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Primary Care Corner with Geoffrey Modest MD: Fructose and NASH

7 Mar, 17 | by EBM

By Dr. Geoffrey Modest

A recent study found that fructose consumption and serum uric acid were independently associated with non-alcoholic steatohepatitis (NASH) in obese kids with non-alcoholic fatty liver disease (NAFLD), (see doi.org/10.1016/j.jhep.2016.12.025).

Details:

  • 271 obese children (by BMI) with NAFLD were studied
  • NASH was diagnosed by biopsy, with a NAFLD score of at least 5, and by the fatty liver inhibition of progression (FLIP) algorithm (another algorithm for the diagnosis of NASH)
  • Fructose intake was determined by a food frequency questionnaire
  • Hyperuricemia was defined as a serum uric acid level >5.9 mg/dl

Results:

  • NASH occurred in 37.6% of the children
  • Mean age 11.5, 38% female, BMI 27, waist circumference 87cm, AST 48/ALT 62, uric acid 5.8, LDL 100/HDL 45, BP 112/68, TNF-a Of note, there were significant differences between those with NASH and those without, but only for: waist circumference, AST/ALT, total cholesterol (but not LDL, HDL alone), triglycerides, fructose consumption, and TNF- a
  • Hyperuricemia was found in 47% of the kids with NASH, vs 29.7% without NASH (p=0.003)
  • Adjusting for multiple measured confounders:
    • Uric acid level was associated with NASH, OR 2.49 (1.87-2.83), p=0.004
    • Fructose consumption was associated with NASH, OR 1.61 (1.25-2.85), p=0.001
    • These associations with NASH were independent of each other
    • Though, fructose consumption was still independently associated with hyperuricemia, OR 2.02 (1.66-2.78), p=0.01
    • These data on NASH were confirmed by using the FLIP algorithm

Commentary:

  • As noted in prior blogs, there seems to be a pretty consistent relationship between fructose consumption and uric acid levels, as was shown in this study. And there are data suggesting that dietary fructose can be part of the pathogenesis of NAFLD (induction of de novo lipogenesis, inflammation, insulin resistance). Studies in adults have found that hyperuricemia is associated with insulin resistance, type II diabetes and metabolic syndrome.
  • There are many dietary sources of fructose. The major ones for most people are table sugar (sucrose, a disaccharide of glucose and fructose) and high fructose corn syrup (in a surprising number of foods, as a very cheap and potent sweetener). Perhaps the “low-hanging fruit” here is sodas, consumed by very large numbers of people (https://www.cdc.gov/mmwr/preview/mmwrhtml/mm6332a2.htm#Tab2 , finding that on average 26.3% of US adults consume at least one sugar-sweetened beverage daily, up to 41.4% in Mississippi, the highest of states, and that soda by itself was consumed by 24.5% of those 18-34 yo, and 47.4% in Mississippi). And a NHANES study (Welsh JA. JAMA 2010; 303(15): 1490) found that on average, 15.8% of calories came from added sugars, and that >25% of the patients got >25% of their total energy from added sugar. My experience is that it is easier to help people stop sodas and juices, substituting water, than other dietary interventions.
  • I am not sure why we focus so exclusively on BMI, since the data are pretty consistent over the decades that abdominal obesity is really the bad actor, more metabolically active and associated with inflammatory markers, diabetes/insulin resistance/metabolic syndrome and is independently associated with cardiovascular risk (BMI is not: its association is mediated by its association with other risk factors, such as blood pressure, lipids). Waist circumference is a much better, though not perfect, marker of visceral obesity than BMI. That being said, there is a pretty strong relationship (but not always) between BMI and waist circumference, especially in those with BMI >35. The most reasonable recommendations I have seen is to measure the waist circumference regularly, especially if the BMI is between 25-35. Although practically we should reinforce lifestyle changes in all patients with high BMI, independent of waist circumference, I think the patient should understand that for those with a high waist circumference, their cardiometabolic risk is even higher. See http://blogs.bmj.com/ebm/2015/12/02/primary-care-corner-with-geoffrey-modest-md-central-obesity/ for the fuller argument

So, this study does add some important information: it confirms that both uric acid levels and fructose are associated with NASH in kids that they are associated with each other, but that they are also independent predictors (and there are several studies which show that decreasing fructose consumption, as in sodas, is associated with decreased uric acid levels. See blogs below). So, bottom line is that fructose consumption is bad and should be decreased, even if the uric acid level is just fine.

See http://blogs.bmj.com/ebm/2015/12/11/primary-care-corner-with-geoffrey-modest-md-fructose-restriction-and-cardiometabolic-and-weight-improvement/ for prior blog of fructose consumption in kids and cardiometabloic and weight improvements

http://blogs.bmj.com/ebm/2016/09/13/primary-care-corner-with-geoffrey-modest-md-non-alcoholic-fatty-liver-disease-3/ is one of 3 articles on NAFLD, highlighting an important role of fructose

http://blogs.bmj.com/ebm/2016/03/18/primary-care-corner-with-geoffrey-modest-md-microbiome-changes-and-severity-of-nafld/  more on the microbiome and hepatic changes with fructose

Primary Care Corner with Geoffrey Modest MD: Metformin in those with CKD, CHF, CLD

6 Feb, 17 | by EBM

By Dr. Geoffrey Modest

A systematic review from the VA synthesized data on use of metformin in patients with chronic kidney disease (CKD), congestive heart failure (CHF), or chronic liver disease (CLD) with hepatic impairment (see doi:10.7326/M16-1901). The goal was to assess all-cause mortality, major adverse cardiac events (MACEs), and other outcomes in patients with these underlying diseases (patients with these diseases having been the ones in whom the FDA initially had warned against using metformin).

Details:

  • 17 observational studies that included patients with CKD, CHF, or CLD with hepatic impairment were analyzed. These studies compared patients on diabetes regimens that included Metformin vs those that did not.

Results:

  • CKD
    • 6 studies were included, with sample sizes ranging from 1246 to 11,481 patients, median age ranging from 65 to 76. Only one study reported median daily metformin dose (1100 to 1900 mg in the different subgroups)
    • All-cause mortality
      • 22% lower for patients on metformin, HR 0.78 (0.63-0.96)
      • 2 studies reported CKD severity subcategories:
        • eGFR of 30 to <45 had neither benefit nor harm
        • eGFR of 30 to 60 had clear benefit of around 38%
        • eGFR <30 (one study) had neither benefit nor harm
      • MACEs:
        • 2 studies were evaluated, finding no difference in outcomes with metformin in the subgroups of patients with eGFR <45
        • And much, much more hypoglycemia in those on non-metformin-based regimens (specifically, glyburide or insulin)
      • CHF
        • 11 observational studies were included, with sample sizes from 346 to 13,930 patients, median age 55 to 77 years old. No studies included median metformin dose
        • All-cause mortality:
          • 22% lower for patients on metformin, HR 0.78 (0. 71-0.87)
          • 2 studies reported CHF severity subcategories:
            • One study looked at LVEF, finding that both an LVEF of 30-39% and LVEF<30% had a nonsignificant 13% decreased mortality; another study looked at patients with LVEF < 40%, finding a nonsignificant 21% decrease
          • MACEs:
            • The relative chance of readmission for CHF during follow-up was 13% lower for patients on metformin: HR 0.87 (0.78-0.97)
            • The relative risk for cardiovascular mortality was 23% lower in those on metformin (their figure shows that the three studies that looked at this found statistically significant improvement with metformin, but their overall summary said it was nonsignificant?????)
          • CLD
            • 3 observational studies included, with sample sizes ranging from 82 to 250 patients, median age 60-61. No studies reported median metformin dose.
            • All cause mortality:
              • The one study with low risk of bias (n=250) found significantly longer survival: HR 0.43 (0.24-0.78), regardless of cirrhosis severity. Post hoc analysis found a positive association between metformin and survival only in those with nonalcoholic steatohepatitis, though the number of patients in the other subgroups was small.
            • The other studies in those with moderate-to-high risk of bias showed a trend to lower all-cause mortality with metformin

Commentary:

  • Metformin is accepted as the first line drug for diabetes in the US and other countries that I know of. It is such a good and appropriate drug, given both its positive effects on diabetes (including its being weight-neutral or leading to weight loss) as well as data suggesting decreased cardiovascular disease and all-cause mortality. As a result, many clinicians have been using it despite FDA precautions/contraindications, with estimates that 20-30% of patients have been prescribed metformin who have had these precautions/contraindications. The FDA itself has been progressively relaxing these restrictions. In 2006 they removed CHF as a contraindication (though acute or unstable CHF remains a precaution). In addition in 2016, the FDA changed the warning for CKD to be based on eGFR instead of creatinine, making approximately 1 million additional patients with moderate CKD eligible to receive metformin. See blogs noted below for other studies promoting the use of metformin.
  • Most of the above conclusions were based on studies which had low strength-of-evidence, moderate risk-of-bias. However there was consistency in their finding that metformin therapy was associated with reduced all-cause mortality among patients with moderate CKD, CHF, or CLD; fewer CHF admissions among those with moderate CKD or CHF; and a much lower hypoglycemia rate among those with moderate CKD
  • There are other concerns about a meta-analysis such as above, including the fact that they don’t have data on doses of metformin for most studies, what other medications were being used in addition to metformin (the studies did not have rigorous details about which patients were on which other hypoglycemic medications), whether there was “confounding by indication” (where people might have been selected to be on or off metformin based on unknown individual clinical considerations), or even more than baseline data on metformin use in most studies (i.e. patients may have started on metformin but somewhere during the study had stopped it; or alternatively patients may have started off metformin but then put on it during the course of the study)

But, bottom line, these studies reinforce not just the safety of metformin in what had previously been considered concerning underlying comorbidities, but strongly suggest a significant benefit of metformin-based regimens. I.e., there really is an imperative to use metformin as the first-line therapy. We know through our clinical practice that metformin’s major adverse reactions are GI. This is clearly less the case in those on lower doses or if metformin is taken with meals. The somewhat skimpy data suggest that much of the benefit of metformin is conferred by much less than full doses (one oft-repeated quote is that about 80% of the benefit of metformin is by giving 1000mg vs 2000mg). My personal experience is that many people get much better glucose control on just 500mg once a day (which is my starting dose, though I leave it there if there is good control, as happens pretty frequently), and I even have a person on 250mg (1/2 tablet) because of GI intolerance, who seems to get benefit…

Relevant past blogs:

http://blogs.bmj.com/ebm/2015/01/23/primary-care-corner-with-geoffrey-modest-md-metformin-in-renal-failure/ is a systematic review of studies in patients with chronic kidney disease, finding for example no cases (as in, zero) of lactic acidosis in 70,490 patient-years on metformin

http://blogs.bmj.com/ebm/2016/04/26/primary-care-corner-with-geoffrey-modest-md-fda-changes-metformin-guidelines/​  which gives the updated FDA changes for metformin prescribing in those with CKD, with reference to a study of 813 patients with creatinine >6 who did NOT have increased mortality on low dose metformin (<= 500 mg/d), as well as the study finding that metfomrin induces changes in the microbiome, which leads to decreased insulin resistance.

Primary Care Corner with Geoffrey Modest MD: Hepatitis C Treatment Leads to Lower Complication Rate in Prospective Study

11 Oct, 16 | by EBM

By Dr. Geoffrey Modest

A large prospective cohort study confirmed that successful treatment of hepatitis C infection led to many benefits, including decreased hepatocellular carcinoma (HCC) and hepatic decompensation, but also lower cardiovascular risk, bacterial infections and both liver- and nonliver-related overall mortality (see doi:10.1053/j.gastro.2016.09.009, though at this point the paper was an accepted manuscript and not formally published).

Details:

  • 1323 patients from the prospective CirVir cohort from 335 centers in France recruited from 2006-2012 with biopsy-proven cirrhosis, Child Pugh class A, and no prior liver complications. All patients received anti-HCV with interferon, and then direct antiviral agents (DAAs) starting in February 2014, had ultrasound every six months and endoscopic evaluation. Analysis of data was done January 2016.
  • 63% male, mean age 55, AST 58, ALT 63, normal serum albumin/bilirubin/prothrombin time, 31% with esophageal varices, 68% genotype 1, 16% genotype 3, 5% HIV co-infected, 32% excessive alcohol consumption and 25% ongoing alcohol consumption, 38% current smokers, 31% past substance abuse, BMI 26, 90% diabetes, 9% past CV event
  • Follow-up average of 58.2 months.
  • 94% of the patients had undergone antiretroviral therapy at the time of inclusion, of whom 20% had SVR. During follow-up, 1183 treatments were recorded in 793 patients, 287 had first-generation anti-protease agents in genotype 1 infections and 328 had DAA regimens.
  • Propensity match scoring was used to control for morbidities, etc by multivariate analysis, to decrease confounding by indication of treatment or capacity to achieve sustained viral response (SVR)

Results:

  • Overall 215 patients (16%) had at least one episode of liver decompensation or GI bleeding; 422 patients (32%) developed a first hepatic focal lesion of which 55% were considered indeterminate or benign. A total of 1550 extrahepatic events occurred in 697 patients (140 vascular events, with 33 having heart failure, 30 ischemic heart disease), 204 patients had a bacterial infection (27% UTI, 25% pulmonary infections, 11% spontaneous bacterial peritonitis, 12% skin infections). 83 patients had extrahepatic cancers (lymphomas 15, gynecologic 15, colorectal 12, lung 12, oral 12)
  • Factors related to complications:
    • HCC: age, low platelet count, high GGT levels, past excessive alcohol consumption. In those with SVR, risk factors included low PT, low platelet count, high GGT, high AST, and some metabolic syndrome features (BMI >25 and or diabetes and/or dyslipidemia; overall found in 60% of the population).
    • Bacterial infection: age, low albumin, low GFR
    • Cardiovascular events: low albumin, smoking, past history of CV events, hypertension
    • Hepatic decompensation: age, low platelet count, high GGT levels, low albumin, esophageal varices.
    • Overall death: age, low platelet count, high GGT, low albumin, past excessive alcohol consumption, past history CV events, tobacco, hypertension. In those with SVR, only 18 patients died but these patients had low platelet count, diabetes, a past history of cardiovascular events, or a past history of malignancy
    • Extrahepatic cancer: age
  • 668 patients (50.5%) achieved an SVR, associated with (vs. those not achieving SVR):
    • 71% decrease in HCC, HR 0.29 (0.19 – 0.43), p<0.001
    • 74% decrease in hepatic decompensation, HR 0.26 (0.17 – 0.39), p<0.001
    • 58% decrease in cardiovascular events, HR 0.42 (0.25 – 0.69), p=0.001
    • 56% decrease in bacterial infections, HR 0.44 (0.29 – 0.68), p<0.001
    • 73% decrease in total mortality, HR 0.27 (0.18 – 0.42), p<0.001
    • There was no effects of SVR on extrahepatic cancers
  • Similar results to the above were obtained through propensity score-matched population.
  • The curves for HCC, hepatic decompensation, and bacterial infections continued to increase in those without SVR over 108 months of follow-up, but were basically flat in those with SVR. The curves for major adverse cardiac events continued relatively parallel after about five years, and overall survival diverged till about 84 months, then curves were parallel.
  • Overall, there was no difference in outcome in SVR patients whether they achieved their SVR through interferon-based regimens or DAAs, though the follow-up in the latter group was too short to be definitive.

Commentary:

  • This large study adds to prior studies finding that those who achieved SVR had improvement in liver-related complications: including fibrosis and necrosis, portal hypertension and splenomegaly, HCC, risk for liver-related mortality and transplantation; as well as some non-liver related ones: non-Hodgkin’s lymphoma and other lymphoproliferative disorders, and all-cause mortality (see http://www.hcvguidelines.org/full-report-view , which has a regularly updated review of hepatitis C overall, with emphasis on therapy). This new study basically confirms the liver-related benefits but also includes non-liver benefits in cardiovascular and infectious diseases.
  • One important feature of this study is that this one involved a more inclusive prospective cohort study of HCV-treated cirrhotic patients, with most of the prior studies being retrospective cohorts and observational. This was also a rigorous study which required biopsy-proven cirrhosis.
  • There were a few findings of potential concern: in those who developed SVR, the incidence of hepatic decompensation seemed to be lower in those who were on interferon-based regimens. Those who had a protease inhibitor-based regimen had a higher risk of bacterial infections. But overall, there were no clear differences based on the regimens to achieve SVR.
  • The increase in cardiovascular events could be related to several conditions, including adverse cardiac effects from the metabolic syndrome, and the chronic inflammation associated with ongoing hepatitis C infection. There even is argument for a direct effect of HCV itself on cardiovascular disease (e.g. there seems to be a correlation between higher HCV viral loads and cardiovascular morbidity)
  • Of note, there was a recent FDA alert about DAAs (see http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm523690.htm ), where they note that there were 24 cases of patients dually-infected with hepatitis B and C who had reactivation of their hepatitis B.
  • So, this current study brings up  several points regarding successful treatment of hepatitis C:
    • It reinforces the remarkable decrease in many adverse hepatic and extra-hepatic outcomes of hepatitis C infection in those with cirrhosis
    • It tangentially raises the likely utility of treating chronic hepatitis C infections earlier, in the pre-cirrhotic and even pre-fibrotic stages, since many patients with SVR still have complications (though much less than without SVR). Also, from other studies, those with fibrosis often do not get significant reversal of their fibrosis with SVR and are therefore still potentially at risk for HCC and subject to on-going HCC surveillance
    • Unfortunately, this study looked only at hard endpoints: other studies have found important improvements in quality of life, including physical, emotional and social health.

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).

Recommendations:

  • 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.

Commentary:

  • 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 http://blogs.bmj.com/ebm/category/diabetes/ , or you can go to the blog website as at http://ebm.bmj.com  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: http://blogs.bmj.com/ebm/2016/07/15/primary-care-corner-with-geoffrey-modest-md-w-3-fatty-acids-decrease-heart-disease/ )
  • 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 http://blogs.bmj.com/ebm/2016/05/16/primary-care-corner-with-geoffrey-modest-md-use-of-statins-in-patients-with-hepatitis-looks-like-a-yes/ ).
  • 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 http://blogs.bmj.com/ebm/2016/08/17/primary-care-corner-with-geoffrey-modest-md-weight-loss-and-resting-metabolic-rate/ ). 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.

Exercise

  • 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.

Coffee

  • 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

Probiotics

  • There are interesting studies finding disruptions in the gut microbiome are associated with the pathogenesis of NAFLD and the progression to NASH (see http://blogs.bmj.com/ebm/2016/03/18/primary-care-corner-with-geoffrey-modest-md-microbiome-changes-and-severity-of-nafld/). 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.

Commentary:

  • 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.

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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)

Commentary:

  • 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, http://blogs.bmj.com/ebm/2015/12/11/primary-care-corner-with-geoffrey-modest-md-fructose-restriction-and-cardiometabolic-and-weight-improvement/ , 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.

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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 http://blogs.bmj.com/ebm/category/microbiome/ 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

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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.

Commentary:

  • 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 http://blogs.bmj.com/ebm/2016/05/16/primary-care-corner-with-geoffrey-modest-md-use-of-statins-in-patients-with-hepatitis-looks-like-a-yes/ 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: Statin Use Lowers Cirrhosis Risk in Hep B

26 Aug, 16 | by EBM

By Dr. Geoffrey Modest

A new study looked at a large number of patients with chronic hepatitis B (CHB) who were on a statin, finding improved hep B outcomes (see Huang Y. Am J Gasstroenterol 2016). This blog follows a recent one I sent out: see http://blogs.bmj.com/ebm/2016/05/16/primary-care-corner-with-geoffrey-modest-md-use-of-statins-in-patients-with-hepatitis-looks-like-a-yes/ , which reviewed a recent study showing statin benefit in those with hepatitis c, also comments on the benefit of statins in NAFLD, and mentions that the data on hep B is more mixed. Details of the current study from Taiwan, where 15-20% of the population has CHB, half of which is by perinatal transmission:

  • Population-based cohort study in Taiwan, with 298,761 patients with chronic hepatitis B (but without concomitant hep C, biliary cirrhosis, or alcoholic liver disease) and 6,543 on statins
  • Mean age 50, 53% male, 5 year follow-up on cirrhosis and same for decompensated cirrhosis, more comorbidities in the non-statin group (including more cardiovascular and pulmonary diseases)
  • Compared on 1:1 ratio with non-statin taking patients, with propensity scoring (to mathematically attempt to eliminate confounders). Also controlled for “inception point” of when statins started, to make sure that the comparisons between patients happened at the same approx time (to decrease likelihood that they were treated differently because of treatment changes over time)

Results:

  • Those on statins had:
    • 57% lower risk of developing cirrhosis [RR=0.43 (0.34-0.52, p<0.001)]: in 30,000 person-years of follow-up, 173 of those on statins developed cirrhosis (incidence rate 0.561/100 person-years), vs 400 not on statins (1.338/100 person-years)
    • 53% lower risk of developing decompensated cirrhosis [RR=0.47 (0.34-0.64, p<0.001)]: in 30,000 person-years of follow-up, 59 on those of statins developed decompensated cirrhosis (incidence rate 0.190/100 person-years), vs 126 not on statins (0.411/100 person-years)
    • Adjusted for age, gender, comorbidity index (which includes MI, CHF, PVD, rheumatic disease, chronic pulmonary disease, dementia, renal disease, cancers, HIV), hypertension, diabetes, hyperlipidemia, hepatocellullar carcinoma, obesity, NAFLD, aspirin use, diabetes medication, CHB treatment, non-statin lipid meds, and triglyceride meds: those on statins had
      • 49% lower risk  of developing cirrhosis [RR=0.51 (0.41-0.63, p<0.001)]
      • 47% lower risk of developing decompensated cirrhosis [RR=0.53 (0.43-0.66, p<0.001)]
    • In looking at the length of time taking statins, there was a dose response for the adjusted hazard ratios:
      • Cirrhosis
        • 15% lower if statin use 28-90 days (nonsignificant)
        • 53% lower if 91-365 days (p<0.001)
        • 80% lower if >365 days (p<0.001)
      • Decompensated cirrhosis
        • 7% lower if statin use 28-90 days (nonsignificant)
        • 39% lower if 91-365 days (borderline significant  at p=0.053)
        • 77% lower if >365 days (p=0.001)
      • The Kaplan-Meyer curves for both of the above showed widening curves over 12 years, with the major divergence in the first 6 years of follow-up
    • Also, overall mortality over 12 years of follow-up was lower in those on statins (13% vs 17%, with p<0.001)

Commentary:

  • The reason I bring up this article is that I still hear clinicians who feel that it is dangerous to prescribe statins in those with underlying chronic liver disease. As mentioned in the prior blog noted above, there are some reassuring data for NAFLD and Hep C. This huge trial, I think, pretty clearly adds Hep B to the mix. Although these are mostly retrospective/observational studies, and therefore not rock-solid RCTs, they pretty much show that statins at least are not harmful to an already-inflamed liver, and may well be beneficial. Of course, with observational studies, there always is the issue of unequal treatment in the different groups (were those on statins perceived to be less sick with their CHB and therefore getting more aggressive cardiovascular treatment??), but the use of propensity-matched scoring for lots of potential confounders and making sure that people were compared during the same time-frame (to minimize differences in overall treatment during differing time periods) do strengthen the conclusions.
  • There is reasonable biologic plausibility: studies have shown that simvastatin lowers portal pressure in patients with cirrhosis, and improves portal hypertension and sinusoidal endothelial dysfunction in rats (presumably by increasing nitric oxide and decreasing hepatic vascular resistance). And reduction in portal pressure correlates with protection from complications from cirrhosis. Also statins seem to inhibit fibrosis through several mechanisms (e.g. decreasing procollagen I and a-smooth muscle actin, connective tissue growth factor, etc.) and may directly decrease hepatitis B viral replication
  • The dose-response curve (the longer on statins, the more protective) also strengthens the likely conclusion that statins are protective against disease progression
  • And statins may be particularly useful in those with chronic inflammatory conditions such as hepatitis, since these patients are more predisposed to cardiovascular disease
  • So, it seems to me, that for the major international causes of chronic liver disease (hep B, hep C, NAFLD), we should not hold off using statins for fear of increasing the liver problems. That being said, I do check and follow liver function tests a bit more closely, though I have never found any problems in these patient groups.

Primary Care Corner with Geoffrey Modest MD: Carvedilol, Best Drug For Portal Hypertension?

24 Jun, 16 | by EBM

By Dr. Geoffrey Modest

A recent review looked at the varying efficacies of different nonselective b-blockers in patients with portal hypertension in cirrhosis (see Li T. BMJ Open 2016; 6: e010902), finding that carvedilol may be more effective than propranolol or nebivolol and as effective as the combo of nadalol plus isosorbide mononitrate.

Details:

  • 12 RCTs were evaluated, though mostly not-so-great quality

Results:

  • 7 trials (379 patients, about 2/3 male, mean age around 50, most with alcoholic cirrhosis but some hepatitis B or C) compared carvedilol vs propranolol for hemodynamic outcomes: hepatic venous pressure(HVPG) reduction, hemodynamic response rate, post-treatment arterial pressure (mean arterial pressure, MAP). Most follow-up of only up to 6 weeks. Finding:
    • Carvedilol was associated with a greater (%) HVPG reduction within 6 months (mean difference -8.49 (-12.36 to -4.63) and improvement in hemodynamic response rate, both being consistently found in each of the trials. There was a nonsignificant decrease in MAP in almost all of the trials
  • 3 trials compared carvedilol vs endoscopic variceal band ligation (EVL) for clinical outcomes: all-cause mortality, bleeding-related mortality, upper GI bleeding.
    • 1 trial was secondary prevention, 64 patients, 26 months follow-up, Child-Pugh class B. No significant difference in clinical outcomes, though very wide confidence intervals
    • 2 trials of primary prevention, 341 patients, 13-26 month median follow-up, mostly Child-Pugh class A. Also no significant difference in clinical outcomes
  • 1 trial compared carvedilol vs nadalol plus isosorbide mononitrate, 121 patients, 30 month follow-up:
    • No significant difference in mortality or bleeding. carvedilol group had fewer adverse events (5/61 vs 23/61)
  • 1 trial compared carvedilol vs nebivolol, 20 patients, 14 day follow-up:
    • Carvedilol had greater reduction in HVPG, mean difference of -10.9 percentage of HVPG reduction

Commentary:

  • Acute variceal bleeding has 6 week mortality of 10-20%, depending on Child-Pugh class; and a 60% 1-year rate of recurrent variceal bleeds
  • HVPG is the strongest predictor of bleeds: if >10 mmHg, it predicts varices; if >12 mmHg, it is associated with high rate of bleeds; if >20 mmHg, there is a high mortality.
  • Risk of bleeding decreases if HVPG decreases to <12 mmHg or by 20% from baseline
  • Nonselective b-blockers work by both decreasing cardiac output (b1) and constricting splanchnic vessels (b2); but only 40% of patients reach therapeutic levels
  • Carvedilol (blocking both a1 and b1/b2) also decreases intrahepatic resistance. Prior reports have found that >50% of propranolol non-responders do respond to carvedilol, though there are concerns about systemic hypotension and renal failure (and perhaps increased mortality) especially in people with refractory ascites.
  • The above trials were pretty short-term. It is somewhat reassuring that in the carvedilol studies looking at hemodynamic outcomes, there was not much difference acutely and at 6 months, suggesting that the benefit was, and might continue to be, sustained
  • Studies suggest that there is not much additional effect of higher doses of carvedilol in terms of HVPG (i.e., it may be reasonable to start with 3.125 mg bid, then increase as tolerated to 6.25 mg bid)
  • There is not a lot of data comparing carvedilol to EVL, but the limited data above suggest relative equivalence, and the quality of evidence is low. Other studies have found that EVL is superior to nonselective b-blockers.

What does this all mean?

  • Interestingly (and anecdotally), I happened to see a patient today who was not tolerant of nadolol (made her feel weak, trouble exercising/walking). And, having seen this review, I started her on carvedilol 3.25mg bid.  We’ll see….
  • There are concerns about EVL, since it requires endoscopy and a procedure, and about 50% need retreatment within one year. The data comparing EVL and nonselective b-blockers is a bit unclear: a review (Cheung J. Alimentary Pharmacology and Therapeutics 2009; 30: 577), which included only propranolol and nadolol as meds, found pretty poor quality of evidence (significantly, no documentation of the number of patients actually achieving target heart rate). Their comparison noted that EVL was better than b-blockers if the mean dose was <80mg. But given other studies finding lots of people not achieving optimal b-blocker dose, it is hard to be sure that EVL really is better than even the old b-blockers.
  • So, I am a bit concerned about the reports of more hypotension with carvedilol, since many of my patients with cirrhosis have pretty low blood pressures to begin with, and the reported concerns of possible increased acute kidney injury/mortality in patients with advanced decompensated liver disease/refractory ascites is a tad worrisome. Since the above data are mostly based on not-so-great quality studies with small numbers of patients, I think it is important to have bigger, better, and longer comparative studies before using carvedilol as first-line. so, my approach will be to continue using nadolol or propranolol initially, but as in the case I saw today, to try carvedilol gingerly if the other b-blockers are not tolerated/target heart rate not achieved (reduction of 25% or down to <55-60 bpm)

Primary Care Corner with Geoffrey Modest MD: Hep C Treatment and Regression of Cirrhosis

16 Jun, 16 | by EBM

By Dr. Geoffrey Modest

A recent study provides up to 12-13 year follow-up showing long-term improvement in important clinical outcomes (liver cancer, decompensation and death) in patients treated successfully for hepatitis C (see doi.org/10.1053/j.gastro.2016.03.036). The value of this study, using PEG interferon/ribavirin, is that it has long-term results which I think are applicable to our newer and much better therapies.

Details:

  • 444 patients with hepatitis C (HCV) infection and compensated cirrhosis were treated with PEG interferon/ribavirin (PEG- IFN/RBV) in Italy, from 2001-2009, with mean of 7.6 years of follow-up
  • Mean age 58, 62% male, BMI 27, ALT 150, bili 1, albumin 4, 27% with diabetes, 83% genotype 1, 26% IL28B SNP CC/74% either CT or TT (those with the CC genotype have a stronger immune response to HCV than the non-CC genotypes and historically have been more likely to be cured of HCV infection)
  • They looked at 2 groups of cirrhotic patients: those without (n=218) and those with esophageal varices (EVs) (n=226) on baseline endoscopy
  • Routine ultrasounds were scheduled every 6 months, and EGD every 3 years for those without baseline EV and every 2 years in those with EV. Those who developed larger EVs were put on b-blockers or got banding
  • Results (and, feel free to skip over the mass of statistics):
    • SVR was achieved in 67 patients (30.7%) of those without EV and 41 (18.1%) in those with EV (p=0.003); and more often in those with higher ALT, albumin, non genotype 1, and those with IL28B  SNP CC polymorphism [all pretty much as expected with this therapy]
    • Risk of developing/progression of EV:
      • In those without baseline EV: those achieving SVR had 77% less likelihood of developing EV [HR 0.23 (0.11-0.48), p<0.001], and those developing EV had small ones. The rate was 2.1%/yr for those with SVR and 9.1% without. These curves continued to diverge over the 12-13 years of follow-up
      • In those with baseline EV: no significant difference in developing more EVs. 22% had varices regress, 44% were stable, and 34% had progression
    • SVR was associated with 75% lower risk of developing hepatocellular carcinoma (HCC): [HR 0.25 (0.12-0.55), p<0.001]. In those without EV the HCC rate was 0.7%/yr vs 2.9%/yr if no SVR; in those with EV, the respective rates were 0.9% vs 3.6%/yr. and the severity of the HCC was much less in those who developed SVR. The HCC incidence curves for those with and without EV diverged over time.
    • For liver decompensation (LD): those without EV who developed SVR, none developed LD, though 1.7%/yr did if no SVR. In those with EV with SVR, 2.3%/yr developed LD vs 4.9%/yr if no SVR.
    • For overall survival: 2 of 67 SVR patients without EV died (both from HCC), vs 27 of 151 without SVR (18 from HCC and 9 from LD): 0.4%/yr vs 2.1%/yr (p=0.0035).  in those with EV, 1.8%/yr died in the SVR group and 4.6%/yr without SVR (p=0.005)
  • For those with EV at baseline (vs those without), independent of SVR, were at higher risk for
    • Liver decompensation:  [HR 2.82 (1.73-4.59), p<0.001]
    • Death:  [HR 1.77 (1.12-2.80), p=0.015]
  • In those without baseline EV
    • HCC: 2.9% with SVR died from HCC vs 11.9% in those who did not develop SVR (p=0.03)
    • Liver decompensation: in none with SVR but 7.1% without (p=0.009)
  • In those with baseline EV:
    • HCC: 2% with SVR died from HCC vs 18.4% in those without (p=0.003)
    • Liver decompensation was not statistically significant, though trend to improvement with SVR (12.1% vs 25.4%,  p=0.15)

Commentary

  • There were some limits inherent in this study
    • They excluded patients with any history of decompensated cirrhosis, or those with more advanced EV (moderate to large varices) or on prophylactic b-blockers. Also those with co-infection with hepatitis B or HIV, or prior to getting cirrhosis.
    • They only looked at patients treated with PEG-IFN/RBV
    • There might be inherent biases in this outcome analysis of this prospective review, including a response  bias (i.e., did those patients with SVR by PEG-IFN/RBV differ from those who did not respond because of some unmeasured difference in the aggressiveness of the virus, comorbidities, or intrinsic issues of their immunologic response)
  • BUT, there are, I think, some reasonable and probably generalizable conclusions
    • This study offers us the ability to look at really long-term conclusions about important clinical events after SVR. Although possible, it seems likely that the meds used to achieve the SVR are not particularly important to outcomes years later (and, the effect of any selection bias introduced by those responding to the old meds is unlikely to be significant anyway with the new direct acting antivirals, DAAs, since they pretty uniformly lead to SVR). So, the application of these results to the new era of DAAs seems pretty reasonable
    • It is quite remarkable how well patients did who had initial cirrhosis without EV: basically they do not develop liver decompensation, and only rarely develop HCC. And, they have a very low risk of mortality from liver disease
    • And, for those with EV at the time of treatment, effective treatment significantly reduced the risk of HCC, liver decompensation, and mortality, though there was still a risk of EV progression (though the risk of progression from small EV is still less: those with SVR had progression at an annual rate of 5.9% vs 9.0% in those who did not achieve SVR)
    • But, even in those without SVR, the presence of EVs portended a poorer prognosis, also reinforcing the benefit of earlier treatment
    • For the future, it will be important in this era of DAA therapies that we look at the long-term efficacy of successful hep C treatment in those excluded in the above long-term study, including those with both less advanced liver disease, those with more advanced cirrhosis (e.g. with history of liver decompensation), and in those with co-infection with hep B and HIV

So, based on this:

  • It seems appropriate to aggressively pursue hep C treatment at an earlier stage, and specifically prior to developing significant portal hypertension/esophageal varices. And I would add that the continued risk of HCC in those with cirrhosis even without EVs and the need for future HCC monitoring supports treating HCV prior to developing cirrhosis (which some insurance companies seem reluctant to do).
  • But this study still confirms that even those with more severe cirrhosis/earlier stages of portal hypertension derive major benefit from effective HCV treatment (i.e., still important to treat HCV even in later stages of cirrhosis/portal hypertension)
  • It will be important to develop a granular database in this age of DAA to guide future monitoring. For example, in HCV infection, given the predictable progression of liver disease to fibrosis prior to HCC, are there clear markers where SVR will make it unnecessary to do continued routine surveillance for HCC? For example, is there a stage of liver disease, perhaps some degree of cirrhosis regression or other markers after SVR, when we do not have to continue doing serial RUQ ultrasounds? Or in the group with EVs, continuing to do follow-up EGDs?

Primary Care Corner with Geoffrey Modest MD: Use of Statins in Patients with Hepatitis? Looks Like a “Yes”

16 May, 16 | by EBM

By Dr. Geoffrey Modest

One question that comes up a lot in patient care is whether it is safe to use statins in patients with ongoing hepatic inflammation. A new retrospective VA study of hepatitis C (HCV) patients found an actual benefit for statins, as has been found in some other studies (see DOI 10.1002/hep.28506).

Details:

  • From the Electronically Retrieved Cohort of HCV Infected Veterans (ERCHIVES) database, they looked at subjects initiated on anti-HCV therapy from 2001 to 2014, as well as all incident cases of cirrhosis and hepatocellular carcinoma (HCC). Those coinfected with HIV or hepatitis B were excluded, as well as those with baseline cirrhosis
  • Mean age 53, 65% white/18% black/6% Hispanic, 95% male, ALT 75, AST 53, FIB-4 score 1.7 (see below), median length of follow-up was 7-8 years. More statin users were diabetic (24% vs 9%), on metformin, other lipid-lowering agents, ACE-I, and they had a higher baseline LDL , triglycerides, and lower HDL). 90% were treated with PEG/RBV, 10% with PEG/RBV/telaprevir (i.e., the old drugs)
  • 9135 eligible people, of whom 1,649 developed cirrhosis, and 239 developed incident HCC [cirrhosis was defined by a FIB-4 score of >3.5, where the FIB-4 score is a mathematical calculation based on age, AST, platelet count, ALT]

Results:

  • Statin use was associated with
    • Higher likelihood of sustained viral response (55.1% vs 47.5%, p<0.0001)
    • A 36% reduction in development of cirrhosis, adjusted HR: 0.64 (0.53-0.68), p<0.0001.
    • Lower fibrosis progression, with a dose-response curve revealing progressively decreasing risk
  • Of the statins used, the highest decrease in FIB-4 score was with atorvastatin and fluvastatin (though only 34 patients were on fluvastatin): those without statin had FIB-4 increase of 0.26, those on simvastatin had increase of 0.11, but those on atorvastatin had decrease (-0.17), p=0.04,after adjustment for baseline FIB-4 score and established predictors of cirrhosis.
  • Statin use was also associated with a 49% reduction in incident HCC (adjusted HR: 0.51; 95% CI: 0.36, 0.72). A similar dose-response relationship was observed. [Interestingly, the decrease in HCC was independent of changes in the FIB-4 score. Though with hep C, the progression to HCC is tied in with presence of fibrosis].

So, does this make sense?

  • There are several mechanisms by which statins could decrease progression of liver fibrosis:
    • They have lots of “pleiotrophic” (non-lipid) effects: anti-inflammatory, antiproliferative, anitangiogenic, pro-apoptotic, immunomodulatory. And there are data suggesting they can inhibit cell growth, decrease proteolysis, block tumor spread, and may be chemoprotective against such malignancies as HCC.
    • Hepatitis C virus depends on cholesterol to replicate, so interference by statins might well help control hep C (statins do inhibit hep C in vitro; and people with hep C have lower LDL levels, which increase after the virus is cleared)
    • Statins also decrease components of the metabolic syndrome, and there are several studies suggesting that the combination of hep C infection and metabolic syndrome, present in about 20-25% of people with hep C, leads to a higher incidence of HCC
    • Humans studies (including another one from the above VA database: Butt AA. Hepatology 2015; 62: 365) have found decreased risk of hepatic fibrosis progression and development of cirrhosis by 43%; a Taiwanese study found that just using statins in patient with hep C infection found a reduced risk of cirrhosis in a dose-dependent fashion, also found in the HALT-C study. Another VA study of patients with compensated cirrhosis found a 45% decreased risk of decompensation and a similar mortality benefit
  • For patients currently on DAAs (direct-acting antiretrovirals) for hepatitis C, I found the following drug-drug interactions:
    • Ledipasvir/sofosbuvir possibly increases the levels of the statins (I checked atorvastatin, pravastatin, rosuvastatin, and simvastatin), though the warning for atorvastatin seems the most benign
    • Elbasvir/grazoprevir increases atorvastatin dose by 94%, rosuvastatin by 126%, simvastatin has likely interaction but not studied, no interaction with pravastatin
    • Daclatasvir expected increases in levels of atorvastatin, pravastatin, simvastatin — not studied, and 58% increase in rosuvastatin
    • Ombitasvir/paritaprevir/ritonavir increases levels of rosuvastatin 1-2 fold and pravastatin by about 33%. do not use with atorvastatin or simvastatin
    • And, none of the statins seemed to affect the levels of the DAAs

Effects of statins on other hepatitides:

  • NAFLD: statins have been shown also to decrease liver inflammation in those with NAFLD
  • One of my favorite studies, because of its name, was the GREASE study, which in fact was a study of Greek people with high lipids!! (Athyros VG. Lancet 2010; 376: 1916). They looked at 437 patients with baseline elevated ALT (but < 3x the upper limit of normal), 90% with metabolic syndrome, and all with LDL>100 and documented CAD, finding that atorvastatin for 3 years led to 1/3 the rate of recurrent CAD events (30% in placebo and 10% with atorvastatin), but 89% had normalization of their LFTs on the statin (although a simultaneous increase in ALT in those on placebo)
  • Hepatitis B: data on hepatitis B is somewhat mixed:
    • There are case reports of asymptomatic hepatitis B reactivation in a patient on atorvastatin, which resolved with discontinuation of the atorvastatin (see Wu DC. Intl J Infect Dis; 2013:e1069). Though, I should add that I had a patient with chronic hepatitis B, who was asymptomatic but developed a dramatic increase in his ALT to 450 on routine check after being on atorvastatin for 8 years, and the hepatic inflammation spontaneously resolved within weeks even while continuing the atorvastatin. So, it seems that even if statins did cause the hep B reactivation, there are not necessarily bad outcomes (perhaps my patient had HBV reactivation related to the statin, but then enough of an immunologic response to contain it).
    • On the other hand, a recent 2-year Chinese study (Hsiang JC. J Hepatol 2015; 63: 1190) in patients with chronic HBV infection found a 32% decreased risk of HCC in those on statins, and on subgroup analysis, those on a statin and nucleos(t)ide analog had a 59% risk reduction compared to those on a nucleos(t)ide analog alone (i.e., the combo might even be better: which may be really significant for HBV, since unlike hep c, the development of HCC is not so dependent on having baseline cirrhosis)
    • In general, it is pretty well accepted that there is no significant relationship between statin use and liver disease. In most large trials, there is no increase in statin-induced liver disease. As a result, the FDA changed their recommendations in 2012: check LFTs prior to starting statins, then only if clinically indicated

So, what does this all mean in the era of the potent new hepatitis C drugs?

  • My guess is that it is very unlikely that a statin will improved the efficacy of these new hep C drugs, since they are so powerful on their own
  • The issue of statin effect on decreasing the progression of fibrosis/cirrhosis is interesting, as well as the decreased likelihood of developing HCC. Unclear exactly why: it may well be that the effect of statins is not a direct effect on the development of these conditions, but simply its anti-inflammatory effect (though that is still welcome, and still could have long-term effects in preventing cirrhosis). And this could also be different in the current era of hep C treatment
  • If someone is on a statin prior to starting hep C DAA therapy, it makes sense to check the most up to date drug interactions (e.g. at http://www.hep-druginteractions.org/checker ) and likely decrease the dose of the statin, stop or change the statin, as indicated
  • For someone with hepatitis C who is not currently on treatment, it looks to me like there are good reasons to use a statin, probably best for atorvastatin (in part for its role in preventing CAD in those with this chronic inflammatory state — though it would be important to have confirmatory RCTs; and in part based on the above studies of its anti-hep C potential)
  • And, overall, it seems very likely than statins may be useful for those more generally with inflammatory liver disease, with reasonably impressive data for NAFLD and probably as well for hepatitis B. It would be really great to have more long-term data, preferably based on RCTs, which looked at real clinical outcomes and not just changes in ALT as with the NAFLD data (though I should add that the dramatic decrease in CAD events seems to justify the use of statins independent of their hepatic effects. And there are some data suggesting that simvastatin is less effective in decreasing biopsy-proved hepatic inflammation than atorvastatin). So, I have been using atorvastatin in particular in my patients with NAFLD and both hepatitis B and C, but following their LFTs more regularly, even in asymptomatic patients.

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