Sunday, November 21, 2010

Long known Vitamin D ..and physiology

Of all the vitamins..Vitamin D has recently featured in almost all medical journals..given the huge prevalance(57% of hospitalised pts in US) of Vitamin D deficiency and the association of it to many important disease processes known to man! 
Vitamin D has properties of both being a hormone..and a vitamin. Lets get a quick recap of the physiology.

There are 2 main forms of vitamin D: vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). Vitamin D3 is formed in the skin, after exposure to ultraviolet B radiation, from 7-dehydrocholesterol that resides in cell membranes.Vitamin D2 is obtained through irradiation of ergosterol in plants from sunlight, and enters our circulation through diet. Vitamin D3 also is available from animal sources, such as cod liver oil, salmon, mackerel, and herring. 
After vitamin D is ingested from the diet or synthesized in the skin, it is metabolized in the liver to a biologically
inactive 25-hydroxyvitamin D, 25(OH)D, which is the major circulating form of vitamin D. It is this form( 25-hydroxyvitamin D) of vitamin D that is used to determine a person’s vitamin D status. 25(OH)D is then converted into its active form 1,25 (OH)D by the kidneys. This then interacts with vitamin D receptors in the intestine and bone to augment intestinal calcium absorption and mobilize osteoclast activity. Non-calcium regulating tissues, such as the prostate,colon, and breast, locally convert 25(OH)D to 1,25(OH)2D....and this forms the basis of Vitamin D being involved in prevention of malignancy in these tissues,aas it facilitates programmed cell growth.

Although controversies exist regarding the cut off for calling deficiency( due to summer Vs winter, morning Vs evening etc)......widely accepted value of < 20ng/ml of 25(OH)D is considered deficient ....21 - 29 is considered Vit D insufficiency......and > 30 ng/ml signifies sufficiency.  Without vitamin D, only 10% to 15% of dietary calcium and approximately 60% of phosphorus will be absorbed. The efficiency of calcium absorption is increased by 30% to 40%, and phosphorus by 80%, with the interaction of 1,25(OH)2D to its receptor.
I frequently got confused with the different names vit D has! 25(OH)D is an inactive form..but this is what we measure to diagnose deficiency. 1,25(OH)D is the active form..and we dont measure it. D2 & D3 are just numbers to describe the source of VitD....D2 (cholecalciferol) from human skin, and D3(ergocalciferol) from food products. 

Monday, November 15, 2010

PCP prophylaxis in non-HIV patients

Many clinicians routinely prescribe sulfamethoxazole-trimethoprim (SMX-TMP) or another agent to prevent the development of Pneumocystis jirovecii pneumonia (PCP) in patients receiving immunosuppressive medications, with the assumption that the risks are same as some one who is immunosuppressed from HIV. Evidence justifying such a policy is sparse.
A recent study published in J Am Acad Dermatology tried to find the right way to do this. The authors of this retrospective study examined the frequency of PCP in 198 HIV-negative patients who received immunomodulatory medications for dermatologic disorders, such as psoriasis, dermatomyositis, vasculitis, and pemphigoid.
Systemic corticosteroids, methotrexate, antimalarials, and azathioprine were the most common immunosuppressive medications used by these patients; approximately 25% received a biologic agent, such as etanercept. About 25% were concurrently receiving a prophylactic medication to prevent PCP. During an average follow-up of 8 years, PCP developed in only one patient (94 years old) not receiving PCP prophylaxis (0.7% incidence). Serious reactions to the PCP-preventive medication developed in 6% of SMX-TMP recipients and 37% of dapsone recipients.
The very low risk for PCP is too small to justify routine prophylaxis. In addition to their expense, these medications are frequently associated with adverse effects. The authors sensibly recommend that clinicians avoid routine prophylaxis in patients receiving immunosuppressive agents and that we remain alert to the uncommon possibility of PCP, especially in those with apparent risk factors, which include age >60, concurrent pulmonary disease, leukopenia, hypoalbuminemia, and CD4 counts <300/dL.
This above issue was brought on by one of my colleagues, Dr.Dioverti.. during a friendly chat she had a patient on bactrim prophylaxis due to chronic steroid use. This study will help those questions for now.

Thursday, November 11, 2010

Vitamin B and cognition.......doesnt work

High plasma homocysteine levels are associated with cognitive impairment in a few epidemiologic studies.In multiple clinical trials researchers have examined whether vitamin B supplementation — which lowers homocysteine levels — improves cognition or delays onset of cognitive impairment in older adults; results have been mostly negative.Have a look at the Cochrane review from 2008 .But Vitamin B deficiency has been implicated a causative factor for dementia, as it does affect the homocysteine levels.

In a new study published in Neurology 2010, Australian researchers randomized 299 community-dwelling hypertensive men (age>75) without dementia to receive either placebo or a combination of vitamin B6, vitamin B12, and folic acid.
During 2 years of treatment, no differences between groups were noted on several measures of cognition. Even in subgroups in which benefit seemed likely — men with high baseline homocysteine levels (15 ┬Ámol/L) and men with mild cognitive impairment at baseline — the investigators found no benefit from vitamin B supplementation.

The study adds more evidence to the fact that vitamin B does not improve cognition ..or prevent or improve dementia. The increased homocysteine levels may just be a marker of dementia than being a predictor of dementia. Its time to look at other things that might be important and probably stop emphasizing on Vitamin B!!

Tuesday, November 9, 2010

Linezolid or Vancomycin for nosocomial pneumonia

Nosocomial pneumonia due to MRSA is not very uncommon these days. Vancomycin is being increasingly prescribed ..keeping this in mind (atleast in my institution). Many studies have shown that Linezolid is better as it achieves higher lung epithelial lining fluid concentration which may correlate with improved efficacy.
A recent metanalysis(Crit care Sept 2010) was done to compare the efficacy /clinical outcomes of Linezolid versus Vancomycin .The theoretical advantage of Linezolid did not turn into a superior clinical benefit. The clinical cure rate, MRSA eradication rate and mortality were similar between the two antibiotics. There were significant 2 fold increased risk of thrombocytopenia and GI events in the Linezolid group compared to Vancomycin group.

Vancomycin holds its fort as the same reliable drug for MRSA nosocomial pneumonia. Teicoplanin and Linezolid will be effective alternatives to Vanco. But Linezolid will be the drug of choice for Vancomycin resistance (again...not an uncommon problem these days!!)

Generic Vancomycin is $4- $8 for a 1000mg vial(usual dose is 1g daily)
Teicoplanin is not available in USA
Linezolid(Zyvox) is $120 for a 600mg vial (usual dose is 600mg bid)

Monday, November 8, 2010

The risk of stopping antiplatelet therapy

Antiplatelets , especially Aspirin and Clopidogrel have established their importance in management of coronary artery diseases. But they also pose a bleeding risk. This risk is high if a procedure needing tissue sample is done. We had a 66 yo male ..4 months after a STEMI for which he received a drug eluting stent , and was started on Aspirin and clopidogrel. This clinic visit he is complaining of 6 month h/o early satiety, loss of apetite..and our records show a weight loss of 15lb in last 3 months.He needed a upper GI endoscopy ..with a possible biopsy. What do we do with his antiplatelets? ....Lets look at some facts from AHA
· Cessation of all antiplatelet therapies after PCI, at any time, for any stent, is associated with an increased risk of thrombotic events, including late stent thrombosis. These events are likely to occur within 7 to 30 days of drug discontinuation. 

·Cessation of clopidogrel (alone) during the early period after PCI (within 30 days of either DES or BMS placement) is associated with an increased risk of events. 

·Cessation of clopidogrel (alone) beyond 30 days from the time of BMS placement is common in clinical practice and does not confer increased risk of thrombosis over a brief period of time. 
·Cessation of clopidogrel (alone) upon completion of 6 months of treatment after DES placement is controversial (in terms of long-term risk) but does not seem to confer a significant short-term risk(within the subsequent 30 days) in a majority of patients if aspirin is continued. 

 The importance of continuing aspirin in the above scenarios was shown by a review in JACC 2005, where the median duration of stent thrombosis when both drugs were stopped, was 7 days...compared to 122 days when only clopidogrel was stopped and aspirin was continued.In addition, many retrospective studies have shown safety of continuing aspirin during GI procedures. The GI prcedures have been classified into high & low risk based on the risk of bleeding.
Considering the urgent need for endoscopy, the fact that UGI endoscopy is a low risk for bleeding, and the STEMI 4 months ago....we had our patient continue Aspirin, but stop Clopidogrel 5 days before procedure. He will continue his dual antiplatelet therapy the day after his procedure. As always.....the befits & risks were, and have to be discussed with the patient!

Thursday, November 4, 2010

I forgot to apply my brakes !!

The population with dementia is increasing ...and will probably increase for ever! An interesting article from Alzheimers association showed that the health care cost for managing dementia is almost thrice the profit of Walmart! Anyway our topic is not that. I had a patient today brought by his son, who takes care of dad's finances. His Mini mental state exam(MMSE) was 22, and the question of driving came up. Can this patient drive with this MMSE score? or will he forget to apply his brakes one day ?!!

First of all ......MMSE alone cannot be used to assess driving. It has a low sensitivity when used alone assess suitability of driving. A score of <25 is possibly useful in this aspect according to the latest guidelines from American Academy of Neurologist(AAN April 2010). If its not MMSE ..what predicts safety of driving?

Based on a number of studies Clinical Dementia Rating (CDR)scale appears to be useful for predicting unsafe driving. CDR mainly relies on memory ,but also has other factors like orientation, judgement, personal care, home& hobbies etc(altogether memory is the major category...with other 5 as secondary categories). A score of  0.5 to 1 may predict unsafe driving ....but it has a wide confidence many pts with that score passed the on road driving test(which is best at predicting unsafe driving........unfortunately can't be done in the office!!!)
The Academy of Neurology has the following as recommendations...

The CDR scale (Level A)
• A caregiver’s rating of a patient’s driving ability as marginal or unsafe (Level B)
• A history of traffic citations (Level C)
• A history of crashes (Level C)
• Reduced driving mileage (Level C)
• Self-reported situational avoidance (Level C)
• MMSE scores of 24 (Level C)
• Aggressive or impulsive personality characteristics (Level C)

Factors not useful in assessing safe driving are

• A patient’s self-rating of safe driving ability (Level A)
• Lack of situational avoidance (Level C)

Our gentleman had CDR score of 1, with a marginal caregiver rating, situational avoidance. He was advised to stop driving. Hope he doesn't forget this advice!

Tuesday, November 2, 2010

Plumbing paradigm might work!

I recently presented a morning report in my Clinic about preventive Cardiology...and I had mentioned about 'plumbing paradigm' ( relieving coronary blockage whenever we find one) does not make things better compared to a medical & lifestyle approach. I based this on two studies done on patients with stable coronary artery disease -

1.COURAGE trial - 2200 patients with stable CAD(ST depression or T wave inversion on resting ECG, inducible ischemia with exercise, or at least one coronary artery stenosis of at least 80% and angina. EF <30were excluded ). 2/3rds of pts had multivessel disease. Pts were randomised to PCI with bare metal stent Vs medical therapy. Over a period of nearly 5 years..there was no difference in primary outcome of all cause mortality, non fatal MI between 2 groups. Angina relief , stroke, hospitalisation for MI did not differ as well. But..a subgroup(n=314) were further enrolled to undergo nuclear study at baseline and after 1 year. PCI did show a significant reduction in ischemic myocardium compared to medical therapy.
2. BARI 2 trial - 2300 patients with type 2 diabetes and CAD(>50% stenosis of major coronary artery with +ve stress test or >70% stenosis with classic angina. Class 3 & 4 heart failure, creatinine>2 were excluded).Over a period of 5 years there was no significant difference between PCI/CABG  Vs medical therapy alone terms of survival, MI, and angina. 

But ..recently ..the MASS 2 trial was published in Circulation -  a randomised controlled trial of 611 patients with CAD ( with proximal multivessel stenosis .70%, stable class 2 or 3 CHF, HTN or diabetes). Pts were randomised to either CABG or PCI with BMS or medical therapy alone. Follow up for 10 years showed a significant improvement in cardiovascular mortality, recurrent MI, angina ...compared to medical therapy.PCI was associated with an increased need for further revascularization, a higher incidence of myocardial infarction, and a 1.46-fold increased risk of combined events compared with CABG. A thing to that majority of patients in this study had aither triple vessel disease or proximal LAD disease....and this is likely why CABG showed a great benefit. 

So.....based on these studies.....PCI /CABG may be superior to medical therapy in patients with stable multivessel disease( and the plumbing paradigm seems to work). But this cannot be generalized for others with stable and mild CAD ..where medical therapy has equal mortality and antianginal benefit as intervention...provided the disease is stable.

Monday, November 1, 2010

Multiple sclerosis- a few pearls

As we all know MS is an inflammatory, demyelinating disease affecting the central nervous system. MS is a dynamic disease with constant formation of new lesions and a progressive clinical course resulting in disability. 

 *For every 8-10 new lesions detected on magnetic resonance imaging (MRI), only one clinical manifestation typically can be demonstrated.
*Patients with relapsing remitting MS have an average of 5-10 new lesions per year and 1 or 2 clinical exacerbations
*no etiologic agent for MS has been identified

*MRI of head and spine with and without gadolinium shows the lesions(plaques). Enhancement of a lesion on T2 weighted image is indicative of an active lesion. Lesions that dont enhance are chronic lesions. Usually its a mixture of both. One differential here in a patient with 10 or more enhancing lesion on first presentation is Acute Disseminated Encephalomyelitis(ADEM). A history of recent vaccination/viral illness points more towards ADEM than MS in this scenario.
*CSF oligoclonal bands (which are IgG) is elevated in nearly 85 -90% of patients and serves as a good test with high sensitivity. So if negative....the likelihood of MS is low. IgG Index, which is calculated as follows (IgGCSF/albuminCSF)/(IgGserum/albuminserum) is usually elevated. ( Normal is < 0.77)
*Management is usually a multidisciplinary approach( as it is with most of the neurological illness)

* An acute exacerbation, if it is severly disabling should be treated with 1mg/kg/day of i.v methylprednisone for 3-5 days with a taper over next 2-4 weeks. This has shown to reduce the duration of disability, but does not improve the degree of resulting disability. (Neurology 1998 )
* Options for reducing relapses are many. interferon beta-1a IM (Avonex), interferon beta-1b SC (Betaseron and Extavia), glatiramer acetate SC (Copaxone), & interferon beta-1a SC are immunomodulators used in this aspect. In general these agents reduce the relapses by one third...with efficacy being high for high dose high frequency(HDHF) interferon  Betaseron (34), Rebif (33%), Copaxone (29%). But on the whole ...studies had shown variable results. for eg. INCOMIN study in 2002 showed benefit with HDHF interferon compared to low dose....which was later disproved by Danish MS study in 2006.
* The latest drug approved by FDA is Fingolimod...based on the recent TRANSFORMS study in NEJM 2010 which showed fewer relapses compared to interferon 1a over 1 year period. One advantage of fingolimod id that it is a oral opposed to all other meds(either im or sc).
*Modafanil or amantadine can be used effectively for symptoms of fatigue pts with MS.

Its not much to choose in between the terms of efficacy. So therapy can be guided by patient profile and side effect profile of the drug.