Success!!! got my patient's LDL to 50mg/dl

First question.......What's the benefit of doing the above? We all know that lower the cholesterol..lower the cardiovascular risk. Latest evidence supports lowering it to < 70 mg/dl for the high risk patients. Well...is there a downside to overdoing this? Yes there is... at least theoretically ..for now.
The normal LDL level is 40 - 70 mg/dl. Cholesterol (mainly LDL particles) play a major role..and are the corner stone for synthesis of many steroid hormones including cortisol, tetosterone, androstenidione, Vitamin D etc. So by looking at this...obviously driving LDL to a much lower level can affect these important physiological processes.
There were a few studies done to see if reduction in LDL with statins affect endogenous steroidogenesis. In a cross sectional study of 350 type 2 diabetic patients on a statin (Diabetes care 2009) showed a significant reduction in total testosterone level with atorvastatin compared with no treatment. But the free bio available testosterone levels were normal. A pharmacology study from Holland shows the same above possibility with Statins.(British J of Clin Pharmacology )

A subgroup analysis of reproductive age group women from WISE trial showed no significant decrease in levels of estrogen or progesterone in pts with LDL < 70 Vs pts with LDL >70. (AJM 2002).
An earlier study from 1994 showed no decrease in levels of adrenal and gonadal steroids in patients with a low LDL on a statin. Most of the above studies...didnt drive down the LDL levels to < 70mg/dl.
A recent study published in 2009 comparing gonadal hormones in pts with LDL <70 with LDL <100...in pts on a statin..showed no significant difference in the sex hormone levels..over a period of 12 weeks. This may be a short duration to assess a reasonable outcome.

On the whole...driving the LDL levels to < 70 may have little or no negative effect on sex &/or adrenal hormone levels. But this possibility can be considered if a pt..with a LDL of <70 complains of decreasing libido.(these pts may also be on Spironolactone..which can make this worse).
Statins have shown some benefit in treating prostate cancer( again..may be due to their effect on lowering levels of testosterone!). Another theoretical concern with excessive lowering of cholesterol will be the possibility of a lack of adrenergic response needed during stress (especially in sepsis, ICU admissions etc) due to low cortisol production. Whether this is true remains to be answered !!

Fasting for 72 hours ..for the diagnosis?

Well..I recently admitted a patient for exactly  the same....72 hour fasting test.

A 43 yo male with 4 year history of many ER and walk in clinic visits with symptoms of sweating ..feeling of hunger and many episodes of syncope where he suddenly looses consciousness.Twice this happened while driving ..but he was also drunk at that time(so was arrested.....happened twice in jail!). Regains consciousness in minutes. Eating something just before the episode prevents it. Twice there was documented glucose levels of 45 & 50 during these episodes. His fasting glucose in clinic was 78 with a Insulin level of 78(high), and a C peptide level of 2.3 (normal).He also has a 5 year h/o abdominal pain.
The differential in this guy is 1.Insulinoma 2.Factitious hyperinsulinemia 3.Autoimmune hyperinsulinemia 4. Nesidioblastosis (islet cell hypertrophy)

The test entails admitting patient after a overnight fast ..to the hospital. Get baseline glucose, Insulin level, proinsulin level, and C peptide. Keep the pt NPO( nil per oral) with a maintenance iv fluid without glucose...or can be allowed to drink water. Monitor glucose every 4-6 hours. We are looking for hypoglycemia (glucose <45 mg/dl) or hypoglycemic symptoms. Do the same blood tests  at that point and stop the test.(for this...start checking glucose every hour once it reaches 60 mg/dl). If the above two criteria are not met...continue test until 72 hours. The idea ..is pts with Insulinoma will become hypoglycemic, and their C peptide, Insulin and proinsulin levels will be high when he has hypoglycemia. This is explained in this article from 2007. 72 hour fasting seems like..cruel..So researchers looked at options with lesser duration..and they have shown that a 48 hour fast would be enough to identify almost all patients with endogenous hyperinsulinemia(Clin Endo & Met 2000). Our patient has been on the fast for 20 hors now...without any hypoglycmeia or symptoms...

A quick look at evaluation of hypoglycemia(in absence of anti diabetic meds):
1. Whipples triad has to be satisfied( hypoglycemia, neuroglycopaenic symptoms, and prompt relief of symptoms with the administration of glucose).
 2.Then do a 72 hr formal fasting. A positive test is a glucose <50, Insulin > 3microIU/ml & C peptide >200 pmol/L. This confirms endogenous hyperinsulinemia. ( also get a drug screen for sulphonylureas...as they can mimic the same).
3. Once confirmed..then start the localisation process--- CT angiography, trans esophageal US can help. Or an experienced surgeon can go in..and find the insulinoma. If not possible...a Selective arterial calcium stimulation with hepatic venous sampling(SACST) ..where a catheter thru femoral vein lies in hepatic vein..and a 2nd catheter thru femoral artery goes into splenic/mesentric/gastroduodenal aa. and infuse Ca.This stimulates release of Insulin as picked up by the catheter in hepatic vein. ...this has a sensitivity of> 90%

Another complication of Obesity

NASH is a diagnosis showing up more and more in primary practices these days.  The main reason is the epidemic of OBESITY. NASH is on the upper end of a spectrum of disorders called Non Alcoholic Fatty Liver Disease (NAFLD). Other end of the spectrum is the relatively benign Hepatic steatosis.
NASH comprises heaptic steatosis associated with necrosis and inflammation. The main pathophysiology behind NASH is 1. Insulin resistance leading to.... 2.Hyperinsulinemia and 3. increased free fatty acids. Also implicated are oxidative injury due to induction of CYP450 in these pts. An evidence to show insulin resistance as a cause is a study comparing incidence of NASH in Type1 Vs type2 diabetics....showing a significantly higher incidence in the latter.Due to above pathophysiology..it is common to find NASH in patients with metabolic syndrome.   

Usually patients with NAFLD do not have specific symptoms from the disease. They might complain of malaise, lethargy, nausea etc. Its rare to have right upper quadrant pain or jaundice. What they will have is a slightly elevated AST /ALT (< 4 x normal..and ALT > AST). So we are not going to jump to this diagnosis straight away in this scenario. The first and important thing to exclude is the presence of alcoholic liver disease. (History..history..history!!). then we round the usual suspects(viral hepatitis, toxins, drugs etc). But its reasonable to suspect NAFLD in pts..with above characteristics without alcohol exposure...in the first place

.The risk factors are the same as for met syndrome- Obesity(prevalant in 75% of pts with body wt >10% of ideal!), Diabetes type 2, hypertriglyceridemia, equally present in males Vs females ( but likelihood of fibrosis is increased in females). Because of this association....pts with NAFLD have an increased cardiovasscular risk...have a look at this EASL statement 2008 & a latest abstract from a study on adolescents with obesity(Am J of Epi 2010)Imaging can show fatty liver.Liver biopsy is the only tool that can differentiate a benign steatosis to NASH. 8-20% of obese individuals with hepatic steatosis will have NASH..........and risk of development of fibrosis and cirrhosis from NASH is 10-50%. NASH leading to cirrhosis is the cause for 1% of liver transplantations.

Management is going to be the same as for metabolic syndrome----loosing weight, improving insulin sensitivity( Metformin & Pioglitazone are modestly effective in reducing the fat in the liver..and improving the histology in diabetic pts...and less so in non diabetic pts).Urodeoxycholic acid which was previously used as treatment...is no longer recommended..due to lack of efficacy as shown in this randomised trial ( Hepatology 2004)The latest trial published in NEJM May 2010, was on Vitamin E . Vit E @ 800 IU /day showed a significant improvement in NASH histology(mainly in no diabetics), improvement in liver enzymes..without any benefit on development of fibrosis. It will be reasonable to have these pts on Vit E (but remember that Vit E @ high doses have shown to increase mortality!).....All these measures are aimed at improving inflammation in the liver....but whether these will result in a mortality benefit..remains to be known.

A Nobel reward after 32 years!

Prof Brown in 1998

The Nobel Prize in Medicine for 2010 was announced this week. And it goes to Professor Robert Edwards of Britain for his research on Invitro fertilisation...which resulted in the first test tube baby in the history of the world. His achievement has helped bring 4 million infants into the world and raised challenging new questions about human reproduction.
Robert Edward Brown(born in 1925) was a reproductive Biologist at Cambridge University . With the help of surgeon Patrick Steptoe (died in 1988)..he pioneered conception through IVF...and the first test tube baby , Louise Brown was born on 25th July 1978. She is now aged 32 living well and gave birth to a son 3 years ago..which was a natural conception. She lives in Bristol, UK. 
The delay of 32 years in presenting this Nobel Prize....was because of the initial concern about the health of these babies. Now it has been proved beyond doubt that it is safe for the babies born. But still I think...the Nobel Prize comittee took a looooong time for this. Luckily Prof Brown is alive but  to receive this award which comes with $1.5 million. He also features as one of the TOP 100 LIVING GENIUSES published by Newyork Times (This list also has Nelson Mandela, Gary Kasparov, Steven Spielberg,Bill Gates, Steven Hawking & Mikhail Klasnikov). 


There are still many ethical issues unresolved...relating to IVF.Some of the interesting ones..
1. With IVF..a child can have upto 5 parents - the sperm donor, the egg donor, a surrogate mother who brings the child to term in her womb, and the couple intending to raise the child.In some countries..the legal mother is one who gives birth. Well this is definitely a confusion!
2.IVF clinics routinely fertilize more eggs than are implanted, at least at first. The resulting extra embryos can be frozen for storage. The parents decide about what to do with them. They might be destroyed ....for finding genetic defects, donating to someone else.
3. The child's right to access to information about his or her genetic background or mode of conception.


Whatever these ethical considerations/confusions are...Prof Brown (& Dr. Steptoe) both deserve the Nobel Prize. Prof Brown is currently admitted in his hospital in Cambridge for long term illness..but expected to be present at the ceremony. The Nobel Prize for other departments..are yet to be announced.

My chances with Polycystic Ovarian Syndrome ?

Today was endocrine clinic day...and I saw a 22 yo black female with secondary amenorrhea of 3 years duration.sought medical attention 3 weeks ago.....found to have diabetes....started on Metformin...and referred to us. She was obese & had some facial hair. Her labs are Hb- 12.8, MCV- 76, LFT- normal, Na,K, BUN, Creatinine - normal. Her TSH- Normal, LH- 6.1 mIU/ml, FSH -4.6mIU/ml, testosterone lvl- 49ng.dl (high normal is 40), DHEAS, androstenidione, 17OH progesterone - Normal. US - no ovarian cysts. She had a progesterone challenge...following which she had bleeding. She has anovulatory PCOS.
Her main concern was about her chances of getting pregnant?


Lets first look at the criteria for diagnosing PCOS. The latest criteria is from 2003..called Rotterdam Criteria ...and calls for presence of 2 of following 3 ...... a)Oligo‐ and/or anovulation b)Clinical and/or biochemical signs of hyperandrogenism c) Polycystic ovaries ...and exclusion of other causes. Our pt had 2 of the above(a & b).


There has been a good amount of evidence linking ovarian problems in PCOS to hyperinsulinemia and Insulin resistance. Insulin affects stromal proliferation etc.Have a look at this review. This forms the basis of treating these pts with Metformin......also there is more regularisation of menstrual cycle with Metformin(NEJM 2008). Other main treatment options for anovulation are Clomiphene(frequently used as first line) and lastly GnRH or lap surgery for cysts. A combination of these drugs (meformin & clomiphene) does not offer an added benefit for inducing ovulation ( Clin Endocrine 2009 & Cochrane 2009)


What are the chances of this lady getting pregnant? Well...few facts..... 
6- 10 % of fertile women satisfy criteria for PCOS. 
PCOS is the underlying cause in 70% of pts with anovulatory infertility.
In patients with anovulatory PCOS..the infertility rate is high and varies widely. Its difficult to find the exact prevalance of infertility among patients with PCOS. But ..look at this long term study (10-20 years)showing a spontaneous fertility rate of 87% in PCOS(mostly with oligomenorrhea) compared to 91% in normal controls. Also.. treatment with Clomiphene has shown pregnancy rates of 70%   just after 4 ovulatory cycles (Hum Reproduction). 
So our patient has a very good chance of getting pregnant with treatment. For now she is going to be on Metformin ( she needs to be..due to diabetes) hoping it might help with ovulation as well. If not..she will be started on Clomiphene for ovulation induction. Then we have IVF which also has good success rates.

Nutrition in ICU - a lot of calculation...can be made simple

Nutrition in ICU is an important aspect of Critical management of patients..as they are all in a catabolic state due to the high levels of circulating Catecholamines, cytokines and lymphokines. It has been emphasized that nutrition (either parenteral or enteral ) be started  as early as possible..within 24 hours of ICU admission.

Which route --Enteral Vs Parenteral - This is not a big issue...as enteral is easier and less expensive & less complicated to start......and there is some evidence that using the gut might prevent bacterial translocation. Also splanchnic circulation increases with enteral feeding..preventing mucosal breakdown. Use parenteral if contraindication to enteral feeds. e.g - GI bleed, Pancreatitis etc
What food -- In US...many types of enteral feeds are in use depending on the clinical scenario.These are pre-prepared. They can be classified according to the calorie concntration..or based on special additives. Some e.g are Osmolite- 1Kcal/ml, Jevity- 1.2Kcal/ml, Twocal-2Kcal/ml. Useful in case fluid restriction is needed!. Secondly.... use Glucerna - Diabetes, Nepro for renal disease, Oxepa for ARDS etc (we will discuss these at a later date). 
How much -- Always start low @ 20ml/hr...and increase every 4-6 hours by 20ml..upto the goal. Sooooo what is the goal?? Well here is a rough calculation.... First calculate the calories needed
Basal Energy Expenditure : 66.5+(13.8 x wt in kg) + (5 x ht in cm) - (6.8 x age in yrs)     .........for men
                                                65.5 +( 9.6 x wt in kg) + (1.8 x ht in cm) - (4.7 x age in yrs) ..........for women


Rougly for a 60 yo male 6 ft tall and 80 kg....BEE will be around 1800 Kcal/day (or if the above formula is too complicated!.....simply use 25Kcal/kg/day)
The Total Energy Expenditure will be = BEE x 1.2 x stress factor ( I add 1.5- 2.0 for being in ICU- Sepsis) (Critical Care 2003)
For our gentleman above...it will be roughly 3200 kcal/day. 
Nitrogen Balance - This is how we assess response to nutirional response. Its simply... Nitrogen intake – Nitrogen losses. 
Nitrogen intake = Calculate as 1gm of Nitrogen for each 150 Kcal of feed ( eg. for 3200 Kcal /day,it is 21 gm nitrogen)
Nitrogen losses = Urinary Urea Nitrogen (g/day) + 4g ( this is for extra renal loss of Nitrogen - stools, sweat etc)
If net nitrogen balance is > 2gm...it can be called a positive nitrogen balance........if <2 gm negative NB.To do this calculation..we need the Urine urea Nitrogen (UUN....same as BUN...but in urine) - this is done on a 24 hr collection of urine( can be done easily in a ICU setting). Do it atleast 2 days after starting tube feeds. Do this once a week...and present the Nitrogen balance to your attending!!! ( you will look more smart!)

Honey..... STOP!! I have a headache

A case that was briefly discussed in our Neurology morning report...presented by Dr.Dadu .
A 30 yo female with h/o tension headache, presented to ER with 2 episodes of headache(different than her tension headache) during sex with her boyfriend(of long time).each time it lasted for 2 hours. not associated with nausea or vomitting. Physical exam did not reveal any abnormality. Should this lady be investigated ?
Lets see....
Headache associated with sexual activity-HSA (also..orgasmic headache, beningn sexual headache, coital headache) as termed by ICHD -II, has been described as bilateral and occipital lasting anywhere between 10min to 6 hours. More common in men than women (4:1). Comorbidity with other headaches(migraine, tension etc) is common. It can be further divided into
 Preorgasmic Headache - A) Dull ache in the head and neck associated with awareness of neck and/or jaw muscle contraction and B) Occurs during sexual activity and increases with sexual excitement
C) Not attributed to another disorder
Orgasmic Headache - A) Sudden severe (‘explosive’) headache B) Occurs at orgasm
C) Not attributed to another disorder

Orgasmic headache is considered to be mostly of vascular origin.In a study done with trans cranial doppler in pts with orgasmic headache showed impaired cerebral autoregulation leading to reversible vasoconstriction. (1976) . Indomethacin seems a good treatment option...with propranolol being a good prophylactic.

But what shall we do for our patient while she is in the emergency room. Have a look at this study from Spain where they looked at 6500 pts with headache. Of these 18 pts had HSA. All patients with HSA had CT head and followed by lumbar puncture if needed. This diagnosed 2 of the 18 patients with Sub arachnoid hemorrhage. Based on this ..and some other studies..the incidence of HSA is around 1%. Of the pts presenting with HSA, sub arachnoid hemorrhage(SAH) or a aneurysm may be an underlying diagnosis in upto 10%. The rest are all benign sexual headache.
Given the risk of high mortality & successful treatment with SAH........even if the prevalence is low..it will be reasonable to image them on first presentation with CT head ..followed by lumbar puncture if needed. So our lady had these investigations..and they were negative.She has benign HSA.