Dietary Management of Metabolic Liver Disease

Metabolic liver diseases encompass several different inherited conditions that affect metabolism and can lead to hepatic dysfunction. Understanding the role of dietary interventions is critical, as nutrition continues to play a large role in management of these diseases and at times can even be lifesaving. Despite novel genetic and enzymatic therapies, dietary management remains fundamental in inherited metabolic diseases of the liver. Appropriate restriction, supplementation, and overall nutrition must be taken into consideration for optimal growth and hepatoprotection. Understanding the pathophysiology of diseases, as well as how nutritional approaches fit into treatment paradigms, allows for optimal care of patients with metabolic liver disease. Treatment should be multidisciplinary and include a dietician with expertise in metabolic disease.


Introduction
Metabolic liver diseases are rare disorders that occur due to disruptions in various metabolic pathways. These disturbances can be due to enzyme deficiencies or disorders of protein transport which lead to disruptions in proteins synthesis or degradation involved in carbohydrate, protein, or lipid metabolism. Liver disease occurs when enzyme deficiency leads to disruption in metabolic pathways subsequently causing accumulation of toxic upstream products or synthesis of an aberrant protein in the liver. As a result, these disorders can lead to hepatocyte injury, cirrhosis, and even death if left untreated. Clinically, patients with metabolic disease may present with life-threatening symptoms in the neonatal period or more chronic findings that manifest in adolescence or adulthood.
Due to the metabolic nature of these conditions, dietary interventions can be lifesaving as stand-alone treatment or in conjunction with pharmaceutical therapy. Nutritional monitoring includes serial assessment of growth anthropometrics, regular evaluation of dietary intake, and monitoring of laboratory parameters. The goal of nutritional therapy is correction of said metabolic imbalance, as well as provision of adequate energy, protein, and nutrition required for adequate growth and development [1]. Laboratory parameters monitored will of course depend on the type of metabolic disease and should be individualized.
Treatment is based on the specific metabolic defect in question and is aimed at correction of primary metabolic imbalance via reduction of available substrate through dietary restriction, supplementation of products of blocked pathways, provision of cofactors, and/or medications that aid in excretion and detoxification of harmful metabolites [1]. A This article is part of the Topical Collection on Nutrition * Rohit Kohli rokohli@chla.usc.edu Tanyaporn K. Kaenkumchorn tkaenkumchor@mcw.edu multidisciplinary team approach that includes a metabolic disease specialist or biochemical geneticist, endocrinologist, metabolic dietician, gastroenterologist, physical therapist, genetics counselor, and social worker is necessary to effectively care for both children and adults with metabolic disease (Fig. 1). Patient education and ongoing guidance from a dietician with expertise in management of metabolic diseases can help to provide knowledgeable and safe care to patients and families. Frequent, small changes in diet are often needed for metabolic stability and optimal growth [1]. Consensus guidelines are largely lacking due to the rarity of these entities. This review will address dietary approaches to various metabolic liver diseases with a focus on findings in recent literature.

Disorders of Carbohydrate Metabolism
The liver plays a key role in management of glucose homeostasis and metabolism. Glucose production can occur via gluconeogenesis or the degradation of glycogen. Glucose, galactose, and fructose are the main dietary carbohydrates. Disorders of carbohydrate metabolism often present during infancy. Inborn errors of carbohydrate metabolism leading to hepatic injury include galactosemia, hereditary fructose intolerance, and glycogen storage diseases I, III, and IV/IX [2]. Clinically, these disorders manifest as hypoglycemia, metabolic acidosis, hepatic dysfunction, and growth failure. Dietary consideration plays a large role in management of these disease to limit intake of substrates that are unable to be metabolized.

Galactosemia
Galactosemia is an inborn error of galactose metabolism caused by a deficiency in one of three enzymes involved in the conversion of galactose to glucose: (1) galactokinase (GALK), (2) galactose-1-phosphate-uridyltransferase (GALT), and (3) uridine diphosphate galactose 4-epimerase (GALE) [3]. Galactose is a key source of energy, particularly in early development [4]. The liver is the main site of galactose metabolism. Dysfunctional metabolism of galactose leads to accumulation of galactose-1-phosphate and galactitol, toxic by-products, in the liver, eye, brain, and kidney [2]. GALT deficiency, also known as hereditary or classic galactosemia, leads to the most severe and most common phenotype. Classic galactosemia presents in infancy after a child has ingested breast milk or lactose containing formula. Symptoms include failure to thrive, jaundice, feeding difficulties, vomiting, diarrhea, and Escherichia coli sepsis.
Current treatment for galactosemia is lifelong dietary elimination of lactose and galactose. If there is any clinical suspicion for galactosemia after birth, infants should be fed soy-based formula, casein hydrolysate formula, or elemental formula while awaiting diagnosis [5••]. Soy formula is recommended over elemental formula except in pre-term infants [6]. Breastfeeding should be avoided [7]. As diet advances to include solid foods, patients with galactosemia should continue to avoid lactose and galactose from milk and dairy products, the main source of dietary galactose [7]. Beyond this, there continues to be debate over the extent of galactose restriction necessary in adults [8]. Studies have shown no short-term adverse effect in diets allowing limited amounts of galactose [9]. Though consensus guidelines are lacking, recent publications recommend allowing fruit, vegetables, legumes, and mature cheeses in unrestricted amounts, while fermented soy-based foods can be allowed in small quantities [5••, 6]. Unfortunately, dietary therapy is not adequate to prevent long-term cognitive, social, and reproductive adverse outcomes [10,11].

Hereditary Fructose Intolerance
Hereditary fructose intolerance (HFI) is characterized by a deficiency in the enzyme aldolase B leading to inability to metabolize fructose-1-phosphate effectively. Aldolase B catalyzes the conversion of fructose 1,6-bisphosphanate and fructose 1-phosphate into triose molecules in the liver, kidney, and small intestine [12]. In HFI, the buildup of fructose-1-phosphate and depletion of adenosine triphosphate (ATP) lead to clinical manifestations including hepatic and renal dysfunction (Fanconi syndrome). Clinically, symptoms of  HFI appear in infancy when neonates are fed fructose-containing formulas or are introduced to fruits and vegetables containing fructose during the first year of life [13]. Patients present with vomiting, hepatomegaly, decreased oral intake, and failure to thrive [14].
The cornerstone of treatment is dietary restriction of fructose, sucrose, and sucralose [15]. Sucrose is hydrolyzed into fructose and glucose. Sorbitol should also be avoided because it leads to endogenous fructose production via the polyol pathway. Fructose is found in a wide variety of foods including dairy, meat, cereal, all fruits, bread, condiments, desserts, and vegetables with the exception of asparagus, cabbage, cauliflower, celery, green beans, green peppers, onions, potatoes, and spinach [15]. Reduced fruit and vegetable intake is a requirement in HFI. Additional ingredients to avoid include high fructose corn syrup, honey, agave syrup, molasses, palm sugar, coconut sugar, sorghum, and inverted sugar [15]. Complete elimination may not be feasible due to the widespread nature of fructose in foods [14]. Daily supplementation with a multivitamin including ascorbic acid and folate is necessary to prevent micronutrient deficiencies related to dietary restriction of fruits and vegetables [15,16]. Periodic evaluation of hepatic function, renal function, and growth is needed after the diagnosis of HFI is made [15]. Dietary elimination of these substances are effective in preventing clinical manifestations with good overall prognosis with normal growth and intelligence [12].

Glycogen Storage Disease
Glycogen storage diseases (GSD) are a group of disorders characterized by enzyme defects involved in the glycogen synthesis and degradation. Clinically, hypoglycemia is the predominant feature seen with GSD due to the inability to convert glycogen to glucose. While more than 16 forms of GSD have been identified, this review will focus on GSD types I, III, and IV/IX which are the types most associated with hepatic dysfunction. Nutritional therapy is the mainstay of treatment for all types of GSD; there are no pharmacologic treatment options. The goals of nutritional therapy in GSD are to prevent hypoglycemia, avoid metabolic derangement and acidosis, prevent short and long-term complications, and optimize quality of life [17•, 18••].

GSD Type I (Von Gierke Disease)
GSD type I is caused by a deficiency in glucose-6phosphatase (G6Pase) activity. The final step for glycogenolysis and gluconeogenesis is affected, and glucose-6-phosphate is unable to be converted to glucose. GSD type Ia represents 80% of GSD type I. It is caused by a defect in the catalytic subunit located inside the endoplasmic reticulum. GSD type Ib is caused by a defect in transporters for the entry of glucose-6-phosphate and export of glucose and phosphate into and from the endoplasmic reticulum. Hypoglycemia is the main clinical manifestation of GSD type Ia and Ib. Prolonged hypoglycemia can lead to seizures, developmental delay, impaired growth, and even death [19]. Additional clinical manifestations include hepatomegaly, poor linear growth, kidney enlargement, and excess adipose tissue deposition on the cheeks [19]. GSD type Ib has the additional clinical manifestation of neutropenia and neutrophil dysfunction. GSD type I presents in infancy, often when a child begins to sleep through the night without feeding.
Nutritional therapy focuses on providing foods high in complex carbohydrates such as starch which help maintain euglycemia [20,21]. During the day, a carbohydrate balanced diet is administered with frequent feedings [14]. Meals should be small and frequent. In addition, the diet should be low in galactose and fructose, which are unable to be converted to glucose in the absence of G6Pase. Thus, fruit, juice, and dairy intake is limited or restricted. In general, sugar-sweetened food products are not allowed [19]. Ideal dietary nutrient distribution is 60 to 70% carbohydrate, 10 to 15% protein, and 20 to 30% fat [19].
At night, continuous feeds are administered with or without cornstarch [14]. Infants with GSD type I rely on continuous glucose therapy via nocturnal enteral feeds with formula free of sucrose and lactose. The rate of formula feeds is 8 to 10 mg of glucose per kilogram body weight per minute (mg/ kg/min) for infants and 4 to 8 mg/kg/min in older children [19].
Uncooked cornstarch has been used in the treatment of GSD type I since the late 1980's and continues to be used today. Raw cornstarch slowly releases glucose after hydrolysis by pancreatic amylase and supplies exogenous glucose for several hours [22]. Cornstarch is introduced between age 6 and 12 months, as it may not be welltolerated until 1 year of age when amylase is fully functional. It may be mixed in water, soy milk, or lactose-free sucrose-free formula. Cornstarch requirement varies by age, with adults needing less per body weight than children [23]. For infants, dosing of cornstarch is 1.6 g/kg of body weight given every 3 to 4 h. For young children, the dosing is 1.7 to 2.5 g/kg every 4 to 5 h [24]. Young adults may lengthen the interval between cornstarch doing to 6 to 8 h. Adults may require only one bedtime dose of 1.7 to 2.5 g/kg [24]. Lowering the amount of cornstarch with age is imperative, as overtreating leads to excessive weight gain, hepatomegaly, hyperinsulinism, and rebound hypoglycemia [23]. More recently, waxy maize heat modified starch (extended release cornstarch) has also been used to help achieve stable nocturnal glucose control in both adults and children [25, 26•]. This allows for improved quality of life by avoiding an overnight dose of cornstarch while maintaining metabolic control. In all patients, blood glucose monitoring is essential. Goal glucose is greater than 70 mg/dL. GSD types Ia and Ib are the same with the addition of granulocyte colony-stimulating factor to GSD type Ib to treat neutropenia and defective phagocytic cell function [14]. A complete multivitamin is recommended due to risk of nutritional deficiencies including vitamin B12, folic acid, and vitamin D [24]. With good dietary compliance, long-term complications can be delayed but are often still prevalent [19].

GSD Type III (Glycogen Debrancher Deficiency, Cori Disease, Forbes Disease)
GSD type III is caused by deficiency in amylo-1,6-glucosidase, a debranching enzyme, which leads to accumulation of an abnormal variant of glycogen. Gluconeogenesis remains intact. In GSD type IIIa, which accounts for 80% of GSD type III, the debranching enzyme is deficient in both liver and muscle tissue [27]. In GSD type IIIb, only liver debranching enzyme is missing.
While GSD type III presents very similarly to GSD type I in infancy, the diet is considerably less restrictive since sugar is not limited [19]. Dietary breakdown should be 50% carbohydrate, 25 to 30% protein, and 20 to 25% fat [19]. A diet high in protein is thought to provide alanine as a source of glucose during fasting, improve muscle protein synthesis and function, and replace carbohydrate with protein thereby reducing glycogen storage [28•]. Several case reports have demonstrated improvement of myopathy in pediatric and adult patients after introduction of a high protein, low carbohydrate diet [29,30]. Likely GSD type I, small, frequent feeds are recommended to prevent hypoglycemia.
Nutritional therapy depends on whether a patient has GSD type IIIa or IIIb. Children with GSD type IIIa with myopathy and growth problems should be started on a high protein diet which has been shown to reduce myopathy and improve growth [31]. Children with GSD type IIIb may only need cornstarch therapy [32]. Some older infants and young children may require cornstarch at decreased doses as compared to GSD I (1 gm/kg body weight over 4 h or longer) [32]. Cornstarch can be mixed in with milk and formula. Adults often do not need cornstarch therapy. Vitamin and mineral supplements are prescribed on an as need basis since all food groups are allowed.

GSD Type VI (Hers disease) and Type IX
GSD type VI is due to deficient liver glycogen phosphorylase. Glycogen phosphorylase catalyzes the conversion of phosphorylase to its active form. GSD type IX is caused by deficient phosphorylase kinase. With both GSD types VI and IX, glycogenolysis is impaired. The clinical presentation is variable but is generally mild with presentation in the first years of life with hepatomegaly, transaminitis, and dyslipidemia. In more severe cases, short stature and cirrhosis have been described [27]. Nutritional goals are to improve metabolic control in order to prevent primary complications including hypoglycemia, ketosis, and hepatomegaly, as well as further manifestations of chronic disease such as short stature, cirrhosis, and delayed puberty [33].
The nutritional approach to GSD type IX is the same as type VI [33]. A minority of patients with mild phenotype may not need nutritional modification. Patients who experience hypoglycemia or ketosis should avoid fasting and eat small, frequent meals [33]. A diet high in protein providing 2 to 3 g protein/kg body weight daily, providing 20 to 25% of total calories, is recommended [33]. Carbohydrates should provide 45 to 50% of total calories [33]. Simple sugars such as sucrose, fructose, and lactose should be limited to prevent excessive glycogen storage but are not prohibited [33]. Fats should provide 30% of total calories.
In general, the cornstarch requirement for GSD VI and IX is generally less than that needed for GSD type I. In children, cornstarch starting at 1 g/kg body weight may be necessary at bedtime to prevent overnight hypoglycemia [33]. Overnight cornstarch should be titrated to maintain blood glucose levels between 70 and 100 mg/dL.

Fatty acid Oxidation Defects
In fatty acid oxidation disorders (FAOD), there is impairment of energy production from endogenous and exogenous fatty acids. Fatty acid oxidation provides energy to heart and skeletal muscle. The major role of beta-oxidation is to provide energy by maintaining glucose levels during fasting. Thus, clinical symptoms arise during catabolic states such as fasting or illness. This section will approach nutritional management of long-chain and medium-chain fatty acid oxidation defects. Nutritional guidelines focus on fasting and emergency catabolic states like illness and stress [34].

Long-Chain Fatty Acid Oxidation Defects
Long-chain fatty acid oxidation disorders (LCFAO) comprise of inherited metabolic diseases because of disruption in the processing or transport of fats into the mitochondria to perform beta oxidation [35]. The inability of utilize long-chain fats for energy leads to the clinical manifestations of FAO disorders. These disorders include very long chain acyl-CoA dehydrogenase (VLCAD) and long chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD).
Nutritional therapy aims to avoid reliance on long-chain fat as an energy substrate by avoiding prolonged fasting, modifying diet composition, and treating illness aggressively [36]. Dietary management includes restricting intake of long chain fats, supplementation with medium chain triglycerides (MCT), and moderately increasing intake of carbohydrates [37]. Long chain fat content should comprise 40 to 45% of total energy intake in health infants and 30 to 35% in children [34]. In patients with severe forms of LCFAO, long-chain fat should be restricted to 8 to 25% of energy intake [36]. A diet high in fat and low in carbohydrates should be followed [35]. Exercise tolerance may be improved with supplementation of MCT and carbohydrate [36]. With this diet, essential fatty acids should be supplemented, optimally with walnut oil, soy oil, or wheatgerm oil [34]. Overfeeding should be avoided.

Medium Chain Fatty Acid Oxidation Defects
Medium chain acyl-CoA dehydrogenase (MCAD) deficiency is the most common FAOD. MCAD is a mitochondrial matrix enzyme that catalyzed the initial dehydrogenation step in beta oxidation of medium-chain fatty acids. MCAD is responsible for the metabolism of acyl-CoAs with 4 to 12 carbon atom chain lengths. Clinical manifestations include metabolic decompensation with fasting (lethargy, vomiting, coma) and hepatomegaly due to accumulation of toxic acyl-CoA compounds [1].
The mainstay of treatment of MCAD avoidance of fasting. Carbohydrate and glucose supplementation can be used to avoid catabolism, particularly during systemic illness [38]. No vitamin supplementation is needed. 1 Despite treatment, children have increased rates of developmental delay [39].

Short-Chain acyl-CoA Dehydrogenase Deficiency
Short-chain acyl-CoA dehydrogenase deficiency (SCAD) is an enzyme that catalyzes the first step of FAO using acyl-CoAs with 4 to 6 carbons [40]. It is considered a benign condition with no nutritional restrictions.

Lipid Storage Diseases
Lysosomal acid lipase (LAL) disease is a storage disorder caused by deficiency in the enzyme LAL which results in cholesteryl esters and triglyceride accumulation in the liver and vascular system leading to hepatic dysfunction and dyslipidemia [41]. There are two phenotypes, Wolman disease and cholesterol ester storage disease (CESD), depending on how much LAL enzyme activity is present [14]. Wolman disease, the more severe, infantile onset form, has clinical features of failure to thrive, diarrhea, hepatomegaly, hepatic dysfunction, and adrenal calcification. CESD, the less severe, later-onset form, presents in childhood or adulthood. Associated liver manifestations include hepatic dysfunction that progresses to cirrhosis, cardiac disease, and cerebrovascular disease.
Treatment of LAL involves a combination of diet, lipidreducing medications, and enzyme replacement therapy (ERT) [41]. The aim of these measures are to prevent progression of disease [42]. Previously, in Wolman disease, infants were treated with hematopoeietic stem cell transplant for survival past one year, although outcomes were variable [43,44]. Sebelipase alfa, a recombinant enzyme replacement therapy, was FDA approved in 2015 for treatment of pediatric LAL deficiency [43].
In Wolman disease, malnutrition should be prevented. Use of parenteral nutrition may be necessary [43]. With CESD, nutritional considerations include management of failure to thrive in children and weight loss in adults [43]. For both entities, diet should be low in cholesterol and triglycerides [43].

Disorders of Amino Acid and Organic Acid Metabolism
Tyrosinemia Type I Tyrosinemia type I, also known as hepatorenal tyrosinemia, is caused by a deficiency of the enzyme fumarylacetoacetate hydrolase (FAH), which is expressed in the liver and kidney. The upstream compounds to this reaction, maleylacetoacetate and fumarylacetoacetate, are toxic products. The liver is the major organ affected in tyrosinemia type I, with manifestations including acute liver failure, chronic liver failure, cirrhosis, and hepatocellular carcinoma [45]. Other manifestations of the disease include poor growth, vomiting, ascites, hypoalbuminemia, hypoglycemia, hyperbilirubinemia, and coagulopathy [14].
Historically, treatment options were limited to a diet restricted in tyrosine and phenylalanine, with liver transplant if needed. In 1992, the medication 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione, or NTBC, was introduced. Now the gold standard of therapy, NTBC inhibits the activity of 4-hydroxyphenylpyruvate dioxygenase thereby preventing downstream production of maleylacetoacetate and fumarylacetoacetate [46]. Dietary therapy continues to play an important role in tyrosinemia type I, because NTBC results in elevated concentrations of tyrosine and phenylalanine which could lead to poor neurocognitive development. Thus, dietary restriction of phenylalanine and tyrosine are necessary in patients treated with NTBC to prevent adverse cognitive effects of hypertyrosinemia. Formulas with restriction of tyrosine include Tyrex® and Tyros® and should be used. Goal tyrosine levels are between 200 and 400 µmol/L; goal phenylalanine levels are above 40 µmol/L [45]. This is achieved via protein restriction, while the rest of daily protein requirement is administered via an amino acid mixture free of phenylalanine and tyrosine.
Refer to Table 1 for further detail on disorders of amino acid and organic acid metabolism.

Urea Cycle Defects
Urea cycle disorders (UCD) result from defects in the metabolism of protein and disposal of excess nitrogen and nitrogen containing molecules, primarily ammonia. 2  In general, nutritional management plays a large role in preventative or chronic management, while acute crises have more directed care aimed at treatment of hyperammonemia. The goals of chronic therapy for UCD are prevention of metabolic derangement which can cause irreversible brain damage due to high ammonia levels while achieving normal growth and development. Long-term management aims to avoid triggering hyperammonemic events. A low protein diet is the main treatment for patients with UCD. The low protein diet should restrict protein while providing enough protein for adequate growth [47]. Protein requirement varies greatly with age, with requirements being much high infancy and lower later in life [48]. Useful tools for determining dietary allowances for protein and amino acids in children, adults, pregnant women, and lactating women are available [49]. A meta-analysis of studies assessing nitrogen balance found protein requirements to be 10% higher with no difference in gender or age [50]. Table 2 describes dietary therapy based on enzyme deficiency for UCD. Essential amino acids are supplemented, including arginine in ASS and ASL deficiency, and citrulline in OTC and CPS deficiency [51••]. Additional pharmacologic therapy is necessary in many patients [48].

Wilson Disease
Wilson disease (WD) is a defect in a copper transporting ATPase expressed in hepatocytes due to a mutation in the gene ATP7B leading to its dysfunction or absence. Copper accumulates in the liver leads to cellular injury and eventual liver failure if unchecked. If hepatic, neurologic, or psychiatric symptoms are present, patients should be treated with chelation therapy either with d-penicillamine or trientine [52]. If symptoms are absent, treatment options include zinc salts or reduced dosages of d-penicillamine or trientine [52]. Historically, patients with WD have been advised to follow a low copper diet.
Recommendations have included avoiding copper rich foods such as nuts, kidney, liver, cocoa, shellfish, beans, peas, and mushrooms [53]. There is ongoing investigation about the role of copper consumption or restriction in the management of WD. Some authors recommend a less restricted approach with the only dietary copper restriction being avoidance of shellfish and liver in the first year of treatment, followed by a weekly serving of shellfish and continued rare liver consumption [54].

Conclusion
Metabolic diseases of the liver are a heterogenous group of disorders that range in their severity and prognosis. Due to their rarity, randomized controlled trials and consensus guidelines and overall lacking. Despite various treatment options that have been introduced with time, nutrition continues to play a large role in management of these diseases. Understanding the critical role of diet in these disorders is key to successful treatment.
Funding Open access funding provided by SCELC, Statewide California Electronic Library Consortium

Declarations
Conflict of Interest Tanyaporn Kaenkumchorn serves as a consultant for Kids Eat in Color. The rest of the authors declare no conflicts of interest.

Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
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