Nutrition in the Management of Nonalcoholic Fatty Liver

| January 21, 2010

by Jacqueline Jacques, ND

Bariatric Times. 2010;7(1):18–22

This is a CE-accredited article. Instructions and post-test are at the end of the article. A downloadable PDF of instructions and post-test are also available here.

Abstract
Non-alcoholic fatty liver disease, which includes nonalcoholic steatohepatitis, is common in patients qualifying for weight loss surgery. The enlargement of the liver due to fatty infiltration and, in the case of nonalcoholic steatohepatitis, inflammation can significantly interfere with the surgical field in weight loss procedures. This article reviews the diagnosis and treatment of nonalcoholic fatty liver prior to surgery, including weight reduction and pharmacologic therapies, with an emphasis on supportive nutrition.

Key words
Nonalcoholic fatty liver disease, NAFLD, weight loss surgery, nonalcoholic steatohepatitis, NASH, micronutrition, nutrition, probiotics

Introduction

Nonalcoholic fatty liver disease (NAFLD), which includes non-alcoholic steatohepatitis (NASH), is common in patients qualifying for weight loss surgery (WLS). Risk factors for NAFLD include obesity, diabetes, and insulin resistance. Of these, obesity is considered to be the greatest single risk factor. Incidence of NAFLD in patients with obesity or type 2 diabetes can be as high as 90 percent.[1] It is estimated that between 50 and 60 percent of preoperative bariatric surgery patients meet the diagnostic criteria for NASH.[2]

The enlargement of the liver due to fatty infiltration and, in the case of NASH, inflammation, can significantly interfere with the surgical field in WLS procedures. Obscuring of the surgical field, especially portions of the stomach, can prolong surgical times, increasing risk to the patient. Inability to retract the liver in a laparoscopic procedure is cited as the single most common cause for conversion to an open procedure, accounting for roughly half of such conversions,[3] according to some reports.

Diagnosis
Liver biopsy and histology are currently the only accurate ways to diagnose NAFLD. Precise, noninvasive screening for NAFLD and NASH in preoperative patients still has not been demonstrated. Laboratory studies have not proven to be accurate predictors. Amonitransferases (aspartate aminotransferase [AST] or alanine aminotransferase [ALT]) may be elevated, but can also be normal. The same is true for alkaline phosphatase, hyperlipidemia, and serum triglycerides. Elevated fasting insulin may be a more sensitive marker, especially if other evidence of insulin resistance exists (elevated triglycerides, hypertension, and central obesity). Some studies have shown elevated serum ferritin or serum iron to be a relatively common finding in NASH. If this is present, patients should likely undergo additional evaluation to rule out hemochromatosis.

Imaging studies can contribute to a diagnosis of NAFLD, but may be challenging or even impossible in larger patients. Ultrasound, computed tomography (CT), and contrast magnetic resonance imaging (MRI) can all identify fatty liver to some degree. The accuracy of ultrasound is significantly affected by the presence of fatty tissue.[4] Both CT and MRI are limited by patient weight and girth. CT weight limits are in the range of 425 to 450 pounds with a limit of 87 inches in body circumference; MRIs have a general weight range of 300 to 450 pounds and a body circumference limit of 74 inches. While open MRIs may accommodate larger patients, the image is weaker and less accurate for this diagnosis. See Table 1 for current definitions of NAFLD.

Because of the diagnostic challenges, coupled with high rate of occurrence, presumed diagnosis is not uncommon in programs wishing to implement precautionary interventions, such as preoperative weight loss. Some programs limit these interventions to patients with higher body mass index (BMI), greater waist circumference, or those meeting the diagnostic criteria for metabolic syndrome. A study conducted by Dixon et al5 in preoperative WLS patients found insulin resistance and hypertension—the diagnostic features of metabolic syndrome—to have a high association with more advanced cases of NASH in patients with morbid obesity. As patients who are both obese and meet the diagnostic criteria for metabolic syndrome are statistically most likely to have fatty liver, this may be the easiest, most cost-effective screen currently available.

Therapeutics
According to the American Association for the Study of Liver Disease clinical practice guidelines, “There are no published controlled trials of treatment modalities for NAFLD. It is, therefore, not possible to make any statements on relative risk of improvement with any modality. In the absence of treatment modalities of proven efficacy, therapy is directed toward correction of the risk factors for NASH (i.e., insulin resistance, decreasing delivery of fatty acids to the liver, and decreasing use of drugs with potentially hepatotoxic effects).”

It is important to keep in mind that in relation to WLS the intent of treating NAFLD is not for lifelong management of the condition itself but rather is to reduce liver volume such that the surgery itself is easier for the surgeon, with a lower risk of complications for the patient. The fact is that most emerging data on NAFLD in obesity point to surgery itself an important option (if not the best option) for treatment of this condition.

Weight reduction. Weight loss is the most widely accepted therapy for NAFLD, and many surgical programs are beginning to recognize that even small losses of body weight can eliminate close to 100 percent of liver concerns that relate to surgery. While some studies have linked rapid weight reduction to increased liver inflammation, this risk appears to be low in short-term, medically monitored conditions such as would be used in preoperative patients.[6] In their report titled “Effects of Weight Loss Surgeries on Liver Disease,”[7] Blackburn and Mun recommend that, “All WLS patients should be encouraged to lose weight prior to surgery. Those with a BMI of >50kg/m2 or such comorbidities as sleep apnea, type 2 diabetes, glucose intolerance, and hypertension should attempt to lose 5 to 10 percent of their initial weight.”

There is currently no agreement on the degree, duration, or method of weight loss for reduction of NAFLD in preoperative patients. A single study examined the effects of an eight-percent weight loss in women with obesity, insulin resistance, and high liver fat content compared to an equally obese control group. Weight was lost on a low calorie (600–800Kcal/day) formula diet, over a 2- to 3-month period. The group of women with high liver fat and insulin resistance demonstrated preferential loss of liver fat stores over loss of peripheral fat stores.[8] In those who do present with elevated liver enzymes, weight loss of 10 percent of total body weight has both normalized enzymes levels and reversed liver enlargement.[9] A 10-percent weight loss is also recommended by the National Heart, Lung, and Blood Institute-National Institute of Diabetes and Digestive Kidney Diseases (NHLBI-NIDDK).

This study and others have used low calorie formula diets with success. There is currently a substantial selection of formula diets available to clinicians. There is no substantial evidence that any one program would be of greater value for this purpose than any other. Factors such as cost to the patient (insurance does not usually cover the cost of product) and ease of use should be taken into account. It is advisable to seek products that are designed for medical use as meal replacements, as these products must meet specified formula requirements for nutritional content. Alternately, calorie-restricted food programs can be attempted, but there is less research to support their efficacy in the treatment of NAFLD.

Because evidence indicates that losing weight too rapidly may increase liver inflammation and, in rare cases, precipitate liver failure, the NHLBI-NIDDK advises that weight loss not exceed 3.5 pounds per week. Patients with morbid obesity often lose more rapidly than this in the early weeks of a low or very low calorie diet. Serological tests, including liver function tests, do not appear to be accurate for the assessment of liver inflammation in these patients.[10] Fortunately, the studies that have assessed these changes through biopsy generally report the majority of cases to show only slight worsening of inflammation or fibrosis, while still demonstrating significant hepatic fat loss.[11] With continued weight loss, which will occur after WLS, inflammation and fibrosis almost universally improve. Generally, clinicians should be aware of the risk and may consider increased frequency of visits with patients reporting more rapid weight loss. As more bariatric surgeons now routinely collect liver biopsies, we may eventually be able to compare the liver histology of patients who have undergone preoperative weight loss with those who have not. This data, when available, will allow us to understand the real risk (if present) to WLS patients.

Pharmacologic therapies. Drugs that improve insulin resistance, such as biguanides (metformin) and thiazolidinediones (rosiglitazone and pioglitazone), have drawn interest for the treatment of NAFLD, as have some lipid-lowering agents and ursodeoxycholic acid (UDCA). Metformin has been shown to lower liver enzyme levels in patients with NAFLD at a dose of 500mg three times daily.[12] Among early trials of thiazolidinediones, troglitazone had shown some promise before being removed from the market for, interestingly, liver toxicity. Similarly, rosiglitazone[13] and pioglitazone[14] have demonstrated improvement in small pilot studies. All of these agents likely deserve further study.

The lipid-lowering agent atorvastatin has been evaluated in NAFLD treatment, and early data indicate it may be of benefit for patients who have significant hypercholesterolemia.[15,16] Gemfibrozil has been shown to lower liver enzymes in NASH patients.[17] Potentially more promising is ursodeoxycholic acid (UDCA). A naturally occurring bile acid, UDCA was evaluated in a controlled trial in NASH patients and was associated with lowering of liver enzymes and decreased liver fat content.[18] However, a later randomized trial showed no significant benefit over placebo.[19]

Supportive nutrition. The use of natural therapeutics in the management of NAFLD and NASH has largely focused on hepatoprotective agents (Table 2). Use of substances that protect the liver and reduce liver inflammation may make sense in conjunction with weight loss, since increased liver inflammation is a known risk. It is believed that the increase in liver inflammation and fibrosis seen with more accelerated weight loss is likely due to rapid mobilization of free fatty acids. These fatty acids are metabolized through mitochondrial b-oxidation, which produces hydrogen peroxide and lipid peroxides—potent free-radicals. Individuals with NAFLD and NASH are already likely to have a higher degree of oxidative stress in the liver and higher levels of lipid peroxides. This additional, if only temporary, elevation in free fatty acid burden increases inflammation by placing further demands on an already stressed system.

Vitamin E. Vitamin E is a potent fat-soluble antioxidant known to effectively combat lipid peroxidation. Since lipid peroxides are thought to be primary in the pathogenesis of liver injury in NASH, several clinical trials have sought to validate the use of vitamin E in this condition. In an open-label trial in a pediatric population, a dose of 400IU of vitamin E was initiated at the start of a three-month trial. Vitamin E was increased by an additional 400IU each month when transaminases levels remained elevated. Five of 11 participants demonstrated normalization of enzymes after one month; an additional four participants demonstrated normalization after two months; and all 11 participants had returned to normal by the end of the third month. No changes in liver size or fatty infiltration were seen on ultrasound, indicating that the effect of vitamin E therapy was to reduce inflammatory changes only.[20] A more recent study of 28 children had similar results with a dosage of 100 to 400IUs.[21] A second study evaluated the combination of vitamin E with a weight reduction diet in 22 adults with obesity.[22] Presence of NAFLD or NASH was determined by biopsy. After six months of weight loss, 300IU per day of vitamin E was added for 12 months. At the end of this time, repeat biopsies demonstrated significant improvement in both inflammation and fibrosis in 5 of 12 patients and decreased steatosis in an additional four. The inflammatory marker transforming growth factor-b1 (TGF-b1) was found to be unchanged with weight loss alone, but significantly reduced after vitamin E therapy.

Vitamin E with C. Several studies have sought to evaluate the combination of high-dose vitamin E and C in NASH with mixed results. Vitamin E and vitamin C are nutrient synergists. When vitamin E neutralizes a free radical and, in turn, generates the potent tocopherol radical, vitamin C is one of the antioxidants that can regenerate vitamin E to the non-radical state. A 2003 study placed 45 patients with NASH (diagnosed by biopsy) on a weight loss regimen together with 1000IU of vitamin E and 1000mg of vitamin C.[23] After six months, repeat histology demonstrated significant reduction in liver fibrosis, yet liver enzymes remained unchanged. Of two small additional trials, only one was able to reproduce similar results.[24] It is uncertain why the researchers chose to use such a high dose of vitamin E, given that the successful trials (cited previously) used much lower doses. The risk of excessive vitamin E is creation of very high levels of tocopherol radical, which may itself act as a free radical and inflammatory agent. Since the exact dose of vitamin C needed to recycle this amount of vitamin E cannot be accurately predicted, it may have been more logical to use a dose of vitamin E already known to produce desirable results in NASH. Hopefully, future studies will give greater consideration to antioxidant homeostasis.

N-acetylcysteine (NAC). N-acetylcysteine is a sulfur-containing antioxidant and is the primary precursor to hepatic glutathione. NAC is a well established hepatoprotective agent and is best known in the medical world for its therapeutic use as an antidote to acetaminophen-induced liver toxicity. One small, three-month trial of 1000mg per day of NAC showed markedly lowered transaminase levels in patients with NASH.[25] NAC has also been shown to benefit insulin sensitivity at doses of 1.8 to 3 grams per day.[26] NAC is an extremely safe antioxidant with well understood pharmacokinetics. The LD-50 is greater than 6000mg/kg in rodent models, and no teratogenic evidence has been seen at doses as high as 2000mg/kg in animal fertility studies.[27] More studies of NAC in NAFLD should be considered.

Betaine and SAMe. Betaine, also known as trimethylglycine, is a natural metabolite of choline. Betaine is known to act as a methyl donor and is able to raise levels of S-adenosylmethionine (SAMe). It is also one of the nutrients, along with B12, folate, and B6, that can recycle homocysteine back into methionine in the liver. High homocysteine is found commonly in patients with metabolic syndrome and is often found to be elevated in NASH.[28] Past studies have shown much promise for the use of SAMe in alcoholic liver disease.[29] One small trial in 10 patients with NASH followed both biopsies and liver enzymes in patients taking 20 grams per day of a betaine oral solution for one year. Significant reductions were seen in enzymes levels, as well as in fibrosis, inflammation, and fatty depositions in the liver.[30] Hypothetically, the use of SAMe itself might also prove effective. Other nutritional methyl donors, such as folate or vitamin B12, may hold potential, especially inpatients with high homocysteine.

Other possible therapeutic agents. Pantethine. Pantethine is a natural derivative of pantothenic acid (vitamin B5). Pantethine is marketed in both Europe and Asia as a therapeutic agent for lowering cholesterol and triglycerides; in the United States it is considered to be a dietary supplement. Daily doses of 600 to 1200 milligrams have been demonstrated to effectively lower total cholesterol, low density lipoprotein (LDL) cholesterol, apolipoprotein B, and tryglicerides.[31,32] Some studies have also demonstrated elevated HDL.[33] Sixteen patients presenting with both NAFLD and elevated triglycerides were given 600mg of pantethine for six months.[34] Evaluation using abdominal CT scan showed complete resolution of fatty liver at the end of the study. Researchers found a corresponding increase in subcutaneous fat and hypothesized that fat mobilized from the liver and viscera was redistributed to subcutaneous deposits.

Omega-3 fatty acids. The omega-3 fatty acids, eicosapentanoic acid (EPA) and docosahexanoic acid (DHA), from fish oil have proven to be helpful in the management of dyslipidemias, especially in high triglycerides.[35] Therapeutic doses for lowering triglycerides fall between 2 and 4 grams of fish oils per day.[36] In a trial that compared use of omega-3 fats to atorvastatin and orlistat in patients with NAFLD and hyperlipidemia, 23 patients were placed into the omega-3 arm. Patients were selected for this therapy if they presented with primary hypertriglyceridemia. For 24 weeks, participants took 5mL of an omega-3 oil containing 751mg of EPA and 527mg of DHA. After 24 weeks, all patients had reductions in triglycerides, cholesterol levels, and liver enzymes. Thirty-five percent of the omega-3 group reverted to normal findings on ultrasound (compared to 86% of patients receiving orlistat and 61% of those on atorvastatin). Given the overall health benefits of omega-3 fats and the short duration in which improvement was seen, this would appear to be a potentially useful intervention in appropriate patients. A review article published in late 2009 found that animal and human studies to date support the use of omega 3 fatty acids in NAFLD.[47] The authors also pointed out that current human trials are largely open label and that rigorous randomized, blinded and placebo controlled trials are now needed to confirm these findings.

Probiotics. Probiotics are beneficial microorganisms that reside in the digestive tract and are thought to play a role in digestive health and immunity. Probiotics have long been available as dietary supplements and can be obtained from cultured foods like yogurt. Common strains include Bifidobacterium bifidum, Bifidobacterium longum, Lactobacillus acidophilus, Lactobacillus casei, Lactobacillus ruterii, and Saccharomyces boulardi.

Interest in the use of probiotics to treat NAFLD has a historical connection to WLS and the now obsolete jejunoileal bypass (JIB) procedure. JIB fell from medical favor due to the high risk of developing complications, including diarrhea, night blindness, osteomalacia, protein-calorie malnutrition, and kidney stones. However, the worst complications, including inflammatory arthritis, dermatitis, malaise, and serious liver pathology (ranging from steatosis to liver failure), were caused by overgrowth of toxin-producing bacteria in the gut.[37] It was realized that in some of these cases, liver damage could be reversed through the use of metronidazole to kill the abnormal flora.

Medically, the presence of these abnormal flora is referred to as small intestinal bacterial overgrowth (SIBO). Later animal models of SIBO produced hepatic lesions identical to those found both in JIB patients and in patients with NASH.[38] It is now proposed that endotoxins produced by SIBO create liver inflammation and injury through the production of pro-inflammatory cytokines (namely TNF-a) and the promotion of free radicals. A 2001 study in NASH patients confirmed that half of them had findings for SIBO compared to 22 percent of controls.[39] A study in a rodent model of NASH used probiotics or TNF-a antibodes and found improved liver histology and lower liver enzymes in both groups. It is believed that therapeutic use of beneficial probiotics can restore normal floral balance to the intestines, thereby eliminating toxin-producing species.
Currently the National Institutes of Health is funding a phase II clinical trial at Johns Hopkins University to evaluate the efficacy of probiotics in humans with NASH.

Milk thistle. The herbal medicine milk thistle is known by the botanical names Silybum mariabum (var. albiflorum). Medical herbalists use the term Silymarin to refer to both species. Most commercial products sold in the United States are standardized for content of the flavonoid silybin, a well-studied hepatoprotective agent. Silybin is believed to act primarily as a potent antioxidant and cellular protective agent. It has been shown to protect liver cells from a long list of negative effects resulting from iron, alcohol, carbon tetrachloride, radiation, acetaminophen, and ischemic injury.[40]

Silybin has been shown to be effective against a wide range of liver toxins. Most notably, it is known to be able to prevent liver destruction caused by poisoning from Amanita phalloides mushrooms (Fly Amanita, Death Cap). In a series of 41 mushroom poisonings treated within 48 hours with silymarin, there were no deaths.[41]

Silymarin has been well-evaluated in trials with alcoholic liver disease. At doses of 240 to 420mg per day, significant improvements in both histology (fibrosis) and serology (AST, ALT, GGT, bilirubin, and alkaline phosphatase) are seen.[42–44] Silymarin also has demonstrated anti-inflammatory[45,46] and antifibrotic[47] effects in hepatic tissue.

For all of these reasons, researchers studying NASH have taken an interest in this herbal medicine. Currently, investigators at the Mayo Clinic Foundation are working on a phase II, open-label, pilot study of silymarin in patients with NASH. They will study 30 NASH patients taking doses of 600mg of silymarin standardized extract for two years. Until these results are available, it is not known if silymarin will prove effective for NASH as it has for other liver concerns.

Conclusions
NAFLD is a common occurrence in patients presenting for WLS, which can prolong or complicate surgery. Modest preoperative weight reduction should be able to eliminate most concerns of liver size and retraction. Natural therapeutics may additionally benefit the health of patients by reducing associated risk factors, including inflammation, fibrosis, and hypertriglyceridemia. When looking at overall patient wellbeing, it may prove beneficial to selectively incorporate these therapies for use if indications are present.

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Funding:
There was no funding for this article.

Financial disclosure:
Dr. Jacques is Chief Science Officer for Catalina Lifesciences LLC.

Author affiliation:
Dr. Jacqueline Jacques is a Naturopathic Doctor with more than a decade of expertise in medical nutrition.  Dr Jacques has spent much of her career in the dietary supplement industry as a formulator, speaker, writer and educator.  She is the Chief Science Officer for Catalina Lifesciences LLC, a company dedicated to providing the best of nutritional care to weight loss surgery patients.

Editors Note:
This CE-accredited article was excerpted from Micronutrition for the Weight Loss Surgery Patient by Dr. Jacqueline Jacques. Copyright © 2006 Matrix Medical Communications • 148 pages • ISBN 0976852624

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