremia in hypothyroidism are due to
Reduction in GFR, impairement of water excretion
Inappropriate release of ADH
When there is unexplained reduction in serum sodium, always evaluate thyroid function
Hyperprolactinemia,headache may be a rare manifestation of hypothyroidism.It may be due to increased TRH production,thyrotrope  hyperplasia  and pituitary  enlargement.Normalization of symptoms occur with thyroid replacement.

What are the clinical manifestations of thyrotoxicosis?

The clinical presentation of thyrotoxicosis  depends on the  
  • Severity of thyrotoxicosis 
  • The duration of disease
  • Individual susceptibility to excess levels of  thyroid hormone 
  • Age of patient
Common symptoms of thyrotoxicosis are the following
Weightloss inspite of increased appetite.
Heat intolerance and sweating
Hyperactivity, irritability, dysphoria 
Fatigue and weakness
Insomnia and impaired concentration
Oligomenorrhea, loss of libido

Signs of thyrotoxicosis
Tachycardia; atrial fibrillation is commonly seen in the elderly
The high cardiac output produces a  
Bounding pulse
Widened pulse pressure 
Aortic systolic murmur 
Warm, moist skin 
Fine tremor of hands
Goiter- diffusely enlarged thyroid,firm,bruit may be heard over the thyroid
Muscle weakness, proximal myopathy 
Lid retraction or lidlag due to sympathetic overactivity 
Ophthalmopathy and dermopathy are specific for Graves' disease

Thyroid dermopathy
Seen in <5% of patients with Graves' disease, usually associated with moderate or severe ophthalmopathy.
It is most frequent over the anterior and lateral aspects of the lower leg so called as pretibial myxedema), but the  skin changes can occur at other sites,  particularly after trauma. 
The typical lesion of thyroid dermopathy is a noninflammed, indurated plaque which is deep pink or purple in  color and an orange skin appearance. 
Nodular involvement of skin can occur, and the condition may rarely extend over the whole lower leg and foot, thus  mimicking elephantiasis
Thyroid acropachy 
This is a form of clubbing found in <1% of Graves' disease. It is strongly associated with thyroid dermopathy.

Thyroid ophthalmopathy 

Adrenal gland - Functional anatomy

Adrenal gland - They are suprarenal - they sit on top of the kidneys.
Each is composed of 2 distinct regions:
A. Adrenal Medulla
- the inner region
- comprises 20% of the gland
- secretes epinephrine and norepinephrine
- derived from ectoderm 
B. Adrenal Cortex
- the outer region
- comprises 80% of the gland
- secretes corticosteroids 
- derived from mesoderm

Following are the parts of adrenal cortex

  1. Zona Glomerulosa (outermost region) - produces mineralocorticoids (aldosterone)  
  2. Zona Fasiculata (middle region) - produces glucocorticoids (cortisol) as well as estrogens and androgens.
  3. Zona Reticularis (innermost region)  produce  adrenal androgens.