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: