Sunday, July 19, 2015

Menopause - Definition, symptoms and hormone replacement therapy



 Menopause  refers to a point in time that follows 1 year after the permanent cessation of menstrual periods that occurs naturally or is induced by surgery, chemotherapy or radiation.

On average, natural menopause occurs between 50 and 51 years (range 45–59) and is part of the process of normal ageing. It has been noted that smoking advances the age of menopause by approximately 2 years.
The diagnosis can only be made retrospectively and it is usually preceded by months or years of irregular cycles, that is not associated with some other physiological or pathological causes.

If the cessation of menses occurs before the age of 40, then it is referred to as the "Premature ovarian failure".
The older terms perimenopause or climacteric generally refer to the time period in the late reproductive years, usually late 40s to early 50s. Characteristically, it begins with menstrual cycle irregularity and extends to 1 year after permanent cessation of menses. The more correct terminology for this time is menopausal transition. This transition typically develops over a span of 4 to 7 years, and the average age at its onset is 47 years

Up to 75% of women will experience adverse symptoms related to menopausal transition while the others may not have any symptoms at all. Although symptoms associated with menopause occur as a result of oestrogen deficiency, replacing it is not always the treatment of choice.
The use of HT should be made on an individual basis, after careful consideration of quality of life and personal risk factors. In addition to any pharmacological treatments considered, lifestyle modifications are essential.

Below a few of the symptoms are discussed and whether hormone replacement may be helpful:

Hot flushes are characterised by a feeling of intense warmth, often accompanied by profuse sweating, anxiety, skin reddening and palpitations. They are sometimes followed by chills.
In most cases, they will resolve in around 1 year or less without any treatment.
1/3 rd of the patients will have symptoms for up to 5 years after natural menopause and in 20% they may persist for up to 15 years or more.
Menopause induced by surgery is associated with about a 90% probability of hot flushes during the first year. In these cases, symptoms are often more abrupt and severe and can last longer than those associated with a non-surgical menopause.

Hormone therapy is the most effective (80% efficacy) treatment for vasomotor symptoms associated with menopause at any age, but benefits are more likely to outweigh risks for symptomatic women before the age of 60 years or within 10 years after menopause.
Extra care must be taken in women with a history of hormone-dependent cancer, e.g. breast cancer.


Genitourinary symptoms due to menopause can affect up to 50% of women, however it is under diagnosed and under treated. The pathology here is that there is a loss of estrogen which results in urogenital ageing. The tissues of the vaginal walls becomes thinner since the amount of collagen and elastin is reduced. The walls become pale, thin and lose their elasticity. A reduction in vaginal secretions and decreased tissue elasticity also increases the susceptibility to trauma and pain or irritation during or after intercourse.

In addition to vulvo-vaginal symptoms, the less acid pH of the estrogen-deficient vagina increases the likelihood of urinary tract infections.

Vaginal symptoms become apparent 4–5 years after the menopause. 25–50% of all postmenopausal women have some objective changes as well as subjective complaints.
Symptoms may include vaginal dryness (75%), dyspareunia (38%), vaginal itching, burning and pain (15%).
Locally administered vaginal estrogens (creams, pessaries, tablets and vaginal rings) are equally effective in the treatment of menopause-related vulval and vaginal symptoms. Local estrogen therapy will lower vaginal pH, thicken the epithelium, increase blood flow and improve vaginal lubrication.

There are no evidence to support the use of hormone replacement for the urinary symptoms.


The decline in estrogen results in a decrease in the bone mineral density and a subsequent significant increase in the prevalence of osteoporosis.

General management includes:
1) assessment of the risk of falls and their prevention,
2) maintenance of mobility and
3) correction of nutritional deficiencies, particularly of calcium, vitamin D and protein.

Pharmacological interventions include bisphosphonates, denosumab, parathyroid hormone peptides, raloxifene and strontium ranelate. All have been shown to reduce the risk of vertebral fracture and some have been shown to reduce the risk of non-vertebral fractures. However, all are associated
with side effects and many women will fail to comply.
Hormone therapy reduces the risk of spine and hip, as well as other osteoporotic fractures even in women at low risk. It would appear that half of the traditional bone conserving doses are effective in conserving bone mass and are successful means of fracture prevention. However, hormone replacement is not the first line therapy in treating post menopausal osteoporosis.


The incidence of CVD increases with age and menopause may have an adverse effect. Hormone therapy was thought to confer CVD risk reduction but some studies demonstrated an increased number of coronary heart disease events and strokes and concluded that the risks outweighed the benefits. These studies were carried out on elderly women though and probably there was already an element of atherosclerosis that influenced the outcomes. Recent studies suggest that if hormone replacement is started soon after menopause, it may actually be beneficial.


Since the sex hormones are known to be thrombogenic there is an expected increase in the risk of deep vein thrombosis and stroke when using oral replacement therapy. The risk is further increase if the patient is a smoker.



Tuesday, April 21, 2015

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Hyperhomocysteinemia

Introduction:
Homocysteine is a sulphur containing amino acid that is produced during the conversion of methionine to cysteine.

Hyperhomocysteinemia results when there is an abnormality in the homocysteine metabolism.
It is an independent risk factor for stroke, MI, peripheral arterial disease and venous thrombotic disease.

Even mild to moderate hyperhomocysteinemia is a significant risk factor for vascular disease.



Pathophysiology:

The amino acid homocysteine is normally metabolized via the transsulfuration pathway by the enzyme cystathionine-β-synthase (CBS), which requires vitamin B6 as co-factor and via the
remethylation pathway by the enzymes methylenetetrahydrofolate reductase (MTHFR),
which is folate dependent and methionine synthase, which requires vitamin B12 as co-factor.


1 - Methylenetetrahydrofolate reductase
2 - Methionine synthase










Hyperhomocysteinemia can be either:
1) Inherited or
2) Acquired.

Inherited
Inherited severe hyperhomocysteinemia (plasma level >100 µmol/L), as seen in classic homocystinuria, may result from homozygous MTHFR and CBS deficiencies and more rarely from inherited errors of cobalamin metabolism. Classic symptoms for homozygous patients include premature vascular disease and thrombosis, mental retardation, ectopic lens and skeletal abnormalities.

Inherited mild to moderate hyperhomocysteinemia (plasma level >15 to 100 µmol/L) may result from heterozygous MTHFR and CBS deficiencies, but most commonly results from the thermolabile variant of MTHFR (tlMTHFR) that is encoded by the C677T gene polymorphism. Heterozygous carriers of the tlMTHFR mutation have normal plasma homocysteine levels unless folate levels are
reduced.

Acquired
Acquired hyperhomocysteinemia may be caused by folate deficiency, vitamin B 6 or B 12 deficiency, renal insufficiency, hypothyroidism, type II diabetes mellitus, pernicious anemia, inflammatory bowel disease, advanced age, climacteric state, carcinoma (particularly involving breast, ovaries or pancreas) and acute lymphoblastic leukemia, as well as methotrexate, theophylline and phenytoin therapy.

VTE risk is most closely related to elevated fasting plasma homocysteine levels, regardless of etiology. Hyperhomocysteinemia (plasma level >18.5 µmol/L) has been associated with a two- to fourfold increased VTE risk.

The precise mechanisms underlying the thrombogenicity of homocysteine remain unclear. Several diverse mechanisms have been proposed, including endothelial cell desquamation, low-density lipoprotein (LDL) oxidation, promotion of monocyte adhesion to endothelium and factor V activation and promotion of thrombin generation.
Homocysteine also enhances platelet aggregation and adhesiveness as well as turnover, presumably as a result of endothelial cell injury.

Laboratory Diagnosis:
The initial step in the evaluation of the patient with suspected hyperhomocysteinemia involves measurement of fasting total plasma homocysteine (the sum of nonprotein-bound and proteinbound).
A normal value in the nonfasting setting does not normally require repeating.

Standardized methionine loading test
Testing 2 to 8 hours after an oral methionine load (100 mg/kg) increases the sensitivity of detecting occult vitamin B6 deficiency and obligate heterozygotes for CBS deficiency, but methionine loading is not routinely recommended.
Vitamin B12 and folate deficiency do not affect post-methionine loading homocysteine values.
After 4-6 hours the level of homocysteine is measured again.
A level 5 times that of the fasting one or an increase by 40 µmol/L is considered a positive test for hyperhomocysteinemia.
In patients found to have elevated levels of homocysteine, testing for vitamin B12 deficiency is advocated to avoid missing subclinical deficiency before
beginning oral folic acid therapy.

Treatment:
1) Folic acid supplementation is the mainstay therapy. The usual recommended dose is 0.4 to 1.0 mg daily. This causes a 25% decrease in the homocysteine level.
2) Because patients with subclinical vitamin B12 deficiency may be prone to developing
peripheral neuropathy if they receive folic acid supplementation alone, additional treatment with 0.5 mg/day of oral vitamin B12 has been advocated. An additional 7% reduction of homocysteine levels was noted with vitamin B12 supplementation.
Vitamin B12 administration results in normalization of homocysteine levels in B12-deficient individuals. In these patients, a monthly intramuscular injection of 200 to 1,000 µg of vitamin B12 is considered adequate replacement.
3) Vitamin B6 supplementation did not appear to have any effect on homocysteine levels.
4) Thrombotic events in hyperhomocysteinemic patients should be treated accordingly.

Monday, March 9, 2015

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kussmaul breathing pattern - description and causes

This type of breathing pattern was first described by Adolph Kussmaul, a german physician in 1874. He noticed that his patients with diabetic ketoacidosis had a pattern of breathing which he first labelled as having "air hunger".

In the Kussmaul type of breathing, the patient is breathing heavily i.e hyperventilating along with tachypnea.
So we will find that the amplitude of the breaths along with the rate will be increased.
There is usually no pauses between the breaths.

This is not specific for diabetic ketoacidosis. It can also appear in other types of severe metabolic acidoses e.g alcoholic ketoacidosis .

Sunday, February 15, 2015

Adverse effects of Amiodarone

1) Hypotension can occur especially with the intravenous form due to vasodilation and depressed myocardial performance. Long-term oral therapy can also cause depressed contractility but it is unusual.

2) Nausea can sometimes be seen during the loading phase. All we have to do is to decrease the daily dose of the medication.

3) Pulmonary fibrosis is the most serious adverse effect during chronic amiodarone therapy. The fibrosis can be rapidly progressive and fatal. The risk factors include: underlying lung disease, doses of 400 mg/day or more and recent pulmonary insults such as pneumonia. Early amiodarone toxicity can be detected using pulmonary function tests and serial chest X-rays.

4) Other adverse effects that may be seen during long-term therapy include
a) corneal microdeposits (which often are asymptomatic),
b) hepatic dysfunction,
c) vivid and disturbing dreams
d) neuromuscular symptoms (most commonly peripheral neuropathy or proximal muscle weakness), e) photosensitivity and
f) hypo- or hyperthyroidism.


Sunday, February 8, 2015

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Aminoglycosides - why -mycin and -micin

The aminoglycoside group includes gentamicin, amikacin, netilmicin, kanamycin, tobramycin, streptomycin, paromomycin and neomycin.

These drugs have a good action against aerobic gram-negative bacteria.

They are rapidly bactericidal. Bacterial killing is concentration dependent: The higher the concentration, the greater is the rate at which bacteria are killed.

As noted above, some of the names end by -micin while others by -mycin. The reason behind this lies in the origin of the antibiotics.

All the antibiotics ending with -mycin are either natural products or semisynthetic derivatives of compounds produced by a variety of soil actinomycetes notably Streptomyces.
Those ending with -micin are derived from other actinomycetes e.g Micromonospora.

Saturday, January 24, 2015

Atrial septal defect device closure

This procedure is called as Atrial septal defect (ASD) device closure.


Transesophageal echocardiography (TEE) is must before procedure for:
1) actual sizing of the defect
2) defining the rims - to hold device in place
3) ruling out anomalous pulmonary venous drainage
4) ruling out significant mitral regurgitation (MR).
Intraprocedural TEE is not mandatory.


N.B How to distinguish between an ASD device and a patent foramen ovale (PFO) device? Left atrial (LA) disk (green arrow) is larger than Right atrial (RA) disk (yellow arrow), thus it is an ASD device.For a PFO device, RA disk will be larger than LA disk.

Further readings:

Friday, January 23, 2015

A case of Mycobacterium marinum infection in a fisherman

Historically recognized as “swimming pool” or “fish tank” granuloma.

Clinical features:
Most infections occur 2 to 3 weeks after contact with contaminated water from one of these sources. The lesions are most often small violet papules on the hands and arms that may progress to shallow, crusty ulcerations and scar formation. Lesions are usually singular. However, multiple ascending lesions resembling sporotrichosis can occasionally occur.
Most patients are clinically healthy with a previous local hand injury that becomes infected while cleaning a fish tank or patients may sustain scratches or puncture wounds from saltwater fish, shrimp, fins and other marine life contaminated with
M. marinum. Swimming pools seem to be a risk only when non-chlorinated.

Diagnosis:
Diagnosis is made from culture and histologic examination of biopsy material, along with a compatible history of exposure.

Treatment:

No treatment of choice is recognized for M. marinum. However, successful treatments have traditionally been a two-drug combination of Rifampin (600 mg/day) plus Ethambutol (15mg/Kg) or monotherapy with Doxycycline, Minocycline (100 mg BD), Clarithromycin (500mg BD) or Trimethoprim-Sulfamethoxazole given for a minimum of 3 months. Clarithromycin has been used increasingly because of good clinical efficacy and minimal side effects, although published experience is limited.








The following is the case of a fisherman who got injured while handling his fishing cage and presented with extensive papular lesions on his forearm. He was started on two drug-combination therapy for 5 months.











The second image is the same patient after 3 months of treatment.

Monday, January 19, 2015

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COPD exacerbation - definition, assessment, management

COPD exacerbation:

Definition:
Exacerbation of COPD is defined as an acute episode, characterized by the worsening of the patient’s respiratory symptoms that is beyond normal daily variations and that will eventually lead to a change in his medications.
Those having 2 or more exacerbations per year are known as “frequent exacerbators”.

Precipitating factors:
1) Respiratory tract infections – viral or bacterial. Most common cause. There may be an increased bacterial burden in the lower airways or new strains of bacteria are acquired during an exacerbation. Commonly implicated viruses
include rhinovirus, respiratory syncytial virus, coronavirus and influenza virus.
2) Air pollution.
3) Interruption of maintenance therapy.
4) Unknown causes – 30% cases.


Diagnosis:
Diagnosis should be made clinically whereby the patient complains of an acute aggravation of his symptoms out of proportion to his day to day variations. 

Assessment:
Medical history:
1) Severity of COPD before this exacerbation
2) Duration of the worsening or any new symptoms
3) Number of previous exacerbations or hospitalizations
4) Associated comorbidities
5) Present medications
6) Previous uses of mechanical ventilation.
Clinical examination:
1) Use of accessory respiratory muscles or paradoxical chest wall movements
2) Development of central cyanosis or exacerbation of pre-existing cyanosis
3) Change in mental status
4) Development of peripheral edema
5) Hemodynamic instability




Tests to assess severity include:
1) Pulse oximetry – good for monitoring.
2) Arterial blood gases and acid base status – shows whether there is an acute or acute on chronic respiratory failure.
3) Chest radiography – excludes alternative diagnoses and can show infections.
4) EKG – may help to assess any pre-existing cardiac problems.
5) Complete blood count – white cells may be elevated, hematocrit may be elevated
6) Blood biochemistry.
Spirometry is difficult to perform during an exacerbation and it may not be of enough accuracy. Therefore it is not recommended.

Treatment:
More than 80% of cases can be managed as outpatients but if the following conditions are seen, it is better to admit and if necessary give intensive care:
1) Dyspnea occurring at rest
2) Old age
3) Frequent exacerbator
4) Failure of response to change in/addition of medication to control the exacerbation
5) New onset of arrhythmias or peripheral edema.


Medical therapy consists of:
1) Short acting inhaled bronchodilators – beta-2 agonists with or without anti-cholinergics are preferred. It is better to use a nebulizer as the patient usually is dyspneic and lacks coordination to inhale from a metered-dose inhaler. IV methylxanthines are considered as second line of therapy for bronchodilation and are to be used only in selected cases, especially if there is poor response to short acting inhaled bronchodilators.
2) Corticosteroids – oral prednisone 40 mg/day for 5 days has been shown to shorten recovery time and improve lung function as well as arterial hypoxemia.
3) Antibiotics – these are indicated if the patient has clinical signs of bacterial infections e.g. increased in sputum purulence.  Procalcitonin III may help to indicate antibiotic therapy as it is increased in cases of bacterial infections. Usually in the following conditions antibiotics should be considered:
- 3 cardinal symptoms present: increase in dyspnea, sputum volume and sputum purulence,
- 2 cardinal symptoms, with purulence being one of the symptoms,
Antibiotics are recommended for 5-10 days.
4) Adjunct therapies – proper control of comorbidities is advised. Thromboprophylactic measures should be enhanced.

Respiratory support:
1) Oxygen therapy: Oxygen is titrated to correct the hypoxemia of the patient aiming to achieve a saturation of 88-92%. Usually Venturi masks are preferred to nasal prongs. After 30-60 minutes of oxygen therapy, arterial blood gases should be checked.
2) Non-invasive mechanical support
3) Invasive mechanical support.