The Fatty Inflamed Liver

The obesity epidemic in the UStoday, whereby 70% ofthe populationis now overweight, obese, or grosslyobese, has dangerous implicationsfor hepatic health in our country.The most commonly diagnosed liverdisease in the US is nonalcoholicfatty liver disease (NAFLD), whichcan progress to nonalcoholicsteatohepatitis (NASH).' NAFLD alsois the main reason that patients haveelevated hepatic function tests in theUS.

PathophysiologyThe liver typically contains

about 57o fat, and when the amountincreases to 107o, or the liver isdefined as having steatosis, this is afatty liver. If this is not due to alcoholintake, it is termed NAFLD. Whenpatients have abdominal fat, there isa regular flow of free fatty acids tothe liver. This innately is a benigncondition that causes macrovesicularfat accumulation in the liver, wherebyfat in the hepatocyte, the liver cell,displaces the nucleus to the edgeof the cell and risks causing thehepatocyte to burst.

In stage 2 of this condition, whenit advances, the patient developsNASH. The inflammation developsdue to lack of antioxidants and"ballooning degeneration" (BD). BDoccurs when the swollen hepatocytesburst, which attracts lymphocytes andother inflammatory cells that releasecytokines, TNF-alpha, interleukins,hydrogen peroxides, and Superoxides,causing hepatocellular damage, whichover the years can destroy the liver.In fact, the three main reasons that

by Dr. Mona Morstein

the liver develops scarring, fibrosis,cirrhosis, and failure, requiring livertransplantation, are alcohol use,chronic hepatitis C, and NASH.̂

NAFLD StatisticsApproximately 30% of the US

population in all ages has NAFLD;37o has progressed to NASH. It isseen most in Caucasian and Hispanicpatients, but occurs in all races.It's closely connected to metabolicsyndrome. In fact, more than 907oof NAFLD patients have at least oneof these problems: obesity, insulinresistance, impaired fasting glucose,elevated triglycérides, elevated LDLcholesterol, hypertension. 337o ofNAFLD patients have at least threeof those features associated withmetabolic syndrome. In the reverseview, patients with metabolicsyndrome have a 3 times greater riskof developing NASH and fibrosis.NAFLD is seen in 707o of type 2diabetic patients, and up to 207o ofthese patients with NAFLD/NASHdevelop cirrhosis. Last, specificallyregarding obese patients, 707o to 807oof obese patients and up to 1007oof morbidly obese patients haveNAFLD.3

NAFLD EtiologyThe main etiological risk factorfor developing NAFLD is insulinresistance, especially in theoverweight or obese patient."

There are many causes of NAFLDoutside obesity and insulin resistance.The other risk factors for developingNAFLD include:

• fulminant or chronic hepatitis,usually C;

• drugs used for more thansix months: valproic acid,corticosteroids, tamoxifen,estrogens, methotrexate;

• environmental factors: organicsolvents, PCBs, petrochemicals,dimethylformamide;

• metabolic abnormalities:galactosemia, glycogen storagedisease, homocystinuria, Wilson'sdisease, hemochromatosis;

• nutritional status: overnutrition,starvation diet, total parenteralnutrition, protein energymalnutrition, celiac disease/malabsorption syndromes, vitaminA toxicity

• surgery: bariatric surgery causingrapid weight loss;

• conditions: alpha-! antitrypsindeficiency, hyper- orhypothyroidism, primary biliarycirrhosis, primary sclerosingcholangitis.^

NAFLD/NASH Signs and SymptomsIn the majority of patients, patients

present asymptomatically, and it's theinitial labs that uncover the NAFLD.Some patients can feel fatigue ormalaise, but identifying that as solelyfrom NAFLD is difficult, as patientspresent with obesity, poor diet intake,lack of exercise, and other factorsthat in themselves could cause poorenergy and stamina.*"

Signs of NAFLD/NASH mayinclude: BMI >30; insulin resistancesigns such as acanthosis nigricans,skin tags, waist measurement.

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Fatty Inflamed Liver

hypertension, high triglycérides;abdominal fat; hepatomegaly;splenomegaly; signs of cirrhosissuch as spider angiomas, esophagealvarices, gynecomastia, ascites,jaundice.

DiagnosisOf course, basic blood work would

likely pick up insulin resistance andmetabolic syndrome, as mentionedabove. However, there are lab valuesmuch more specific to NAFLD/NASH.

Usually the very first lab resultelevated indicating that NAFLD hasdeveloped is serum ferritin.'' Serumferritin is elevated for three mainreasons - hemochromatosis, bacterialinfection, or as an acute inflammatorymarker. In its latter role it is elevatedwith fatty liver. A physician shouldalways include ferritin in a basicblood work panel, and if it is elevatedin a patient, rule out severe bacterialinfection by patient presentation,and rule out hemochromatosis via aniron panel. If the percent saturation isnormal, that genetic condition is ruledout. The next step would be to do anabdominal ultrasound.

Other lab values that may beelevated include GGT, although inmy experience, ferritin is elevatedmuch more often than GGT. If NASHis developing, then one might seeALT (alanine aminotransferase) andAST (aspartate aminotransferase)elevation; but for NASH, ALT > AST.Elevated aminotransferase enzymesdo not correlate with intensity ofNASH. In those cases, one wouldalso have to rule out chronic viral orautoimmune hepatitis conditions (orother etiological factors), as well asalcoholism.

Some labs also do blood work tohelp discern if the liver has developedfibrosis, as otherwise occasionally apatient must undergo a liver biopsy.These tests, such as FibroSpect II fromPrometheus Labs or FibroSure fromLabCorp, measure various biomarkersthat are used to help interpret if there

is no/mild or severe fibrosis; theyare both poor in the middle-groundinterpretation, if there is moderatescarring.

The abdominal ultrasounddiscerns fatty liver when at least 15%fatty content exists, but it cannotdifferentiate NAFLD from NASH.The lab report will read positiveechogenic areas consistent withfatty liver. Neither a CT scan norMRI is helpful in further diagnosis. Iffurther understanding of liver tissueis required, to know the cellularhealth of the hepatocytes, the goldstandard is a liver biopsy, which thengrades (macrovesicular steatosis 0-3;necroinflammatory activity 1-3) andstages (fibrosis 1-3; cirrhosis) the livertissue.*''

NAFLD/NASH PrognosisWhen a patient has NAFLD, 30%

will progress to NASH, 30% willremain stable, and 30% will improvewithout pharmacologie intervention.NAFLD is reversible if the liver is notyet cirrhotic. An article in Hepatologyjournal proved that patients who lost5% or more of their body weightover nine months had improvementin insulin resistance and loss of fattyliver. The Southern Medical Journalhad a study showing that reversal offatty liver was seen based on exercise,weight loss, and the completeavoidance of alcohol. ^°

Treatments for NAFLD/NASHStandard Allopathic Care

There is not standard treatmentspecific for NAFLD/NASH. Alcoholis avoided, weight loss is advocated,exercise is recommended, andbariatric surgery is considered forparticularly grossly obese patients.

The most important aspect ofcontrolling fatty liver and reversing itis weight loss. However, weight lossmust occur slowly - rapid weightloss or starvation diets or bariatricsurgery can worsen NASH and leadto cirrhosis and liver failure. Rapid

weight loss is defined as > 3.5 Ib (1.6kg) a week, with the ideal weight lossfor effectiveness and hepatic safetybeing 1 to 2 Ib/week. In this way, theliver is not flooded with a massiverelease of free fatty acids and theirinflammatory irritation.^'

MDs have used various pharma-ceuticals, such as thiazolidinediones,but those are pretty much oft themarket due to established side effectsof their usage. Other drugs, suchas Glucophage (metformin), Byetta(exenatide), statins, antiobesity drugs,and ursodeoxycholic acid, have beentried with various degrees of success.

Bariatric surgery has included bothgastric banding, which regressedNASH, and the more extreme Roux-en-Y, which reversed fatty liver in897o to 1007o of patients but causeddumping syndrome, stomach staplefailure, nutritional deficiencies, bowelcomplaints, follow-up operations,osteoporosis, infections and ulcers,deep vein thrombosis, stomal stenosis,and cholelithiasis, among otherchronic conditions. The last surgeryperformed is a liver transplantationin fully cirrhotic patients with liverfailure.'^

NaturopathidAlternative CareThe best regimen to control insulin

resistant in our overweight and obesepatients is a low-carbohydrate, low-glycemic diet. The recommendeddiet by the Nutrition and MetabolismSociety, it was confirmed to havepatients burn more calories in a recentstudy.''''" This diet consists of:

1. few or no grains - patients can eatshiritaki noodles, alternative grainsmade from almond flours, ftaxcrackers;

2. vegetables - excluding thehigh-carbohydrate ones such aspotatoes, sweet potatoes, yams,carrots;

3. some fruit, excluding bananas andfocusing on berries;

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Fatty Inflamed Liver

4. proteins - beans/peas/legumes,seeds/nuts, non-GMO soy,omega-3 organic eggs, grass-fed-finished organic animal products,fish (excluding the ones on theEnvironmental Working Groupstoxic list), organic dairy andalternative unsweetened dairyproducts;

5. oils: organic butter, unrefinedorganic olive oils, unrefinedorganic coconut oil,monounsaturated high oleicsafflower oil, avocado oil, walnutoil, flax oil (raw). The focus shouldbe on increasing omega-3 oils,from leafy greens, walnuts andwalnut oils, flaxseeds and flaxseedoils, oily fish, omega-3 eggs, grass-fed and -finished organic meal andpoultry;

6. beverages: water, herbal teas,green/black tea, sparkling water,coffee or coffee substitutes,green/vegetable juices, proteinsmoothies, unsweetenedalternative milks (soy, almond,hemp, coconut, hazelnut).

7. sweeteners: stevia, erythritol,xylitol (found in beverages such asZevia, Virgil's Zero, Blue Sky Free)

Diets high in saturated fat, softdrinks, and meat, and low in fruits,vegetables, antioxidants, and omega-3-containing fish increase the risk ofdeveloping NAFLD/NASH.'=

Due to the liver inflammation,absolutely no alcohol can be ingested.Alcohol intake is the largest abuserof the liver and expedites furtherdegeneration and damage. Otherfoods to avoid include the obvious:refined sugar, particularly high-fructose; fast foods; very processedfoods; excessive caffeine. Foodsto increase include the cruciferousvegetables: broccoli, cauliflower,brussels sprouts, cabbage, kale, andso on, which with their elevatedsulfur content promote detoxificationof the liver. Also, the liver respondspositively to "bitter" foods, such asarugula, cauliflower, chicory (in coffee

substitutes), and dandelion greens,which should be included in the dietas well. Hydrotherapy techniquessuch as castor oil packs over theliver area as well as "constitutionalhydrotherapy" as created and usedby naturopathic physicians are alsohighly recommended.

Exercise is required to encourageweight loss, lower glucose and lipidlevels, decrease insulin resistanceand hyperinsulinemia, help sleep,improve mood, and increase bowelmovements. Exercise lowers therisk of NAFLD, by reducing hepatictriglycéride concentration.^''""' Onehour five days a weeks of mixedaerobic with resistance/weightwork is suggested. Physicians needto analyze if their patients need acardiac evaluation before engaging inexercise. Personal trainers should beused to help learn proper ergonomicswith the weight machines.

Sleep is vital. A NHANES studyshowed that the risk of obesityincreased 2357o for those who didnot get more than 5 hours of sleepa night.^' Also, if patents are notsleeping well or are very tired all daylong, a sleep apnea study should beconsidered. Sleep has a marked effecton appetite-controlling hormones.Having the patient get 7 to 9 hoursof good sleep each night lowersghrelin, a hormone associated with anincreased appetite for carbohydrates,so that patients eat less in generaland do not crave carbohydrates. Itincreases leptin, a hormone whichlowers the appetite, so that patientsnaturally desires to eat less. It lowerscortisol, which reduces the risk ofabdominal weight gain.

Given the analysis of a patient, aninvestigation into how "toxic" he orshe may be is a good idea. Chemicalsknown to cause insulin resistanceinclude bisphenol A, Teflon, andphthalates. Arsenic and lead havebeen shown by the WHO to causeinsulin resistance.̂ "

Other analyses are recommended.Checking vitamin D3 levels is good.

as well as F/T testosterone, particularlyin middle-aged men on statin drugs,in whom studies have shown thatstatins lower testosterone production.Also, a thyroid panel includingTSH, Ft3, Ft4. And a saliva analysisof morning, noon, afternoon, andevening cortisols and DHEA-S couldbe helpful, although since abdominalweight produces intracellular cortisol,which may have some systemic effect,cortisol measurements may not reallybe able to discern abdominal vs.adrenal hypercortisolism.

There are many supportivesupplements used to help theliver when it is fatty and inflamed.Supplements can have many benefitssuch as:

• support for correcting nutrientdeficiencies

• support for encouraging weightloss

• antioxidant and anti-inflammatoryprotection

• appetite control• support for lowering glucose and

insulin• support for lowering hypertension

and lipids• decreased risk of diabetes and

diabetic complications

In general, supplements shouldhelp reduce insulin resistance andprovide antioxidant protection as twomain treatment foci.

Supplements associated withreducing insulin resistance include:

1. chromium: 200-1200 meg/day2. zinc: 15-50 mg/day3. vitamin D: as per individual

requirements4. increased fiber5. Cymnema sylvestre6. Momordia charantia

Supplements associated withprotecting the inflamed liver byreducing AST/ALT, inhibit cytokineexpression, inhibiting fibrosis,inhibiting mitochondrial injury,preventing lipid peroxidation:

TOWNSEND LETTER - NOVEMBER 2012 57

Fatty Inflamed Liver

1. R-alphalipoicacid^^: 600-1000mg/day; also reduces insulinresistance

2. selenium^': 200-600 meg/day3. milk thistle'^: 200-400 mg/day^^4. N-acetylcysteine: 1200-1800

mg/day; also reduces insulinresistance "

5. mixed carotenoids, mixed vitaminE, vitamin C

6. probiotics7. licorice"8. curcumin and resveratrol9. green tea "̂'̂ ^10. Cordyceps sinensis^^: 1 g three

times a

Patients should be clearly told thatNAFLD and NASH are reversible liverconditions. No one has to developcirrhosis from them, ever. Losingthe weight is the first and foremostmethodology for curing theseconditions. Ensuring that the weightloss is slow and antioxidant protectionis well established are vital aspectsof a safe and responsible treatmentprogram. Follow-up proof of improvedliver status can be elicited by thenormalizing of the AST/ALT/ferritin/GGT lab numbers, and liver U/s

showing nonechogenicity illustratingthe classic fatty liver. Regular follow-ups, support and encouragement, andtroubleshooting will make the journeytoward a healthy liver reasonable andattainable.

Notes1. Sears D, Katz J. Fatty liver [online article].

Medscape. http://emediclne.medscape.com/article/1 75472-overview#showa[l.

2. Yeh M, Younes M. Pathology of nonalcoholicsteatohepatitis [online article]. Medscape. http://emedicine.medscape.com/art¡cle/2038493-overview#showal I.

3. Sears et al. Op cit.4. de Alwis NMW, Day C. Non-alcoholic fatty liver

disease: the mist gradually clears. I Hepatol.2008;48:S104-S1l2.

5. Sears et al. Op cit.; Wieckowska A, CareyWD. Nonalcoholic fatty liver disease [onlinearticle]. Cleveland Clinic. http://www.clevelandcl inicmeded.com/medicalpubs/diseasemanagement/hepatology/nonalcoholic..fatty-liver-disease.

6. Sumida Y, Nakashima T, Yoh T, et al. Serumthioredoxin levels as a predictor of steatohepatitisin patients with nonalcoholic fatty liver disease. /Hepatohgy. 2003 )an;38(1):32-38.

7. Wieckowska et al. Op cit.8. Sears et al. Op cit.9. Wieckowska et al. Op cit.; de Alwis NMW. Op cit.10. Rich HG. Resolution of focal fatty infiltration ofthe

liver. South Med I. Oct 1996;89:10:1024-1027.11. Cleveland Clinic. Op cit.12. Clark JM et al. Roux-en-Y gastric bypass improves

livery histology in patients with non-alcoholic fattyliverdisease. Obes Res. 2005 Jul;13(7):l 180-1186.

13. Nutrition and Metabolism Society [website], http://www.nmsociety.org.

14. Ludwig D. Effects of dietary composition on energyexpenditure during weight-loss maintenance.MM/\.]une2012;37O7:206-22O.

15. de Alwis NMW. Op cit.16. ]ohnson N, Sachinwala T, Walton DW, et al.

Aerobic exercise training reduces hepatic andvisceral lipids in obese individuals without weightloss. Hepatology. 50(4).

17. I Cardiopulm Rehab. 2002;22; Physician SportsMed. 1999;27(10).

(8. Physician Sports Med. 1999;27(10). Arct] InternMed. 2004;164:31-39.

19. Gangwisch ] et al. Inadequate sleep as a risk factorfor obesity: analyses of the NHANES I. 5/eep.2005;28(10).

20. Tseng CH. The potential biological mechanismsof arsenic-induced diabetes mellitus. ToxicolAppI Pharmacol. 2004 ]un 1;197(2):67^83.Abstract available at http://www.ncbi.nlm.nih.gov/pubmed/15163543

21. Berkson BM. A conservative triple antioxidantapproach to the treatment of hepatitis C. Med Klin(Munich). 1999 Oct 15;94 SuppI 3:84-89. Abstractavailable at http://www.voy.eom/l 7059/189.html.

22. Baumgardner | et al. NAC Attenuates progressionof liver pathology in a rat model of NASH. / Nutr.2008. Abstract available at http://jn.nutrition.org/cgi/content/abstract/138/10/1872.

23. Zhang L, Wu X. Prevention of free fatty acid inducedhepatic lipotoxicity by 18beta-glycyrrhetinic acidthrough lysosomal and mitochondrial pathways,Hepatology. 2008 jun;47(6):1905-1915. http://www.ncbi.nlm.nih.gov/pubmed/18452148.

24. ]in XI et al. green tea consumption and liver disease.Liver Int. 2008;28(7):990-996. Available at http://www.medscape.com/viewarti cl e/578882_1.

25. Bruno RS, Dugan CE, et al. Green tea extractprotects leptin-deficient, spontaneously obesemice from hepatic steatosis and injury. / Nutr. Feb2008;138:323-331.

26. Silymarin as therapy of liver disease. NIDDK,NCCAM, and NIAAA seminar. March 2004.Available at http://www2.niddk.nih.gov/NR/rdonlyres/0AECDEC8-10B4-47Al-A7BA-0939D1050E5 3/0/DDICC_March_2 2_2004_workshop_summary.pdf.

27. Mycology News. 1(9).

Dr. Mona Morstein is a naturopathic physician. She is chair of nutrition, gastroenterologyprofessor, and clinical supervisor at Southwest College of Naturopathic Medicine,Tempe, Arizona. Dr. Morstein has a generalized practice seeing all ages, both genders,and acute and chronic disease, but she does focus on prediabetes and diabetes,gastroenterological conditions, and women's health. Dr. Morstein frequently lectureson diabetes and gastroenterological conditions in North America. She has created theInsulin Intensive Seminar, a two-day conference wherein medical professionals andstudents learn a comprehensive program of using insulin with all types of diabeticpatients in all situations.

m.morstein(@scnm.edu

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