I.  Introduction

 

Providing adequate and appropriate nutrition is essential for the well being and support of patients with acute and chronic liver disease. Nutrient metabolism may be disturbed in these patients with severe consequences, and proper dietary management may modify and ameliorate the severity of liver disease and prevent or revert complications.

 

Dietary modification, supplementation, and restrictions may be necessary in patients with liver disease, and the nutritional status and dietary intake and composition of these patients should be assessed and monitored regularly.

 

Patients with cirrhosis are often found with protein malnutrition, and the point prevalence of protein malnutrition in cirrhotic patients in cross sectional studies ranged between 10% -100% ^1-6. When patients with alcoholic hepatitis were categorized according to the severity of liver disease, Mendenhall and coworkers ² found that 4.7% of patients with mild liver disease had protein malnutrition, compared to 47% of those with moderate liver disease, and 72.2% in those characterized as having severe liver disease.

 

In addition, liver disease may also arise as a result of dietary insufficiencies or excesses, or from certain dietary constituents.

 

 

II. Role of the Liver in Intermediary Metabolism

 

A.  Carbohydrate Metabolism ⁷

 

The liver is of utmost importance in carbohydrate metabolism and homeostasis. It receives digested carbohydrates, stores them as glycogen, and releases glucose in the fasting state maintaining an even supply to the extrahepatic tissue.

 

Dietary carbohydrates are digested and absorbed as monosaccharides (the most important of which are glucose and fructose), and are delivered to the liver through the portal vein.

 

Most of the portal fructose is removed in the first pass, two thirds of which are phosphorylated immediately, and the remainder is metabolized to pyruvate and lactate to enter the citric acid (Kreb’s) cycle.

 

The liver removes about 50% of the absorbed glucose, where it is used for energy, converted to fat, or stored as glycogen. The normal liver in the fed state  contains about 80 mg/g glycogen. As blood glucose concentration falls, the liver provides glucose to the extrahepatic tissues by glycogenolysis and gluconeogenesis. In a healthy individual, after an overnight fast, the hepatic production of glucose is around 150 mg/min/1.73 m² surface area. About 75%-80% of this supply of glucose is through glycogenolysis and the remainder is through glucose synthesis from pyruvate, lactate, amino acids, and glycerol. After an overnight fast, the liver glycogen store drops to around 44 mg/gm. After 18-24 hour fast, the contribution of glycogenolysis to hepatic glucose production decreases markedly, and maintenance of glucose level depends mainly on gluconeogenesis. The latter process requires more energy than glycogenolysis, and is stimulated by glucagon. Thus after prolonged fasting maintaining the blood glucose level is at the cost of increased resting energy expenditure (REE).

  

B. Lipid Metabolism

 

The liver is important for the digestion and absorption of lipids by virtue of the bile salts which are synthesized in the liver from cholesterol, and secreted through bile to the intestine. The liver also plays a major role in lipid metabolism.

 

Dietary fat is mainly triglycerides, consisting of a glycerol skeleton and 3 fatty acids. Long chain fatty acids are 16 C atoms long or more, and may be saturated (no double bonds as palmitic and stearic), monounsaturated (one double bond as oleic) or polyunsaturated (more than one double bonds as linoleic, linolenic, and arachidonic). Medium chain triglycerides (MCT) contain fatty acids shorter than 16 C atoms. Adequate dietary fat is essential for immune function, and decreased dietary fat is associated with impaired cellular immune function and decreased bacterial clearance ⁸.

 

Ingested  fat  is emulsified by bile salts, and  split  by  pancreatic  lipase to 2-monoglycerides and free fatty acids. These, together with bile acids and phosphatidyl choline combine to form micelles, which incorporate fat soluble vitamins and cholesterol. The enterocytes uptake the contents of the micelles, and re-esterify the 2-monoglycerides and fatty acids to triglycerides. These are packaged with apolipoproteins, phospholipids, cholesterol esters, and fat soluble vitamins  into chylomicrons which pass with intestinal lymph through the thoracic duct to the circulation. MCTs pass directly to the portal blood and are bound to albumin in the circulation. They do not require bile acids for their absorption ⁷.

 

Plasma lipids are carried mainly as lipoproteins. These are synthesized mainly in the liver, and contain triglycerides, cholesterol, and phospholipids in varying proportions, together with an apoprotein. They are classified according to their electrophoretic mobility to chylomicrons, VLDL, LDL, and HDL. Triglycerides are mainly carried in chylomicrons and VLDL, and cholesterol in LDL and HDL. Lipoproteins are broken down by lipoprotein lipases in the liver and peripheral tissue where triglycerides are hydrolyzed and fatty acids and cholesterol are uptaken by the cells. Remnant VLDL and LDL are removed from the circulation by the liver ⁷.

 

Cholesterol in cell membranes and bile is free cholesterol, but cholesterol in plasma and most tissue including the liver is in the form of cholesterol esters esterified to long chain fatty acids, a process carried out in plasma by the enzyme LCAT, which is synthesized mainly in the liver ⁷.

 

The liver is also the major site of excretion of cholesterol, where it is secreted into bile to form mixed micelles with bile acids and phospholipids, thus allowing the solubilization of cholesterol and preventing its aggregation and nucleation.

 

C. Protein Metabolism

 

The liver plays a central role in protein and amino acid metabolism. It processes dietary amino acids and reprocesses amino acids released from muscle protein degradation. It utilizes amino acids for protein synthesis and gluconeogenesis, regulates the supply of amino acids to the peripheral tissues, and converts excess amino acids and ammonia (derived from the intrahepatic deamination of amino acids, from extrahepatic metabolism of nucleotides, from the metabolism of glutamate in the gut wall, and from the bacterial degradation of intestinal proteins and urea) to urea by the enzymes of the urea cycle ⁷.

 

The body of an average 70 Kg adult contains 12 Kg of proteins. These turn over at a rate of 200 - 300 gm/day ⁹. The amino acids resulting from protein degradation may be used locally for protein synthesis (50% of amino acids released in liver and muscles are utilized locally under normal dietary supply) ¹⁰,  and what remains of local use enter the body amino acid pool.

 

Dietary protein is digested to its amino acid constituents, and enters the portal vein. This is supplemented by the amino acids released from the breakdown and digestion of exfoliated GIT cells, enzyme proteins and a small amount of exuded plasma proteins. The portal amino acid pool contains 50% dietary protein, 30% exfoliated intestinal cellular protein, 10% enzyme protein, and 1% exuded plasma proteins. The liver extracts amino acids from the portal pool at variable rates, with alanine having the highest extraction coefficient, and the branched chain amino acids (BCAA) (leucine, isoleucine and valine) having the lowest extraction as they are preferentially metabolized by extrahepatic sites. The extraction rate of all amino acids increases with supply and concentration in portal blood, but the rate of increase varies, with increases in BCAA much less than other amino acids ¹¹. Following a large protein meal, the liver extracts 2/3 of the incoming portal amino acids (converting 57% to urea, and utilizing 6% for plasma protein synthesis, and 4 % for local liver protein synthesis). The remaining 1/3 passes to body amino acid pool. In the post absorptive state, net amino acid release from the liver stops, and there is a net uptake of amino acids delivered to the liver from the degradation of muscle protein via the amino acid pool. These amino acids together with those from intrahepatic amino acid breakdown are utilized for gluconeogenesis, and maintenance of the urea synthesis, though at a reduced rate. Repletion of liver protein and muscle protein takes place in the fed state.

 

The concentration of amino acids in plasma depends on the net result between entry into the pool and utilization. The turnover is rapid, and fluxes from the gut do not lead to  major changes in amino acid concentrations, except with very large protein meals. The plasma free amino acid composition differs with age, sex, dietary intake, and exercise habits.

 

D. Energy Balance ⁷

 

The average healthy adult requires 30-35 kcal/kg/day (2000-3500 kcal/day) for energy expenditure. In a normal individual, carbohydrates provide 50-55% of daily energy, fat provides 30-35%, and proteins 10-20%. This mixed fuel system leads to a respiratory quotient (RQ*) of 0.80.

 

The mixed composition of diet and energy supply is essential for the proper function and metabolism of all organs and for the adequate supply of essential nutrients. Carbohydrates should include at least 60% in the form of complex carbohydrates and starch, and 25% as sucrose. A daily minimum of 30 gm fat is required for palatability, and 30-35% of total energy should be supplied as this form, and this is sufficient to meet the requirements of fat soluble vitamins and essential fatty acids. A diet which provides less than 10% of daily energy as protein usually leads to deficiencies in other nutrients as iron, vitamin B₁₂, nicotinic acid, and trace elements.

 

 Energy expenditure is divided into : ⁷

 

Total energy expenditure (TEE) =      Resting energy expenditure (REE) +

Thermal effect of food (TEF) +

Energy Expenditure for activity (EEA)

REE  =            Basal energy expenditure (BEE) in a normal state.

                        ~ 20 kcal/kg in normal individuals

                        ~ 25-30 kcal/kg during stress or disease

TEF  =     ~ 10% of REE in foods given orally as 3 meals.

EEA =      Variable depending on activity. Around 10-30% of REE for hospitalized patients.

 

Usually the REE needs are calculated using the Harris-Benedict equation:

REE =             66 + (13.7xweight) + (5 x height) - (6.8 x age) for males,

655 + (9.6 x weight) + (1.7 x height) - (4.7 x age) for females

(weight in kg, height in m, age in years). This equation gives a fair estimate of basal energy requirements. In patients with advanced liver disease, water retention must be taken into consideration, and “ideal” body weight should be used instead of actual body weight.

 

    * The respiratory quotient (RQ) is the ratio of CO₂ production to O₂ consumption of an individual, an organ, or an experimental system. The RQ of CHO is 1.00, as a CHO molecule (as glucose) contains C₆H₁₂O₆, and requires 6 O₂ molecules to produce 6 CO₂ and 6H₂O + energy. The RQ for fat is 0.70, indicating that it uses more O₂ to produce CO₂ and water, and that for proteins is an average of 0.82.

 

E. Vitamins ⁷

 

1. Fat Soluble Vitamins

 

Fat soluble vitamins are absorbed with digested lipids together with bile acids, cholesterol, and phosphatidyl choline via micelles, and are incorporated into chylomicrons.

 

Retinol enters the liver via chylomicron remnants. It is stored in the liver as retinyl esters, where its concentration is 300 times that in other tissue and 30 times that in retinal visual epithelium. Plasma concentrations of retinol are maintained at a  constant level by release from liver stores.

 

Absorbed calciferols are stored unchanged in the liver, skeletal muscles or adipose tissue, or hydroxylated to its active forms.         25- Hydroxylation occurs in the liver, and it circulates in plasma bound to liver synthesized vitamin D binding protein.

 

Free tocopherol is transported in chylomicrons, and is uptaken by the liver in chylomicron remnants. It is then secreted in VLDL and is uptaken by the tissues where it inhibits oxidation of fatty acids.

 

Vitamin K₁ and K₂ are transported to the liver in chylomicrons. They are uptaken and rapidly metabolized by the liver, and metabolites excreted in bile and urine. The body stores of vitamin D are small, but take several days to weeks to become depleted. In the liver, vitamin K is essential for the synthesis and gamma carboxylation of the clotting factors II, VII, IX, and X, and protein C and protein S.

 

 

2. Water Soluble Vitamins

 

The liver plays an important role in the metabolic processes involving all water soluble vitamins. It plays on important role in storage of folic acid and vitamin B₁₂.

 

Folates are taken up by the liver by a carrier mediated transport. Half the body stores of folate are present in the liver. 5-Methyl-tetrahydrofolate is excreted in bile, and undergoes an enterohepatic circulation.

 

The liver contains 90% of the body stores of vitamin B₁₂. Vitamin B₁₂ is not catabolized, and losses occur by excretion, mainly into bile. The liver converts vitamin B₁₂ to its active form, methyl cobolamine. Indeed, pernicious anemia has been reported to regress spontaneously in patients who developed acute hepatitis, indicating that not all hepatic stores are available for hemopoiesis.

 

 

 

III.  Metabolic Abnormalities in Liver Disease

 

A. Energy balance

 

Most studies have shown that patients with chronic liver disease have increased energy expenditure and hypermetabolism  when REE is related to lean body mass ^12-14. This is partly due to decreased hepatic glycogen stores so that the response to normal overnight fasting is mainly via gluconeogenesis, an energy requiring process. In addition, ascites increases REE by around 10% ¹⁵.

 

In cirrhosis, the metabolic response to exercise is not normal. Patients have decreased exercise tolerance, associated with a significantly lower maximal oxygen uptake and altered fuel substrate utilization, together with increased protein breakdown and hyperammonemia during exercise ^16-18. These factors should be taken into account when planning dietary regimens and exercise schedules for these patients.

 

B. Carbohydrates

 

Carbohydrate metabolism is disturbed in patients with liver disease. In fulminant hepatic failure, hypoglycemia is common, and is probably due to impaired glycogenesis, glycogenolysis, and gluconeogenesis.

 

In chronic liver disease, hypoglycemia is rare. These patients, however, have a 50% chance of becoming hypoglycemic during severe ¹⁹.

 

Patients with cirrhosis become hyperglycemic following an oral glucose load. There is peripheral insulin resistance, compensatory increased insulin secretion, and impaired clearance of insulin with decreased hepatic extraction on first pass  ²⁰. This  results in a normal fasting blood sugar and a high post prandial sugar level.

 

In some patients, the pancreatic response to insulin resistance is blunted, with delayed appearance of C-peptide after oral glucose, leading to delayed peripheral utilization of glucose ²⁰. With more severe insulin hyposecretion, and continued glucose production unchecked by insulin ²¹, frank diabetes may become apparent

 

Serum fructose levels are higher than normal in cirrhotics after an oral load due to impaired hepatic extraction. This, however, is of no clinical significance ⁷.

 

C. Lipids

 

Patients with chronic alcoholic liver disease have increased plasma concentration of cholesterol, triglycerides, and fatty acids ⁸. The former is due in part to reflux from the liver and in part to deficiency of hepatic synthesis of LCAT. Clinically significant steatorrhea is rare, and patients tolerate well a normal fat intake ⁸.

 

In patients with cirrhosis, Cicognani et al. ²² found that the levels of LDL, HDL and total cholesterol were significantly lower than in patients with CAH or controls. LDL cholesterol was also significantly lower in cirrhotics than in controls. They found that the decrease in plasma lipoproteins and lipids was more marked with advancing Child class. They suggested that measurement of LDL cholesterol may be of prognostic significance in chronic liver disease. This supports earlier unpublished observations by Reynolds (Reynolds TB, 1993, personal communication),  that the total cholesterol level in patients hospitalized for alcoholic cirrhosis correlated with outcome, and that cholesterol levels below 70 mg/dl usually indicated a high chance of mortality.

 

In cholestatic liver disease, serum cholesterol increases, and may reach very high values and lead to xanthomas. These appear on the eyelids, palms, soles, and over bony prominences. Plasma triglycerides are also increased mainly in the LDL fraction. Lipoprotein X is found in cholestasis, appearing on electron microscopy as bilamellar discs ²³.

 

LCAT deficiency alters the ratio of cholesterol to phospholipids in red cell membranes. This leads to alterations in red cell shape, most marked in alcoholic cirrhosis, leading to spur cells (acanthocytes), which have reduced deformability and hemolyse easily. This may lead to “spur cell hemolytic anemia” in advanced alcoholic liver disease ²⁴.

 

D. Proteins

 

Whole body turnover of protein is increased in patients with advanced chronic liver disease ²⁵ and protein catabolism is thought to increase to compensate for the body’s unmet energy requirements. In stable compensated cirrhosis, however, isotope amino acid tracer kinetic studies (employing ¹⁴C-tyrosine, ¹⁴C-leucine, or ¹⁴C-glycine) have shown that protein breakdown is normal in the unstressed state, but increases during stress more than in normal individuals ^26-28. Studies on protein synthetic ability in cirrhosis showed that, in the stable state, the synthetic ability of the liver is maintained, but this is impaired in periods of stress including exertion, poor nutritional intake, and intercurrent illness ¹⁶.

 

This indicates that stable cirrhotics have, on the whole, normal protein turnover, but with stress or decompensation, protein breakdown increases to meet energy requirements, and this is not compensated for by the limited hepatic synthetic reserve. With repeated stress and decompensation, patients enter a negative N₂ balance and loss of lean body mass, and malnutrition become apparent.

 

Significant changes occur in plasma amino acid concentrations in patients with liver disease, and these relate to the severity and etiology of the liver injury ^29,30.

 

In fulminant hepatic failure, plasma concentrations of all amino acids are high, except BCAA whose concentrations are normal or low ³¹. These changes represent release into the plasma of  amino acids from the necrosing liver and from peripheral tissue breakdown, coupled with failure of hepatic amino acid uptake. As BCAA are utilized by peripheral tissue and mainly by muscle, their concentration is unaffected, or may decrease.

 

In chronic liver disease, plasma levels of the aromatic amino acids phenylalanine, tyrosine and tryptophan are increased, so is methionine, while BCAA are reduced ^29,32.

 

The increase in level of aromatic amino acids and methionine is because the liver is their main site of catabolism, and with the presence of liver cell failure and portal-systemic shunting, their concentration increases. This is coupled with a slight increase in the rate of protein breakdown in chronic liver disease, contributing to the increase in amino acid pool.

 

The decrease in the level of BCAAs is mostly due to increased utilization by adipose tissue and muscles, secondary to stimulation of BCAA entry to the cells and the enzyme branched chain oxy-acid dehydrogenase (BCOA-DH) by the hyperinsulinemia, and stimulation of the enzyme BCAA-transaminase by the hyperammonemia associated with cirrhosis. The levels of BCAA in plasma of patients with mild CLD who have no hyperinsulinemia or hyperammonemia are also slightly reduced due to unexplained mechanisms.

 

Most patients with chronic liver disease require at least 0.75 g protein/kg body weight /day to maintain nitrogen balance ³³, and 1.5 g/kg is considered optimal. Hepatic protein synthetic ability is relatively well maintained in compensated cirrhosis in the unstressed state, and is often impaired by the lack of dietary essential amino acids rather than by the liver disease itself ⁸.

 

E. Vitamins ^7,8.

 

Liver disease, and particularly cholestatic chronic liver disease, impairs the absorption of fat soluble vitamins.

 

Vitamin K deficiency is almost invariable in patients with cholestasis, and is not uncommon in non cholestatic chronic liver disease. In the former it is mainly due to impaired absorption, and in the latter it is due to both decreased absorption and increased requirements due to subclinical DIC ⁸.

 

Vitamin D deficiency is also common and is due to impaired absorption, decreased exposure to sunlight, and interference of jaundice with UV ray effect on vitamin D synthesis. 

 

Vitamin A deficiency is present in most patients with cholestasis. Absorption is impaired in cholestasis, and hepatic synthesis and release of retinol binding protein is impaired in parenchymal liver disease. Retinol-retinol binding protein complexes are prevented from loss in urine by being bound to transthyretin, which is synthesized by the liver, and whose concentration decreases in liver disease increasing urinary loss.

 

Vitamin E deficiency is present in cholestasis, and in children may be clinically relevant and may occasionally cause neurological deficits (peripheral neuropathy, central pontine myelinosis), or hemolytic anemia. Deficiency in adults is of no known clinical consequence ⁸.

 

Water soluble vitamin deficiencies are present to variable degrees in alcoholic liver disease, and depend on dietary intake rather than the liver disease. Deficiencies have been relatively constant on biochemical assessment for thiamine, pyridoxine, riboflavin, niacin and folic acid ⁸.

 

In patients with non alcoholic cirrhosis, folic acid deficiency is the most commonly reported B vitamin deficiency, and deficiencies of thiamin and B₆ occur less frequently.

 

F. Minerals

 

Poor intake of calcium , together with decreased activity of vitamin D results in changes in bone density. Iron deficiency has been reported in almost 25% of patients with cirrhosis and is due to poor dietary intake or blood loss. Zinc and magnesium deficiencies have also been described in patients with chronic liver disease ⁸.

 

 

 

IV.  Dietary Management of Liver Disease:

 

Dietary regimens should depend on the nature, duration, and severity of liver disease, as well as the nutritional status of the patient and the presence of complications. The dietary principles are constant for different liver diseases and different stages, but the dietary regimen should be individualized. Periodic follow up of patients should include nutritional assessment and diet regimen modifications. With progress of liver disease, further dietary supplementation or restriction may become necessary ⁸.

 

A.  Nutritional Assessment

 

Nutritional assessment should be part of every patient examination, aiming at identifying whether malnutrition exists, and its degree and type, to aid in planning a rational approach to treatment and dietary recommendations. Each patient should be evaluated individually.

 

In patients with minimal liver disease and no nutritional problem, thorough history and examination should be sufficient. Dietary history should be obtained, inquiring about appetite, anorexia, nausea, vomiting, abdominal pain, diarrhea, steatorrhea. and weight loss. Attention should be paid to food preferences and eating habits. Recent weight loss is always significant, and correlates with the morbidity of advanced liver disease.

 

During physical examination, the nutritional status should be assessed, and attention should be paid to evaluating muscle wasting (specially temporal, masseters, and shoulder muscles), manifestations of vitamin deficiency (glossitis, cheilitis, pallor), and fluid status (edema, ascites, skin turgor).

 

If malnutrition  is suspected, anthropometric measures and laboratory methods can be used. In practice, anthropometric measures are sufficient for patient evaluation, with triceps skin fold thickness and mid arm muscle circumference (MAMC) the easiest to perform and give more valuable information on the nutritional state of patients than biochemical studies ³⁴. Sophisticated laboratory methods that accurately measure nitrogen balance, body water, body fat and body cell mass or muscle mass are used as research tools. Weight based measurements (body weight, weight for height, body mass index) are of limited value in advanced cirrhosis due to fluid retention.

 

Anthropometric measures include: ⁷

 

Body weight             Weight for height from standard tables, and percent of ideal body weight.

 

Body mass index:       weight in kg ¸(height in m)²

 

Skin fold thickness : Gives an indication to the body fat stores, compared to standard tables for age group and sex, and levels below the 5^th percentile are considered low. The triceps skin fold is mainly used. Usual measures are 7.5-12.5 mm for males and 10-16.5 mm for females. Levels below 3 mm indicate severe fat depletion. Subscapular (measured I cm below the angle of the scapula), and iliac (measured 1 cm above the highest point of the iliac crest) are not usually used in patients with liver disease, as the triceps skin fold thickness is rarely affected by edema.

 

MAMC:                      Arm Circumference (in cm) - p x TSF ¸ 10.

                                 Gives an indication of lean body mass. Also compared to standard tables for age group and sex, with levels below the 5^th percentile considered low. Normal values are 18.5-25.5 cm for adults. Measures below 15 cm indicate protein depletion.

 

Creatinine height index :         Creatinine excretion is a good predictor of muscle mass in the absence of impaired renal function. This index is the ratio of 24 hour urinary creatinine excretion to the expected excretion of a sex and height matched normal adult expressed as percentage.

 

Muscle mass:          Can be approximately measured from urinary creatinine excretion. 24 hour urinary creatinine is calculated where 1 mg of creatinine equals 18 gm of muscle in women and 23 gm of muscle in men.

 

Biochemical Assessment:      Albumin has its limitations in patients with liver disease due to several factors: Dilutional effect due to fluid retention, maldistribution  in ascites (as evident by the fact that in cirrhosis 80% of newly synthesized albumin may be delivered to the ascitic fluid compartment), and decreased synthesis in advanced liver disease ⁸. Transferrin and retinol binding protein have similar limitations.

 

Body composition:  Bioelectric impedance calculates fat free mass (FFM) or lean body mass (LBM), body cell mass (BCM), extra-cellular mass (ECM). Total body Potassium in a whole body counter can calculate FFM  (LBM) assuming 68 mmol K/KG LBM in men and 64 mmol K/kg LBM in women. ³⁵.

 

Nitrogen Balance:    After 2 days of stable intake, 24 hour urine is collected and analyzed for urinary urea N₂ (UUN). Intake of N₂ = Dietary protein intake in grams ¸ 6.25. N₂ output = UUN + 4 grams (to correct for urinary non urea N₂, skin and fecal N₂ loss). Provided that: collection is complete, GFR > 50 ml/min, and no large non urinary N₂ loss.

  

B. Acute Liver Disease

 

1. Acute Hepatitis

 

Patients with acute hepatitis are usually adequately nourished before the illness. Acute hepatitis is usually a mild disease, associated with only a few days of anorexia, nausea, and occasionally vomiting. These are usually well tolerated by the patients, who require no nutritional supplementation, and are encouraged to eat normally. Usually they can take some food by mouth and enough fluids to prevent dehydration. In a few days the appetite returns, and patients can eat an adequate intake.

 

Daily requirements are around 2000-3000 kcal/day (35-40 kcal/kg/day), with 1.5 g/kg/day proteins. Old literature emphasized lipid restriction. This, however, is not true, and lipid restriction has no role in acute hepatitis unless fats aggravate nausea in an individual patient. Patients fed a high fat diet did not recover any slower from acute hepatitis than fat restricted patients. Similarly, high protein high calorie diet with fat restriction should not be enforced as it showed no difference in outcome than liberalized diets in several studies ³⁶.

 

Dietary restrictions have no place in the management of mild or moderate acute parenchymal liver disease. Patients should be advised to take nutrients in the form most appealing to them, and to avoid whatever increases nausea or induces vomiting ( which is different in different patients).

 

Nutritional supplementation and iv fluids and nutrients are reserved for the patients with excessive nausea and vomiting who cannot maintain a sufficient fluid balance. Because some patients with acute hepatitis cannot excrete a normal water load, large quantities of iv glucose should be avoided, and care should be taken to correct Na and K losses due to vomiting ³⁶.

 

Most investigations show that alcohol should be avoided in acute hepatitis and for the 6 months following recovery ⁷. Some studied have shown that moderate alcohol intake did not adversely affect the outcome of acute viral hepatitis, and that regular moderate consumption after recovery had no deleterious effects ³⁶.

 

2. Fulminant Hepatitis

 

In FHF, hypoglycemia is a major threat, and may be severe. It is due to a combination of decreased live glycogen, impaired glycogenolysis, impaired glycogen synthesis in the fed state, impaired gluconeogenesis, and increased insulin production.

 

Patients may become malnourished rapidly due to the hypercatabolic state, and the marked loss of N2 secondary to the endocrine response to massive hepatic necrosis.

 

These patients require a continuous parenteral glucose infusion as 10-25% glucose, providing 150-200 gm glucose/day, with repeated monitoring of blood glucose. They should, in addition, receive nutritional support to suppress protein hypercatabolism and help liver regeneration. The infusion of amino acid / glucose mixtures supplying 3 g amino acids and 5 g glucose per hour were well tolerated and associated with decreased protein catabolism, and improved plasma amino acid profiles in patients with fulminant hepatitis ³⁷.

 

3. Acute Cholestasis

 

Patients with acute biliary obstruction require immediate surgical or endoscopic relief. There is no need for nutritional supplementation except for parenteral vitamin K to correct the prothrombin time prior to the procedure (unless there are pre-existing disorders that compromised the nutritional status).

 

 

C. Chronic Liver Disease

 

1. Nutritional Abnormalities in Chronic Liver Disease

 

a. Malnutrition:

 

Most studies have shown that malnutrition is a constant accompaniment of chronic liver disease and cirrhosis, and that the prevalence  of malnutrition increases with increasing severity of liver disease ^38-41.

 

The relationship of the nutritional status to prognosis and mortality has been established in different situations, and malnutrition is accepted as an independent risk factor for prediction of outcome in patients with chronic liver disease. The Child-Turcotte classification ⁴², which was based on the outcome of portal hypertension shunt surgery, included the nutritional status in the criteria for dividing the patients into different classes. Other studies have shown the relationship of malnutrition to survival in alcoholic hepatitis ^38,40, hospitalized patients with ascites ⁴³, cirrhotic patients undergoing abdominal surgery ^44,45, hospitalized alcoholic cirrhosis patients ⁴⁶, and transplant recipients ^47,48. A worldwide epidemiological survey in 38 countries showed that malnutrition had a deleterious effect in patients with liver cirrhosis ⁴⁹. Most of these studies were, however, conducted on patients with mostly alcoholic liver disease.

 

Muller et al. ⁵⁰ in a study of 123 mostly non alcoholic cirrhotic patients awaiting transplantation, found that malnourished patients with a body cell mass <30% of body weight had slightly more variceal bleeding and overall mortality awaiting transplantation, and significantly more (threefold increase) mortality following transplantation than adequately nourished patients. Malnourished patients were electively chosen for transplantation slightly more frequently. More recent studies out of Italy showed that malnutrition is present in around 30% of patients with viral induced cirrhosis, that it increased with the increase in severity of liver disease, and that it was related to short term and 1 and 2 year mortality ^51-53. Similar results were also reported from a US study ⁵⁴, where severely malnourished patients as determined by triceps skin fold thickness and MAMC had significantly lower survival rates, whether the etiology was alcoholic or viral hepatitis induced cirrhosis.

 

b. Metabolic Basis of Malnutrition

 

Inadequate dietary intake is the major factor in the malnutrition that accompanies chronic liver disease ^8,55-57. This is often due to anorexia, and is compounded by poor dietary advice. This is in addition to some degree of maldigestion and malabsorption ⁵⁸, and small bowel dysmotility ⁵⁹  present in patients with liver cirrhosis. Low protein intake which is sometimes necessary in chronic encephalopathy augments the malnutrition.

 

Acute and chronic liver disease have been found to have a negative effect on appetite. Patients with cirrhosis have disturbed taste, and were less likely than controls to describe food as sweet, and more likely to feel a bitter taste with different foods ⁶⁰. Smith and coworkers described altered taste threshold for salt, sucrose, HCl and urea in patients with acute and chronic liver disease ⁶¹. Similarly, taste and smell disturbances have been described in acute hepatitis, which improve with improvement in liver disease ⁶². The cause of these alterations is not known, but may involve the presence of abnormal organic compounds in breath or saliva affecting the flavor of food, or derangement of neural function affecting the processing of gustatory information ⁶³. A recent study showed that cirrhotic patients had less gustatory sensitivity for salt, bitter, sweet and sour, and a higher gustatory score than controls, and that lower serum magnesium levels were correlated to these taste impairments ⁶⁴. The liver may also play a part in food preferences through reflex pathways as has been shown by Todroff and colleagues in animal experiments ⁶⁵.

 

Forty percent of patients with PBC and 12% of patients with chronic hepatitis were found to have signs of malnutrition despite normal dietary intake, suggesting that other factors may be involved in malnutrition in these patients ⁴.

 

In patients with cirrhosis, hepatic glucose production is low ^66,67, gluconeogenesis is enhanced ⁶⁷, and hepatic glycogen stores decreased ⁶⁸.  Malnourished cirrhotics require higher energy supply to maintain nitrogen balance compared to controls ⁶⁹.

 

Muller et al. ⁵⁰ found that patients with advanced chronic liver disease awaiting transplantation had an RQ of 0.73 after an overnight fast, compared to an RQ of 0.84 in the control group. The found that the fuel composition in these patients was 20% glucose, 66% lipids, and 14% proteins. The lipid contribution to the REE increased slightly with advancing Child class. These results confirm earlier studies that showed a reduced RQ in patients with liver cirrhosis ^14,34,67, indicating that 75% of the energy production in the fasting state in cirrhotics is derived from fat compared to 35% in the normal control.

 

These changes indicate that cirrhosis is a disease associated with accelerated starvation and early recruitment of alternative fuels. Consequently cirrhotic patients should not fast for long periods of time and need frequent interval feeding.

 

 

2. Dietary Management

 

a. Energy Requirements:

 

Patients with chronic liver disease should be encouraged to maintain adequate energy consumption. Patients usually need 35-45 kcal/kg/day, or REEx1.5 or REE+500 kcal. Excess calories should be avoided, particularly as carbohydrates, as this promotes hepatic lipogenesis, liver dysfunction, and increase CO₂ production and the work of breathing ⁷⁰. Carbohydrates should be sufficient to maintain normal blood glucose levels, and should not exceed insulin reserves. They should supply 60-76% of non nitrogen calories.

 

Patients often do better on multiple small meals with a late bed-time  meal, which has been shown to reduce the need for gluconeogenesis and conserve proteins and nitrogen balance after an overnight fast, and prevent protein breakdown ⁷¹.

 

b. Lipids:

 

Around 30-40% of total calorie intake should be supplied as fat. Lipid emulsions depend little on the liver for metabolism, are well tolerated in patients with cirrhosis ⁷², and have a protein sparing effect. A mixed fuel system improves nitrogen balance compared to glucose alone ⁷³. Even in  decompensated cirrhosis, high lipid containing parenteral mixtures were found to be well tolerated and improve encephalopathy ⁷⁴. Thus lipid restriction has no scientific basis in patients with cirrhosis. Lipids have the advantages of increasing palatability in oral feeding, and low water content per energy supplied in parenteral infusions.

 

Fat content should always be less than 100 g fat/day, and over supply of fats has been associated with deleterious effects in patients with advanced liver disease. In a randomized controlled trial in postoperative cirrhotics, those receiving 50% of their daily calories as iv fat emulsions had significantly higher mortality than those receiving glucose alone ⁷⁰. Fat should be provided as polyunsaturated fatty acids, with less than 50% long chain triglycerides.

 

c. Proteins:

 

Proteins should not be restricted in patients with liver disease unless they become protein intolerant due to encephalopathy. Protein intake should be in the range of 1-1.5 g/kg/day in the absence of encephalopathy ⁸.

 

Several studies have shown that a daily protein supply of 0.8-1.0 g/kg/day may be sufficient to prevent negative N₂ balance in cirrhosis ^33,75. With mild stress, this has to increase to 1.5 g/kg/day, and with acute exacerbations of hepatitis or decompensation to 2.0 g/kg/day ^33,76.

 

Special attention should be paid to patients on beta-blockers for prevention of variceal bleeding, (who are increasing in frequency with the realization that beta blockers are the prophylactic method of choice for prevention of first variceal bleed). Beta-blockers increase protein oxidation (an alternative method of protein metabolism without energy production), and may increase protein requirement ⁷⁶, and patients on propranolol should be placed on the higher end of the protein intake.

 

d. Diet Composition

 

Patients should be allowed to eat wholesome, well seasoned, tasty meals to encourage intake and maintain energy and nitrogen balances. Dietary restrictions should be made only when necessary, and then patients should be advised for seasoning and variability of food. Many patients are anorexic or suffer from nausea or abdominal distention. They should be offered small amounts of attractively prepared foods at frequent intervals, since large meals often provoke nausea. If a reasonable intake could be achieved and weight is maintained, nothing further needs to be done.

 

Patients who cannot maintain an adequate dietary intake can be given blenderized or homogenized diet to take at frequent intervals between meals. If needed, specialized formula or diet supplement can be used as drinks between meals. Oral intake is always, however, better.

 

e. Route of Feeding

 

Whenever possible, nutritional deficiencies should be treated by increasing oral intake in patients with liver disease (and as a general principle of therapy in all patients). Enteral feeding is more physiological, and a mixed food contains many of the micronutrients and trophic factors important to the gut and the liver. Many of these micronutrients exert trophic effects on the liver during first pass effect through the portal circulation ⁷⁸.

 

One of the deficient factors in parenteral solutions that has become of importance in liver disease patients particularly with alcoholic hepatitis is glutamine. Glutamine is unstable in aqueous solutions, and is not included in parenteral amino acid mixtures. Glutamine forms 60% of muscle free amino acid pool, and accelerated synthesis is needed during catabolism. Glutamine is also essential for gut epithelial growth and integrity, and glutamine feeding in starved rats increases mucosal thickness and villous height.  With glutamine deficiency, the gut mucosal barrier becomes disrupted, and this increases bacterial translocation and allows endotoxins and cytokines (which are now thought to be responsible for alcoholic injury) to enter the portal circulation ⁷⁹.

 

If oral intake is not sufficient and the GIT can be used safely, nasoenteric feeding should be the second choice. The presence of esophageal varices is not a contraindication to placing thin PVC feeding tubes ⁸⁰.

 

Whenever parenteral feeding is required, short term peripheral vein parenteral nutrition (PPN) should be preferred, and central lines and TPN reserved for patients with inadequate peripheral access.

 

f. Supplementation

 

Several investigators studied the benefits of oral nutritional supplementation in patients with liver cirrhosis ^80-87 (appendix I). All studies showed an improvement in N₂ balance in the patients receiving oral enriched formula supplement in addition to regular diet. Patients with moderately severe disease were most likely to benefit from oral supplementation, with different studies showing improvement in liver tests, plasma amino acid profiles, and anthropometric measures. Supplementation with protein enriched formula did not exacerbate azotemia, edema or ascites, and did not precipitate encephalopathy. No effect on mortality was seen in most studies. Only two studies, one in alcoholic hepatitis with oxandrolone supplementation ⁸⁴, and the other in non alcoholic cirrhosis where the controls failed to achieve adequate calorie intake ⁸⁷,  showed significant reduction in mortality in the supplemented groups.

 

Several published controlled trials examined the effect of parenteral amino acid supplementation in acute alcoholic hepatitis ^88-94 (appendix II). The majority of the studies showed improvement in liver function tests with amino acid supplementation. A positive N₂ balance was achieved in all supplemented patients, with improvement in potassium and phosphorus balance, and improvement in lean body mass, albumin, prealbumin, RBP, and transferrin. The N₂ balance in the control patients in different studies varied with the study population. All control groups were given supplemented oral diet providing 35 kcal/kg/day, with 70-100 gm proteins. In the studies where the control groups achieved an intake of >1500 kcal/day, a positive balance was achieved, though less positive than the supplemented patients. These studies included patients with less severe form of acute alcoholic hepatitis, and in this patient population, no benefit of parenteral supplementation on short or long term mortality was found. In the 2 studies where the patient population had severe form of hepatitis, the control group could not achieve an intake of >1400 kcal/day, and in these patients, a negative balance was maintained, and the supplemented patients had less short term mortality in one study ⁸⁸, but not the other ⁹⁴.

 

In conclusion, supplementation, aiming at improving nutritional status, should be reserved for the severely malnourished patients who cannot maintain an adequate oral diet. If patients can maintain an intake of 35-40 kcal/kg/day and 1-1.5 gm protein/kg/day, no added benefit of supplementation is seen. Oral supplementation by enriched formula or tube feeding if tolerated is effective and reduces mortality in non alcoholic cirrhotic patients who cannot maintain a sufficient oral intake ⁸⁷. The lack of a clear cut beneficial effect on mortality should not prevent efforts to improve the nutritional status of patients with chronic liver disease.

 

 

g. Branched Chain Amino Acids (BCAA)

 

BCAA have an anticatabolic effect in patients with chronic liver disease because of their ability to serve as an energy substrate for muscles, and because of their effects on protein synthesis and degradation. It was found that muscle catabolism significantly decreased over 3 days following daily infusion of 40 g of BCAA enriched mixtures ⁹⁵. Leucine is the most active in promoting protein synthesis and inhibiting protein breakdown. Isoleucine and valine increase nitrogen balance and increase tissue concentration of leucine.

 

BCAA are well tolerated in protein intolerant patients because of their beneficial effects in hepatic encephalopathy ⁹⁶, and BCAA enriched mixtures have proved to be effective as nutritional supplements in patients with chronic liver disease.

 

In a crossover study on 22 cirrhotic patients, BCAA supplements led to significant improvement in N₂ balance compared to periods of regular diet.  McGhee et al. ⁸³ found that BCAA supplements were as effective as casein in improving N₂balance in cirrhosis. Another trial showed that BCAA in a dose of 1 g/kg/day improved the N₂ balance similar to a balanced amino acid mixture, but the balance remained negative in patients receiving 0.5 mg BCAA/kg/day, with a better N₂ balance in the patients receiving regular amino acid mixture supplements ⁹⁷. Marchesini et al. ⁹⁸ similarly found increase in N₂ balance on both BCAA and casein, but the increase with BCAA was significantly more. Cabre et al. ⁸⁷ found that BCAA supplementation in advanced decompensated cirrhosis allowed a better calorie intake than regular hospital diet, with decrease in mortality.

 

h. Branched Chain Keto Acids (BCKA)

 

BCKA are the first products of BCAA metabolism, and are reversibly transaminated to BCAA by the enzyme BCAA-transaminase. BCKA supply the backbone for protein synthesis in muscles as BCAA, without the additional nitrogen. They are aminated to form amino acids, thus decreasing the ammonia pool. BCKA given to cirrhotic patients, have been found to be converted to amino acids  and to improve N₂ balance. They were found to be more efficient in increasing peripheral protein synthesis than BCAA in cirrhotic patients ⁹⁹.

 

In a review of the studies using BCKA as nutritional supplementation in liver cirrhosis and encephalopathy, Morgan ¹⁰⁰ stated that there was no clear benefit for BCKA in treatment of encephalopathy, and that uncontrolled trials showed promising results for their use as nutritional supplements in spite of their limited solubility.

 

i. Effects of Nutritional Modification (repletion)

 

Nutritional state modification has been found to improve outcome of surgery, resection for HCC, and transplantation. Immune system function, ascites, and laboratory tests improve, and the incidence of SBP is reduced. No studies however have shown that nutritional supplementation and correction of malnutrition improved mortality except in acute alcoholic hepatitis ⁸⁴, where malnutrition correlated with severity of liver disease and mortality, and improved food intake correlated with improvement and survival.

 

 

3. Decompensated Liver Disease