Low Protein Diet For Hepatic Encephalopathy

Ammonia Levels In Individuals Deficient In Cps1

CPS1 deficiency is a rare autosomal recessive genetic disorder that results in very little CPS1 activity . Individuals experience extreme hyperammonemia and the many detrimental effects that come with it . The prevalence of CPS1 deficiency is about 1 in 800,000 . Assuming strict Mendelian inheritance, if a mother and father each are heterozygous for a complete loss of function allele and have decreased CPS1 activity, there is a 1 in 4 chance that their children will have CPS1 deficiency. Working backwards from this assumption, the odds that both parents are heterozygous are 1 in 200,000. The odds that one parent is heterozygous is roughly 1 in 447. Therefore, heterozygosity for disease-causing CPS1 mutations is almost as prevalent as liver cirrhosis. However, regulatory effects may partially compensate for CPS1 heterogeneity, a scenario not explored in this study. The model predicts that individuals with CPS1 activity 50% of normal levels will have high blood ammonia levels. Most CPS1 disease allele carriers are likely unaware that they possess a mutation in one CPS1 allele that may result in higher than normal levels of blood ammonia. Lifelong exposure to high levels of blood ammonia may have unknown, deleterious effects on neural function.

Strategies To Increase Protein Intake In Older Adults With Cirrhosis

Due to the altered metabolism seen in cirrhosis, simply increasing calorie intake is not adequate enough to improve a patients nutritional status. Moreover, excessive calories may confer negative consequences on glycemic control, obesity rates, and steatosis. It is evident that increased protein intake is effective at managing cirrhosis, preventing complications of cirrhosis, and beneficial in preserving muscle mass and strength in older adults. Additionally, increased protein intake would bypass the potential complications seen with increased energy intake alone. Several different strategies have been explored as options to increase protein and amino acid intake in both older adults and cirrhosis.

Minimum Protein Intake at Every Meal

Timing of Protein Supplementation

Branched Chain Amino Acid Supplementation in Older Adults with Cirrhosis

What Is Hepatic Encephalopathy

HE is a brain condition that is caused by liver disease. Liver diseases such as cirrhosis prevent the liver from removing ammonia and other harmful substances from the blood. The harmful substances build up in the blood and prevent the brain from working correctly. Early treatment is needed to reverse the damaging effects of this condition and restore proper brain function.

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Plasma Ammonia Levels Likely Rise After A Meal

Our model predicts that blood ammonia levels will rise slightly by consumption of a high protein diet. Surprisingly, we could not find many studies in the literature examining dietary-induced changes in blood ammonia levels in healthy humans. One study found increased blood ammonia levels in women following consumption of a test drink containing whey protein. The ammonia level peaked at a value 20% higher than the initial level at 90min after consumption . Another study found increasing breath ammonia levels after a high protein challenge ammonia levels plateaued roughly 5h after the dietary challenge . However, breath ammonia levels do not always correlate well with blood ammonia levels. A further study using Huntingtons disease patients who were put on a high protein diet did not find any association between the high protein diet and blood ammonia levels .

Model Results Approximated Physiological Steady State Ammonia Levels

A computational model estimating blood ammonia levels in individuals without disease and those with liver disease was constructed. The model was first simulated using the parameters for a liver without disease and the recommended protein content in the diet to determine if the resulting steady state levels were consistent with clinical data. The recommended protein intake was taken to be 71g per day. The reference range for normal blood ammonia levels was taken to be 1132M . Normal blood urea levels are considered to be 3.67.1mM . The initial conditions in this study are 0M ammonia and 5.5mM urea. Fig. a shows the results of 774s of simulation of our model. The steady state ammonia level was 17.5M , and the steady state urea level remained around 5.5mM , both values well within the normal range.

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Reduce Salt To Help Manage Fluid Retention And Bloating

The liver plays a major role in regulating the balance of water and sodium in your body. When cirrhosis develops, the liver may lose this ability, leading to fluid retention. This can result in swelling of the feet and legs and in a build-up of fluid in the abdomen . The presence of ascites may cause abdominal discomfort and make it difficult to eat without feeling bloated and uncomfortable.

Fluid retention is generally managed with diuretics and in certain circumstances, by the drainage of fluid from your abdomen . Your health professional might also advise you to cut down on salt for example by following a no added salt diet.

If you are cutting down on salt, it is very important that you receive advice from a registered dietitian about the foods you can eat and those you should avoid. Some foods can surprise you and be much higher in salt than you would expect. And some products labelled as low-salt can have other ingredients that you should not have too much of. For example potassium can increase the risk of heart problems.

Tips to reduce the amount of salt you eat:

It is also important to be aware that some prescription and over the counter medications have a high salt content. If the sodium content on the labelling of your medication is not clear, or you are unsure if it is suitable, your pharmacist or doctor should be able to advise you.

• Lemon juice on fish or meat
• Olive oil and vinegar with salad and vegetables
• Mustard powder or nutmeg with mashed potato

Altering Dietary Protein Consumption In Cirrhosis Patients

Previous research has shown that there was an 80% reduction in GLUL activity and a 30% reduction in CPS1 activity in a rat model of liver cirrhosis . Results from adjusting the model to these parameters suggest that ammonia levels will increase with liver disease. Furthermore, a high protein diet will likely exacerbate these effects. We recognize that liver cirrhosis is a complex disease with many changes besides altered CPS1 and GLUL activity, so this model is a simplified representation of liver cirrhosis. Using an upper limit of 32M for the reference range of normal blood ammonia levels, the model indicates that a high protein diet with liver cirrhosis will result in a blood ammonia level that is at least 20% higher than the upper limit for the normal range . This elevation may contribute to HE. The model suggests that controlling protein intake could be one method to slightly reduce the likelihood of developing HE in some patients with liver cirrhosis.

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Hepatic Encephalopathy And Protein Intake

Nitrogen metabolism is significantly involved in the development of hepatic encephalopathy in cirrhotic patients . Therefore, modulation of this important relationship is necessary in the management of hepatic encephalopathy.

Early clinical observation revealed that bouts of overt hepatic encephalopathy among patients with cirrhosis could be controlled by reducing protein intake . The American College of Gastroenterology Practice Guidelines on Hepatic Encephalopathy recommend that for cirrhotic patients with acute encephalopathy, protein intake should be started at 0.5 g/kg/day with subsequent progressive increase to 1.01.5 g/kg/day, depending on patient tolerance .

Dietary Management Of Hepatic Encephalopathy

Copyright and License informationDisclaimerCopyrightThis article has been corrected. BMJ. 2000 January 22 320: 234

Myths are difficult to dispel and may delay good evidence based clinical practice. This is illustrated well by a paper in this weeks issue on the dietary management of hepatic encephalopathy in patients with cirrhosis .1 Protein restriction in symptomatic patients with hepatic encephalopathy has been the cornerstone of treatment since the 1950s,2 yet there is no evidence that it has any clinical benefit.

Hepatic encephalopathy is a syndrome of impaired mental status and abnormal neuromuscular function which results from major failure of liver function. Important factors contributing to it are the degree of hepatocellular failure, portosystemic shunting, and exogenous factors such as sepsis and variceal bleeding.3 The pathogenesis of the syndrome is still uncertain, although current hypotheses include impaired hepatic detoxification of ammonia absorbed from the gut4 and an increase in aromatic amines, which are precursors for false transmitters in the brainfor example, octopamineand which alter the balance between neuronal excitation and neuronal inhibition.5 Furthermore, increased expression of benzodiazepine receptors in hepatocellular failure suggests that the -aminobutyric acid-benzodiazepine inhibitory neurotransmitter system may be implicated in the development of hepatic encephalopathy.6

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Protein Recommendations For Older Adults With Cirrhosis: A Review

Jennifer Iiames, John V Logomarsino

Jennifer Iiames, MS, RD, Central Michigan University, 5115 Troy, Urbana Rd, Casstown, OH 45312, the United StatesJohn V Logomarsino, PhD, RD, LD/N, Central Michigan University, Dept of Human Environmental Studies, Mt. Pleasant, MI 48859, the United StatesCorrespondence to: Jennifer Iiames, 5115 Troy Urbana Rd, Casstown, OH 45312, the United StatesEmail: Henry1jn@cmich.eduPublished online: April 21, 2015

Changes In Enzyme Activity Levels Caused By Liver Cirrhosis Affected Blood Ammonia Levels

Liver cirrhosis has been shown to decrease the activities of two of the enzymes in the model, so decreasing the Vmax values accordingly can create a simple model of liver cirrhosis. As mentioned above, the recommended protein intake for a typical adult male is 71g of protein per day. The average American diet is about 100g of protein per day, and a high protein diet in our model was taken to be 122g of protein per day. The amount of protein in the high protein diet was calculated by using the highest values of ammonia and urea excretion in the published reference ranges and assuming nitrogen balance . To model liver cirrhosis, the Vmax of CPS1 was reduced to 70% of the normal value, and the Vmax of GLUL was reduced to 20% of the normal value . Following simulation, the steady state ammonia and urea levels were determined as described above. The steady state ammonia levels under the various conditions are shown in Fig. a. Ammonia levels increased with increased dietary protein intake and with decreased liver function. For simulations of a liver without disease, increasing protein consumption from the recommended protein intake to the high protein diet increased ammonia levels by roughly 59%. Simulations of cirrhosis led to increases of blood ammonia levels of 41 to 130% depending upon the level of protein intake.

Fig. 3

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Benefits Of Increased Protein Intake In Older Adults With Cirrhosis

Multiple studies have shown benefits to increasing protein intake in older adults, especially those with liver cirrhosis. The Recommended Dietary Allowance for protein in older adults is 0.8 g/kg. However, this amount has been shown to only prevent deficiency. Furthermore, it is the same as the RDA for younger adults and does not take into account changes that occur with aging including reduced muscle mass, increased fat mass, changes in food intake and physical activity, and more-frequent illness. Higher protein intake in older adults has been associated with reduced risk of strength loss and incident frailty. Also, women aged 60 and older with protein intakes of 1.2-1.76 g/kg/day tended to have fewer health problems than those with protein intakes of < 0.8 g/kg/day. General protein supplementation in bed rest studies has shown further evidence of the benefits of increased protein intake. Studies that did show benefit from protein supplementation had baseline diets of 0.6-0.8 g/kg/d and increased the protein given to 1-1.4 g/kg/d during the experimental phase. Studies with no benefit had baseline diet already at 1.0-1.2, further supporting the theory that an increased protein intake has a positive impact on older adults. While it is evident that increased protein intake has a beneficial effect on older adults in general, the same may also hold true for individuals with liver cirrhosis.

Supplements For People With Or At Risk Of Bone Disease

If you have established osteoporosis or are at risk, you should be given calcium and vitamin D supplements. Factors that contribute to bone loss need to be minimised, including alcohol and tobacco use. Steroid medication should be reduced whenever possible. If you have questions about your medication speak to your doctor.

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Effects Of Proteins In Patients With Cirrhosis And Prior Hepatic Encephalopathy

Hepatic encephalopathy is a major complication of cirrhosis associated with poor prognosis and poor quality of life. Appearance of HE occurs in the setting of precipitating factors that increase plasma ammonia. The gastrointestinal tract is the primary source of ammonia, which is produced by enterocytes from glutamine and by colonic bacterial catabolism of nitrogenous sources, such as ingested proteins. This is the rationale for proposing low-protein diet as strategy to reduce ammonia production and as standard diet in patients with cirrhosis and hepatic encephalopathy. However, low-protein diet could cause wasting muscle and predispose to recurrence of hepatic encephalopathy, since muscle is an important site for extrahepatic ammonia removal.

Administration of a normal-protein diet containing oral branched-chain amino acids may reduce recurrence of hepatic encephalopathy as compared to a low-protein diet.

Software And Statistical Methods

The model was built and simulated using the MATLAB R2016a SimBiology software package. Data was analyzed using Microsoft Excel and GraphPad Prism v7.0. For cell culture studies, three independent experiments were performed and data was analyzed with a repeated measures one-way ANOVA with Fishers post hoc test.

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What Are The Signs And Symptoms Of He

At first, you may have only mild symptoms. Over time, you may develop more severe symptoms:

• Mood changes, a short attention span, and drowsiness
• Confusion and forgetfulness
• Changes in sleeping habits and difficulty with speaking or writing
• A musty, sweet odor to your breath
• Flapping motion of your hands when your arms are outstretched
• Sleepiness and decreased awareness

Vegetable Versus Animal Protein As A Treatment And Prevention Strategy In Cirrhosis

Another treatment option that is popular in cirrhosis and hepatic encephalopathy is the focus of more vegetable protein and less animal protein. Mercaptans are by-products of methionine metabolism and are thought to contribute to development of HE in cirrhotic patients. It has been shown that vegetable proteins have significantly less methionine than animal protein. Vegetable proteins also have the benefit of having a higher fiber content, which causes decreased transit time and fecal ammonia excretion. Plasma arginine and citrulline concentrations are also higher in vegetable protein which facilitates ammonia removal via the Krebs-Henseleit cycle. It is because of these factors that some studies have examined whether vegetable proteins are better tolerated in HE than animal proteins.

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How Is He Diagnosed

Your healthcare provider will examine you and do a neurological exam. A neurologic exam can show healthcare providers how well your brain works after an injury or illness. Healthcare providers will check how your pupils react to light. They may check your memory and how easily you wake up. Your hand grasp and balance may also be tested. You may also need blood and urine tests to look for infection or test liver function. Healthcare providers may also use the tests to get information about your overall health.

Enzyme Activity Changes Had Different Effects On Ammonia And Urea Levels

To investigate the relative influences of CPS1 and GLUL on blood ammonia levels, enzyme activities were individually varied stepwise in the model for an individual without disease with a recommended protein intake, and steady state levels of ammonia were determined. The results show an inverse, non-linear relationship between CPS1 activity and ammonia levels . The steady state urea level did not show much change under any conditions tested likely because much larger changes are necessary to cause differences in the millimolar concentrations of urea compared to the micromolar concentrations of ammonia. Decreasing GLUL activity had almost no effect on steady state levels of ammonia . However, decreasing GLUL activity does affect the kinetics of ammonia formation. Eliminating GLUL activity caused the simulation to reach steady state ammonia levels much more quickly. In an individual without liver disease, the rate of ammonia formation for the first 12.9s of the simulation was 0.55 moles per second, but this rate increased to 0.83 moles per second when GLUL activity was inactivated . A sensitivity analysis of the kinetic parameters revealed that, as expected, changes in CPS1 activity have by far the strongest effect on blood ammonia levels of any enzyme in the model.

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Ammonia Levels In Individuals Deficient In Glul

Human subjects with decreased GLUL activity have been shown to have blood ammonia levels of 100150M , while mice with liver-specific GLUL knockout showed a blood ammonia level of roughly 150M . Our model, under otherwise normal conditions, shows no change in ammonia steady state levels when GLUL is reduced . This is a major limitation of the study possibly due to the enzyme kinetics data available, but it could also be due to the way we have modeled the hepatic acinus, the functional unit of the liver. The ratio of CPS1 to GLUL activity or the amount of time that ammonia is associated with CPS1 activity compared to GLUL activity may be too high in our model, resulting in deviations from in vivo results. This suggests that some of the changes in ammonia levels observed in our model may be too conservative. However, CPS1 deficiency has been demonstrated to lead to higher plasma ammonia levels than GLUL deficiency , indicating that GLUL does not exert as strong an effect on blood ammonia levels as CPS1.