A liver disease tsunami

The extent and consequences of nonalcoholic fatty liver disease (NAFLD) are far-reaching and like a tsunami will be quite destructive (Gastroenterology 2011; 141: 1249.)  In this article, the epidemilogy of nonalcoholic steatohepatitis is discussed.  NAFLD was  the 3rd most common cause of liver transplantation in this cohort (n=35781).  It is projected to be the #1 reason for liver transplantation by 2025.  Although the outcomes in NAFLD are similar to other liver transplant patients, it is difficult to imagine that so many patients will need such an aggressive treatment approach.

Another recent article, discusses the correlation of vitamin E, uric acid, and diet composition with histology in NAFLD (JPGN 2012; 54: 90-96).  This study involved 149 patients.  The study demonstrates that in these patients, their diet is insufficient in Vitamin E intake. Also, although reported sugar-sweetened beverage consumption was low, uric acid which often reflects total fructose consumption was associated with NASH histology.  As noted in the references below, concerns about low antioxidants, especially Vitamin E, as well as sugary beverages has been an ongoing concern for NAFLD for at least a decade.

For pediatric gastroenterologists/hepatologists, nonalcoholic fatty liver disease is increasingly common but remains difficult to treat; the best treatment is weight loss.  A recent educational pamphlet was published by the NASPGHAN Foundation (http://www.gastrokids.org/files/documents/digestive%20topics/english/NASPGHAN%20Fatty%20Liver%20Fact%20Sheet%2011.2011%20(1).pdf).  The advice for families is the following:

• Avoid sugar drinks

• Drink mostly water and some low fat milk

• Get at least 60 minutes of physical activity every day

• Limit TV and screen time to one hour or less per day

• Make half your plate vegetables at mealtimes

• Eat breakfast everyday

Other things that can harm the liver should be avoided, like drinking alcoholic beverages.  Studies in teens with NAFLD have shown some benefit from the natural form of Vitamin E.

Although this advice applies to patients with NAFLD, it sounds like good advice for everyone.

Additional References:

  • -Hepatology 2011; 54: 1082.  U/S w ~85% sensitivity in detecting fatty liver.
  • -JPGN 2011; 52: 740.  n=20.  Some improvement in LFTs with culturelle
  • -Gastroenterology 2011; 140: 124.  High prevalence in middle aged US cohort: 46% NAFLD, 12% NASH. n=400.
  • -Hepatology 2010; 52: 472.  High dose ursodeoxycholic acid ineffective for NASH in double blind randomized trial. n=185.
  • -Hepatology 2010; 52: 79.  Meta analysis of trials for NAFLD.  No effective Rx at this point.  Thiazolidinediones helped with steatosis/inflammation but caused wt gain.  L-carnitine helped histology in 1 trial.
  • -Hepatology 2010; 51: 1961, 1972. 1– increased fructose assoc with increased fibrosis in NAFLD. 2–increased HCC risk.  Alcohol intake is addt’l risk factor along with NAFLD.  2.6% of NASH pts with HCC (compared w 4% of similar HCV pts).
  • -NEJM 2010; 362: 1675.  n=247.  Vitamin E 800 IU/day helpful.  Pioglitazone not helpful.
  • -Gastroenterology 2010; 138: 905.  Iron overload, but not HFE mutations, associated with more severe NASH
  • -J Hepatol 2009; 51: 918-24.  Soft drinks assoc with fatty liver independent of metabolic syndrome.
  • -Hepatology 2009; 50: 1818.  Lack of benefit from Betaine.
  • -J Pediatr 2009; 155: 469.  Review.  No evidence-based guidelines for treating in pediatrics –main Rx wt loss/exercise.  Consider obtaining ultrasound evidence.
  • -J Hepatology 2009; 51: 371.  risk factors for fibrosis progression.
  • -Hepatology 2009; 50: 68.  Activity helps NAFLD independent of activity level.
  • -JPGN 2009; 48: 587. review of meds.
  • -Gastroenterology 2008; 135: 1961.  Liver biopsy (in pediatrics) still needed as surrogates not accurate for correlating degree of fibrosis/injury.
  • -Gastroenterology 1999; 116: 1413.  spectrum of pathology in NASH.  Bx correlated with outcome
  • -Gastroenterology 1988; 95: 1056.  Sentinel article on NASH ‘alcohol-like liver disease in non-alcoholics’
  • -Clin Gastro & Hep 2008; 6: 1396.  Bariatric surgery appears to improve or resolve NASH. n=15 studies with 766 paired liver biopsies.
  • -Clin Gastro & Hep 2008; 6: 1249.  Cytokeratin 18 levels associated with NASH in at risk patients (bariatric patients). n=99.
  • -Hepatology 2008; 48: 792-98. NASH increased with age and with presence of DM.  Severe fibrosis assoc with ferritin, ALT, and DM.
  • -Gastroenterology 2008; 135: 1176.  n=74.  Use of pioglitazone for NASH was helpful in adult patients.
  • -Hepatology 2008; 48: 119.  Antioxidants Vit C (500mg)/Vit E (600IU) c lifestyle changes was NOT better than lifestyle changes alone. n=53 children. Rx’d for 24 months
  • -Gastroenterology 2008; 134: 1682.  Review.
  • -Clin Gastro & Hep 2008; 6: 26-29.  Review.  Risk factors for NASH: obesity, age>50y, non-black ethnicity, female, type II DM, HTN, AST>45, AST/ALT ratio >0.8-1, low platelet count.  Rec:  exclude other causes, check U/S or CT, if risk factors, conside liver biopsy, lifestyle modification
  • -Gastro 2007; 133: 1814.   Prevalence data for increased ALT from NHANES 1999-2004.
  • -NASPGHAN 2007 Postgraduate Course Jeff Schwimmer.  20% of NAFLD pts have normal wt.  9.6% of all children have NAFLD.
  • -Clin Gastro & Hep 2007; 5: 496.   n=88; 55% of women with PCOS had NAFLD.
  • -Clin Gastro & Hep 2006; 4: 1537.  Combination of Vit E & urso x 2yrs may be beneficial. n=48.  Regression of steatosis  noted in this small study along with improved enzymes.
  • -JPGN 2006; 43: 413.  Invited review of NAFLD.
  • -NEJM 2006; 355: 2297, 2361.  pioglitazone for NASH -helps with histology; not ready for routine use.
  • -Pediatrics 2006; 118: 1388.  Schwimmer.   n=742 autopsy study; estimates 9.6% overall prevalence of fatty liver for ages 2-19 (>6.5 million in U.S.). 38%  obese had steatosis; 23% of all NAFLD had NASH, 9% had bridging fibrosis
  • -Hepatology 2006; 44: 802, 865.  Long term f/u of NASH (avg 13.6yrs): increased cardiovascular deaths (15.5% vs 7.5% control), increased liver-related deaths 2.8% vs. 0.2% controls.  Risk of HCC and cirrhosis proven.
  • -Hepatology 2006; 44: 458.  Prospective study of 84 children; 7%c >grade I fibrosis; 58% with some fibrosis.  Almost all have evidence of insulin resistance
  • -Clin Gastro & Hep 2006; 4: 639.  Orlistat helped decrease ALT and steatosis on U/S beyond its effect on weight reduction.  n=52.  double-blind, placebo-controlled.  Rx 120mg TID x 6 months.
  • -Liver Transplantation 2006; 12: 523.  Review of NAFLD & Liver transplant.  NAFLD likely the main reason for cryptogenic cirrhosis in adults.
  • -Pediatrics 2006; Schwimmer.   n=954 autopsy study, 32% obese had steatosis; 23% of all NAFLD had NASH, 9% had bridging fibrosis
  • -Aliment Pharm Ther 2005; 21: 871.  pilot study of metformin, 500mg bid in children; 50% nl ALT  (equivocal in adults), high insulin in 95% of pts c NASH
  • -J Pediatr 2003; 143:  500-5.
  • -Hepatology 2005; 42: 641-649. pediatric NAFLD pathology
  • -Hepatology 2004; 40: 1387-95.  Nearly 1 in 3 in US have NAFLD.
  • -Clin Gastro Hepatol 2006; 3: 1260.   Alcohol and NASH are synergistically bad. (increase ALT)
  • -J Pedsiatr 2005; 147: 835.  Low adiponectin in children c NAFLD (lower than other overwt children).
  • -Surgery 2004; 135: 48-58.  Wt loss improves liver histology
  • -Gastroenterology 2005; 128: 1898.  Significant sampling variability (can lead to misdiagnosis)
  • -Hepatology 2005; 42: 44. NAFLD in 25% of pts c clinical liver dz & 20% of pts w/o suspected liver dz (n=3345, Italy)
  • -Clin Gastro & Hepatol 2004; 2: 1048 & 1059 (review/editorial) & 1107. pilot study of VIT E vs VIT E/pioglitazone, n=20.
    NASH in 3% lean, 20% obese, & ~50% morbidly obese.  100% of obese/diabetes have at least mild steatosis, 50% c NASH, & ~20% c cirrhosis.
  • -Hepatology 2004; 39: 770-78.  URSO probably doesn’t help NASH.
    -NEJM 2004; 351: 1147.  n=282 obese children; 11% mod obese c incr ALT, 21% of severely obese.
  • -JPGN 2004; 38: 48.  Rx c vitamin E &/or wt loss.  Both are helpful.
  • -J Peds 2003; 143: 500.  Fasting glucose/insulin, ALT/AST, and BMI are predictive of portal inflammation and fibrosis.  1-4% of all children have elevated transaminases (10-25% of all obese patients).
    HOMA-IR =fasting insulin (microU/ml)/ fasting glucose/22.5.  Insulin resistance is when HOMA-IR is greater than 2.  Fibrosis present in 63% of pts, n=43.
  • -JPGN 2003; 37: 342 (47A) use of metformin 500mg bid, n=10; 3 had transient diarrhea/abd pain. (50A) 3/40 children c NASH c early cirrhosis. 31 c portal fibrosis
  • -Gastroenterology 2003; 125: 1053-59.  Obesity increases risk of death due to cirrhosis.
  • -Clinical Gastro & Hepatology 2003; 1: 384-87.  Use of pioglitazone for NAFLD & obesity.
  • -Gastroenterology 2002; 123: 1702-4, 1705-25. AGA position statement and technical review.
  • -Gastroenterology 2003;124: 71-80.  increased ALT in 2.8% of population -mostly in overwt/obese.
  • -JPGN 2002; 36: 54-61.  With MRI,  21 of 22 (BMI>95th%) c elevated hepatic fat; those c abnl ALT, n=12, had more severe cases of fatty liver c fat content >18%.
  • -Ann Intern Med 1989; 111: 473-8.  Clinical dx of nonalcoholic fatty liver dz without Bx has only 59% predictive value.
  • -Gastroenterology 2004; 126: 1287-92.  Pts c elevated liver enzymes (NASH) are not at higher risk for statin hepatotoxicity.
  • -Gastroenterology 2002; 122: 1649-1657.  Review
  • -NEJM 2002; 346: 1221-1231. Review  AST/ALT ratio greater than 1 suggests increased fibrosis.  Consider bx if obese, greater than 45, type 2 DM, or increased AST/ALT ratio.
  • -Hepatology 2002; 35: 1485-93.  significant complications & decreased survival c obesity-related cryptogenic cirrhosis.  higher rates of progressive HCV & HCC c obesity.
  • -Gastroenterology 2001; 121: 710-724.  Review.
    Reasons for Liver Bx  1. poor correlation between clinical/lab findings & histology –thus for staging  2. assure correct dx; may be wrong in ~44%
  • -Clin Gastro & Hepatology 2004; 2: 262.  Coexistant DM worsens outcome in NASH.
  • -J Pediatr 2000; 136: 727. N=2450.  6% of overweight children with increased ALT, 10% of obese children.  1% of obese children with 2x normal.  50% of obese adolescents with alcohol ingestion (4 or more/month) had increased ALT.  Decreased antioxidants, elevated triglycerides, increased age, and increased hgbA1C were addt’l risk factors.
  • -Gastroenterology 2001; 121: 91-100.  HTN, insulin resistance, and ALT were predictors of fibrosis.
  • -J Pediatr 2000; 136: 734. N=11. Daily vitamin E 400-1200 IU/day noramalized ALT in patients c NASH.
  • -J Peddiatr 2000; 136: 739.  Ursodeoxycholic acid is not effective in NASH. N=31.
  • -J Pediatr 1999; 134: 132 & 160..  Low antioxidants with NASH

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