Impact of Nutrition and Obesity o n C h ro n i c Li v e r D i s e a s e Vignan Manne,

MD

a

, Sammy Saab,

MD, MPH, AGAF

a,b,

*

KEYWORDS  Malnutrition  Obesity  Chronic liver disease  Protein-calorie malnutrition  Nonalcoholic fatty liver disease KEY POINTS  The liver is a central organ in total body nutrition, playing a role in the metabolism of all major macronutrient groups as well as multiple micronutrients  Malnutrition has been implicated in causing liver disease and is a common complication, seen in up to 90% of patients with liver disease.  Obesity is associated with the formation of nonalcoholic fatty liver disease (NAFLD), considered to be the hepatic manifestation of metabolic syndrome, and has been shown to be a risk factor for progression of chronic liver disease.  Assessment of nutritional status is still a topic of debate, but measures commonly used include clinical signs, blood tests, and anthropometric assessments such as hand-grip strength.  The management of obesity and malnutrition is important, as it has been shown to increase insulin sensitivity, decrease hepatic steatosis, and have a positive impact on the management of other liver diseases.

INTRODUCTION

Malnutrition, or undernutrition, and obesity are at opposite ends of a spectrum that has an enormous impact on all aspects of liver diseases. Patients with chronic liver disease develop some form of malnutrition that becomes more recognizable as the liver disease progresses.1–3 Cases of malnutrition can be found in 65% to 90% of all patients with advanced liver disease and in almost 100% of liver transplantation candidates.4,5 Specific micronutrient deficiencies are common in patients with liver disease, albeit less obvious than signs seen in protein deficiencies such as muscle wasting.6

a

Department of Surgery, University of California, Los Angeles, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095, USA; b Department of Medicine, University of California, Los Angeles, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095, USA * Corresponding author. Pfleger Liver Institute, UCLA Medical Center, 200 Medical Plaza, Suite 214, Los Angeles, CA 90095. E-mail address: [email protected]

Clin Liver Dis 18 (2014) 205–218 http://dx.doi.org/10.1016/j.cld.2013.09.008 1089-3261/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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Micronutrients, such as fat-soluble and water-soluble vitamins or various minerals, which are seen to be deficient in liver disease, lead to unique complications based on specific deficiencies.7–13 These micronutrients and other nutrient deficiencies are being increasingly recognized as sequelae of liver disease.14,15 At the opposite end of the spectrum, obesity has also been shown to have significant effects on different stages of liver disease. The rate of obesity in the United States has been increasing over the past 3 decades. Obesity in adults has more than doubled in the period between 1970 and 2008, from 15% in the 1970s to 35% in 2008.16 Equally important, obesity has almost tripled in the pediatric population from 15% in the 1970s to 48% in 2008.16 These trends have been used to explain the exponential increase in nonalcoholic fatty liver disease (NAFLD) as a common cause of liver disease worldwide in both adult and pediatric populations.12,17 Not only does obesity cause fatty liver, it also has been shown to increase morbidity and mortality in other existing liver conditions such as viral hepatitis or liver transplantation, and weight loss by itself has been shown to improve treatment outcomes in various hepatic conditions.18 Indeed, morbid obesity is seen as such a poor prognostic factor for liver transplantation that many transplantation centers use a cutoff value above which they will not consider such candidates. The myriad effects of the opposing ends of the nutrition spectrum have led to a wealth of research aimed at elucidating the exact mechanisms of how they cause liver damage. In this article, the role of the liver in nutrient and energy metabolism is discussed, as well as the known and possible effects of specific nutrient deficiencies and obesity. ROLE OF THE LIVER IN NUTRIENT METABOLISM

In metabolism, the liver serves as an intermediary between dietary and endogenous sources of energy and the extrahepatic organs that use such energy.19 The liver accomplishes this role by contributing to the synthesis, storage, or breakdown of most of the major macronutrients used by the body. In Western society these major macronutrient groups include carbohydrates, fats, and protein, and the major micronutrient groups include electrolytes, trace elements, and vitamins.20 The liver also plays a role in the transport and storage of multiple micronutrients, and has various other functions (Table 1). Gluconeogenesis, cholesterol synthesis, fatty acid oxidation, amino acid oxidation, ureagenesis, and bile acid production comprise just a fraction of the many functions performed by the liver.19,21–23 The heterogeneity of these functions requires the liver to be organized in a heterogeneous pattern, allowing for different areas of the liver to specialize in a few of these functions so that other sites can specialize in various other functions.24 MALNUTRITION AND CHRONIC LIVER DISEASE

The fundamentals of how malnutrition occurs in and causes liver disease are 3-fold in nature. Chronic liver disease increases the energy and nutritional requirements of the body because liver disease can induce a hypermetabolic state that increases the resting expenditures of the body.25–31 Patients with liver disease also have issues with increased nutrient losses from the body because of malabsorption resulting from decreased bile production, diarrhea, or other causes (Table 2). The third fundamental cause of malnutrition in patients with liver disease arises from patients having either a decreased intake of nutritional substances or an absolute decrease in food intake.32,33 Mechanisms through which patients have decreased dietary intake are

Impact of Nutrition and Obesity on CLD

Table 1 Role of liver in metabolism Nutrient Group

Select Liver Functions

Protein

Synthesis of plasma proteins (transferrin, albumin, ceruloplasmin, etc) Deamination of amino acids to make urea Transamination and synthesis of amino acids Oxidation of amino acids

Carbohydrates

Gluconeogenesis Glycogenesis Glycogenolysis

Fat

Production of bile for solubilization and fat storage Synthesis of cholesterol and triglycerides Uptake and oxidation of fatty acids Synthesis of lipoproteins

Vitamins

Uptake and storage of multiple vitamins (A, D, E, B12, K) Enzymatic activation of vitamins (B6, B1, D, folic acid) Vitamin transport (A, B12, etc) through carrier proteins synthesized by liver

Minerals

Storage site for multiple minerals (zinc, iron, copper, etc)

Table 2 Select nutrient deficiencies and their relation to liver disease Nutrient Group

Relation to Liver

Some Associated Signs/Symptoms

Protein

Decreased synthesis and transportation in liver disease

Muscle wasting Edema/ascites

Fat

Decreased absorption in liver disease

Scaly skin Soft/brittle nails

Vitamins Vitamin B1 (thiamine)

Increased requirement in liver disease, Cheilosis especially alcoholic liver disease

Vitamin B6 (pyridoxine) Increased degradation in liver disease Weakness Vitamin B12 (cyanocobalamin)

Malabsorption seen in liver disease

Neuropathy

Folate

Deficiency seen in liver disease

Anemia

Fat-soluble vitamins (A, D, E, K)

Malabsorption in liver disease

Night blindness Keratosis Osteoporosis Neuropathy Increased risk of bleeding

Zinc

Malabsorption and increased requirement in liver disease, thought to be a risk factor for encephalopathy52,53

Risk of infections Taste and smell changes Slow wound healing

Magnesium

Deficiency seen in liver disease

Taste changes

Minerals

Data from Morrison S. Clinical nutrition physical examination. Support Line 1997;19(2):16–8; and Jeejeebhoy KN. Nutritional assessment. Gastroenterol Clin North Am 1998;27(2):347–69.

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attributed to a multitude of factors, ranging from simple nausea and loss of taste to early satiety secondary to gastroparesis, ascites, bacterial overgrowth, or abnormal small-bowel motility.34–36 Another major reason for decreased intake is the diet restrictions that must be followed by a person with chronic liver disease. A common form of malnutrition seen in patients is referred to as protein-calorie malnutrition (PCM), the deficiency of protein and/or calories relative to a person’s needs. PCM includes clinical syndromes such as Kwashiorkor, a deficiency of protein intake that is not commonly seen in the developed world but can lead to ascites, hepatomegaly, and NAFLD.32 There is an abundance of evidence detailing the development of fatty liver possibly arising from derangements in lipoprotein synthesis, such as in patients with Kwashiorkor.37,38 The proposed aberration in hepatic synthesis of lipoproteins is directly related to the fundamental principle regarding the decreased proportion of protein in one’s diet leading to the development of liver disease, as amino acids are a major energy source for the liver.19 PCM can occur at any stage of liver disease. The clinical presentation is heterogeneous, and does not have specific histologic or biochemical parameters.4 PCM is caused by a combination of all 3 principles: increased protein loss due to malabsorption, hypermetabolism of the liver, and decreased dietary intake.26,30,39,40 Some of the most significant findings seen in patients with PCM are cachexia and muscle wasting that can sometimes be masked by the edema normally seen in liver disease.6,40 The importance of the liver in fatty acid metabolism, from the production of bile to the synthesis of cholesterol, makes it such that hepatic dysfunction can be assumed to also lead to disorders in fatty acid metabolism. Polyunsaturated fatty acid (PUFA) deficiency is one such characteristic that is commonly seen in cirrhotic patients.14,33,41 The reason for PUFA deficiency in patients with liver disease is related to the synthesis of PUFAs from fatty acid precursors in the liver.42 PUFAs are important constituents of plasma membranes that increase the fluidity of these membranes, and can also be used as a component of secondary messaging systems within the body.42 Although the deficiency of PUFAs is worth noting, the consequences of this deficiency are still unknown.43 Micronutrient deficiencies are also commonly seen in liver disease, and are also associated with many complications. Fat-soluble vitamins can become deficient in patients with liver disease, especially cholestatic liver disease, because of decreased bile production, decreased oral intake, derangement in hepatic synthesis of carrier proteins for transport, and other causes.44 Vitamin D is another fat-soluble vitamin affected by liver disease. Recent studies have shown that vitamin D is used in the body for roles outside of simple calcium regulation, including anti-inflammatory, antifibrotic, and immunomodulatory roles.13 In one study, more than 90% of patients with advanced liver disease were recorded to be deficient in vitamin D.45 Vitamin D deficiency is a common complication of liver disease that has been associated with osteoporosis in cirrhosis for some time.9 The proposed mechanism of vitamin D deficiency involves a defect in hepatic synthesis.8 Vitamin E is a fat-soluble vitamin well known for its antioxidant properties. In one study this vitamin was deficient in nearly half of all the cirrhotic patients in the cohort.46 Studies have suggested a link between vitamin E deficiency and the progression of NAFLD to nonalcoholic steatohepatitis (NASH).47 The final fat-soluble vitamin is vitamin K, which is used in the synthesis of clotting factors. Vitamin K deficiency usually manifests as bleeding. The effects of liver disease on vitamin K are less well studied, but it has been recommended that for patients with impaired prothrombin time and/or International Normalized Ratio, vitamin K supplementation can be considered.48

Impact of Nutrition and Obesity on CLD

Water-soluble vitamin deficiencies also commonly occur in liver disease. The liver is required for the activation and transport of vitamin B1 and B6, and other vitamins.7 Thiamine (vitamin B1) deficiency is a well-recognized complication of alcoholic liver disease (ALD) leading to the Wernicke encephalopathy and Korsakoff syndrome. Thiamine deficiency can also be seen in other chronic liver diseases along with other water-soluble vitamin deficiencies such as niacin (B3), ascorbic acid (C), and pyridoxine (B6) deficiency.7 Rossouw and colleagues7 showed that 88% of patients with decompensated chronic liver disease had deficiencies of all the aforementioned, and a variable number of patients with alcoholic and nonalcoholic liver disease had variable rates of deficiencies in these vitamins. Cyanocobalamin (B12) and folate (B2) have also been found to be deficient in patients with liver disease. The blood test for B12 is usually falsely elevated because of the inclusion of endogenous metabolically inactive forms of cobalamin, even though tissue stores usually are depleted.49 Many minerals are also affected in patients with liver disease. Indeed one of the possible explanations as to why patients have decreased dietary intake in liver disease has been linked to zinc or magnesium deficiencies, which cause dysgeusia or altered taste sensation.35 Zinc deficiency generally has been associated with ALD for some time. Zinc deficiency is thought to be partially due to the same principles stated earlier of decreased intake, increased losses due to malabsorption, an increased dietary requirement and, possibly, diuretic induced.33,44,50 Zinc deficiency leads to many complications including altered taste and smell, immune dysfunction, and altered protein metabolism,44,51 and has also been thought to precipitate hepatic encephalopathy.52,53 Magnesium deficiency affects a person’s appetite, and magnesium levels have been shown to be an independent predictor of muscle strength.54 Whether this is due to cirrhosis or heavy alcohol use is still debated, and whether magnesium supplementation is truly useful is also under debate.55,56 Other minerals, such as selenium, are affected by liver disease but with less obvious effects.51 The complications and deficiencies of nutrients seen in liver disease and the severity of malnutrition do not seem to be directly related to the etiology of liver disease.57 That being said, there is some controversy as to whether ALD leads to poorer nutritional status in comparison with other causes of liver disease.57 Thuluvath and Triger58 and Caregaro and colleagues59 have reported that there is no difference in the prevalence and severity of malnutrition seen in patients with ALD in comparison with viral liver disease, but Caly and colleagues60 found that patients with ALD cirrhosis seemed to have poorer nutritional status when compared with hepatitis C virus cirrhosis. These conflicting data indicate that the effects, prevalence, and severity of malnutrition in chronic liver disease require further study and assessment. OBESITY AND CHRONIC LIVER DISEASE

If malnutrition is one extreme of the nutrition spectrum, it follows that obesity would be on the opposite extreme. Obesity can lead to a variety of health complications such as hypertension, diabetes, increased cardiovascular risk, and metabolic syndrome, and has even been linked to higher rates of multiple cancers including liver cancer.61 To address this problem the American Medical Association has recently classified obesity as a disease, perhaps to give physicians an incentive to discuss the complicated and sensitive subject of weight-related health issues with their patients.62 Obesity has many different causes, from genetics to environmental and psychosocial factors.

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The current increased incidence of obesity is most likely related to the trend of decreased physical activity and increased caloric intake seen in the United States, although genetics also play a role in its development, given the increased rates of obesity seen among family members.63,64 Obesity has been implicated as a risk factor for the development of liver disease. Some population-based studies have shown that almost one-third of the adult population of the United States has hepatic steatosis to some extent.65 The mechanism of how obesity leads to NAFLD is not yet clear, but important issues to note are that the accumulation of triglycerides in the liver occurs through several pathways.66,67 Another important factor believed to play a major role in the development of fatty liver is the development of insulin resistance.63,68–75 In fact, NAFLD is considered to be the hepatic component of the metabolic syndrome.76 The increased uptake and synthesis of free fatty acids (FFAs) in the liver, through the mechanism of inducing free oxygen radicals, can have a direct toxic effect on the liver besides causing hepatic steatosis. Other major targets of research in the development of NAFLD include the study of hormones called adipokines. One such hormone, adiponectin, is secreted by adipose tissue that, along with other functions, enhances lipid clearance from the plasma and increases b-oxidation of fatty acids in muscle.77 Low adiponectin levels have been associated with the presence of NAFLD, hepatic fibrosis, and metabolic syndrome.78 Even though obese patients have increased amounts of adipose tissue, there appear to be decreased levels of adiponectin.79 Another interesting piece of evidence of obesity’s effect comes from Viljanen and colleagues,80 who were able to demonstrate that rapid weight loss directly affected the liver in that it decreased FFA uptake, increased insulin sensitivity, and decreased liver triglyceride content by almost 60%. As well as being a risk factor for the development of NAFLD, obesity has also been shown to be a risk factor for the progression of NAFLD to NASH, and finally to cirrhosis.81 In a study conducted on overweight individuals by Ratziu and colleagues,81 30% of patients with abnormal liver function tests in which liver biopsies were collected had septal fibrosis, and 11% of those patients had silent cirrhosis, proving that simply being overweight can cause liver damage. Obesity is not only associated with the development of liver disease in NAFLD, but also adversely affects the progression, treatment, and complication rates of other liver diseases. Everhart and colleagues82 demonstrated that there was an association between several weight-related measures, such as insulin resistance, and progression of liver disease in patients with hepatitis C. Other liver diseases can also be affected by steatosis, such as ALD, hemochromatosis, or other forms of viral hepatitis.83,84 As obesity is a risk factor for the progression of liver disease to cirrhosis, it can also be extrapolated as a risk factor for liver cancers. It has been shown that in the United States, obesity can almost double the risk of contracting hepatocellular carcinoma.85 Liver transplant recipients are also affected by the presence of obesity. Multiple epidemiologic studies have shown that liver transplantation increases the risk of the metabolic syndrome, with reported rates ranging from 48% to 53%.86–89 Although the risk of metabolic syndrome and related comorbidities that occur in liver transplantation is multifactorial, the role of obesity cannot be understated, and counseling regarding the management of obesity should be initiated in patients undergoing, or who are planning to undergo, liver transplantation.18 The multiple detrimental roles that obesity plays in chronic liver disease makes it an imminent health issue that should be aggressively addressed to both decrease rates of liver disease and increase treatment successes.

Impact of Nutrition and Obesity on CLD

ASSESSMENT OF NUTRITIONAL STATUS

The undeniable importance of a patient’s nutritional status makes the accurate assessment of such status equally important. However, many factors complicate the assessment of nutritional status among patients with chronic liver disease, especially cirrhosis.6 Many common parameters for nutritional assessment may not be as useful. Weight, for example, is usually decreased among malnourished patients with healthy livers, but may be increased in patients with chronic liver disease because of edema and ascites, even though lean body mass is decreased. Methods such as food-frequency questionnaires, food diaries, or calorie counting are effective first tools for the assessment of a patient’s dietary history.90–93 Many of the anthropomorphic measures are not performed in clinical practice (Table 3).94,95 Potential limitations can include problems such as poor interobserver reproducibility or possible overestimation owing to third-spacing of fluid.2 One commonly used measure is the hand-grip strength, which is used to detect for the presence of malnutrition.6,96 Another important tool used to estimate a patient’s nutritional status is the Subjective Global Assessment (SGA).97 This method is a subjective assessment based on a clinician’s knowledge and experience in the context of specific variables. Laboratory testing is also useful in assessing nutritional status. Tests such as serum albumin, retinol-binding protein, transferrin, and others can be useful for detecting deficiencies seen in liver disease.94 Alterations can occur on conventional laboratory testing of patients with chronic liver disease, because the underlying disease makes difficult the distinction between whether the abnormal test was due to the liver disease or the nutritional status.6,98 The combination of laboratory values and physical measurements has been led to the creation of the Prognostic Nutritional Index (PNI). This index is obtained by plugging into a formula the laboratory values of albumin, transferrin, and lymphocyte score with the anthropomorphic measure of triceps skin-fold thickness; the higher the PNI, the higher the risk of malnutrition. The use of this index is controversial because studies have shown that objective measurements such as this underestimate the true prevalence of malnutrition in patients.96,99 GENERAL MANAGEMENT STRATEGIES FOR POOR NUTRITIONAL STATUS IN CHRONIC LIVER DISEASE

The management of obesity and malnutrition in chronic liver disease sounds simple in theory. Modifying dietary and lifestyle habits of patients should correct the issue, but the full effects of this therapy have not been fully elucidated. With obesity implicated as a risk factor for developing NAFLD, it follows that treating this condition by losing weight should help reduce the risk of NAFLD. Indeed, many studies have shown that weight loss and increased physical activity can lead to Table 3 Common anthropometric measurements in liver disease Tool

Measured

Mid-arm muscle circumference (MAMC)

Assesses muscle mass

Skin-fold thickness (triceps, biceps, etc)

Assesses body fat

Hand-grip strength (HGS)

Assesses strength as a measure of malnutrition

Body cell mass (BCM)

Assesses body composition

Body mass index (BMI)

Measures the weight

Waist circumference

Measures abdominal adiposity

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improvement in liver enzymes and liver histology in patients with NAFLD.76,100–105 Other clinically beneficial effects on the liver of weight loss have included decreased fatty acid uptake and storage, and increased insulin sensitivity.80 One study showed that weight loss in excess of 0.28 kg/d can lead to portal fibrosis, whereas patients with weight loss of 0.15 kg/d did not have the same histologic issues, suggesting that rapid weight loss can in fact be detrimental to the liver as opposed to more gradual weight loss.104 Another issue is that other studies have not shown the same improvement in liver histology after weight loss, and have reported even worsening inflammation in NAFLD with a low-fat and low-calorie diet, indicating that further research to evaluate the best method of treatment needs to be conducted.106,107 Another avenue for weight loss in patients, and a common practice today in obese individuals, is bariatric surgery. Multiple studies have been done to evaluate whether bariatric surgery aids in the healing process of NAFLD. Just as for the effect of diet change, the evidence here is also conflicting. One review noted that most studies showed an improvement in liver inflammation and fibrosis, but several studies showed a worsening in fibrosis.108,109 Further data are needed to fully understand whether bariatric surgery will be useful for patients with liver disease. The case for treating malnutrition in chronic liver disease is more complicated than with obesity, in that questions arise as to whether any deficiency seen should be corrected or if specific deficiencies are more important than others. A Cochrane review meta-analysis of available data has found that there is no clear morbidity or mortality benefit in nutrition supplementation, meaning other than the food a patient eats, of any kind, orally, enteral, or parenteral, even when specific nutrient deficiencies have been identified and can be corrected.110 This finding throws into question whether nutrient supplementation should even be attempted. Although there is a good case for the supplementation of certain nutrients, such as vitamins D or E, further study is required to demonstrate such a benefit.13,111–113 SUMMARY

As both malnutrition and obesity have a significant impact on the development and exacerbation of liver disease, it is important to further the understanding of the exact impact of the different nutrients on the liver and the role played by the liver in metabolism. Much of what is known about the impact of these 2 conditions has not kept up with the times, with most of the information still shrouded in mystery. The pathogenesis of how the liver is affected by these 2 conditions is well accepted throughout the medical community, but without specific assessment and treatment guidelines there is still much variation in how these conditions are tackled by different physicians and institutions. Further research into discovering the potential value of treating these 2 conditions in liver disease will pave the way for developing the necessary guidelines. Standardizing treatment to follow specific guidelines should be useful in furthering the approach to treating chronic liver disease. REFERENCES

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