INTRODUCTION

Hepatitis C is a viral infection of the hepatocytes spanning a spectrum from acute infection to chronic progressive liver disease and decompensated cirrhosis in advanced cases. Acute HCV is usually asymptomatic, very rarely leading to hepatic failure. More commonly though, Hepatitis C presents as gradually progressive chronic liver disease with up to 85% of patients going on to develop cirrhosis over the next 20-30 years (Figure1).

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As the primary metabolic organ in the body, liver holds a central role in the regulation of biochemical processes with respect to nutrient intake. Minimal hepatocyte injury in the earlier stages of HCV infection manifests only as subtle nutritional deficits. Only when a significant proportion of hepatocytes have been destroyed, as often seen in chronic liver disease in HCV patients, does the liver function begin to be affected. These alterations in liver function tend to result in poor nutritional intake as well as malabsorption of consumed nutrients and may have significant implications on the body’s nutritional status. Studies have indicated the prevalence of malnutrition to be as high as 60-90% among patients suffering from chronic liver disease (Lautz et al, 1992; DiCecco et al, 1989)

Malnutrition in HCV is a serious complication that negatively impacts survival, quality of life, and response to stressors like infections and surgery (Merli et al, 1996). In cirrhotic patients, it manifests not just in the form of Protein-Calorie Malnutrition (PCM) but also Micronutrient deficiencies, particularly in case of an advanced liver disease. Both PCM and micronutrient deficiencies have been linked with a poorer outcome in patients with compensated as well as decompensated cirrhosis. On the other hand, obesity correlates equally well with a poor prognosis in HCV patients and has been linked to high viral loads and liver damage in patients, particularly the elderly (Petta et al, 2010).  

PCM in chronic HCV has been linked to an increase in mortality as well as morbidity by predisposing patients to complications like Variceal bleeding and Ascites. It manifests as Sarcopenia or loss of lean muscle mass which is regarded as the most objective feature of malnutrition in patients with chronic liver disease.

Deficiency of micronutrients like Vitamins A, C, K, B complexes contributes equally to morbidity by causing skin and vision changes, coagulopathies and neurological symptoms.

HCV patients commonly co-present with obesity and fatty liver, which are thought to potentiate the pro-inflammatory state observed in these patients, as evidenced by the higher circulating and hepatic CRP levels in obese patients with HCV (Jonsson et al, 2008). In addition, Visceral adiposity is also thought to enhance HCV-induced whole-body Insulin resistance due primarily to the role of free fatty acids released by visceral adipocytes. Furthermore, Studies have demonstrated increased levels of ALT in overweight patients, suggesting an increased risk for liver disease (Ruhl, 2003).

Chronic liver diseases like hepatitis C that cause Cirrhosis are among the most common indications for liver transplantation worldwide (Mazurak et al, 2017). The Model for End-Stage Liver Disease or MELD score used by most Liver transplant centers for prioritization of organ allocation, despite its innumerable benefits, is limited by its failure to adequately include nutritional status in the evaluation of patients. For this reason, other tools like the Child-Pugh classification that use objective measures of nutritional status such as the International Normalized Ratio (INR) and Serum Albumin levels are deemed superior to the MELD score, further highlighting the importance of nutritional status as a prognostic indicator in patients with chronic HCV.ETIOLOGY:Malnutrition in chronic liver disease has a multifactorial etiology. Combined disturbances in dietary intake, absorptive capacity, and carbohydrate metabolism, as well as a negative energy balance, predispose patients to nutritional impairment in chronic liver diseases, like HCV (Figure 2).Food aversion and intolerance in hepatitis C secondary to signs and symptoms of CLD such as nausea, anorexia, gastritis, and encephalopathy lead to a reduced dietary intake. Additionally, most patients with hepatitis C treated with Interferons and Direct acting antivirals tend to experience loss of appetite and metallic taste as adverse effects. Deficiencies in Vitamin A and Zinc lead to an altered sense of taste for food, already low in Sodium, further compounding the problem of reduced oral intake.Bile salt deficiency due to reduced entero-hepatic recycling in patients with impaired liver function has been proposed as the primary mechanism of Malabsorption in cirrhotic patients (Romiti et al,1990).  Other contributing factors include altered intestinal motility and mucosal injury that may be secondary to portal hypertension or bacterial overgrowth, which in itself impairs absorption of nutrients via small intestinal mucosal surface. In addition to depletion of glycogen stores, Hepatocyte injury, in conjunction with insulin resistance impairs glucose regulatory processes like gluconeogenesis further increasing reliance on alternative energy fuels such as lipids and fats, for the metabolic needs of the body. In addition to the depletion of vital macromolecules, preferential oxidation of lipids further reduces the respiratory quotient in CLD patients relative to those with normal liver function (Merli et al, 1990)A combination of reduced urea hepatic protein synthesis, impaired intestinal protein absorption, and increased urinary nitrogen excretion predispose cirrhotic patients to sarcopenia and also lead to a lowered ratio of branched-chain amino acids to aromatic acids in the blood.  CLD patients often exhibit an increase in resting energy expenditure, as measured by indirect calorimetry. Hyper-metabolism thought to be due to an increase in beta-adrenergic activity has been found to correlate well with a reduction in survival in CLD patients by some studies (Müller et al, 1999). The increased frequency of hypermetabolism in patients with complications like ascites and its negative impact on survival highlight the need to identify and address these complications earlier on in the disease course. Obesity is often associated with elevated circulating levels of cytokines like Leptin released by adipocytes. These adipocytokines with pro-fibrogenic properties are thought to play an important role in inducing a state of low-grade inflammation and hepatic fibrosis due to their pro-fibrogenic properties (Saxena, 2015), as shown in Figure 3.  Free Fatty acids secreted by visceral adipocytes also impair insulin signaling in the skeletal muscle and liver by activating the lipid-activated protein kinase C family, contributing to insulin resistance in HCV patients (Kawaguchi, 2014).PRESENTATION:Nutritional assessment of patients with Hepatitis C allows for identification of nutritional risks that may contribute further to morbidity and mortality. Recognition of Macro- and micronutrient deficiencies is important as their correction with supplemental nutrition can significantly reduce the risk of infections as well as in-hospital morbidity and improve liver function parameters of such patients. This assessment needs to be much more detailed in patients presenting with decompensated cirrhosis as they are more likely to be at risk for nutrient deprivation. In general, adequate assessment of the nutritional status requires a thorough history, detailed physical examination, and appropriate laboratory investigations. HISTORYPertinent findings in patient history may include changes in weight, which can be quantified as the percentage of weight lost involuntarily over the preceding six months. Generally, weight loss > 10 % is taken as severe. It is important to note however that a patient with decompensated cirrhosis, presenting with salt and water retention may not be able to report an accurate history of weight changes. Dietary intake may be assessed using the 24-hour dietary recall to identify incorrect dietary practices commonly observed in patients with CLD, who are often advised to consume a diet low in protein by ill-informed attendants as well as healthcare practitioners. Other symptoms to inquire about include gastrointestinal disturbances such as diarrhea, vomiting or constipation that may indicate underlying malabsorption.The Severity of the underlying liver disease can be assessed by inquiring about complications like ascites and encephalopathy, that may manifest as increasing abdominal girth, respiratory difficulties and altered mental status or disturbances in sleep wake cycle. Micronutrient deficiencies may present in advanced cases of liver disease with symptoms like night blindness or photophobia (vitamin A), burning of the mouth or tongue (vitamin B12, folate), easy bruising (vitamin C, K), paresthesias (thiamine, pyridoxine) or even skin lesions (zinc, vitamin A, niacin).     PHYSICAL EXAMINATIONA general physical examination should be performed on all patients at risk for nutritional deficiencies with particular attention to the presence of peripheral edema and ascites, muscle wasting and signs of vitamin/mineral deficiencies such as pallor (iron deficiency), hyperkeratosis (vitamin A), dermatitis (vitamin A), bruising (vitamin C, vitamin K), glossitis (vitamin B12, folate, niacin), angular stomatitis (vitamin B12), and reduced lower extremity deep tendon reflexes (vitamins B12, B1). An accurate assessment of the patient’s weight and height needs to be performed and recorded for reference in future as it may facilitate tracking of the patient’s physical parameters.              Screening To date, several nutritional assessment tools have been developed, and although many of these remain in use in various parts of the world, no one tool has been accepted as the Gold standard yet. To be effective, a screening tool needs to be simple, easy to use and patient-friendly, and for that reason, Subjective global assessment is one of the most commonly employed scales to identify patients suffering from nutritional deprivation.It combines multiple elements of nutritional assessment to classify the severity of malnutrition from mild to severe. These components include recent weight loss, changes in dietary intake, gastrointestinal symptoms, functional capacity, signs of muscle wasting, and the presence of pre-sacral or pedal edema.  On the basis of these assessments, Patients are classified as well nourished (grade A), moderately malnourished (grade B), or severely malnourished (grade C)The SGA is a simple bedside method, proven to be adequate for the purpose of identification of malnutrition among patients with HCV. It is an excellent tool to assess nutritional status that can be applied on the bedside as it uses elements that can all be derived from a focused history and physical examination, rendering expensive and time-consuming laboratory tests unnecessary. SGA however, has not been found to be as reliable as handgrip strength, in predicting the complications of cirrhosis, as indicated by some studies (Alvares-da-Silva, 2005LABORATORY EVALUATIONSeveral laboratory and radiologic investigations may provide objective evidence of malnutrition in patients with HCV. Of these, specialized investigations like bioelectrical impedance analysis and Dual-energy X-ray absorptiometry are not performed routinely but may be indicated in certain cases of an advanced liver disease, cirrhosis or patients being evaluated for liver transplant.Serum levels of Proteins including albumin, pre-albumin, transferrin and coagulation factors which are generally regarded as useful indicators of nutritional status in the general population, are not as reliable in patients with decompensated cirrhosis due to hepatic synthetic dysfunction, limiting their use in HCV to patients with acute infection and early cirrhosis. Of these proteins, changes in levels of pre-albumin are more reflective of acute changes in nutritional status owing to its relatively short half-life of two to three days, as compared to albumin which has a half-life of approximately 20 days. Reduced hepatic synthesis, decreased muscle mass and increased tubular secretion are all responsible for decreased Serum levels of Creatinine, another marker of lean muscle mass, in cirrhosis. Serum levels of Fat-soluble vitamins may be normal in HCV patients in the absence of advanced liver disease when fat malabsorption due to impaired entero-hepatic recirculation of bile salts leads to deficiencies of these vitamins. Plasma levels of vitamins A, D and E, as well as INR, may be deranged in such patients. Levels of water-soluble vitamins such as folate and zinc may also be deranged. Serum Vitamin B12 levels may be elevated in chronic HCV and cirrhosis due to hepatic cytolysis and release of stored vitamins and minerals. Patients with a history of concurrent alcohol abuse may also show decreased levels of thiamine. Deficiencies of other B complexes may present with decreased levels of hemoglobin and deranged Mean corpuscular volume of RBC’s.         ANCILLARY TESTS

Anthropometry:Among anthropometric measures used to identify malnutrition in HCV patients, Mid-arm muscle circumference (MAMC) and Hand-grip strength have been found to be the best indicators of protein-calorie malnutrition. Based on studies, A mid-arm muscle circumference of <23 centimeters in combination with a handgrip strength of <30 kilograms is thought to have a sensitivity of 94 % and negative predictive value of 97 % for diagnosing PCM. Meanwhile, Body Fat reserves have found to correlate best with Skin-fold thickness, which has produced similar results as DEXA scans when used in studies on patients without ascites. For this purpose, the SFT over triceps may easily be measured at the midpoint between the acromion and olecranon using a calliper. A value lower than the 5th centile suggest severe malnutrition. Miscellaneous tests:Several other specialized tools for nutritional assessment can be used in certain cases of chronic liver disease, but are not routinely employed primarily due to their cost and limited availability.Bioelectrical impedance analysis (BIA) uses impedance which measures body water to estimate the fat content of the body. One of the limitations to its use is that even small variations in electrode placement tend to result in relatively large errors in measured impedance. Dual-energy X-ray absorptiometry (DEXA) scan can be used to accurately measure fat mass in patients with Chronic Liver Disease but is unable to estimate the lean body mass due to increases in extracellular water in patients with decompensated liver disease (McCullough et al, 1991).An accurate assessment of the nutritional needs using resting energy expenditure can significantly help in management of patients with chronic HCV as well as cirrhosis secondary to other causes. This can be done using either the Harris Benedict equation (HBE) that relies on factors like weight, age, gender, and height, or using Indirect Calorimetry which is considered to be the gold standard assessment (Peng et al, 2007). Because it is not widely available though, its use has been limited to patients unable to meet their nutritional requirements despite adequate therapy.    ManagementEnsuring adequate nutrition can significantly improve quality of life in HCV patients. Good nutrition results in improved compliance with pharmacologic therapy and has also been found to hinder disease progression by preventing the development of HCV complications like Cirrhosis and hepatic encephalopathy.   In the absence of Decompensated cirrhosis or comorbid conditions like Diabetes Mellitus, HCV patients usually do not require special diets. However, it is imperative that they consume a balanced diet, containing an adequate amount of calories and proteins to fight the infection as well as antioxidants to combat free radicals responsible for hepatocyte damage. In addition, frequent small meals have been found to improve nitrogen and substrate use, diminish fat and protein oxidation, and prevent depletion of glycogen stores. Major principles in Management of malnutrition in Chronic HCV revolve around restoring muscle health. In accordance with this, most interventions are focused on providing a diet that is adequate in proteins and calories, and integrate physical activity into the patient's lifestyle. Because management of malnutrition in such patients is directed at addressing the underlying etiology, it is important to obtain a good understanding of the nutritional intake patterns and barriers to healthy eating. The best way to achieve that is through a detailed history and physical exam at each clinic visit, as well as counseling sessions with a dietician, who may be able to further draw up an individualized plan for each patient based on his/her need. Because a dietitian may not be available in many clinical settings, physicians may need to familiarize themselves with guideline recommendations for both diet and activity.HCV Patients who are unable to meet their caloric requirements due to a diminished nutrient intake and early satiety should be advised to take frequent small volume meals up to 4-6 times/day (Amodio et al, 2013). Patients presenting with refractory ascites with a low MELD score and those suffering from portal hypertensive enteropathy may be offered TIPS in order to improve nutrient absorption. Replacement of trace elements such as zinc, magnesium, and vitamin A, may be considered in patients presenting with food aversion due to micronutrient deficiencies, as per their symptoms and serum levels. Enteral feeding via a feeding tube is only recommended for patients who are unable to consume food orally despite the above interventions, as tolerance is often an important issue with a significant number of patients prematurely removing their feeding tubes themselves. Therefore, an oral route should be preferred as the first line intervention, even in the presence of complications like esophageal varices. Due to the high risk of complications, PEG tube placement is discouraged as well. Patients with cirrhosis are prone to fluctuating sugar levels and are thus advised to avoid fasting longer than 6 hours as it may trigger a hypoglycemic episode and lead to additional complications. Cirrhotic patients are also advised to take small frequent meals throughout the day as well as an evening snack of complex carbohydrates to decrease lipid oxidation and reduce skeletal muscle proteolysis.It is generally recommended that HCV patients limit fat to 25% of the total calories in their diet. The general recommendation for diet composition is to limit Carbohydrates to 50%, mostly in the form of complex sugars, protein to 20% and total caloric intake to 30-40 kcal/Kg/day of the desirable body weight. It is also recommended that the consumption of processed sugars like fructose be avoided given its association with increases in the severity of liver fibrosis in HCV patients with genotype 1 (Petta et al, 2013). Substances like alcohol that can significantly enhance the rate of disease progression should also be avoided. DIETARY SUPPLEMENTATIONFor patients with advanced liver disease presenting with steatorrhea due to bile acid deficiency, fat-soluble vitamins and medium chain triglycerides that do not need bile for absorption may be supplemented in their diet. These are often available as nutritional drinks and can be easily taken even by patients with reduced tolerance to oral intake. Consuming vegetable-based proteins that contain fewer aromatic amino acids and supplementing the diet with branched chain amino acids should also be considered in patients at risk for hepatic encephalopathy, which is often accompanied by an impaired balance of these amino acids. Some studies have also implicated treatment with interferon and ribavirin in inducing this imbalance in the early stage of therapy, which further suggests the importance of correcting this imbalance early in the course of the disease.  PHYSICAL ACTIVITYModerate physical activity is recommended for all HCV patients and has shown improvements in muscle mass, exercise capacity and quality of life in general (Román et al, 2014; Zenith et al, 2014; Berzigotti et al, 2017). Exercise will not affect the course of infection, but it can help relieve fatigue, stress, and depression as well as improve appetite and strengthen immunity. HCV patients can also benefit from physical activity due to its effect on obesity. For patients with decompensated cirrhosis however, physical activity needs to be carefully prescribed and individualized to each patient's exercise tolerance and presence of complications like esophageal varices. Deconditioning and fatigue are major issues for patients with cirrhosis that represent significant barriers to physical activity (Ney et al, 2017). Formal guidelines for physical activity in cirrhosis are not yet available. Therefore, it is important that all patients undergo screening for varices and the required variceal prophylaxis before an exercise regimen is initiated (García et al, 1996; Bandi et al 1998).