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Archive for September, 2016

Primary Care Corner with Geoffrey Modest MD: STI Infection Therapy WHO Guidelines

25 Sep, 16 | by EBM

By Dr. Geoffrey Modest

Because of growing antibiotic resistance, the World Health Organization (WHO) published updated guidelines for the treatment of sexually-transmitted infections: see  See end of this blog for links to other relevant blogs on STIs, antibiotic resistance, etc.


  • 131 million people are infected with chlamydia, 78 million with gonorrhea and 5.6 million with syphilis
  • All have increasing antibiotic resistance, especially gonorrhea, where some strains do not respond to available antibiotics (see blogs at end). Quinolones are not recommended, as a result.
  • There is a 7-fold increased risk of transmission of HIV in both ulcerative and nonulcerative lesions (also with other STIs, such as HSV-2, chancroid, trichomoniasis)
  • There is increasing evidence of trichamonas being resistant to nitroimidazoles (and there really is no other rx)
  • Syphilis has more resistance to azithromycin
  • Chlamydia has more treatment failures to tetracyclines and macrolides

Gonorrhea (see ) for details. I will highlight differences with the 2015 MMWR on STIs (see: )

  • Genital and anorectal GC infections
    • Typically cause urethritis in men and mucopurulent discharge in women. Can be asymptomatic, esp in women. Pharyngeal and rectal infections are largely asymptomatic
    • Use local resistance data to determine the choice of therapy
    • If local resistance data not available, use dual therapy:
      • Ceftriaxone 250mg IM as a single dose plus azithromycin 1 g as a single dose, or
      • Cefixime 400mg orally as a single dose plus azithromycin 1 g as a single dose [MMWR: only use if ceftriaxone not available, increasing reports of cefixime resistance)]
    • If recent local resistance data are available, can use single therapy based on the local resistance pattern: [MMWR: no single treatment recommended: there are some data suggesting synergy of the dual therapy and perhaps slower development of resistance]
      • Ceftriaxone 250mg IM as a single dose
      • Cefixime 400mg orally as a single dose
      • Spectinomycin 2gm IM as a single dose
    • Oropharyngeal GC infections (MMWR noted treatment failure after single dose therapy and therefore prefer dual therapy. especially for pregnant women):
      • If local resistance data not available, use dual therapy:
        • Ceftriaxone 250mg IM as a single dose plus azithromycin 1 g as a single dose, or
        • Cefixime 400mg orally as a single dose plus azithromycin 1 g as a single dose [MMWR: this one is not recommended]
      • If recent local resistance data are available, can use single therapy based on the local resistance pattern:
        • Ceftriaxone 250mg IM as a single dose
      • Treatment failure:
        • If reinfection suspected, re-treat with above, reinforce sexual abstinence or use of condom, and provide partner Rx
        • Otherwise, contour treatment to GC susceptibility
        • Retreat with one of the following:
          • Ceftriaxone 500mg IM as a single dose plus azithromycin 2 g as a single dose, or
          • Cefixime 800mg orally as a single dose plus azithromycin 2 g as a single dose
          • Gentamicin 240 mg IM as a single dose plus azithromycin 2 gas a single dose
          • Spectinomycin 2g IM as a single dose (if not oropharyngeal GC) plus azithromycin 2 gas a single dose
          • MMWR: treat as dictated by susceptibility testing. Options include: can try gemifloxacin 320 orally plus azithro 2gm, or single doses of gentamicin 240 mg IM plus azithro 2gm; and get test-of-cure 7-14 days later, preferably by culture. No comment on the double dose treatment proposed by WHO noted above (doubling the dose of cephalosporin and azithro). They also place treatment of sex partners as priority right away, not mentioned in WHO until likely reinfection.
        • GC ophthalmia neonatorum, use one of:
          • Ceftriaxone 50 mg/kg (max of 150mg) IM as single dose, or
          • Kanamycin 25 mg/kg (max of 75mg) IM as single dose, or
          • Spectinomycin 25 mg/kg (max of 75mg) IM as single dose
        • Use topical ocular prophylaxis for all neonates to prevent GC and chlamydia eye infections, as determined by cost and local resistance
          • Tetracycline hydrochloride 1% eye ointment
          • Erythromycin 0.5% eye ointment [MMWR: this is recommended med]
          • Povidone iodine 2.5% solution (water-based, not alcohol-based)
          • Silver nitrate 1% solution
          • Chloramphenacol 1% eye ointment
        • MMWR also suggests treatment for adult gonococcal conjunctivitis with ceftriaxone 1 gm IM plus azithro 1 g orally, both in a single dose

Chlamydia (see )

  • Can be asymptomatic in men and women
  • Uncomplicated genital chlamydia [MMWR recommends the same 2 primary treatments, adds levofloxacin 500mg orally once a day for 7 days, and has ofloxacin as 300 mg bid for 7 days. Does not include tetracycline. And again pushes more for treatment of sex partners]
    • Azithromycin 1 g orally as a single dose (most convenient dosing), or
    • Doxycycline 100mg orally twice a day for 7 days (cheapest treatment). These 2 are the major recommendations
    • Tetracycline 500 mg 4 times a day for 7 days, erythromycin 500mg orally twice a day for 7 days, ofloxacin 200-400 mg orally twice a day for 7 days (alternative regimens)
  • Anorectal chlamydia
    • Priority is doxycycline 100mg bid for 7 days, secondary would be azithromycin 1gm orally as a single dose
  • Genital chlamydia in pregnant woman [MMWR also recommends azithro as primary, then options of amoxacillin or a variety of erythromycin-based therapies similar to WHO]
    • Use azithromycin over amoxicillin (500mg orally 3 times a day for 7 days), and that over erythromycin, regimens as above
  • LGV (lymphogranuloma venereum)
    • Doxycycline 100mg bid for 21 days preferred, can do azithromycin 1 g orally weekly for 3 weeks
  • Neonatal chlamydia conjunctivitis (ophthalmia neonatorum) [MMWR prioritizes the erythromycin regimen]
    • Azithromycin20 mg/kg/day orally once a day for 3 days (preferred), or erythromycin 50 mg/kg/day, orally in 4 divided doses for 14 days
  • Neonatal ocular prophylaxis
    • Same as for GC above

Syphilis (see )

  • Primary syphilis: painless chancre (may be extra-genital, at site of inoculation) after mean incubation of 21 days, and heals spontaneously in 3-10 weeks
  • Secondary syphilis: generalized rash (varies widely, and I have seen a couple of cases looking just like pityriasis rosea), but typically palms and soles, symmetric, non-itchy. In moist areas (anus/labia), can be white-gray raised lesion of condyloma lata, which are teeming with treponemes (i.e., wear gloves…)
  • latent syphilis: positive serology, no clinical signs/symptoms, and divided into early latent (<2yrs) or late latent (>2 years, or if unknown)
  • If untreated, most remain in late latent stage, with 25% developing the late clinical sequelae of tertiary syphilis (can be >30 years after infection). Neurosyphilis can occur at any stage, even within the first few months: acute mental status changes, meningitis, stroke, cranial nerve dysfunction, auditory/ophthalmic/ocular abnormalities. Late neurosyphilis (tabes dorsalis, general paresis) occurs 10 to >30 years after infection
  • MMWR basically agrees with below, though has additional recommendations for kids, treating tertiary and neurosyphilis, as well as coinfection with HIV (not different from non-HIV, though may have more clinical symptoms, such as neurosyphilis.
  • Early syphilis (primary, secondary and early latent)
    • Benzathine penicillin G 2.4 million units IM once (preferred)
    • Procaine penicillin G 1.2 million unit IM for 10-14 days
    • In penicillin-allergic, or above not available: doxycycline 100mg orally bid for 14 days (cheaper and oral), or ceftriaxone 1 g IM daily for 10-14 days, or (last) azithromycin 2 g orally once only (if local susceptibilities support its use)
  • Pregnant women with early syphilis
    • As above with emphasis on penicillin regimens
    • In those penicillin allergic: can use the erythromycin or ceftriaxone or azithromycin, as above. (Can’t use doxycycline in pregnancy, and erythromycin and azithromycin do not cross the placental barrier completely. So if use either of these, should treat the newborn soon after delivery)
  • Late syphilis (infection >2 years, or syphilis of unknown duration without evidence of treponemal infection)
    • Benzathine penicillin G 2.4 million units IM once weekly for 3 injections, and interval between doses cannot exceed 14 days (preferred)
    • Procaine penicillin 1.2 million units IM daily for 20 days
    • If penicillin-allergic: doxycycline 100mg orally bid for 30 days
  • Late syphilis (infection >2 years or syphilis of unknown duration without evidence of treponemal infection), in pregnant women
    • Benzathine penicillin G 2.4 million units IM once weekly for 3 injections, and interval between doses cannot exceed 14 days (preferred)
    • Procaine penicillin 1.2 million units IM daily for 20 days
    • If penicillin-allergic: erythromycin 500mg orally qid for 30 days. And treat the newborn
  • Congenital syphilis
    • Aqueous benzyl penicillin 100,000-150,000 U/kg/day intravenously for 10-15 days (preferred)
    • Procaine penicillin 50,000 U/kg/day IM for 10-15 days
  • Infants who are clinically normal but whose mothers had syphilis which was adequately treated
    • Risk of transmission depends on: maternal titers from non-treponemal tests (e.g. RPR), timing of maternal treatment and stage of maternal infection
    • If decide to treat: benzathine penicillin 50,000U/kg/day as single IM dose


Why is the WHO report important??

  • It highlights the really major issue on increasing antibiotic resistance, and the WHO has really been at the forefront in studying this issue and publicizing pretty dire warnings
  • We are seeing more international patients who may have been treated for an STI and we should know what are the acceptable regimens internationally
  • In the US, I would go by the MMWR recommendations, though I think the suggestions of higher dose meds for treatment failure of gonorrhea make sense, but is supported only by successful reports in individuals who had failed a variety of treatments, and not from formal studies. In someone who is less likely to come back for test-of-cure, based on this I would probably use the higher dose regimen as per WHO. If they are very likely to return, it is reasonable to try the MMWR regimens with close follow-up. I am also still somewhat concerned about the treatment of syphilis in those with HIV, given early reports of failure, and still do use the longer regimen (2-3 shots for early syphilis), as per the relevant blog cited below.

For prior blogs, see , which includes blogs detailing the increasing resistance of gonorrhea ( ), a blog from the WHO highlighting that in 3 of the 6 regions of the world there is >25% resistance of gonorrhea to 3rd generation cephalosporins ( ), a blog which questions the recommendation that those with syphilis and HIV get the same treatment as those without HIV ( , etc.

Primary Care Corner with Geoffrey Modest MD: Normal BMI/Exercise Lower Cancer Risk

23 Sep, 16 | by EBM

By Dr. Geoffrey Modest

The International Agency for Research on Cancer (IARC) working group just assessed the relationship between overweight/obesity and cancers, finding 8 more cancers associated with obesity (see Lauby-Secretan B. N Engl J Med 201; 375: 794). They relied on over 1000 epidemiological/observational studies to assess this association, since there really are no large randomized clinical intervention trials with long-term follow-up assessing the effects of weight-loss vs maintaining weight to see if there is a difference in cancer incidence.

  • Background, worldwide estimates:
    • In 2014: 640 million adults in 2014 (an increase by a factor of 6 since 1975) were obese
    • In 2013: 110 million children and adolescents (an increase by a factor of 2 since 1980) were obese
    • In 2014: prevalence of obesity was 10.8% among men, 14.9% among women, and 5.0% among children; and globally more people are overweight or obese than are underweight.
    • In 2013: 4.5 million deaths worldwide were caused by overweight and obesity; the obesity-related cancer burden represents up to 9% of the cancer burden among women in North America, Europe, and the Middle East.
    • In 2012: 1 million new cancer cases and 8.2 million cancer-related deaths
  • The 8 new cancer associations:
    • Colon or rectum, RR = 1.3, with positive dose response relationships (e., the more overweight, the higher the risk)
    • Gastric cardia, RR = 1.8, with positive dose response relationships
    • Liver, RR = 1.8, with positive dose response relationships
    • Gallbladder, RR = 1.3, with positive dose response relationships (though in their analysis, comparing the top vs bottom decile of activity, this achieved a P=0.06 only)
    • Pancreas, RR = 1.5, with positive dose response relationships
    • Kidney, RR = 1.8, with positive dose response relationships
    • Esophageal adenocarcinoma, RR=8, with positive dose response relationships
  • In general the relative risks increased from 1.2 to 1.5 for overweight and from 1.5 to 1.8 for obesity for cancers of the colon, gastric cardia, liver, gallbladder, pancreas and kidney
  • These results were consistent in different geographic regions, and were similar for men and women
  • The previously known cancers with associations:
    • Breast cancer in postmenopausal women, RR of 1.1 per 5 BMI units, esp in estrogen-receptor positive tumors
    • Endometrial cancer: RR=1.5 for overweight,5 for BMI 30-35, 4.5 for BMI 35-40, and 7.1 for BMI>40
    • Ovarian cancer (epithelial): RR=1.1
    • Multiple myeloma, RR=1.2 for overweight, 1.2 for BMI 30-35, 1.5 for BMI 35-40, and 1.5 for BMI>40
    • Meningioma, RR = 1.5
    • Thyroid, RR=1.1
  • And there is some limited evidence of an obesity association with male breast cancer, fatal prostate cancer, and diffuse large B-cell lymphoma
  • For breast cancer, there was an association between increased BMI at the time of diagnosis and reduced survival
  • In terms of weight loss: the quality of the data are not great, but there are some suggestions that weight loss (including by bariatric surgery) may reduce the breast and endometrial cancer risks.
  • As supporting evidence:
    • Animal data (different animals) confirm an association between obesity and cancer at many different sites
    • Animal data also supports the effect of limiting weight gain vs food ad libitum for some cancers (mammary gland, colon, liver, pancreas, skin, pituitary) but inverse relationship with others (prostate, lymphoma, leukemia)


  • As with all of these observational studies, association does not imply causality. For example, is it the obesity itself which is associated with cancer? Or, are there specific things that obese people do differently than normal weight ones (e.g., eating certain oncogenic foods? not exercising enough? living in more toxic environments?)
  • The above results were similar for BMI and waist circumference when that data was available (waist circumference has a higher correlation with visceral obesity, which is the metabolically more active obesity associated with metabolic syndrome, increased inflammatory markers, )
  • In many of the above associations, the associations persisted in studies using mendelian randomization (see , which describes mendelian randomization and some of its limitations, but overall it is a process that assesses known genetic markers for a disease to help assess causality (to differentiate in this case whether the causality is if those genetically predisposed to obesity are more likely to get the cancer, not vice-versa or as independent phenomena)
  • Possible mechanisms: increased body fat is associated with multiple metabolic and endocrine changes (sex hormones, insulin and insulin-like growth factor, inflammation), which could promote tumor initiation and/or growth
  • It is important to keep in mind the strength of the associations above. Typically, in observational studies, a relative risk of under 1.5-2 often does not pan out as being really significant, despite the fact that it can be really significant in randomized controlled trials. So, a bit of a caution in over interpreting the above results for many of the cancers. The dose-response relationship does add some support the associations, however.


Another recent article came out on the relationship between physical activity and cancer (see doi:10.1001/jamainternmed.2016), finding that leisure-time physical activity was associated with lower risk of many cancers. Details:

  • 12 prospective US and European cohorts with self-reported physical activity from 1987-2004, including 1.44 million participants, looking at 26 different cancers
  • Mean age 59 (19-98), 57% female, mean follow-up 11 years (7-21), mean BMI 26, 54% ever-smokers
  • 186,932 cancers diagnosed
  • Leisure-time activity, defined as high if 6 or more METs. Median activity was 8 MET-h/week (equivalent to 150 minutes of moderate-intensity exercise, e.g. walking)
  • Results:
    • High vs low leisure-time activity was associated with lower risk of:
      • Esophageal adenocarcinoma (HR 0.58, i.e., 42% decreased risk)
      • Liver cancer (HR 0.73)
      • Lung cancer (HR 0.74)
      • Gastric cardia (HR 0.78)
      • Endometrial (HR 0.79)
      • Myeloid leukemia (HR 0.80)
      • Myeloma (HR 0.83)
      • Colon (HR 0.84)
      • Head and neck (HR 0.85)
      • Rectal (HR 0.87)
      • Bladder (HR 0.87)
      • Breast (HR 0.90)
    • In aggregate, there was a 7% lower risk of total cancer in those performing higher levels of physical activity [HR 0.93 (0.90-0.95)]
    • Adjusting for BMI (nullied the relationship above for liver, gastric cardia and endometrium) but otherwise only a small attenuation of the risk, on the order of 5-11% of the HR’s. Smoking status affected lung cancer but not the others
    • Some cancers were associated with more activity
      • Melanoma (HR 1.27)
      • Prostate cancer (HR 1.05)


  • One striking finding is the overlap of cancers which seem to be affected by both BMI and exercise, reinforcing that these lifestyle/environmental issues seem to be particularly important.
  • But, one needs to be particularly careful in meta-analyses in general and huge ones in particular: it is very hard to get granular data over time (what is “ever-smokers”? a few cigarettes at the beginning of the study? stopping smoking 2 packs/day near the end of the study?); how often did they track information, such as changes in BMI or physical activity over time? Was it just a one-shot assessment at the beginning of the study? And how did they then quantitate these typically changing variables over such a long follow-up?  This data acquisition is done differently in different studies, so how is this all put together mathematically? It is pretty striking the range of ages (19-98) and years of follow-up (7-21) in the individual studies, suggesting they were pretty heterogeneous. And, in general, the people in this large meta-analysis were reasonably lean (BMI=26), so it may be difficult to really control for BMI in their data (they divided the patients into BMI <25 vs >25, but did not have the BMI spread of the IARC study). This limits the interpretation of their finding in this exercise study that 3 of the highest risk cancers in the AIRC study for BMI had no relationship to exercise when controlling for BMI.
  • They only looked at leisure-time physical activity. It seems pretty intuitive that people with very physical jobs do have more exercise at work than those with office jobs (i.e., many of my patients are on their feet all day, walking around cleaning office buildings, etc. And it seems they should get some “exercise” credit for that.) There are not great studies which have looked at occupationally-related exercise, probably because it is hard to measure on an individual basis: even those with the same job category may have very different amounts of exercise if they clean a small office vs a large automated office building)
  • One concern is that the burden of obesity and lack of exercise is increasing, especially with migration to larger cities and with increasing Westernization around the world
  • But one potentially positive finding is that exercise is associated with lower cancer risk independent of BMI for many cancers (with above caveat): it is much easier to help people do exercise than to achieve sustained weight loss (see ). And there are reasonable postulated mechanisms by which exercise could decrease cancer: hormonal changes (sex steroids, insulin and insulin-like growth factos, adipokines; similar to the BMI mechanisms postulated above) as well as nonhormonal (decrease inflammation, improve immune function/surveillance, decrease oxidative stress, and increase GI transit time, the latter of which could decrease colon cancer incidence)
  • There are still many questions, even if one accepts the conclusions of these studies
    • Does instituting a more aggressive exercise program lead to decreased cancer (i.e., an intervention study would provide stronger conclusions than an observational study)
    • And how much exercise works? Is there a threshold? Is it different for different cancers? (this might be important in different parts of the world where different cancers predominate)
  • But, the real bottom line is that there have been many studies over the years showing that lifestyle/environment are associated with pretty much all of the chronic diseases in the world. The above studies simply reinforce the association with cancer. And it offers us as clinicians yet another way to talk with patients about the importance of a healthy lifestyle. The association with cancer may be a particularly useful tool in motivating patients to avoid progressing to a less healthy lifestyle over time or instituting changes to improve their lifestyle (for better or worse, patients given equal mortality scenarios from cancer or heart disease, for example, are more afraid of the cancer one…it just sounds scarier)

Primary Care Corner with Geoffrey Modest MD: Fludrocortisone for Vasovagal Syncope

22 Sep, 16 | by EBM

By Dr. Geoffrey Modest

Vasovagal syncope is pretty common, but there are no documented effective treatments. Fludrocortisone has potential by improving venous return: its efficacy was evaluated in the Prevention of Syncope Trial 2 — POST 2 trial (see Sheldon R. JACC 2016; 68: 1).


  • 210 patients (71% female, median age 30, BMI 24, HR 70 bpm, BP 112/70) with a mean of 15 syncopal episodes over 9 years
  • Randomized to fludrocortisone at the highest tolerated doses (from 0.05-0.2 mg/d, titrated over 2 weeks, with most achieving the 0.2  mg dose) vs placebo and followed for 1 year
  • Inclusion criteria: >13 yo, >2 lifetime syncopal episodes; exclusions: diabetes, hepatic disease BP>135/85, “significant comorbidities”, or if when standing 5 minutes they had postural tachycardia of >30 bpm, or orthostatic hypotension of >20/10 mmHg.


  • 96 patients had at least 1 syncopal episode
  • Overall there was a 31% marginally non-significant reduction in syncope in those on fludrocortisone [HR 0.69 (0.46-1.03), p=0.069]: 44.0% vs 60.5%. the most benefit was in those with systolic BP<110, BMI>20, and syncope frequency >7/yr
  • But, in multivariable model, fludrocortisone conferred a significant 37% decrease [HR 0.63 (0.42-0.94), p=0.024]
  • And, when analysis was restricted to being on the fludrocorisone after dose stabilization, there was an even more significant 49% decrease [HR 0.51 (0.28-0.89), p=0.019]: approx 60% vs 30% in those achieving the 0.2 mg dose


  • There are a myriad of etiologies for syncope to consider, especially cardiac or neurologic (all excluded in the above study). And the preferred treatment for the syncope is to treat the underlying condition.
  • The above applies to those with classic “fainting” episodes: vasovagal syncope, which can happen even in patients with underlying cardiac or neuro morbidities, often triggered by stress, noxious stimuli, anxiety (including venipuncture, blood donation), prolonged standing or sitting, heat exposure, exertion, orthostasis,  (and in older people can be associated with micturition, defecation, cough), and clinically associated with the typical prodrome of light-headedness, along with vagal symptoms of nausea, pallor, diaphoresis. Symptoms typically gets better with lying down, though there can be some residual fatigue. And there can be brief episodes of myoclonic/involuntary esp. limb movements. But there should be no post-ictal state
  • Fludrocortisone seemed pretty effective when at the 0.2 mg dose, and likely more effective than midodrine (a few small studies finding effectiveness but less impressively)
  • Fludrocortisone has been used effectively in those with autonomic failure and orthostatic hypotension, presumably from its increased renal sodium absorption and plasma volume expansion.
  • In my experience, fludrocortisone is very well-tolerated in fragile patients with multiple comorbidities: I have prescribed fludrocortisone (sometimes with midodrine) very effectively in my reasonably large group of older patients with orthostatic hypotension, presumably from autonomic dysfunction (workup otherwise negative, or perhaps some diabetes, but often just from aging…). In this young group in the study above, without comorbidities and with just vasovagal syncope, there were no serious adverse events. And for those with orthostatic hypotension, of course, caffeine helps (1-3 cups of coffee/d, or 2-5 cups of tea). And, though I have not used them, NSAIDs can also help when used with fludrocortisone.
  • So, bottom line: vasovagal syncope is common (overall about 20-35% of syncope causes), a pretty high % (up to 34% in one study) have no warning symptoms prior to syncope, and can be associated with bad accidents (e.g., car crashes), so the above study may really prove to be clinically useful. One wonders if using the max dose of 0.3 mg might be even more useful, and I do have several elderly patients tolerating this dose well)

Primary Care Corner with Geoffrey Modest MD: Azithromycin Not Helpful In Acute Asthma

22 Sep, 16 | by EBM

By Dr. Geoffrey Modest

Although antibiotics should not be routinely used in those with asthma exacerbations, per the British Thoracic Society and Global Initiative for Asthma guidelines, they are frequently prescribed at the pains of increased microbial resistance and microbiome changes, as well as potential adverse effects. A recent study found no efficacy for azithromycin for acute exacerbations of asthma (see doi:10.1001/jamainternmed.2016.5664), the AZALEA study.


  • 4582 patients from 31 centers in the UK, though only 199 patients qualified for the study (from their target of 380) and were randomized
  • Mean age 38; 70% female; 85% were on either:  regular preventer therapy, initial add-on therapy  or persistent poor control (i.e., few with either mild intermittent asthma or on continuous/frequent oral steroids); median FEV1=63% of predicted, FEV1/FVC=70%, peak expiratory flow (PEF) of 67% predicted
  • Inclusion criteria: 18-55 yo with any smoking history, 56-65 if less than 20 pack-year smoking, or >65 yo with <5 pack-year; documented asthma for >6 months; recruitment within 48 hours of asthma attack with acute deterioration of asthma control (increased wheeze/dyspnea/cough) necessitating systemic steroids per the attending MDs, and PEF or FEV1 <80% predicted
  • Randomized to azithro 500 daily for 3 days vs placebo, with posttherapy assessment at day 5 and 10, as well as serum sampling at 6 weeks
  • Primary outcome: diary card summary of symptom score (wheezing, dyspnea, cough assessed at 10 days after randomization). Secondary outcomes: acute Asthma Quality of Life Questionnaire, FEV1, FVC, FEV1/FVC, PEF, and time to 50% reduction of symptoms (and a few other measurements)


  • Primary outcome: asthma symptom score from 0-6, latter being severe symptoms — baseline 4.14 decreasing to 2.09 at day 10 with azithromycin, and 4.18 to 2.20 on placebo; i.e. no difference
  • Secondary outcomes: no difference in any (the graphs are basically overlaying for each of the first 10 days, including time to 50% reduction in symptoms)
  • Pathogens detected: 58% of patients provided sputum sample. 11% had bacteria or atypicals (e.g. mycoplasma/chlamydia); 18% had virus on nasal or throat swabs. and no difference by these results in azithro vs placebo groups [though numbers of patients were pretty small]
  • Adverse events: esp GI in the azithro group (35 vs 24 events). Also 4 vs 2 cardiac events. But respiratory/thoracic/mediastinal disorders were more in the placebo group (37 vs 27), none of these adverse effects were further defined


  • It is pretty striking that of the 4582 patients evaluated, 4383 were excluded (96% !!!), and, of these, 2044 (47% !!!!) were excluded because they were already on antibiotics. And this is at 30 secondary care hospitals and 1 primary care center. To me, this is what makes this study important: it is really common practice to give antibiotics to those with asthma exacerbations. Unfortunately the validity of this study was undermined by this recruitment dilemma: they took much longer to recruit patients than expected (took almost 3 years), loosened some of the recruitment exclusions (e.g., allowing people longer time until presentation to the ED), and still did not achieve their target number, getting only 67% of what they planned.
  • The expectation going into the study was, I think, that azithromycin would help because:
  • Respiratory URIs and atypical bacterial (mycoplasma and chlamydia, which can be as high as 40-60% by serology) are frequently associated with asthma exacerbations
  • Asthmatic patients have increased carriage of bacterial pathogens, susceptibility to bacterial infections, and impaired immunologic barriers (impaired interferon and type 1 T-helper cell responses)
  • Viral infections themselves impair innate antibacterial immune responses and increase bacterial adhesion to bronchial epithelium
  • So, clinically, acute bacterial infections are more common and more severe in asthmatic patients
  • Azithro has several appealing traits: it has broad anti-microbial activity (including against the atypicals), is anti-inflammatory (though all of these patients were on steroids), even has anti-viral properties, and augments the production of interferons (deficient in asthmatic patients)
  • And, as a marginally related issue, azithro can decrease recurrent COPD exacerbations (see Albert RK. N Engl J Med 2011; 365: 689)
  • There was a study showing that the antibiotic telithromycin works in decreasing asthma symptoms and leading to faster recovery (N Engl J Med 2006; 354: 1589), and telithromycin has less anti-viral activity than azithro. And has more hepatotoxicity to boot
  • There are some concerns about the AZALEA study: there may have been a real selection bias in who was recruited (i.e., most got antibiotics prior to the study. Were they sicker than the ones in this study, or did they have a disease that really was more amenable to the azithro?); and there were pretty low numbers of patients with atypical bacteria (chlamydia/mycoplasma) compared to many other studies (which also suggests a bias in the previously-treated excluded group). The telithromycin study had a  much higher percentage of atypicals, and most patients were not on steroids, which is a possibly major difference with the AZALEA study)
  • So, one question is whether there are ways to stratify patients who may or may not benefit. A recent blog (see ) reviewed community acquired pneumonias, noting for example that serum procalcitonin is quite specific for pneumonia (I.e. if <0.1 mg/L, one can either withhold or stop antibiotics). Or perhaps CRP levels are useful.
  • The bottom line: it would be great to have a more definitive study, with better recruitment than this one (i.e. early on and before antibiotics were prescribed), and which assessed potential biomarkers for more serious disease (e.g. procalcitonin, crp, ?others) to see if some group of patients might benefit from antibiotics. But at this point it seems that antibiotics are given to patients with acute asthma attacks probably much more often than necessary. My guess is that the patients who did qualify for this study probably should be on a short course of oral steroids and not antibiotics, and that we should be following them closely. Perhaps a phone call the next day or so, with re-evaluation if they are not improving.

Primary Care Corner with Geoffrey Modest MD: Microbiome and Type 1 Diabetes, etc

19 Sep, 16 | by EBM

By Dr. Geoffrey Modest

The NY Times had a recent story looking at the role of the microbiome (sorry to those microbiome-phobic) in the development of type 1 diabetes (T1D), see . This article was based on a recent clinical study (see

  • 33 infants genetically predisposed to T1D through specific HLA alleles, following changes in their gut microbiota frequently
  • Though microbiota varied greatly between individuals, it remained stable throughout infancy in each individual
  • After 3 years, 4 of the children developed T1D
  • At the time of T1D diagnosis, there was a marked 25% drop in diversity of the microbiome occurring after anti-islet cell autoantibody development/seroconversion (not found in those who did not seroconvert) but 1 year before clinical T1D, along with spikes in inflammation-favoring organisms, gene functions and serum plus stool metabolites.


  • Initial colonization of the human gut begins in utero, is influenced by microbial exposure at birth, then gets gradual increase in diversity in part related to the introduction of table foods. The microbiome largely stabilizes at approximately 3 years of age
  • T1D: an autoimmune disorder resulting from T cell-mediated destruction of insulin-producing pancreatic b-cells. 70% of T1D cases carry HLA high risk alleles for T1D, yet only 3-7% of children with those alleles develop T1D. The incidence of T1D has been increasing rapidly over the past few decades. All of this suggests that there are important non-genetic factors influencing the development of clinical T1D. In Finland, the incidence of T1D is particularly high: 1 in 120 children develop T1D before age 15 (the US is about 1 in 300).
  • Mouse data show that in those susceptible to T1D, changing the gut microbiota can lead to protection from T1D.
  • Other studies have found a decreased intestinal microbial diversity in children with long-lasting b-cell autoimmunity, as well as in inflammatory bowel disease and C difficile-associated diarrhea (in mice, decreased diversity is associated with increased in IgE levels and predisposition to immune-mediated disorders).
  • The probability of progression to T1D after positivity of 2 islet autoantibodies is >80% after 15-year followup, though there is significant variability as to when this happens. so even though in the above study the microbiome seemed to influence the development of clinical T1D but not the autoantibody seroconversion, it does suggest that the effect of an adverse microbiome is associated at least with earlier development of clinical disease.


A follow-up of the above but now larger study looked the “hygiene hypothesis” in general, which posits that early exposure to specific microorganisms/parasites in infancy benefits the development of the immune system, leading to protection from the development of allergic and immunologic disease. This study looked at microbiome changes in North Karelia, Finland, where those from the same genetic pool but living on the Russian side have about 1/5 the development of early-onset autoimmune diseases as the European side, and noting important microbiome changes, which might explain these clinical differences (see Vatanen T. Cell 2016; 165: 842).

  • Background:
    • Several studies have shown that improved sanitation seems to be associated with increased incidence of type 1 diabetes (T1D), multiple sclerosis, and early childhood infections
    • Rates of asthma, hayfever and allergic sensitization are decreased in kids growing up on traditional farms
    • Mice with their gut colonized by with protective microbiota have decreased risk of autoimmune diabetes and allergies
    • There is a 2- to 6-fold increase in allergies and 5- to 6-fold increase in T1D and other autoimmune disorders in the Finnish vs Russian sides of North Karelia; in nearby Estonia, the incidence of T1D and atopy are transitioning with economic development from rates historically similar to the Russian side to the Finnish side
  • The study:
    • Approx 1000 infants in the three areas (Russian Karelia, Finnish Karelia, and Estonia) were followed from birth to 3 yo with monthly stool samples, with metagenomic characterization of 785 gut microbial communities. These 3 areas have similar genetic makeup as well as similar climate and latitude.
    • 74 kids were selected from each country based on similar HLA risk class distribution and gender, getting monthly stool samples and information on breastfeeding, diet, allergies, infections, family history, etc.
  • Results:
    • The resident country was the major source of variation of gut microbiome, especially during the first year of life. The diversity of the microbiome overall increased with age. The specific microbiome findings below are corrected for major confounding factors or birth mode, breastfeeding and other dietary factors, antibiotic use and age
    • The Finnish and Estonian kids harbored more Bacteroides species and enrichment in lipopolysaccharide (LPS) biosynthesis-encoding genes; Russian kids had more Bifidobacterium species (esp B. bifidum)
    • The abundance of Bacteroides correlated with serum insulin autoantibody levels
    • More lipopolysaccharides (endotoxins) were produced in Finnish and Estonian kids,
    • This LPS differed from that in the Russian kids, which developed almost exclusively from E coli. (And, the Bacteroides LPS inhibits immune stimulation and inflammatory cytokine responses to E coli LPS in human cells.) This Russian-side LPS, unlike that from Bacteroides as in the Finnish and Estonian kids, elicits endotoxin tolerance (further studies in mice of the specific endotoxins found that the LPS from E coli, as in the Russian kids, also increased their immune tolerance and decreased diabetes): i.e., different LPS produce different constituents in the human gut microbiome, with either stimulatory or inhibitory activity on components of the immune system (though, of note, the specific LPS differences are quite different in mice and human gut microbiomes)
    • Assessment of T1D anti-b cell autoantibody seropositivity revealed a gradient: 16 in Finland, 14 in Estonia and 4 in Russia


  • This article and the NY Times commentary reinforce that the microbiome is a major mediator of the environment into human disease. Colonization by different bacteria in the first year of life leads to changes in attendant lipopolysaccharides, which seem to have a direct effect on immune tolerance/susceptibility, and seems to be related to diabetes autoantibody seropositivity (not found in the first study) and potentially to the increased incidence in T1 diabetes in certain areas. One of the important components of this study is that the potential genetic differences between these communities is pretty much mitigated, since they all derive from a common gene pool and only recently had such dramatic differences in environmental exposures.
  • Again, this type of study reinforces that what seems intuitive: it makes sense that being brought up in a natural environment with natural exposures, as in farming, allows for evolutionary adaptation; recent human changes, which do not allow for evolutionary accommodation, in farming and hygiene have the potential to disrupt the complex interaction between us and nature.
  • Some unresolved issues: is it just the microbiome? Are there undetected viruses which either promote or protect from T1D development? Is it when one is exposed to the virus (e.g. it seems that several diseases such as EBV seem to confer less likelihood of developing MS if the EBV infection happens earlier. same with the clinical results from polio infection). Though the very well-controlled mice experiments seem to suggest an important role for the microbiome itself, and the effect of specific bacterial changes.
  • This does not mean that modernization has no benefits: Russian Karelia has life expectancy 66.6 years, 13 yrs less than Finns.
  • The hygiene hypothesis does not mean personal cleanliness. It refers to specific environmental exposures. So, eating food off the ground is not necessarily protective….

—————————————————————————————————                                     The Amish of Indiana and the Hutterites of South Dakota are groups of farmers who emigrated from Europe in the 1700s and 1800s during the Prostestant Reformation, have similar genetic ancestries, but very different prevalences of asthma: the Amish schoolchildren have a prevalence of 5.2% vs 21.3% in the Hutterites; and the prevalence of allergic sensitization is 7.2% vs 33.3%. This is despite similarities in many of the risk factors for asthma, including: large sibship size; high rates of childhood immunization; diets rich in fat, salt and raw milk; low rates of childhood obesity; long duration of breast-feeding; minimal exposure to tobacco and air pollution; and taboos against indoor pets. But they have very different farming styles: the Amish practice traditional farming using horses for fieldwork and transportation, and live on single-family dairy farms; the Hutterites live on large communal industrialized farms. The current study (see Stein MM. N Engl J Med 2016; 375:411) assessed environmental exposures, genetic ancestry, and immune profiles of 60 Amish and Hutterite children, measuring levels of antigens and endotoxins, and the microbial composition of indoor dust samples. They also looked at the effect of dust extracts from each grouping on the immune and airway responses in a mouse model of experimental allergic asthma. Results:

  • Of the 30 children from each group, mean age 11, 30% girls, 14 sibs, but they found: no asthma in the 30 Amish kids and 6 cases in the Hutterites, similarly much higher allergen-specific IgE  and total serum IgE levels in the Hutterites. No other immunoglobulin differences. Also decreased peripheral eosinophils in the Amish children
  • Genome-wide SNPs revealed “remarkable genetic similarities” between the 2 groups of children (confirming that these groups are from similar genetic backgrounds)
  • Median endotoxin levels were 6.8 times as high in the Amish house dust; common allergens (cats, dogs, house dust-mites, cockroaches) were 4 times as high in the Amish homes
  • There were profound differences in the microbial composition of mattress dust samples
  • There were profound differences in the proportions, phenotypes, and functions of innate immune cells of the 2 groups of kids
  • Intranasal instillation of dust extracts from Amish but not Hutterite houses significantly inhibited airway hyperreactivity and eosinophilia in the mice


  • Unfortunately they did not assess microbiome changes (both in the gut and in the respiratory tract) in these children. This study does suggest that there are profound effects of the environment (likely related to the differing farming techniques) which translate into quite dramatic differences in immune responses and ultimately into clinical allergic asthma.
  • The tie-in with microbiome is a bit opaque (at least translucent) in this article, but was addressed in a Canadian study, which looked at the effect of microbiome changes associated with antibiotic exposure and the development of asthma, along with comments on other studies about T1D, gluten-sensitivity, etc. (see prior blog
  • So, the bottom line: there are pretty clearly very important associations between the human microbiome and an array of disorders (see; the microbiome is sometimes referred to as the “missing organ”, but seems quite susceptible to external/environmental stimuli. Preserving a healthy microbiome relies on a healthy diet and exercise (and reducing the barriers to them…). And there are even some data finding that stress itself leads to changes in the microbiome and conversely that changes in the microbiome lead to changes in how the body reacts to stress through the hypothalamic-pituitary axis (e.g. see Gur TL. Front Psychiatry 2015; 6:1, or the whole issue of Science from June 08, 2012, including the article by Nicholson JK. Science. 2012; 336: 1262). So, to me, this issue really does reinforce some of the current initiatives: reducing the use of antibiotics both in humans and especially in farming where farm animals get antibiotics to increase their weight; and increasing a healthier lifestyle with better nutrition, exercise, and decreasing stress (though these last ones are not really getting better….).



Primary Care Corner with Geoffrey Modest MD: Non-alcoholic fatty liver disease 3

13 Sep, 16 | by EBM

By Dr. Geoffrey Modest

And, the final blog on NAFLD (finally): Clinical practice guidelines from European Association for the Study of Liver Diseases, and others (see  J Hepatol 2016; 64: 1388). Several of the studies referenced here were included in the prior 2 blogs.

  • NAFLD is characterized by increased hepatic fat, insulin resistance (IR), and steatosis in >5% of hepatocytes. Diagnosis of NASH requires a liver biopsy. The NAS score (NAFLD activity score) cannot be used to diagnose NASH and has a low prognostic value
  • Diagnosis is based on exclusion of secondary causes (hepatitis C, drug and other causes of liver injury) and daily alcohol consumption of >30g/d for men or >20 g/d for women (it’s arbitrarily considered alcoholic liver disease if above that).


  • Patients with IR (and/or metabolic syndrome or obesity) should get “diagnostic procedures for the diagnosis of NAFLD” (which from reading the text seems pretty clearly to be RUQ ultrasounds) to look for excessive liver fat. And vice versa: all with steatosis should be evaluated for metabolic syndrome.
  • In those with risk factors for more advanced liver disease (age >50, type 2 diabetes, metabolic syndrome) “case finding for advanced disease (i.e. NASH with fibrosis) is advisable”.
  • If steatosis present, assess for alcohol and other secondary causes, remembering that there can be other liver diseases coexisting with NAFLD.
  • Unhealthy lifestyles can lead to the development and progression of NAFLD. So, important to do good assessment of diet (esp. high calorie/refined carbohydrate diets, sugar-sweetened drinks, high fructose intake, Western diet) and exercise
  • Do NOT screen for the various genetic polymorphisms associated with higher liver fat content and increased risk for NASH
  • Consider a combo of biomarkers and transient elastography to monitor fibrosis progression (they suggest one “may rely” on these markers “although this strategy requires validation”), especially if imaging not available or feasible. But the identification of advanced fibrosis/cirrhosis is less accurate with these noninvasive markers and needs to be confirmed by liver biopsy
  • In those at high risk of liver disease progression, consider repeat liver biopsy after at least 5-year follow-up
  • The HOMA-IR (a calculation of the product of fasting insulin and fasting glucose, divided by  22.5) in patients without diabetes is a reasonable surrogate marker for IR, but does not diagnose NAFLD (but does identify patients at higher risk of NASH or fibrosis progression, and provides further impetus to reinforcing weight loss, interventions to improve components of the metabolic syndrome)
  • Follow-up is “mandatory” in those with obesity, but also consider in lean patients (even with BMI<25) with visceral fat adiposity  or “dysfunctional adipose tissue” who can have NAFLD with either normal or abnormal LFTs (most lean patients will have features of IR)
  • In people with NAFLD, always screen for diabetes.  And, in those with diabetes, look for hepatic steatosis irrespective of liver enzyme levels (i.e. check ultrasound)
  • NASH patients with fibrosis associated with hypertension should receive closer monitoring because of higher risk of disease progression
  • All patients with NAFLD should have screening for cardiovascular disease, at least by detailed risk factor assessment [they do not specify further, but note that CRP and procoagulant/prothrombotic risk factors are elevated, as well as higher prevalence of abnormal echocardiograms and EKGs]
  • In terms of HCC (hepatocellular carcinoma), NAFLD is a risk factor; HCC can develop in pre-cirrhotic patients (especially older ones, where 1/3 of cases are pre-cirrhotic), and if certain polymorphisms are present, but no recommendation regarding timing or cost-effectiveness of screening

Treatment recommendations:

  • Stresses role of lifestyle changes: structured programs for healthy diet and physical activity, focus only on lifestyle changes in those without NASH or fibrosis (i.e., no drugs), 7-10% weight loss in those overweight/obese, avoid NAFLD-promoting foods (processed food, high fructose food and beverages), trying to implement the Mediterranean diet. Exercise should be both aerobic and resistance training, tailored to the patient’s preferences
  • Drugs for NASH, esp with significant fibrosis (F2 or higher). No firm recommendations, but “pioglitazone (most efficacy data, but off-label if used outside of type 2 diabetes), or vitamin E (better safety and tolerability in the short-term) or their combination”
  • Optimal treatment duration unknown. But in those with baseline increased ALT, stop if no reduction in transaminases after 6 months. No recommendation if normal ALT
  • Statins “may be confidently used to reduce LDL and prevent cardiovascular risk, with no benefits or harm on liver disease”. Also n-3 polyunsats, but there are “no data to support their use specifically for NASH”
  • Bariatric surgery should be considered (prospective data show improvement in all features of NASH including fibrosis), and liver transplantation, if it comes to that, for liver failure and/or HCC.


  • One of the big issues above is screening: they do push ultrasounds for all with evidence of IR or diabetes, even suggesting that all obese get one. As per my prior NAFLD blogs, I think this might be quite reasonable, given the high prevalence of NAFLD, the potentially bad outcomes from NAFLD (including cardiovascular in those with NAFL in addition to hepatic in those with NASH), the potentially powerful benefit of lifestyle changes in improving NAFLD (which I think can be more effectively discussed through motivational interviewing in the context of documented NAFLD), potentially avoiding end-stage liver disease (given that probably most cases of “cryptogenic cirrhosis” are from NAFLD and not really so cryptogenic), and the potential for real impact: because of its striking prevalence, picking up NAFLD early dwarfs the potential benefit of many screening tests we do regularly. And it may well be reasonable to repeat ultrasounds at some unknown interval to pick up new cases or (though insensitive) changes suggesting increasing liver damage
  • In terms of noninvasive markers of disease: NAFLD fibrosis score (NFS) and fibrosis 4 calculator (FIB-4) are externally validated in different NAFLD populations and predict overall mortality, cardiovascular mortality and liver-related mortality. NFS predicts subsequent diabetes. But these tests are better at distinguishing advanced vs non-advanced fibrosis though not significant vs no fibrosis. I.e., they can pretty well exclude severe disease. So, these biomarkers and scores of fibrosis (as well as transient elastography) are “acceptable” non-invasive procedures for identifying cases at low risk of advanced fibrosis/cirrhosis, and “might save a number of diagnostic liver biopsies”. Again, this is not a “recommendation” by the US authorities or by the extensive reviews in the first 2 blogs, but I suspect we will be moving more and more to these noninvasive tests (already being done much more frequently in several academic centers in Boston), though would be great to have more substantial data to support them.
  • NAFLD is also present in 7% of normal-weight people, more often in females, at a younger age, and with normal liver enzymes, though the liver disease may still be progressive [so, should we do ultrasounds on everyone??? not sure how they expect this statement to be actualized in practice]
  • In terms of drugs, in their text they mention:
    • Scant evidence of benefit on hepatic fat. But I use pretty much all the time as first line drug in those with evidence of insulin resistance or dysglycemia/diabetes (see multitude of blogs in , or you can go to the blog website as at  and search for “metformin”
    • Thiazolidinediones: (see PIVENS study as described in the second blog). Pioglitazone improved all histological features except fibrosis. And more resolution of NASH than placebo. I am still somewhat hesitant given the associated weight gain and other adverse effects, but seems reasonable overall to use pioglitazone. I agree with them that I would use vitamin E before that, and would use the 400 IU strength to see how the transaminases respond, then increase to 800 IU if no/minimal response.
    • GLP-1 agonists: small study of liraglutide showing NASH remission without worsening fibrosis. Again, as in my diabetes blogs, I have been using more of the GLP-1 agonists as my second line, behind the metformin. NAFLD is another reason.
    • Vitamin E (PIVENS): improved steatosis, inflammation and ballooning and induced resolution of NASH in 36% (vs 21% on placebo). Reduction in ALT correlated with histologic improvement. Concerns about long-term safety.
    • -PUFA data inconsistent. I do suggest increased fish consumption and/or fish oil supplementation, given the potential cardiovasc benefits as well, especially in those with IR and high triglycerides (also see: )
  • In 20% of patients, fibrosis rapidly progresses. Overall the rate of progression corresponds to 1 fibrosis stage in 14 years with NAFL and every 7 years with NASH. But this is twice as fast in those with hypertension. Hence the recommendation to monitor patients with NASH and fibrosis who are hypertensive should get closer monitoring. I’m not sure what they mean in this document by closer monitoring. But I would consider doing more regular FIB-4 and transient elastography, probably every 1-2 years.
  • Cardiovascular disease (most common cause of death): higher with NAFLD and driven by the higher risk by the components of metabolic syndrome. The risk increases further with NASH and more so in those with advanced fibrosis. So, I would tend to be even more aggressive in cardiovasc risk reduction, including earlier use of statins (they underplay their potential benefit for NAFLD, though the prior blogs to highlight their likely benefit –e.g. see ).
  • NAFLD also associated with colorectal cancer, metabolic bone disease (vitamin D deficiency, osteoporosis).
  • The potential role of iron as an hepatoxin: it acts as an inducer of necroinflammatoin (?thru generation of free oxygen radicals), and of note insulin resistance is associated with increased hepatic iron stores and improving glycemic control is associated with decreased serum and hepatic iron levels. And prior blogs comment on ferritin levels as predictors of worse prognosis.
  • But, alas, it is with a deep heart, no doubt to all of us, that they do not even mention the microbiome…..

Primary Care Corner with Geoffrey Modest MD: Non-alcoholic Fatty Liver Disease 2

8 Sep, 16 | by EBM

By Dr. Geoffrey Modest

This is the second part of the series on NAFLD, a review of therapies, with more detail on a couple of topics (e.g. the roles of fructose and the microbiome)


(see Hannah WN. Dig Dis Sci 2016; 61:1365)

It is pretty clear that weight loss in those overweight/obese is the best documented therapy for NAFLD. Those who can lose 3-5% of their body weight tend to improve hepatic steatosis; and those who can lose >5% in one large study found 58% had resolution of NASH and 82% had a 2-point reduction in their NAS (NAFLD Activity Score on biopsy). Those who lost >10% of their body weight (n=29) had 100% had resolution of NAS, 90% had resolution of NASH, and 45% had regression of fibrosis. Other studies suggest that the type of diet is not so important: it’s the weight loss. But, we know that losing weight is really hard, and maintenance of weight loss is even harder (e.g., see ). So, it is useful to look at individual components (micronutrients, macronutrients, etc.) to see if there can be some utility of specific dietary changes, even in patients who cannot lose sufficient weight.

Mediterranean Diet

  • Small studies suggest that, comparing Mediterranean diet vs low fat diet and achieving comparable weight loss and with a cross-over design: there was decreased hepatic steatosis and improved insulin sensitivity with the Mediterranean diet.


  • Observational and some intervention studies find exercise without weight loss in patients with NAFLD improves markers of insulin resistance and liver enzymes, some find decrease in hepatic steatosis, some suggest a dose-response curve with the more exercise the better. But other studies did not find much effect.

Diet and exercise

  • One study of 293 patients with histologic NASH on a 52-week diet and exercise program leading to a mean weight loss of 4.6 kg found: 25% had resolution of NASH, 47% a reduction in NAS, and 19% a resolution of fibrosis, all with a dose-response relationship.

Monounsaturated fats (an important component of the Mediterranean diet)

  • Very small studies suggest decrease of steatosis with high monounsaturated fat diet, but hard to disassociate this from other dietary changes (see Mediterranean diet, above)

Polyunsaturated fatty acids (PUFA’s, esp n-3)

  • One study found that supplementation with 4 g/d of PUFAs led to a significant improvement in hepatic fat and ALT levels. Another, at lower dosages (up to 2.7 g/d) found no benefit, including in biopsies

Fructose: see next article, but probably really important causally in NAFLD

Vitamin E

  • A few studies have found some benefit: the PIVENS study (see N Engl J Med 2010;; 362: 1675) randomized 247 nondiabetic patients with NASH to vitamin E 800 IU vs pioglitazone 30mg vs placebo, found that vitamin E led to improvement in NAS (43% vs 19% on placebo) though nonsignificant improvement with pioglitazone vs placebo (34% vs 19%, which actually had p=0.04 but not considered significant in this study). Both led to improvement in LFTs, as well as decreases in hepatic steatosis and lobular inflammation, but there was no improvement in fibrosis with either therapies. Another trial in kids comparing vitamin E 800 IU vs metformin 1000mg vs placebo found that vitamin E led to significant improvement in hepatocellular ballooning and NAS, and those with NASH had significantly more resolution of the NASH with vitamin E than metformin. There are some concerns that higher doses of vitamin E is associated with increased all-cause mortality (see Miller ER. Ann Intern Med 2005; 142:37), leading some specialists to suggest the unproven benefit of using only 400 IU/day, and pioglitazone was associated with significant weight gain in the PIVENS and other pioglitazone studies.


  • The wonder drug…. though in this case the data are not so compelling: mostly retrospective analyses, with a couple of studies: a population-based study finding that those drinking >= 3 cups/d had lower odds of significant fibrosis; another found less NASH on biopsy, and those who developed NASH had lower fibrosis scores


  • There are interesting studies finding disruptions in the gut microbiome are associated with the pathogenesis of NAFLD and the progression to NASH (see And see the review below. A few remarkably small trials have found some benefit from probiotics: one had 20 patients with NASH followed 6 months finding improvements in intrahepatic triglycerides, and reduction in ALT; another of 44 obese kids found significant improvement in hepatic steatosis by giving a product containing one strain of streptococcus thermophilus, three strains of bifidobacterium and four strains of lactobacillus in defined ratios.


  • The data on interventions to improve NAFLD is quite impressive for weight loss. Unfortunately, the studies on most of the more specific dietary and other interventions is quite limited by very small short-term studies and of mixed quality. That being said, I think there are enough data to support the following interventions:
    • which also helps with initiating and maintaining weight loss through diet, and has a multitude of physical and psychological benefits
    • Mediterranean diet (low fat, high fruit/vege) seems to help with NAFLD, as well as improving insulin sensitivity/diabetes/metabolic syndrome, and general cardiovascular risk reduction (and the old secondary prevention Lyon Heart Study found decreased recurrent cardiovascular events, on the order of taking statins).
    • Monounsaturated fats. Really minimal data on benefit for NAFLD per se, but pretty clear that they improve lipid profiles and improve glycemic control. Also data that they have anti-inflammatory properties and improve endothelial function. And this is a relatively easy intervention for many people: change their oils to olive/canola/etc., avoid saturated fats…
    • N-3 polyunsaturated fats (e.g. fish oils). Also not much data on NAFLD, but PUFAs are depleted in the liver in those with NAFLD, and there are limited data that they improve steatosis. Also there are reasonably good data that eating more fish is good for many clinical outcomes (heart, etc.). In terms of supplements, it is not really clear how much is needed to take to get a positive effect (or the specific composition of those supplements), and this also depends on background consumption of fish in the diet. And the caveat: high fat fish, rich in PUVAs, also tend to concentrate more environmental toxins in the oils (many toxins are fat-soluble), leading to potential concerns about mercury poisoning, etc.
    • There are other medical therapies in the wing, though it is clear that diet is the most effective so far.


Role of fructose: (see or Softic S. Dig Dis Sci 2016; 61:1282)

  • Fructose may well be the worst dietary actor:
    • Fructose is the most commonly consumed sugar, largely through high fructose corn syrup
    • The major hepatic abnormality leading to increased hepatic lipids in NAFLD is enhanced de novo lipogenesis (DNL)
    • Dietary fructose increases DNL more strongly than a high-fat diet
    • Fructose metabolism: absorbed via portal vein (higher concentrations in liver than other tissues); increases protein levels of all DNL enzymes in its conversion to triglycerides; fructose does not require insulin for its metabolism, furthering lipogenesis in setting of insulin resistance, fructose leads to ATP depletion and suppression of mitochondrial fatty acid oxidation (and more reactive oxygen species); and it promotes uric acid production (which itself may promote hepatic steatosis by the generation of mitochondrial oxidative stress). And fructose potentiates its own metabolism (i.e., no negative feedback loop).
    • Short-term carbohydrate overfeeding in overweight humans for 3 weeks led to 27% increase in liver fat, while total body weight increased only 2%; a 6-month hypocaloric diet in the same people led to 25% of loss of liver fat and 4% decrease in body weight: all reinforcing the profound and disproportionate effect of carbohydrates on liver fat. High fat also has a role, and some studies suggest that this is predominantly by saturated trans fats. But the data for fructose may be more robust, given the above. Studies have found that fructose-sweetened drinks (but not glucose) is associated with increased visceral adiposity, insulin resistance and hepatic de-novo lipogenesis (as noted above); also more hepatic inflammation and higher likelihood of progression of liver disease to fibrosis. Conversely, looking at adults with biopsy-proven NAFLD, their fructose consumption is 2-3 times higher. In kids, sugar and fructose consumption is higher than adults (and even though sucrose is 50% fructose, this is a lesser source than high-fructose corn syrup)
    • Animal models show that a high fructose diet leads to NAFLD (as well as changes in microbiome and increased endoplasmic reticulum stress and apoptotic activity)


  • 1 billion people worldwide have NAFLD.
  • The consumption of fructose has dramatically increased in the US: before 1900, it was 15g/d (4% of calories, mostly from fruits and vegetables), by 1994 it was 55g/d (10% of calories). And in adolescents it is 15% of calories, but 10% of teens consume >25% of their calories from refined sugar (and high fructose corn syrup is the major source)
  • As mentioned in prior blogs (see, for example, , though a search for “fructose” at that site finds many additional blogs), I am very concerned about the amount of fructose (largely high fructose corn syrup) in the diet. I have had several patients with hyperuricemia and gout who were able to stop consumption of soft drinks, and had significantly lowered their uric acid levels. This physiologic relationship between fructose and NAFLD is another strong reason to encourage decreasing fructose consumption (especially since NAFLD is still pretty common in patients without glucose intolerance and who are not overweight…). And the low-hanging fructose fruit for most of my patients is soft drink consumption, which seems to be the easiest profound dietary change for many.


Microbiome. (see Abdou RM. Dig Dis Sci 2016; 61: 1268)

  • 20-30% of adults with NAFLD develop NASH, and a subgroup of these develop severe morbidities of cirrhosis, hepatocellular carcinoma and liver failure.
  • The human intestinal microbiome has 150-fold more genes compared to the human host: the intestinal microbiome (IM) is sometimes referred to as the “missing organ”
  • The liver may be a more important target of action for the IM since 70% of its blood supply is from the portal vein, directly draining the intestine
  • Data summary of microbiome studies for obesity:
    • Germ-free (GF) mice who were resistant to developing obesity on a high fat/high sugar diet, then had their cecal IM colonized by conventionally raised non-GF mice, had a 60% increase in body fat and increased insulin resistance (IR) within 2 weeks despite decreasedfood intake.
    • Astrain of mice with the ability to increase the amount of energy extracted from food were able to transfer this ability to other mice by transferring their IM.
    • GF mice colonized with IM from a lean human twin had less adiposity and weight gain vs mice colonized from the obese twin of the dyad.
    • In humans, there are differences in the IM of people with obesity or NASH, with the ratio of Firmicutes and Bacteroidetes species (the vast majority of known species) disturbed in these patients. Bacteroidetes have higher levels of complex carbohydrate-digesting enzymes with the potential to harvest more energy. [SCFAs (short-chained fatty acids), in particular acetate, butyrate, and propionate) are the end-product of this polysaccharide digestion, and higher SCFAs are found in obese and overweight adults on a Western diet]. High fructose diets affect the microbiome, as mentioned above.
  • Data summary for microbiome studies and NASH
    • One interesting finding is that adolescents with NASH have more Escherichia species in the gut, this species is associated with more mixed-acid fermentation and the endogenous production of alcohol. And those non-alcohol drinking adolescents who have higher blood alcohol levels have more NASH. Other studies have found that obese children with ultrasound-diagnosed NAFLD have more ethanol metabolites in their stool. Also, alcohol dehydrogenase is one of the most dramatically upregulated hepatic genes in adolescents with NASH. Higher serum alcohol levels are also found in a small study adults with histologically-proven NAFLD vs controls, with NAFLD subjects actually drinking somewhat less alcohol than the controls (1.9 gm/d in the NAFLD group vs 2.4 gm/d in controls). Another study found that blood alcohol levels are positively associated with IR (insulin resistance). There are differences in LFTs between alcoholic liver disease and NAFLD (the former with AST/ALT ratio typically >2, then latter <1), which makes this a bit hard to interpret. But AST reflects more mitochondrial injury to the hepatocytes (ALT is from the hepatocyte cytoplasm, AST is 20% cytoplasmic and 80% mitochondrial). Perhaps there are nutritional differences between those who have very high alcohol intake and alcoholic liver disease vs NAFLD?? Perhaps related to the array of micro/macronutrients often found to be depleted in alcoholic patients?? Or perhaps there direct mitochondial toxic effects of higher-dose alcohol causing mitochondrial damage. I.e., it conceivable that the increased endogenous alcohol production related to microbiome changes and associated with NAFLD is causative or contributory to NAFLD in some patients, despite the different LFT presentations.
    • The microbiome changes also lead to increase in permeability of the intestinal barrier, making it even easier to get endogenous alcohol-related hepatic damage.
    • Also, fibrosis (likely the bad actor, as above) is often independent of steatosis, and fibrosis itself is associated with changes in the microbiome. Some studies have found some specific microbiome changes in those with higher levels of fibrosis (more Bacteroides and Ruminococcus, less Prevotella)
  • So, bottom line, it does make sense to protect our “missing organ”, the microbiome. And the best protection is probably eating healthfully, exercise, avoiding antibiotics whenever possible (including those put into meats in agribusiness), avoiding added chemicals to foods whenever possible (e.g., artificial sweeteners), etc. (see for an array of blogs on the potential health effects of changes in the microbiome. but it often comes down to, as Michael Pollan says, sticking to foods your grandmother would eat…..)

Primary Care Corner with Geoffrey Modest MD: Non-alcoholic Fatty Liver Disease 1

7 Sep, 16 | by EBM

By Dr. Geoffrey Modest

There have been several articles recently on non-alcoholic fatty liver disease (NAFLD) in a recent special issue of the journal Digestive Diseases and Sciences, as well as a recent release of NAFLD clinical management guidelines by the European Assn for the study of NAFLD. Since NAFLD is so common throughout the world, since it is amenable to lifestyle interventions, and since there was so much interesting info on NAFLD but so many unresolved questions, I will devote 3 blogs to this:

  1. Natural history of NAFLD
  2. Review of therapies, with more detail on a couple of topics (e.g. the role of the microbiome and of specific dietary components, esp. fructose)
  3. A review of the EASL guidelines for NAFLD


NAFLD Natural history (see Goh G. Dig Dis Sci 2016; 61: 1226)

  • NAFLD (nonalcoholic fatty liver disease) was first defined only in 1980, which is rather surprising given that it is: incredibly common (in the US its prevalence has increased from 5.5 to 11% between 1988 and 2008), the most common liver disease in the world with estimated prevalence of 20-30%, the most rapidly rising indication for liver transplantation, and likely to be the number one indication for liver transplantation by 2020. The fact that the prevalence is increasing, however, is not so surprising, since NAFLD is so closely related to insulin resistance, obesity and metabolic syndrome. It is important to keep in mind that with all of these statistics, there are real issues of differing definitions and ascertainment bias overall. For example, in one study the prevalence of ultrasound-diagnosed hepatic steatosis with normal liver enzymes was 16.4%, but the prevalence of hepatic steatosis with abnormal LFTs was 3.1% (i.e., determining NAFLD by ultrasound vs abnormal LFTs as the NAFLD yields very different prevalences).
  • NAFLD is formally defined as the accumulation of >5% fat in the liver, not attributable to alcohol, drugs or other secondary causes, and represents the spectrum from NAFL (non-alcoholic fatty liver, or steatosis) to necroinflammatory changes of NASH (non-alcoholic steatohepatitis), advanced fibrosis, cirrhosis and HCC (hepatocellular carcinoma). The biopsy may be indistinguishable from alcoholic steatohepatitis.
  • Long-term prognosis: the most common causes of death are cardiovascular (the number one cause: see Mantovani A. Dig Dis Sci 2016; 61: 1246), malignancy and liver disease. And it seems likely that a large % of those diagnosed with “cryptogenic cirrhosis” actually have NAFLD. The extent of these outcomes varies in different studies, from not much of an increase to being equivalent to hepatitis C. However, it seems that most studies find the mortality increases significantly as one goes from NAFL (steatosis only) to NASH, and seems overall to be much worse with more severe stages of NASH (e.g. one study with 18.5 years of follow-up found that liver-related mortality increased from 3% in non-NASH to 18% in those with NASH). A meta-analysis found that mortality was not much higher in those with simple steatosis vs the general population, but in those with NASH there was still an 81% increase in overall mortality  and 471% increase in liver-related mortality.
  • Progression of NAFLD: in a meta-analysis of 133 patients with simple steatosis, 39% developed progressive fibrosis, 53% remained stable and 8% improved. This translates to an average annual progression rate of 1 fibrosis stage over 14 years. Also, NASH progresses: a study of 221 patients found that 37% had progressive fibrosis on repeat biopsy over 5 years. Overall, it seems that in patients with NASH and no fibrosis, there is a 1 stage progression of fibrosis over 7 years. BUT there are a small group who have much more rapid progression.
  • 10-25% of patients with NASH progress to advanced fibrosis/cirrhosis. In a small Australian study comparing patients with NASH cirrhosis to those with hepatitis C, about 40% of each group developed liver-related complications over 7 years, though other studies have found lower mortality rates than hep C (but with more cardiovascular mortality). There are some data suggesting that higher serum ferritin levels (> 1.5x upper limit of normal) is associated with a higher likelihood of NASH and more advanced fibrosis.
  • BUT, one counterintuitive point that makes it difficult to rely simply on noninvasive testing: there is no relationship with the height of serum transaminases and the degree of hepatic inflammation or fibrosis. And, there can be significant hepatic inflammation without increased transaminases.


  • These data make it very difficult to figure out what is best to do with patients who have increased ALT levels (really common). In general, we screen for other causes of increased LFTs, especially for viral hepatitides (esp hep B and C, but I also check to make sure either immune to hep A naturally or by immunization, and immunize against hep B if nonimmune), autoimmune hepatitis (e.g. ANA, anti-smooth muscle, anti-liver-kidney microsomal antibody-1), iron overload (iron, TIBC, ferritin). And get an ultrasound.
  • One concern with NAFLD as an entity is that it really is a diagnosis of exclusion. That makes it more likely that NAFLD is not a single condition: there could well be unknown causes of fatty liver that are lumped together in “NAFLD”; there seem to be a variety of predisposing conditions (though insulin resistance is the most common, there are many people with NAFLD without that); and there are such variable prognoses (some never progress, some regress, some advance, and some advance very quickly).
  • Should we be screening for NAFLD (not currently recommended)? From the NHANES data, its incidence has increased from 5.5% around 1990 to 11% in 2008, and the % of cases of chronic liver disease attributable to NAFLD has increased from 47% to 75% during this time. (i.e., much more common than for other causes, which we do screen for). And there are interventions that help (see later blog). I personally do screen with LFTs in obese kids and all adults, and (not surprisingly, given the frequency of NAFLD, have found many cases, much more than hepatitis C). And I have had some success in convincing patients to lose weight and do more exercise based on these results. But should we be doing more inclusive screening with an ultrasound, to pick up the many cases where the LFTs are normal (and we know that LFT changes can be transient, and may never be found, despite the possibility of significant hepatic inflammation)????? I am not doing that, but it certainly seems reasonable….
  • What is the best way to follow those with steatosis on ultrasound or raised ALT levels suggestive of NAFLD? Should we be following ultrasounds routinely to look for progression? And if we do serial ultrasounds, how often? Biopsy is currently considered the only method to really see if there is active inflammation or fibrosis. Hopefully in the not-so-distant-future we will have reliable non-invasive tests: e.g. transient elastography which might helpdifferentiate NAFL from NASH and also track its progression (some small studies found it was able to differentiate degrees of steatosis, and another finding a stepwise increase in liver stiffness that correlated with the degree of biopsy-proven hepatic fibrosis). And there are potential serum markers: e.g. FIB-4 (a calculation involving age, AST, ALT and platelet count), which correlates well with the degree of hepatic fibrosis; and other markers look promising (e.g., cytokeratin-18, which reflects hepatocyte apoptosis). More studies are needed on these, but there are glimmers of hope that we can avoid biopsies.
  • And if we decide to do a liver biopsy, how often should they be done, in light of the pretty high progression rate to NASH and fibrosis? What about trying to pick up those who are rapid progressors?
  • One other consideration: since NAFLD is so common and has an attendant increased risk of cardiovascular disease, I have a low threshold to prescribe a statin, especially in middle-aged and older patients. See blog which reviews several of the studies, in patients with NAFLD, hepatitis B and C, finding clinical benefit. In NAFLD, there are some data showing that statins both reduce cardiovascular mortality, but also have some benefit in improving NAFLD histology or its future complications (advanced fibrosis, etc.), as well (also see Mantovani A. Dig Dis Sci 2016; 61: 1246 for more info).

Primary Care Corner with Geoffrey Modest MD: Omega-3 Fatty Acids and Cardiovascular Disease

1 Sep, 16 | by EBM

By Dr. Geoffrey Modest

AHRQ (Agency for Healthcare Research and Quality) just released their updated systematic review on omega-3 fatty acids and cardiovascular disease (see ).


  • Omega-3 fatty acids (n-3 FA) include both marine oils, predominantly EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) which come from fish, seafood, other ocean life; and ALA (alphalinolenic acid) which comes from vegetable oils (esp soybean, canola and flaxseed oils) and nuts (esp walnuts)
  • There are large differences in consumption of these n-3FAs overall: though ALA ingestion is pretty consistent across developed countries at about 0.3-1.0% of energy (in the US it is 0.6%), EPA and DHA consumption vary a lot (0.13 g/d combined in the US, vs 0.4 g/d in South Korea)
  • Older epidemiological observational studies have found significantly less cardiovascular disease in those on high fish diets. The rates of cardiovascular disease in the US has declined sharply in the past several decades, likely related to more use of statins, antihypertensives and aspirin


  • RCTs (essentially all done with marine oils):
    • For many of these trials, there were very mixed results, with a few studies finding efficacy, others none, and the meta-analyses combining them therefore not finding significant benefit
    • All-cause death: 2 of 17 trial found lower all-cause death, others not, so overall no benefit
    • Major Adverse Cardiovascular Events (MACE): 2 of 10 trials found significant reductions, so meta-analysis found no significant benefit
    • Total MI: no trials found benefit
    • CVD death: 2 of 7 trial found significant benefit, so meta-analysis found no significant benefitin those with existing CVD
    • Sudden cardiac death: no trials found benefit
    • Angina: 1 trial found benefit along with statins for unstable angina after 5 years in patients with dyslipidemia, other trials without benefit. Same for heart failure
    • No benefit in RCTs for total stroke death, revascularization, CHD deaths, atrial fibrillation, heart failure deaths
    • BP: no  benefit for blood pressure, in 19 RCTs
    • Lipids: many trials. Increase in LDL of 1.98 mg/dL, increase of HDL of 0.92 mg/dL. Triglycerides more complex: each increase in baseline Tg level by 1 mg/dL was associated with a net decrease by marine oils of -0.15 mg/dL; and each increase of EPA+DHA dose by 1 g/d was associated with a greater decrease in Tg of -5.9 mg/L (i.e.: more effect of marine oils if higher Tg level to start with, and with higher doses marine oils.) And EPA may be more effective than DHA
  • Observational studies (meta-analysis of 21 studies):
    • CVD death: statistically significant benefit with marine oil intake
    • CHD death: non-significant
    • All-cause death: overall non-significant, but there was decrease in those on high dose marine oil intake. Same with CHD itself
    • Stroke: significant, and more protective at higher doses of marine oils. Same for ischemic stroke. No change in hemorrhagic strokes
    • Heart failure: significant benefit of marine oils
  • There was insufficient evidence of benefit in studies looking at only EPA or DHA individually (or other n-3FAs DPA, SDA; or if look at marine oils vs ALA (though very few studies looked at ALA, and not many looking at the individual marine oils)
  • Adverse events: no serious adverse events felt to be related to the study interventions in 25 RCTs.

Overall conclusions

  • Omega-3 fatty acids raised HDL and LDL a little (<2gm/dL) but did lower triglycerides, more so in those with higher baseline triglyceride levels and higher doses of n-3 FAs, based on RCTs
  • In those at increased risk of cardiovascular disease, RCTs found that omega-3 fatty acids do not change one’s risk for: overall major adverse cardiovascular events, all-cause death, sudden cardiac death, coronary revascularization, or atrial fibrillation
  • Observational studies do find that those with higher intake of fish high in omega-3 fatty acids may lower one’s risk of ischemic stroke due to atherosclerosis
  • RCTs and observational studies differ in benefit for cardiovascular death, and total stroke (fatal and nonfatal, ischemic and hemorrhagic stroke) outcomes. RCTs show no benefit, observational studies show some possible benefit.


  • Meta-analyses are often hard to interpret. They are usually considered the definitive determination of benefit by including lots more patients and then averaging all of the studies with their individual biases and differing patient characteristics to achieve a real, representative average, and one which might compensate for the individual biases of the different studies. But the reality is that meta-analyses are usually trying to combine mathematically very different studies, often with mathematical correction for comorbidities, etc. (e.g., propensity scoring). In the above case, the meta-analysis used different n-3 FAs, in different doses, in different patients from different backgrounds, with different comorbidities, and for different follow-up times. So, it might be that an individual well-done study which more closely reflects the patient you are seeing might be much more useful than a meta-analysis which dilutes the effect by adding in other non-applicable studies (which perhaps exclude patients like you are seeing, have too small a dose of n-3FAs, don’t last long enough to see an effect….). So, a meta-analysis of 7 trials with 2 showing benefit (as in CVD death above), may be meaningless: perhaps the 2 trials with benefit are much more rigorous, with longer follow-up, higher dose of meds, etc., are really more useful and applicable than the mathematical combination with less appropriate studies. [Another issue, not in the above meta-analysis, is that sometimes a huge study will dwarf many smaller studies by being disproportionately represented in the mathematical combination. The bottom line: don’t just accept the meta-analysis; it is important to look at the individual studies to see if the meta-analysis makes sense to you. And it is not so uncommon that there are almost simultaneous meta-analyses on a subject, printed in different journals, coming out with different conclusions, based on how they do their statistics or which studies they decide to include as appropriate]
  • One reason why observational studies and RCTs may differ in their results on omega-3 fatty acids is that almost all of the observational studies were done in healthy populations and almost all of the RCTs were in those at high risk of CVD. And so many people in the US in the high risk group are on statins, antihypertensives, and low-dose aspirin; these drugs act on metabolic and biochemical pathways that the n-3FAs also impact (anti-lipid, anti-inflammatory, anti-coagulant, improved endothelial function). So the studies on patients at high cardiovascular risk are less likely to show benefit from n-3FAs, since the patients are likely on the above drugs, and any incremental benefit of the n-3’s may have been too small to measure. For low risk patients not on these medications (as in the observational studies), it would take a very long and large study of these patients randomized to n-3 FAs vs placebo to show clinical benefit (the event rate is so low in the short- to moderate-term), and I suspect this study will never happen. The data on intermediate outcomes (lipids, blood pressure) were from both average and high cardiovascular risk populations.
  • Nonetheless, it is pretty clear to me that n-3 FAs do have a role in those with high triglycerides, and I have had some success in lowering Tg levels in some patients with very high Tg’s. And I do encourage increased fish consumption when possible and do not discourage the use of supplemental fish oil to patients who ask about them (the concern with fatty fish, as mentioned in prior blogs, is that many environmental toxins released into the water are lipid-soluble and concentrated in the fat of fish, e.g. PCBs, or mercury. So I do encourage eating wild fish, when possible)


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