Diagnostics Presentation

8/8/2019 Diagnostics Presentation

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Cushing's Syndrome

Thyroid

Parathyroid


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Caused by prolonged exposure to elevated levels of either endogenousglucocorticoids or exogenous glucocorticoids.

Normal cortisol metabolism

In response to stress or a to low level of blood glucocorticoids.

Hypothalamus secretes corticotropin-releasing hormone (CRH) which triggers

pituitary secretion of adrenal corticotrophic hormone (ACTH)

ACTH is then carried by the blood to the adrenal cortex where it triggers Cortisol

secretion.


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ACTH Dependant Pituitary adenoma secreting ACTH (this is know as Cushings

Disease)

Non-ACTH-Dependant Iatrogenic (chronic glucocorticoid therapy eg for asthma)

Adrenal Adenoma

Adrenal Carcinoma

Pseudo-Cushings Syndrome

(Cortisol excess as part of

another illness)

Alcoholism

Major depressive illness

Primary obesity

Classification Of Cushings Syndrome


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History

Patients with Cushing syndrome may complain of weight gain, especially in the face,supraclavicular region, upper back, and torso.

Patients notice changes in their skin, including purple stretch marks, easy bruising, and othersigns of skin thinning.

Patients may have difficulty climbing stairs, getting out of a low chair, and raising their armsbecause of progressive proximal muscle weakness.

Menstrual irregularities, amenorrhea, infertility, and decreased libido may occur in women

Men may complain of decreased libido and impotence.

Psychological problems such as depression, cognitive dysfunction, and emotional labilitymay develop.

Difficulty with wound healing, increased infections, and osteoporotic fractures may occur.

Patients may complain of developing headaches, polyuria and nocturia, visual problems, orgalactorrhea usually due to an ACTH-producing pituitary tumour (Cushing disease)


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Physical Obesity

Patients may have increased adipose tissue in the face (moon face), upper back at thebase of neck (buffalo hump), and above the clavicles (supraclavicular fat pads).

Central obesity with increased adipose tissue in the mediastinum and peritoneumIncreased waist-to-hip ratio greater than 1 in men and 0.8 in women

Skin Flushed face may be present, especially over the cheeks.

Striae are observed most commonly over the abdomen, buttocks, lower back, upperthighs, upper arms, and breasts.

Skin bruising may be present.

Cutaneous atrophy with exposure of subcutaneous vasculature tissue and dehydrationmay be evident.

If glucocorticoid excess is accompanied by androgen excess, as occurs in adrenocorticalcarcinomas, hirsutism and male pattern balding may be present in women.

Steroid acne, consisting of papular or pustular lesions over the face, chest, and back,

may be present. Hyperpigmentation of the skin (Acanthosis nigricans), which is associated with insulin

resistance and hyperinsulinism, may be present. The most common sites are axilla andareas of frequent rubbing, such as over elbows, around the neck, and under the breasts.

Cardiovascular and renal Hypertension and possibly oedema may be present due to cortisol activation of the

mineralocorticoid receptor leading to sodium and water retention.


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GI

Peptic ulceration may occur with or without symptoms.

Endocrine

Galactorrhea may occur when anterior pituitary tumours compress the pituitary stalk,

leading to elevated prolactin levels.

Low testosterone levels in men may lead to decreased testicular volume from inhibition

of LHRH and LH/FSH function.

Skeletal/muscular

Proximal muscle weakness may be evident.

Osteoporosis may lead to fractures and increased kyphosis, height loss, and axial

skeletal bone pain.

Avascular necrosis of the hip is also possible from glucocorticoid excess.

Neuropsychological

Patients may experience emotional liability, fatigue, and depression.

Visual-field defects and blurred vision may occur in individuals with large ACTH-

producing pituitary tumours that impinge on the optic chiasma.


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InvestigationsTest Protocol Interpretation

Urine free cortisol 24-hr timed collection (some centres use

overnight collections corrected for creatinine)

Normal range depends on assay

Overnight dexamethasone suppression test 1 mg orally at midnight; measure plasma

cortisol at 0800-0900 hrs

Plasma cortisol < 60 nmol/l (< 2.2 g/dl)

excludes Cushing's

Diurnal rhythm of plasma cortisol Sample for cortisol at 0900 hrs and at 2300

hrs (requires acclimatisation to ward for at

least 48 hrs)

Evening level > 75% of morning level in

Cushing's

Low-dose dexamethasone suppression test 0.5 mg 6-hourly for 48 hrs; sample 24-hr urine

cortisol during second day and 0900-hrplasma cortisol after 48 hrs

Urine cortisol < 100 nmol/day (36 g/day) or

plasma cortisol < 60 nmol/l (< 2.2 g/dl)excludes Cushing's

Insulin tolerance test Peak plasma cortisol > 120% of baseline

excludes Cushing's

High-dose dexamethasone suppression test 2 mg 6-hourly for 48 hrs; sample 24-hr urine

cortisol at baseline and during second day

Urine cortisol < 50% of basal suggests

pituitary-dependent disease; > 50% of basal

suggests ectopic ACTH syndrome

Corticotrophin-releasing hormone test 100 g ovine CRH i.v. and monitor plasmaACTH and cortisol for 2 hrs

Peak plasma cortisol > 120% and/or ACTH >150% of basal values suggests pituitary-

dependent disease; lesser responses suggest

ectopic ACTH syndrome

Inferior petrosal sinus sampling Catheters placed in both inferior petrosal

sinuses and simultaneous sampling from

these and peripheral blood for ACTH; may be

repeated 10 minutes after peripheral CRHinjection

ACTH concentration in either petrosal sinus >

200% peripheral ACTH suggests pituitary-

dependent disease; < 150% suggests ectopic

ACTH syndrome


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Management Treatment of Cushing syndrome is directed by the primary cause of the syndrome.

In general, therapy should reduce the cortisol secretion to normal levels.

The treatment of choice for endogenous Cushing syndrome is surgical resection ofthe causative tumour.

The primary therapy for Cushing disease is transsphenoidal surgery, and the

primary therapy for adrenal tumours is adrenalectomy.

When surgery is not successful or cannot be used, as often occurs with ectopic

ACTH or metastatic adrenal carcinoma, control of hypercortisolism may beattempted with medication. However, medication failures are common, and

adrenalectomy may be indicated in ACTH-mediated Cushing syndrome.

Pituitary radiation may be useful if surgery fails for Cushing disease.

The treatment for exogenous Cushing syndrome is gradual withdrawal of

glucocorticoid. Drug agents that inhibit steroidogenesis, such as mitotane, ketoconazole,

metyrapone, aminoglutethimide, trilostane, and etomidate, have been used to

cause medical adrenalectomy.

These medications are used rarely and often are toxic at the doses required to

reduce cortisol secretion.


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Management Hormone replacement:

Patients with endogenous Cushing syndrome who undergo resection of pituitary,

adrenal, or ectopic tumours should receive stress doses of glucocorticoid in theintraoperative and immediate postoperative period.

Hydrocortisone is infused intravenously, continuously (10 mg/h) starting prior to surgery

and for the first 24 hours afterward.

If the patient does well, intravenous glucocorticoid replacement may be tapered over 1-

2 days and replaced with an oral formulation.

The rate of steroid taper may be slowed if severe preoperative hypercortisolism waspresent.

In the event of pituitary destruction or bilateral adrenalectomy, lifelong glucocorticoid

replacement is necessary.


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Primary Secondary

Hormone Excess Graves Disease

MultinodularGoitre

AdenomaSubacute Thyroiditis

Pituitary TSHoma

Hormone Deficiency Hashimotos Thyroiditis

Atrophic Hypothyroidism

Hypopituitarism

Hormone Resistance Thyroid Hormone

Resistance Syndrome 5-

monodeiodinase deficiency

Non-Functioning Tumours Differentiated Carcinoma

Medullary Carcinoma

Lymphoma

Classification Of Thyroid Disease


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Definition

Hyperthyroidism is a hypermetabolic condition (excess synthesis

and secretion of thyroid hormone by the thyroid) associated with

elevated levels of free thyroxine (T4) and/or free triiodothyronine

(T3) and decreased/undetectable serum TSH.


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Graves Disease

The most common cause of thyrotoxicosis is Graves disease (76%)

Graves disease is an organ-specific autoimmune disorder characterized by a varietyof circulating antibodies, including common autoimmune antibodies, as well as

anti-thyroid peroxidase (anti-TPO) and antithyroglobulin (anti-TG) antibodies and

the most important autoantibody is thyroid-stimulating immunoglobulin (TSI).

TSI acts as a TSH-receptor agonist. Similar to TSH, TSI binds to the TSH receptor on

the thyroid follicular cells to activate thyroid hormone synthesis and release andthyroid growth (hypertrophy).

The characteristic picture ofGraves disease is:

diffusely enlarged thyroid

very high radioactive iodine uptake

excessive thyroid hormone levels


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Toxic Multinodular Goitre

Occurs in 15-20% of patients with thyrotoxicosis.

Occurs more commonly in elderly individuals.

Thyroid hormone excess develops very slowly over time and often is only mildly

elevated at the time of diagnosis.

Sign and symptoms of thyrotoxicosis are mild, often because only a slight elevation

of thyroid hormone levels is present.


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Subacute Thyroiditis

The next most common cause of thyrotoxicosis is subacute thyroiditis (3%)

Virus induced (e.g. Coxsackie) transient inflammation of the thyroid gland

Thyroid hormone levels can be extremely elevated in this condition.


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Signs and Symptoms

The presentation of thyrotoxicosis is variable among patients.

Common symptoms of thyrotoxicosis include the following:

Nervousness Anxiety

Increased perspiration

Heat intolerance

Tremor

Hyperactivity

Palpitations

Weight loss despite increased appetite

Reduction in menstrual flow or oligomenorrhea

Common signs of thyrotoxicosis include the following: Hyperactivity

Tachycardia or atrial arrhythmia

Systolic hypertension

Warm, moist, and smooth skin

Lid lag

Stare Tremor

Muscle weakness

Younger patients tend to exhibit symptoms of more sympathetic activation, such as anxiety,hyperactivity, and tremor

Older patients have more cardiovascular symptoms, including dyspnea and atrial fibrillationwith unexplained weight loss.


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Investigations

Blood Tests

Serum TSH Serum T

4

Serum T3

Thyroid autoantibodies

The most specific autoantibody for autoimmune thyroiditis is an enzyme-linked

immunosorbent assay (ELISA) for anti-TPO antibody.

Nuclear thyroid scintigraphy iodine 123 uptake and scan

Hyperthyroidism in older patients often presents with atrial arrhythmias or CHF.

ECG is recommended if an irregular heart rate or CHF is noted upon examination.


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Treatment

Symptomatic relief

Many of the neurologic and cardiovascular symptoms of thyrotoxicosis arerelieved by beta-blocker therapy.

Calcium-channel blockers can be used for the same purposes when beta

blockers are contraindicated or poorly tolerated.

Antithyroid drugs

methimazole inhibit multiple steps in the synthesis of T4 and T3, leading to agradual reduction in thyroid hormone levels over 2-8 weeks or longer.

Surgical Care

Subtotal thyroidectomy or total thyroidectomy


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Definition

Hypothyroidism is an endocrine disorder resulting from deficiency of

thyroid hormone with normal T4

and raised TSH levels.


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Causes

Iodine deficiency remains the foremost cause of hypothyroidism.

The prevalence of antibodies is higher in women, and increases with age.


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Hashimoto thyroiditis

The most frequent cause of acquired hypothyroidism is autoimmune thyroiditis. The body recognizes the thyroid antigens as foreign, and a chronic immune

reaction ensues, resulting in lymphocytic infiltration of the gland and progressive

destruction of functional thyroid tissue.


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Physical Examination (signs)

Hypothermia

Weight gain

Slowed speech and movements Dry skin

Jaundice

Pallor

Coarse, brittle, strawlike hair

Loss of scalp hair, axillary hair, pubic hair, or a combination

Dull facial expression Coarse facial features

Periorbital puffiness

Goitre

Hoarseness

Decreased systolic blood pressure and increased diastolic blood pressure Bradycardia

Pericardial effusion

Abdominal distension, ascites (uncommon)

Nonpitting oedema (myxedema)

Pitting oedema of lower extremities

Hyporeflexia with delayed relaxation, ataxia, or both


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Investigations

Blood Tests

Serum TSH Serum T

4

Serum T3

Evaluation of the presence of thyroid autoantibodies (anti-TPO antibodies)


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Treatment

The treatment goals for hypothyroidism are the reversal of clinical progression and

the corrections of metabolic derangements as evidenced by normal blood levels ofTSH and free T4.

Thyroid hormone is administered to supplement or replace endogenous

production.

In general, hypothyroidism can be adequately treated with a constant daily dose of

levothyroxine (LT4).


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Background

The parathyroid glands regulate serum calcium and phosphorus levels through the

secretion of parathyroid hormone (PTH), which raises serum calcium levels whilelowering the serum phosphorus concentration.

The regulation of PTH secretion occurs through a negative feedback loop in which

calcium-sensing receptors on the membranes of parathyroid cells trigger decreased

PTH production as serum calcium concentrations rise.


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Primary Hyperparathyroidism

Accounts for most hyperparathyroidism cases, results from excessive release of

PTH and manifests as hypercalcaemia. Patients with hypercalcaemia who have normal renal function and no malignancy

must be suspected of having primary hyperparathyroidism and must be

subsequently tested for elevated PTH levels.

Usually the result of a single benign adenoma - a minority of patients have

hyperplasia in all 4 parathyroid glands. Parathyroid carcinoma accounts for an insignificant minority (


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Secondary Hyperparathyroidism

Occurs when the parathyroid glands become hyperplastic after long-term

hyperstimulation and release of PTH. In secondary hyperparathyroidism, elevated PTH levels do not result in

hypercalcaemia.

Tertiary Hyperparathyroidism Tertiary hyperparathyroidism refers to hypercalcaemia caused by autonomousparathyroid function after long-term hyperstimulation.

With long-term hyperstimulation, the glands function autonomously and produce

high levels of PTH even after correction of chronic hypocalcemia.


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History

Symptomatic hyperparathyroidism is characterized by vague, nonspecific symptoms

including generalized weakness

Fatigue

poor concentration

depression.

Mnemonic Painful bones, renal stones, abdominal groans, and psychic moansdisease can be used to recall the typical symptoms of hypercalcaemia.

Painful bones are the result of abnormal bone remodeling due tooverproduction of parathyroid hormone (PTH).

Nephrolithiasis occurs secondary to hyperparathyroid diseaseinducedhypercalcaemia and resultant hypercalciuria.

Abdominal groans refers to hypercalcaemia-induced ileus.

Psychic moans or depression may occur in the presence of persistently elevatedserum calcium levels.


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Physical Examination

Central nervous system Neuropsychiatric illness: Patients frequently display clinical signs of mental depression, poor general

health, low energy levels, decreased ability to complete daily tasks at home or at work, decreased social

interaction, and pain, particularly in the legs. Altered mental status

Cardiovascular system Hypertension, left ventricular hypertrophy, vascular calcification and stiffness

Musculoskeletal system low bone density, osteopenia/osteoporosis

Vertebral collapse

Chondrocalcinosis and pseudogout

Easily fatigued muscle (particularly proximal muscle groups)

GI system Pancreatitis and pancreatic calcification

Peptic ulcer disease

Renal system Nephrolithiasis

Nephrocalcinosis

impaired renal function.


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Investigations PTH levels

U&E

Calcium and phosphate levels

X-ray:

subperiosteal resorption that is best seen at the radial sides of the phalanges,

distal phalangeal tufts, and distal clavicles.

Salt and pepper skull/ground glass appearance on lateral view of skull

Brown tumour

Bone-density measurements based on dual energy x-ray absorptiometry (DEXA)

technetium-99m imaging, ultrasonography, CT scanning, and MRI.


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Management

Treatment of severe hypercalcaemia:

Rehydration with normal saline

To replace as much as a 4-6 l deficit

May need monitoring with central venous pressure in old age or renalimpairment

Bisphosphonates disodium pamidronate 90 mg i.v. over 4 hours

Causes a fall in calcium which is maximal at 2-3 days and lasts a few weeks

Unless the cause is removed, follow up with an oral bisphosphonate

Additional rapid therapy

May be required in very ill patients

Forced diuresis with saline and furosemide

Glucocorticoids, e.g. prednisolone 40 mg daily

Calcitonin

Haemodialysis


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References

http://emedicine.medscape.com/article/121865-overview accessed27.07.2010




Davidsons principals and practice of medicine. 20th ed. 2006. Philadelphia:

Churchill Livingston Elsevier

Longmore, M., Wilkinson, I.B., Davidson, E.H., Foulkes, A. and Mafi, R.M.2010. Oxford handbook of clinical medicine. New York: Oxford Universitypress

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