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

 

With decompensation, diet modifications become necessary, and diet should be tailored individually to each patient according to the clinical state.

 

a) Encephalopathy

 

Diet Related Mechanisms

 

The aromatic amino acids phenylalanine, tyrosine, and tryptophan serve as precursors for the neurotransmitters noradrenaline, dopamine and serotonin. The levels of the aromatic amino acids in CSF depends on their plasma concentration, and they compete for passage through the blood brain barrier with BCAA. With altered amino acid plasma profiles in  cirrhosis, the low BCAA levels allows passage of more aromatic amino acids to the brain. Excess phenylalanine competes with tyrosine for the enzyme tyrosine hydroxylase, leading to decreased production of dopamine. Excess tyrosine is decarboxylated to octopamine, which acts as a false neurotransmitter, having 1/100 of neurotransmitter potency, and competes with neurotransmitters for receptor sites leading to cerebral dysfunction. Increased  tryptophan  leads to increased serotonin, an inhibitory transmitter ^7,23.

 

Increased ammonia increases cerebral glutamine synthesis, which is a competitor for the carrier of amino acids out of the blood brain barrier, leading to further increase in their CSF concentration. In addition, ammonia depresses cerebral blood flow and cerebral glucose utilization ²³.

 

In addition to these mechanisms, several mechanisms contribute to this multifactorial state, and observations have led to treatment options. The encephalopathy is due to passage of intestinal products through portal systemic shunts or through a cirrhotic liver unable to metabolize them. In addition to the ammonia and false neurotransmitters, unidentified intestinal products, of nitrogenous origin, and products of intestinal bacteria are involved, as evident by the effectiveness of enemas, oral antibiotics, and experimental colon exclusion. High protein diet precipitates encephalopathy in susceptible patients, probably through providing substrate for the formation of ammonia and false transmitters ²³. This  is in addition to the increased GABA receptors and benzodiazepin receptors ¹⁰¹.

 

Diet Modification:

 

High protein intake has been known to precipitate encephalopathy in susceptible patients for a long time, and similarly, protein restriction has been known to improve manifestations of encephalopathy ²³. Patients with encephalopathy in whom precipitating factors have been excluded and managed, and who fail to respond to lactulose, will need dietary protein modification or restriction (appendix III, IV).

 

Several studies ^102-104 have shown that vegetable protein is better tolerated in patients with chronic encephalopathy. The mechanism involved is not fully clear, but may be related to the different amino acid composition, fiber content and increasing stool bulk and softness with consequent nitrogen loss, or changes in hormonal response ¹⁰⁵. The first step should be to shift 75% of dietary protein to vegetable protein (appendix V, VI). Vegetables are better tolerated than milk, which is better tolerated than meat. A mainly vegetarian diet is, however, poorly tolerated, and long term compliance is usually poor due to bulky nature and increased flatus production, and occasionally leads to patients decreasing intake and a negative nitrogen balance.

 

Only when lactulose, neomycin, and diet modification fail should protein be restricted, and then this should be at the highest tolerable level compatible with normal mental function. This level should not be constant and attempts at increase should be always made ⁸.

 

Patients in coma should be placed on no protein diet till recovery starts, and a short term protein deprivation can be tolerated without adverse nutritional effects. With recovery, proteins are introduced at 20 g / day increments. Many patients can be maintained at 0.7 g/kg/day.  If this is intolerable, reductions can be made, or BCAA supplementation can be added.

 

Severe prolonged protein restriction should be made carefully, as a low protein diet decreases renal plasma flow and GFR, and this may impair borderline renal function in patients with decompensated cirrhosis ¹⁰⁶.

 

Role of BCAA

 

BCAA have been tried as therapy for hepatic encephalopathy based on the fact that increasing their plasma levels inhibits the brain influx of aromatic amino acids.

 

Several studies have been published using intravenous or oral BCAA supplementation for the treatment of encephalopathy. Eriksson and Conn ¹⁰⁷ analyzed all the published studies till 1989. They concluded that the aggregate wake up rate was insignificantly higher in patients receiving BCAA (68% vs. 58%), but the overall mortality was similar (22% vs. 19%). A later study ⁹⁸ showed slightly better results. In a crossover controlled trial on 64 patients with chronic hepatic encephalopathy, BCAA supplement was compared to an equinitrogenous supplement of casein. BCAA were significantly better in improving liver function, N₂ balance, and encephalopathy.

 

In conclusion, BCAA have no clearly proven benefit over standard therapy in hepatic encephalopathy. In the subgroup of patients with chronic hepatic encephalopathy who are protein intolerant, BCAA supplement may prevent a negative nitrogen balance, as they are better tolerated than standard proteins or standard amino acid supplements, and their use should be reserved to this group of patients. Cost remains a drawback (1 gm nitrogen (6.25 g protein) in BCAA mixtures costs around LE 3.5, i.e. a 1 g/kg supplement costs around LE 40 daily for a 70 kg adult). Another drawback is the absence of other essential and conditionally essential amino acids in the pure BCAA mixtures, further limiting their long term use.

  

Role of Zinc:

 

Zinc levels are decreased in patients with chronic liver disease. The relation of zinc to encephalopathy is controversial, but a report in the 1980s found that dietary supplementation with 600 mg zinc per day improved encephalopathy ¹⁰⁸. The role zinc plays in the pathogenesis of encephalopathy is unknown, but it may influence metabolism of neurotransmitters and their receptors, and zinc deficiency may affect nitrogen metabolism and may elevate blood ammonia level ¹⁰⁹. This needs further studies before zinc supplementation in encephalopathy becomes indicated as standard therapy on scientific basis.

 

b)  Ascites

 

Na Balance in Ascites:

 

NaCl contains 0.4 g Na per gram, or 18 mEq Na. The average intake of Na in an Italian diet (which is close to our diet) is around 3 g/day (equivalent to 7.5 g NaCl, or 135 mEq Na /day. Cirrhotic patients who accumulate ascites on a non sodium restricted diet excrete less than 15 mEq Na in urine (usually around 10); extra-renal Na loss is about 22 mEq / day (total loss 35 mEq or 0.75 g Na or 2 g NaCl). Thus these patients can retain around 100 mEq Na /day or 2.5 grams of Na. Retention of every gram of Na (45 mEq) will cause retention of 200-250 ml of fluid, or a total accumulation of 400-500 ml daily on regular non salt restricted diet ¹¹⁰.

 

Na Restriction, Fluid Restriction

 

For mobilization of ascites, Na has to be restricted to less than the daily losses. If patients have high urinary Na and are able to excrete a water load, they will respond to Na restriction alone, and will lose 200-250 g fluid for every gram Na deficit.

 

A no added salt regimen together with avoiding salty food will result in a diet containing 50 mEq Na daily ¹¹⁰ (appendix VII).

 

Avoiding salt completely in cooking and avoiding Na containing non salty foods (salt containing bread, puffed cakes (baked with baking powder), biscuits, olives, preserved meat, canned food, ice cream, all cheese except unsalted cottage cheese, margarine and butter but not cream), and less than 250 ml milk daily,  will result in a diet containing 22 mEq Na daily (500 mg Na or 1.25 g NaCl) ¹¹⁰  (appendix VIII, IX).

 

A 10 mEq Na (250 mg Na or 0.5 gm NaCl) diet usually results in the loss of 250-300 ml fluid daily without diuretic use, depending on urinary Na excretion. This requires, in addition, the use of salt free bread and avoiding milk and red meat (appendix X). This degree of Na restriction is not tolerated by most patients, and will result either in non compliance or decreased food intake and calorie deficiency. It could be achieved only in hospitalized patients for short periods of time.

 

The Na content of medications should always be taken into consideration when calculating daily Na intake. Effervescent tablets usually contain 300 mg Na (14 mEq) per tablet. Sachets contain around 150 mg (7 mEq Na) per sachet ¹¹⁰.

 

The rationale of severe Na restriction in hospitalized patients to 10 mEq daily is questioned. This regimen allows more rapid mobilization of ascites during hospitalization. However, patients cannot comply with this regimen after discharge. It is better to tailor diuretic therapy in hospital on a tolerable regimen the patients comply with during hospitalization, so they can learn the diet and follow the regimen after discharge. A 22 mEq Na diet is better to adopt in the hospital setting as it is more suitable for the outpatient ¹¹¹.

 

Salt restricted diet could be made more palatable by seasoning with lemon juice, onion, vinegar, garlic, pepper, mustard, salt free ketchup, salt free mayonnaise, salt free béchamel, saffron, and thyme ^23,110.

 

Reynolds and coworkers ¹¹² examined the advantage of treating ascites without Na restriction. Diets were more palatable, and hyponatremia and impaired renal function developed less frequently. The time taken for fluid loss was, however, unacceptably long. Gauthier ¹¹³ later randomized patients to either a 22 mEq or a no added salt diet. AT 2 weeks, reduction in abdominal girth and weight loss were significantly more in the 22 mEq diet patients, who developed slight hyponatremia more frequently, but without renal impairment. Thus a 22 mEq diet seems justified in ascitic patients till ascites is controlled. The salt restriction can be eased, but patients have to be maintained on some salt restriction to prevent reaccumulation. Diuretic use should be tailored to each patient individually, but a small dose of spironolactone is justified ^23,110,111.

 

Fluid restriction of all patients with ascites is inappropriate. Patients should drink ad libidum, but not to excess. Water restriction to treat hyponatremia is indicated only if this is severe. Gradually developing hyponatremia in cirrhosis, though a poor prognostic sign, has no life threatening hazards as rapidly developing hyponatremia, and patients are usually asymptomatic regarding this point till the serum Na drops below 110 mEq/L. Fluid restriction to less than 1 liter daily is justified only in hyponatremic patients, and only when the serum Na drops below 120 mEq/L ¹¹¹.

 

 

c) Variceal Bleeding

 

Patients who bleed from varices are admitted to hospital, and are usually placed on NPO till the bleeding is controlled. Following endoscopy, the use of local xylocaine spray slightly impairs swallowing, and the patients should continue fasting for a few an hour or two or till swallowing is normal.

 

If sclerotherapy is done, a soft diet on the day of the procedure is prescribed, with regular diet starting the following day. The constituents of the diet are determined by the accompanying state of the liver disease and any encephalopathy. Protein intake is usually restricted till the bowels are cleared of blood and no encephalopathy develops.

 

With band ligation, the boluses of varices banded do not obstruct the esophagus, and oral intake is possible. The boluses, however, cause a slight dysphagia to solids, and the patients are maintained on a soft diet for the first 3 days following the procedure.

 

In a recent study, de Ledinghen et al. ¹¹⁴ found that early nasogastric hyperalimentation following sclerotherapy or band ligation had no benefit over standard feeding regimen  (which implied 4 days of low calorie intake) regarding nutritional status, liver function, rebleeding, hospital stay or mortality.

 

D. Chronic Cholestasis ⁷

 

If patients are fat tolerant with no steatorrhea, dietary fat should be modestly reduced to 40 g/day with increase in carbohydrates to balance the calorie requirements. Fat intake should not be reduced markedly as this will reduce the palatability of diet. Medium chain triglyceride supplements should be given, and the quantity increased with increasing fat intolerance and fat restriction. They are best supplied as coconut oil for cooking or salads, or as formula.

 

Fat soluble vitamins should be supplied monthly in the form of intramuscular injections of 10 mg vitamin K, and 10,000 IU of vitamin A and D. Children with cholestasis should be given parenteral vitamin E supplements. Calcium supplements should be given to adults and children.

  

E. Special Diseases ^7,23

 

1. Wilson’s Disease

 

Treatment of Wilson’s disease patients is essentially by Cu removal using penicillamine. Dietary copper intake should be restricted, and patients should avoid eating shell-fish, dried fruits, chocolates, mushroom, and liver. They should restrict salt and pepper seasoning ⁷.

 

Zinc competes with copper for intestinal absorption, and increasing dietary zinc supplement reduces copper absorption, and patients can be kept in a stable or negative copper balance with oral zinc supplementation as their only treatment. This, however, should not replace penicillamine therapy except in patients who are intolerant to penicillamine ⁷.

 

Brewer et al. ¹¹⁵ recently showed that a vegetarian diet was deficient in copper, and that Wilson’s disease patients maintained on a vegetarian diet had a negative copper balance with no therapy. This report has not been validated in further trials.

 

2. Hemochromatosis

 

A low iron diet is not feasible. Patients, however, should abstain from iron containing multivitamin preparations, and eating liver, spinach, and molasses. Alcoholic beverages have a high iron content in addition to the toxic effect of alcohol on the liver, and should be avoided.

  

3. Pediatric Liver Diseases Requiring Diet Modification ⁷

 

a) Glycogen Storage Diseases: Children with GSD I (glucose-6-phosphatase deficiency) are unable to mobilize stored liver glycogen. The have nocturnal and fasting hypoglycemia which may lead to convulsions. They require a continuous source of glucose to prevent hypoglycemia. This may be achieved by continuous nasogastric nocturnal glucose drip, or by raw cornstarch feeding in the evening, which is a slowly digested glucose source. Similar dietary measures may be required in the milder form Type III with debrancher enzyme deficiency.

 

b) Galactosemia: Patients with deficiency of galactose-1-phosphate-uridyl transferase benefit from withdrawal of milk and milk products from food, and this may prevent liver disease.

 

c) Hereditary Fructose Intolerance: Children with aldolase deficiency must have sucrose and fructose restricted diets to prevent liver disease.

 

d) Tyrosinemia:  The acute type leads to death in infancy regardless of dietary management. The chronic type may benefit from restriction of aromatic amino acids, and growth may be normalized and hepatomegaly may be prevented or ameliorated. Hepatocellular carcinoma is, however, not prevented.

   

V.  Diet as a Cause of Liver Disease ⁷

 

Liver disease could result from dietary inadequacies, dietary excesses, and dietary contaminants.

 

A. Protein Energy Malnutrition:

 

Kwashiorkor results from a diet severely restricted in proteins but with adequate calorie intake from carbohydrates. The setting is usually a child weaned from breast milk to a diet formed mainly of starch. The liver is enlarged, often grossly and contains ~50% fat by weight in the form of triglycerides. This results from increased delivery of fatty acids to the liver and enhanced lipogenesis, coupled with a decrease in transport out of the liver due to deficiency of apolipoproteins. Some fibrosis may be present, but cirrhosis does not develop. Serum enzymes are usually normal. Manifestations disappear promptly of protein supply.

 

In marasmus, liver changes are mild and non specific, and the liver is not enlarged. Fibrosis and cirrhosis do not develop.

 

B. Obesity:

 

Obesity is associated with the development of parenchymal liver damage and the formation of gall stones. The most common histological lesion is fatty change (steatosis), and fat is stored as triglycerides, fatty acids, and mono- and di-glycerides. The amount of fat deposited is not related to the degree of obesity. Mild to moderate degrees of inflammation and fibrosis may occasionally be seen. Fibrosis is more severe with morbid and long standing obesity and with severe steatosis.

 

Occasionally, obese patients may develop an inflammation that is histologically similar to alcoholic hepatitis with the formation of Mallory hyaline bodies (Non Alcoholic Steato Hepatitis NASH). This lesion is not related to the degree of obesity, but occasionally is preceded by a short period of weight loss. This is usually a mild slowly progressive lesion, but could progress to cirrhosis.

 

Steatosis is reversible, and near normal histology is observed in obese individuals who achieve and maintain substantial weight reduction to normal ranges.

 

C. Aflatoxins and Hepatocellular Carcinoma:

 

Aflatoxins are derived from the Aspergillus flavus, and contaminate stored grains in tropical conditions. Aflatoxin levels in food correlate with the incidence of hepatocellular carcinoma in several areas of Africa and Asia. They probably alter cellular immune response and may increase the carrier rate for hepatitis B. Danish workers exposed to Aflatoxin inhalation while handling contaminated imported food crops had an increase incidence of HCC.

 

 

D. Others:

 

Hypervitaminosis A:  

 

Results from prolonged exposure to high doses of vitamin A, in the range of 100,000 U daily in adults. The liver manifestations include hepatomegaly, with hypertrophy of fat storing cells, fibrosis, central vein sclerosis, and cirrhosis.

 

Dietary Iron Overload: 

 

Dietary iron overload does not result in liver disease except if massive and prolonged. Increased stores may be seen, but parenchymal changes are seen only in South African blacks who use iron pots for cooking and fermenting beer, and can ingest up to 200 mg iron daily, causing the disease Bantu’s hemochromatosis.

 

Toxic Food and Contaminants:  

 

The fungus Amanita phalloides  contains a potent hepatotoxin and produces steatosis and centrilobular necrosis which may be massive. Plants of the families Seneco, Crotalaria and Heliotropium contaminate grains and bread, and are occasionally used to make herbal tea. They contain pyrrolizidine alkaloids and can cause veno-occlusive disease. Fasciola hepatica infection results from the ingestion of fresh vegetables (specially watercress) contaminated with the encysted metacercariae. Clonorchis sinensis infection results from the ingestion of raw or inadequately cooked fish in endemic areas.

 

 

VI. Drug Nutrient Interaction: ⁸

 

Most diuretics lead to loss of potassium, magnesium and zinc. Spironolactone retains potassium, and supplements are not needed with its use. Cholestyramine results in loss of vitamin A, D, E and K, by binding bile salts. Prolonged neomycin use may cause villous atrophy leading to loss of zinc and an increased incidence of diarrhea. Lactulose can cause diarrhea and loss of Na and fluid loss. Antibiotics cause decreased gastrointestinal bacterial synthesis of vitamin K. Aminoglycosides result in increased loss of K, Mg and calcium due to altered excretion. Beta-blockers increase protein oxidation and increase the dietary protein requirements.

  

VII. Unresolved Issues and Emerging Future Research Areas:

 

·   The value of nutritional supplementation in non alcoholic cirrhosis has not been examined or investigated as much as in alcoholic liver disease. Studies that showed improved survival with aggressive nutritional therapy were mainly carried out in patients with alcoholic hepatitis, a reversible condition. Studies in our patient population are needed to clarify this issue.

·   The value of BCAA and BCKA in encephalopathy is not yet concluded and further studies are needed, specially in a population of non-alcoholic patients. Their value as nutritional supplements also needs further studies.

·   Prevention of malnutrition seems an interesting point to study. Does the prevention of malnutrition alter the progress of liver disease? Is it preventable? Are nutritional supplementation before malnutrition develops warranted and justified?

·   The long term effects of long term nutritional supplementation have not been extensively studied. Most studies were short term, and the value of prolonged use of increased intake is not known.

·   Magnesium supplementation and its relation to taste and dietary intake deserves further evaluation. Magnesium deficiency was found to be correlated to altered taste perception in cirrhosis ⁶⁴. The cause for this correlation is not known. Does correction of the magnesium level improve taste perception and dietary intake? Can this prevent the development of malnutrition? Will magnesium supplementation become standard therapy?

·   The use of anti-oxidants in liver disease has not been settled. Does viral injury involve membrane lipid peroxidation as alcohol injury? Are antioxidants of value? A poster in the Digestive Disease Week in Washington DC in May 1997 showed that vitamin E may ameliorate hepatitis C. This needs further randomized controlled trials. Are other anti-oxidants of value?

·   Lactobacillus feeding has been shown to decrease endotoxemia in experimental alcoholic liver disease ¹¹⁶. Can yogurt decrease endotoxemia clinically? The possibility and the value merits further studies.

·   Polyunsaturated fatty acids, MCT, and vitamin E ¹¹⁷  have been found to prevent alcohol induced experimental hepatitis. Their role in clinical practice needs further studies.

 

 

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Appendix I

Results of Trials Using  Oral Nutritional Supplementation for Malnutrition in Liver Disease

  

First Author, Year, Reference	#	Liver Disease	Treatment Arm	Control	Outcome
Keohane 1983 80	10	cirrhosis	80 gm protein, BCAA supplement	standard hospital	encephalopathy better with ttt (p<0.001) N2 balance positive, albumin increased
Kearns 1992 81	31	alcoholic cirrhosis	casein supplement	standard hospital	both positive N2 balance, no difference in mortality
Galambos 1979 82	16	acute alcoholic hepatitis	naso-gastric hyper-alimentation	no	N2 balance improved, albumin improved, no precipitation of encephalopathy
McGhee 1983 83	4	mixed etiology	2000 kcal, BCAA	2000 kcal, casein	similar, encephalopathy not better in ttt.
Mendenhall 1985 84	57	acute alcoholic hepatitis	standard hospital + 2200 kcal BCAA + oxandrolone	standard hospital	albumin, transferrin, RBP increased, mortality slightly better with ttt.
Calvey 1983 85	64	acute alcoholic hepatitis	standard hospital + 65 g amino acid or BCAA	standard hospital	delayed hypersensitivity improved with ttt, similar mortality
Soberon 1987 86	14	acute alcoholic hepatitis	Nasogastric amino acid mixture	35 kcal + 1.25 g/kg protein	N2 balance significantly better, albumin similar, encephalopathy similar, similar mortality
Cabre 1990 87	35	cirrhosis,  66% alcoholic	2115 kcal, BCAA	standard hospital	Albumin & Child score improved with ttt. mortality better in ttt (p=0.02) control intake very low

 

 

Appendix II

Results of Trials Using Parenteral Nutritional Supplementation for Malnutrition in Liver Disease

 

First Author, Year, Reference	#	Liver Disease	Treatment Arm	Control	Outcome
Nasrallah 1980 88	34	acute alcoholic hepatitis	standard diet + 70-85 g amino acids	standard diet, actual intake <1400 kcal	albumin and bilirubin better with ttt., mortality less (p=o.o6)
Diehl 1985 89	15	acute alcoholic hepatitis	standard diet + 52 g amino acids + 130 g glucose	standard diet, actual intake ~3000 kcal	albumin, RBP improved equally, no mortality in both arms
Naveau 1986 90	40	acute alcoholic hepatitis	standard diet + 2800 kcal glucose and lipid + 88 g amino acids	standard diet, actual intake ~2100 kcal	albumin improved more with ttt., transferrin RBP improved equally, mortality similar
Achord 1987 91	28	acute alcoholic hepatitis	standard diet + 42.5 g amino acids	standard diet, actual intake >1500 kcal	albumin, GEC, and histology improved with ttt., mortality similar
Bonkovsky 1991 92	39	acute alcoholic hepatitis	standard diet + 70 g amino acids + 100 g glucose	standard diet, actual intake >1500 kcal	albumin, transferrin, GEC improved, mortality similar
Simon 1988 93	34	acute alcoholic hepatitis	standard diet + 70 g amino acids, 50 g lipid, 100 g glucose	standard diet, actual intake ~3000 kcal	albumin, transferrin, GEC improved, mortality similar overall, but improved with severe disease
Mezey 1991 94	54	acute alcoholic hepatitis	standard diet + 52 g amino acids + 130 g glucose	standard diet + 130 g glucose	N2 balance better, albumin and mortality similar

 

 

  

Appendix III

Protein Contents of Different Food Portions

modified from the Joslin Clinic Food Lists