Transcript Update in Outpatient Internal Medicine for the Outpatientalist: 2013

Update in Outpatient Internal
Medicine for the Outpatientalist:
2013
GEORGE D. COMERCI, JR., MD,FACP,
DAAPM
PROFESSOR OF INTERNAL MEDICINE
CO-DIRECTOR: PROJECT ECHO PAIN
HEADACHE CLINIC,
UNM PAIN CONSULTATION AND
TREATMENT CENTER
Financial Disclosures
NONE
What to expect….
 Discussion of New Studies pertinent to the internist
 Update on New Disease Prevention
Recommendations
 New Drugs, New uses for old drugs, News about
drugs
Objectives
 Describe the clinical features of the H7N9 flu
 Discuss the relationship of statins to diabetes
 Discuss the emerging knowledge of the relationship
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of the human microbiome to disease
Describe the possible relationship of exercise on
dementia prevention
Discuss the importance of mammographic breast
density as this relates to mammography frequency
Describe the indications for the PCV-13 vaccine
Discuss new information about drugs
Clinical Findings in 111 Cases of Influenza A
H7N9 [N Engl J Med.2013.368:2277-85]
• Novel avian-origin influenza virus appeared in China
• Data on 111 cases evaluated
• H7N9 virus identified by RT-PCR assay
• Clinical Findings
• Pneumonia: 97.3 %
• ARDS: 71.2%
• Shock: 26.1%
• Death: 27%
Lab Findings
lymphopenia
Inc. CK and AST
Origin of the Novel Avian Influenza A H7N9 Virus.
Morens DM et al. N Engl J Med 2013;368:2345-2348.
3 factors a pandemic make….
 A substantial portion of the population should not be
immune
 The virus should be capable of causing human
disease
 Efficient human-human transmission*
Human Microbial Biosphere (Microbiota)
• The microbiota represents the communities of
microorganisms that resides within (and on) us
 10 times more microbial cells than human cells
 The microbiome is the genetic content of the
microbial communities and is far more complex than
the human genetic content
 Our symbiotic relationship to our microbial
biosphere is usually commensal or of mutual benefit,
but occasionally the relationship is pathologic
We Are One with our Microbiota!
The Human Microbiome
[Nutr Clin Pract.2012;27:201-214]
 The Microbiome is studied via gene sequencing
techniques not by culture techniques
 The Microbiome is most similar in twins, differing
some degree within family members and further
differing amongst unrelated family members
 Infant gut microbiota resembles that of an adult by
three years of age
 The microbiota is dramatically influenced by
environment, foods, antibiotics, etc.
Microbiota of different body
surfaces [Harrisons Principles of Internal Medicine.18 ed. 2012]
th
Pharacometabonomic identification of a significant hostmicrobiome metabolic interaction affecting human drug
metabolism [PNAS.106.2009]
Can a host’s metabolic phenotype (their microbiota)
influence drug metabolism?
 Acetaminophen
Acet Sulfate
Acet Glucuronide
Acet N Acetylcysteine
 P-cresol is produced by certain gut microbes and competes
for sulfation with acetaminophen
 Patients who were high producers of p-cresol had reduced
sulfation and reduced metabolism of acetaminophen
Obesity-induced gut microbial metabolite promotes liver
cancer through senescence secretome. [Nature.2013;499:99-103]
 Senescent cells develop a secretory profile consisting
of inflammatory cytokines, chemokines and
proteases (senescence associated secretory profile-SASP)

Some of these SASP promote cell clearance but others promote
tumorigensis
 Dietary changes that promote obesity change the gut
of mice microbiota in such a way that production of
deoxycholic acid (DCA) was increased which in turn
increased SASP phenotype in hepatic cells favored
tumorigensis and increased HCC
 This effect was reduced by administration of
vancomycin which reduced DCA production
Energy-balance studies reveal associations between gut
microbes, caloric load and nutrient absorption in humans.
[AmJClinNutr.2011;94:58-65.]
 Indigestible carbohydrates and proteins account for
10-30% of total ingested energy
 The ability to “harvest” this energy is highly
dependent upon the gut microbiota
 The microbiota of obese individuals is different than
that of lean individuals.
 This study showed that a high caloric diet (3400
kcal/d) increased Firmicutes sp. and decreased
Bacteriodetes sp. resulting in a net increased caloric
absorption of 150Kcal/d
Duodenal Infusion of Donor Feces for Recurrent Clostridium
dificile. [N Engl J Med.2013;368:407-414.]
 Question: Is duodenal infusion of donor feces
effective for the treatment of recurrent Clostridium
dificile infection.
 Methods: 43 patient who had failed a course of
vancomycin for C dif colitis
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17 received vancomycin 500qid x 4 D and subsequent colon
lavage followed by infusion of donor feces
13 received vancomycin 500 qid x 14 D with bowel lavage
13 received vancomycin 500 qid x 14 D
Rates of Cure without Relapse for Recurrent Clostridium difficile Infection.
van Nood E et al. N Engl J Med 2013;368:407-415
Microbiota Diversity in Patients before and after Infusion of Donor Feces, as Compared with
Diversity in Healthy Donors.
van Nood E et al. N Engl J Med 2013;368:407-415
We (our genome) and the microbiome are One!
 Variations in gut microbiome are affected by our
immediate surroundings, our diet and drugs.
 Variations in gut microbiome can affect drug
metabolism
 Variations in the gut microbiome may increase the
risk of certain cancers
 Re-establishment of a damaged gut microbiome can
eliminate disease
Meta-Analysis of Impact of Different Types and Doses of Statins on
New-Onset Diabetes Mellitus
[Am J Cardiol2013;111:1123e1130]
Question: What is the specific the specific risk for
developing DM associated with one statin compared
with another and is there a relationship to dosage and
DM
Methods:
• Meta-analysis of RCTs between 1994-2012
• Studies need have >1000 patients who were followed for >
1 year
Endpoints
• New onset DM
Meta-Analysis of Impact of Different Types and Doses of Statins on
New-Onset Diabetes Mellitus
[Am J Cardiol2013;111:1123e1130]
Results:
• 17 studies:
• 14 compared statin to placebo
• 3 compared high dose vs. moderate dose statin
• 11,3394 patients represented
 Rosuvastatin 20 mg/day: 25% relative increase in the risk
for developing new-onset DM.
 Pravastatin 40 mg/day: lowest risk for DM, almost
comparable with placebo treatment.
 Simvastatin 40 mg/day: approx. = Rosuvastatin 20
mg/day.
1 case of diabetes for every 4 cardiovascular
events prevented. [Circ.2012.126;e282-284]
The Association Between Midlife Cardiorespiratory Fitness
Levels and Later-Life Dementia: A Cohort Study
[Ann Intern Med. 2013;158(3):162-168]
Question:
Is there an association between midlife fitness and all
cause dementia?
Methods:
Study Center: Cooper Center Longitudinal Study
Study Cohort: 19,458 persons who had an exercise
treadmill test between 1999-2009
Exclusion Criteria: MI, stroke, chronic illness leading
to disability, age>65.
Fitness Level: quintiles according to METs on ETT
The Association Between Midlife Cardiorespiratory Fitness
Levels and Later-Life Dementia: A Cohort Study
[Ann Intern Med. 2013;158(3):162-168]
Methods (cont.)
 Quintile 1: 8.1 METS
 Quintile 2: 9.4 METS
 Quintile 3: 10.4 METS
 Quintile 4: 11.3 METS
 Quintile 5: 13.3 METS
Assessment at ages 70, 75, 80 and 85 years
Dementia identified ICD-9 codes (primarily for Alzheimertype dementia but also for vascular dementia)
The Association Between Midlife Cardiorespiratory Fitness
Levels and Later-Life Dementia: A Cohort Study
[Ann Intern Med. 2013;158(3):162-168]
Results:
• Mean follow-up: 24 years
• Hazard ratio: Quintile 5 compared to Quintile 1= 0.64
• No significant effect of educational level (mean =15 yr.)
• No significant difference in those with or without a history
of stroke
From: The Association Between Midlife Cardiorespiratory Fitness Levels and Later-Life Dementia: A Cohort
Study
Ann Intern Med. 2013;158(3):162-168. doi:10.7326/0003-4819-158-3-201302050-00005
Figure Legend:
Dementia-free survival, according to midlife fitness level.
Date of download:
10/8/2013
Copyright © The American College of Physicians.
All rights reserved.
Chronic Opioid Use is associated with increased DNA
Methylation correlating with increased clinical pain.
[Pain.2013;154.15-23]
Does chronic opioid therapy have pharmacoepigenetic
effects which result in decreased opioid
responsiveness?
 The pain response to opioids varies amongst patients
 Most patients develop tolerance to opioids
 Some develop hyperalgesia with opioids
Chronic Opioid Use is associated with increased DNA
Methylation correlating with increased clinical pain.
[Pain.2013;154.15-23]
Methods
Cohort 1:
Cohort 2:
Cohort 3:
Cohort 4:
Addicts on methadone
Matched controls
Pain patients on 115.8 MEDs
Pain patients on no opioids
Quantitative Analysis:
OPRM 1 (Mu receptor gene)
LINE 1 (transposone on mu receptor gene)
The Transposon
DNA Methylation
Comparison of global methylation and pain
scores
Prevention
PCV13 Pneumococcal Conjugate Vaccine
 The “classic” vaccine (PPV23) is a 23 valent vaccine
 In use since 1983
 No anamnestic response, ergo, immunity wanes
 PCV 13 is a conjugate made of a protein + a
polysaccharide capsular antigen
 Large scale clinical trial data not yet available
From: Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine
for Adults With Immunocompromising Conditions: Recommendations of the Advisory Committee on
Immunization Practices (ACIP)
JAMA. 2013;309(4):334-336. doi:10.1001/jama.2012.31377
Figure Legend:
Date of download: 10/1/2013
Copyright © 2012 American Medical
Association. All rights reserved.
Breast Cancer Screening
JT is a 56 y/o female who presents for her yearly
health exam. She has visited the Are You Dense
website, wants to know her breast density “score” on
her recent mammogram. She disagrees with your
recommendation to have mammograms every 2 years
and, furthermore, wants an MRI if her breasts are
dense.
 Is breast density a risk for breast cancer?
 Does she need yearly mammograms if she has dense
breasts?
 Should she have an MRI if her breasts are dense?
Breast Cancer Screening
 Breast “density” correlates with the degree of fat
replacement of breast tissue
 Women with mammographically dense breast have a
higher risk of invasive breast cancer
 Are You Dense, a breast advocacy group, has pushed for
laws mandating that women be informed of the degree of
density of their breast on mammography and have more
aggressive screening if their breasts are dense on
mammography
[J Natl Cancer Inst;2013;105:1043–1049]
Outcomes of Screening Mammography
by Frequency, Breast Density, and Postmenopausal
Hormone Therapy [JAMA Intern Med. 2013;173(9):807-816.]
Purpose:
 To compare the benefits and harms of screening
mammography frequencies according to age, breast
density, and postmenopausal hormone therapy (HT) use.
 Prospective study from data from the Breast Cancer
Surveillance Consortium (BCSC) mammography registries
 Data collected January 1994 to December 2008
 11,474 women with breast cancer and 922,624 without
breast cancer
Outcomes of Screening Mammography
by Frequency, Breast Density, and Postmenopausal
Hormone Therapy [JAMA Intern Med. 2013;173(9):807-816.]
 Women aged 40 to 49 years:
 biennial
mammography vs. annual is associated with
increased risk of advanced-stage cancer (odds ratio
[OR], 1.89 and large tumors (OR, 2.39).
 Women age 50 to 74 years:
 biennial mammography was not associated with
increased risk of less favorable tumor characteristics
regardless of breast density or HT usage.
 Triennial mammography WAS associated with higher
grade lesions only in women with extremely dense
breasts
New Drugs, New uses of Old
Drugs, News about Old Drugs
Zolpidem
 220% increase in ER visits due to toxicity (2005-2010)
[JAMA.2013;309:2203]
 Impaired driving, especially women and elderly
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Women: 5mg IR/ 6.25 mg XR
Elderly:
[JAMA.2013;309:646]
 Increased risk of Hip Fracture in Elderly
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OR = 1.66 for hip fracture in nursing home residents
[JAMA Intern Med. 2013 May 13;173(9):754-61.]
[
Fake and Substandard Drugs
 “falsified drug” misrepresents identify, source or
both
 “substandard drug”: fails to meet accepted standards
of manufacturing
 production
packaging
distribution
JAMA.2013.309.1693-1694
Fake and Substandard Drugs
 Supplements
 Life style drugs
 sildenafil
 Antimicrobials
 TB medications
 Malaria medications
 HIV medication
Bull World Health Organ 2010;88: 247–248
Codeine
• A natural derivative of Opium
 A weak analgesic nearly on the bottom of the WHO
pain ladder
 Converted to morphine by cytochrome P-450 enzyme
2 D6 (CYP2DR)
 CYP2DR activity exists as a spectrum of activity
[slow metabolizers
high metabolizers]
 15% of Middle Eastern and Northern African patients
are high metabolizers
Clin Pharm & Therap .2012; 91:323-326
N. Engl. J. Med.2009; 361, 827–828 (2009).
Fluoroquinolones
 Severe neuropathy
 Usually during treatment
 Potentially irreversible
 Severe fluctuations in glucose levels
http://1.usa.gov/17QhZK3
In summary….
 The H7N9 influenza
 The increased risk of DM with rosuvastatin and
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simvastatin
The complex role of the human microbiome in
disease and metabolism
The role of exercise in dementia prevention
DNA methylation with chronic opioid usage
Breast cancer screening and breast density
PCV-13 vaccine
Updates on Zolpidem, Codeine and Fake drugs
Thank You!