LIVER DISEASE 2024-2025 PDF

LIVER DISEASE Maria Bletsa, MSc, PhDc Clinical Dietician - Nutritionist Academic year 2024 - 2025  Liver anatomy The liver is a large, reddish-brown organ that is located in the upper-right side of the abdomen, just below the diaphragm....

LIVER DISEASE Maria Bletsa, MSc, PhDc Clinical Dietician - Nutritionist Academic year 2024 - 2025  Liver anatomy The liver is a large, reddish-brown organ that is located in the upper-right side of the abdomen, just below the diaphragm. It is the largest internal organ in the body and is divided into two main lobes: the right lobe and the left lobe. The right lobe is much larger than the left lobe and makes up about two-thirds of the liver’s mass. The liver receives blood from two sources: the hepatic artery, which carries oxygen-rich blood from the heart, and the portal vein, which carries nutrient-rich blood from the digestive system. These two blood vessels enter the liver at the porta hepatis, which is located on the underside of the liver. Inside the liver, the blood flows through a network of small tubes called sinusoids. These sinusoids are lined with liver cells called hepatocytes, which perform many of the liver’s vital functions. The hepatocytes are arranged in small groups called lobules, which are roughly hexagonal in shape.  Liver anatomy The liver also has a complex system of ducts that carry bile, a digestive fluid that is produced by the liver and stored in the gallbladder. The bile ducts within the liver eventually join together to form the common hepatic duct, which carries bile out of the liver and into the small intestine. In addition to the hepatocytes, the liver also contains several other types of cells, including Kupffer cells, which are specialized immune cells that help remove bacteria and other foreign particles from the blood. The liver also contains stellate cells, which store vitamin A and play a role in liver fibrosis, a condition where scar tissue forms in the liver due to damage or disease. Liver anatomy Position of the liver and neighboring organs within the thoracic cage  Liver function The liver is an extremely important organ that performs many vital functions in the body. Some of the main functions of the liver include: 1.Metabolism: The liver is responsible for processing nutrients and medications that are absorbed by the digestive system. It also helps regulate the body’s metabolism by converting food into energy and storing excess energy as glycogen. 2.Detoxification: The liver is the body’s main detoxifying organ, breaking down harmful substances such as drugs, alcohol, and metabolic waste products, and removing them from the body. 3.Synthesis: The liver plays a key role in synthesizing important substances such as bile, which is necessary for the digestion of fats; blood clotting factors; and albumin, a protein that helps maintain fluid balance in the body. 4.Storage: The liver stores important nutrients such as vitamins, minerals, and glycogen, which can be released into the bloodstream as needed. 5.Immune function: The liver also plays a role in the body’s immune system, producing immune factors and removing bacteria and foreign particles from the blood. In short, the liver is essential for many of the body’s metabolic processes and plays a crucial role in maintaining overall health and wellbeing.  Liver function lab tests ▪ Hepatocellular labs→ Aminotransferase: alanine transaminase (ALT=SGPT) and aspartate transaminase (AST=SGOT) → markers of hepatocellular injury, which triggers the release of these enzymes into circulation ▪ Cholestasis labs → alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), 5’Nucleotidase (5’NT), serum bilirubin ▪ Synthetic function tests → ▪ total protein and albumin → decreased synthesis or poor Pr intake or protein loss ▪ prothrombin time (PT) → rate of conversion of prothrombin to thrombin (coagulation) ▪ the international normalized ratio (INR) → for patients under anti-coagulation treatment ▪ Serological tests → liver-related antinbodies for diagnosing and classifying autoimmune liver diseases ▪ Cholesterol ▪ Ferritin ▪ Alpha-fetoprotein (AFP) → tumor marker Liver blood tests Normal ranges AST= Πυροσταφυλική τρανσαμινάση ALT=Ασπαρτική τρανσαμινάση GGT= γ-γλουταμυλ-τρανσφεράση ALP= αλκαλική φωσφατάση  Liver imaging ▪ Primary imaging modalities to diagnose liver lesions: ▪ Liver ultrasonography (US) ▪ computed tomography (CT) ▪ magnetic resonance imaging (MRI) ▪ Endoscopy (gastroscopy) ▪ Endoscopic-Retrogade-Cholangio-pancreatography (ERCP) ▪ Biopsy  Hepatitis ▪ Hepatitis is classified as acute or chronic based on the duration of the inflammation and insult to the hepatic parenchyma. ▪ If the period of inflammation or hepatocellular injury lasts < six months → acute hepatitis. ▪ If the inflammation or hepatocellular injury persists > six months → chronic hepatitis. ▪ Common symptoms include fever, nausea, vomiting, fatigue, jaundice, right-upper-quadrant abdominal tenderness, and dark urine and pale stools. ▪ Extrahepatic manifestations may occur, particularly with chronic hepatitis. These include amenorrhea, arthritis, skin rash, vasculitis, thyroiditis, gynecomastia, glomerulonephritis, polyarteritis nodosa, and Sjögren’s syndrome. Complications of chronic hepatitis include end-stage liver disease, decompensated cirrhosis, and development of hepatocellular carcinoma.  Acute hepatitis - causes Infectious causes: Immunologic or inflammatory conditions Hepatotropic viruses: Autoimmune hepatitis Hepatitis A Virus(HAV), Hepatitis B Virus (HBV), Biliary disease such as primary biliary cholangitis Hepatitis C Virus (HCV), Hepatitis D Virus (HDV), or primary sclerosing cholangitis. Hepatitis E Virus (HEV) Metabolic or hereditary Nonhepatotropic virus: Epstein-Barr virus (EBV), Nonalcoholic fatty liver disease Cytomegalovirus (CMV), Herpes simplex virus (HSV), Coxsackievirus, Adenovirus, Dengue virus, Hemochromatosis Coronavirus-19 (COVID-19) Wilson's disease Bacteria, fungi, and parasites Pregnancy-related Toxin or substance-related causes include: Preeclampsia, Acute fatty liver of pregnancy, HELLP Alcohol-related: fatty liver disease, acute alcoholic syndrome hepatitis, or alcoholic cirrhosis Ischemic and Vascular Drugs and toxins Dose-dependent, e.g. acetaminophen (paracetamol), Non-dose- Cardiogenic/Distributive shock, Hypotension, dependent, e.g., idiosyncratic drug reaction most Heatstroke, Cocaine, methamphetamine, commonly related to antibiotics and ephedrine, Acute Budd-Chiari syndrome, anticonvulsants but also statins, NSAIDs, Sinusoidal obstruction syndrome herbal/nutritional supplements, Other toxins, e.g., Miscellaneous: Acute fatty liver of pregnancy, mushroom (Amanita phalloides), herbal and Malignancy, Reye' syndrome, Primary graft non- dietary supplements, carbon tetrachloride function after liver transplantation  Hepatites - causes Viral Hepatitis Hepatitis A Hepatitis B Hepatitis C Hepatitis D Hepatitis E Hepatitis G Autoimmune Hepatitis Alcoholic Hepatitis  Nutritional Considerations to Prevent and Manage Viral Hepatitis Patients with viral hepatitis, both acute and chronic, frequently have changed metabolisms that cause them to eat less and become malnourished. These patients may have higher morbidity and mortality rates if they are suffering from protein and calorie deficiencies. Malnutrition’s prognosis and overall survival are improved by early detection and timely treatment. Sanitation and hygiene: International travellers are more likely to contract hepatitis A (HAV) through handling or consuming contaminated raw fruits and vegetables. HAV must be rendered inactive by boiling or heating food and water for 1 min at 85 C [185 F]. Avoiding game foods and tainted seafood is important, as the majority of acute HAV infections are brought on by eating infected seafood. The microbial pathogens in saltwater can concentrate when shellfish are harvested from waters that have been polluted by sewage. Clams and oysters, for example, that have been harvested from the coastline are especially likely to be pathogenic. Animal products, particularly wild game and contaminated pig, as well as tainted seafood and produce, have all been found to contain hepatitis E (HEV).  Nutritional Considerations to Prevent and Manage Viral Hepatitis Avoiding iron supplements and foods strong in iron is also important, as patients’ hepatitis C progresses as a result of faster hepatic iron intake and the oxidative stress brought on by free radical generation stimulated by iron. A low- iron diet and phlebotomy help these individuals’ risk of developing hepatocellular carcinoma (HCC). Supplemental nutrition might also be necessary. Weight loss has been documented in 11–29% of treated patients who receive interferon treatment. Treatment with interferon can cause digestive symptoms, which can then lead to a decrease in appetite and food consumption. A diet with reduced fat and cholesterol may be beneficial. Hepatic steatosis risk is increased by chronic hepatitis C (CHC) infection. This issue is exacerbated by a larger dietary cholesterol intake, which is also linked to the advancement of liver disease brought on by hepatitis C.  Nutritional Considerations to Prevent and Manage Viral Hepatitis Adequate vitamin D status is important as patients with chronic liver illness frequently have vitamin D shortage and may have a harder time converting vitamin D to its active form. In patients with CHC, vitamin D levels and viral load appear to be inversely correlated. Vitamin D supplementation increases the likelihood that a patient will respond to treatment, but deficiency dramatically reduces the likelihood of a sustained virological response to pegylated interferon and ribavirin. Avoiding B12 status extremes is useful because patients with hepatitis C are better able to eliminate the virus from their systems when their B12 levels are adequate. However, very high serum B12 levels have been linked to hepatitis C RNA levels and may also promote viral replication. Chronic hepatitis C and coffee intake are associated because drinking coffee may be beneficial as it decreases oxidative DNA damage, increases the death of virus-infected cells, stabilises chromosomes, and decreases fibrosis. Acute liver failure GUIDELINES Acute liver failure GUIDELINES  Fulminant hepatitis Fulminant hepatitis (FH) is a severe condition characterized by rapidly progressive impairment of liver function in previously healthy individuals without pre-existing hepatic disease and with nutritional status usually preserved. FH refers to the development of acute liver injury, and may be secondary to a virus, drug, toxin, and autoimmune and metabolic diseases. The processes involved in the liver damage are not well understood, but are multifactorial and depend on the etiology of the disease, age and susceptibility of patients, and extent of hepatic injury. Major pathological liver features include severe necrosis with loss of hepatic architecture, and absence of adequate regeneration. FH is associated with high mortality rates, reported as high as 80%, depending on the etiology of the disease. Early assessment of FH severity and intensive support therapy in a specialized center are crucial for improving survival of these patients. Given that spontaneous recovery is not common, liver transplantation (LT) remains the only life saving treatment in most cases.  Fulminant hepatitis Dietary management  Wilson’s disease Wilson disease (hepatolenticular degeneration) is a rare, autosomal recessive disorder caused by abnormal copper accumulation in the body particularly involving the brain, liver, and cornea. It affects 1 in 30,000 individuals with a carrier frequency of 1 in every 90. Symptoms usually are related to the brain and liver. Liver-related symptoms include vomiting, weakness, ascites, swelling of the legs, yellowish skin, and itchiness. Brain or neurological symptoms include tremors, muscle stiffness, trouble speaking, personality changes, anxiety, and auditory or visual hallucinations. Wilson disease is an autosomal recessive condition caused by a mutation in the Wilson disease protein (ATP7B) gene. For a person to be affected, a copy of the gene from each parent need to be inherited. Diagnosis is difficult and involves blood tests, urine tests, and a liver biopsy along with the clinical evaluation. Genetic testing may be used to screen the family members of those affected. A diet low in copper-containing foods is recommended. Wilson’s disease  Diet low in Copper Food Groups Eat as Desired 6 Portions/Day Avoid Foods low in copper — less than 0.1 mg/portion. beef, eggs, white meat turkey and lamb, pork, pheasant quail, duck, goose, chicken, cold cuts and frankfurters squid, salmon, organ meats including liver, all fish except shellfish 3 oz, dark Meat & meat that do not contain pork, dark heart, kidney, brain, shellfish including meat turkey and chicken 3 oz, substitute turkey, dark chicken, or organ oysters, scallops, shrimp, lobster, clams, and peanut butter 2 Tbsp meats, all others not listed on high crab, meat gelatin, soy protein meat or moderate list substitutes, tofu, nuts and seeds bean sprouts 1 cup, beets 1/2 cup, spinach 1/2 cup cooked, 1 cup raw, most vegetables including fresh Vegetables tomato juice and other tomato vegetable juice cocktail, mushrooms tomatoes products 1/2 cup, broccoli 1/2 cup, asparagus 1/2 cup most fruits except as listed to right mango 1/2 cup, papaya 1/4 average, nectarine, commercially dried fruits including Fruits Fruits dried at home are permitted pear 1 medium, pineapple 1/2 cup raisins, dates, prunes; avocado  Diet low in Copper Food Groups Eat as Desired 6 Portions/Day Avoid Foods low in copper — less than 0.1 mg/portion. whole wheat bread 1 slice, Melba toast 4, dried beans including soy beans, lima whole wheat crackers 6, instant oatmeal 1/2 breads & pasta from refined flour, beans, baked beans, garbanzo beans, cup, instant Ralston 1/2 cup, cereals with 0.1 Starches – rice, regular oatmeal, cereals with pinto beans, dried peas, lentils, millet, to 0.2 mg of copper per serving (check label), breads & 0.2 mg of copper in any form 1/2 cup or small, pumpkin 3/4 cup, not listed on high or moderate list per serving (check label), soy flour, soy parsnips 2/3 cup, winter and summer squash grits, fresh sweet potatoes 1/2 cup, green peas 1/2 cup butter, cream, margarine, mayonnaise, non-dairy creamer, Fats, oils olives 2 med sour cream, oils, salad dressings (made from allowed ingredients) Milk & milk Most milk products, milk flavored all others chocolate milk, soy milk, cocoa products with carob, cheeses, cottage cheese  Diet low in Copper Food Groups Eat as Desired 6 Portions/Day Avoid Foods low in copper — less than 0.1 mg/portion. desserts that contain high most sweets, jams, jellies, and candies made amounts of ingredients rich in Sweets & desserts with allowed ingredients, carob, flavoring licorice 1 oz, syrups 1 oz copper, candy with nuts, dark extracts chocolate, or cocoa instant breakfast beverages, Postum and other cereal coffee, tea, fruit juices, fruit-flavored mineral water, soy-based Beverages, liquids, beverages 1 cup, carbonated beverages, lemonade, soups made with beverages, copper-fortified misc. beverages 12 oz, ketchup 2 Tbsp, allowed ingredients formulas, brewer’s yeast, multiple dehydrated and canned soups vitamins with copper or minerals  Nutrition tips for the patient with Wilson’s disease Nutrition Facts A low copper diet is generally adequate in all the nutrients necessary for good health. However, patients taking D- penicillamine may develop a deficiency of vitamin B-6 (pyridoxine), and the physician may prescribe a supplement of 25 mg daily. Special Considerations 1. The copper content in a specific food can vary depending on a number of factors. The copper content and the location of the soil in which the food was grown, or the method used to process the food, for example, can affect how much copper is in the food when eaten. In general, the low copper diet is meant to restrict foods that are usually high in copper, especially organ meats, shellfish, dried beans, peas, whole wheat, and chocolate that is high in cocoa such as dark chocolate. 2. Drinking water should be analyzed because it may contain too much copper. If the water contains more than 100 micrograms per liter, then bottled demineralized water should be used. This water should contain only 1 microgram of copper per liter. Demineralized water and distilled water are processed differently and may not contain the same amount of copper. Check with the physician or registered dietitian for more information. 3. Avoid drinking alcohol. It can be harmful to the liver, and the liver may already be damaged from Wilson’s disease. 4. Read food labels; some prepared foods list the copper content. Always check the labels of vitamin/mineral supplements to see if they contain copper. 5. For better control of copper intake, choose only average portions or serving sizes of foods. Examples of average portions are 90 to 120 g of meat, fish, or poultry, 1/2 cup of vegetables, one slice of bread. 6. Do not use copper cooking utensils. 7. Patient’s with Wilson’s disease should have initial and periodic consultations with a registered dietitian to make sure copper in the diet is being adequately controlled.  Hemochromatosis Hemochromatosis is a disorder associated with deposits of excess iron that causes multiple organ dysfunction. Iron is a mineral Normally, iron absorption is tightly regulated because the body is incapable of found in certain excreting excess iron. Hemochromatosis occurs when there are high pathologic levels foods. The body of iron accumulation in the body. needs iron to: Help hemoglobin Hemochromatosis has been called “bronze diabetes” due to the discoloration of the in blood cells skin and associated disease of the pancreas. carry oxygen Hereditary hemochromatosis is the most common autosomal recessive disorder in throughout the body. whites. Different types of hereditary hemochromatosis are: Type 1, Type 2a, Type 3, Make red blood Type 4 cells. Secondary hemochromatosis occurs because of erythropoiesis disorders and Produce certain hormones. treatment of the diseases with blood transfusions. After the damage of transfused red blood cells by macrophages, iron freed from heme is accumulated in the body. Secondary hemochromatosis is mainly caused by thalassemia, sickle cell anemia, hereditary spherocytosis, X-linked sideroblastic anemia, and pyruvate kinase deficiency. Excessive iron consumption also can cause hemochromatosis. Historically, this has resulted from drinking beer prepared in steel drums. Accidental and intentional overdoses of iron can result from the consumption of some over-the-counter dietary supplements. Hereditary hemochromatosis is the most common autosomal recessive disorder in whites, with a prevalence of 1 in 300 to 500 individuals.  Hemochromatosis The iron overload that causes hemochromatosis can occur in three ways: Massive oral intake of iron Increased iron absorption with normal iron intake Excessive production or massive transfusion of red blood cells  Hemochromatosis - pathophysiology Organs affected by hemochromatosis include the liver, pancreas, heart, thyroid, joints, skin, gonads, and pituitary. Excessive alcohol intake and viral hepatitis accelerate the pathology associated with hemochromatosis, especially with respect to the liver and pancreatic toxicity. Cirrhosis is present in 70% of patients with hemochromatosis. In these patients, there is a marked increased incidence of hepatocellular carcinoma, which is a significant cause of death. Diabetes is the primary manifestation of pancreatic iron deposition. The incidence of diabetes is approximately 50% in symptomatic patients, and the risk is increased in heterozygotes for hereditary hemochromatosis. Arthropathy manifests as joint pain without joint destruction. Cardiac symptoms result from iron deposition in the cardiac muscle fibers and cells of the conduction system. Symptoms are due to congestive heart failure as a result of dilated cardiomyopathy and cardiac arrhythmias. Hypogonadism, with resultant impotence, is due to iron-induced hypothalamic or pituitary failure, resulting in impairment of gonadotropin hormone release. Skin hyperpigmentation is a result of both iron and melanin deposition. It does not usually occur before the iron stores exceed five times the normal levels. Iron overload of macrophages can cause impaired phagocytosis and lead to decreased immunity, resulting in an increased risk of infection from Listeria, Yersinia enterocolitica, and Vibrio vulnificus. Patients with hemochromatosis should not handle or eat raw shellfish due to the increased risk of sepsis from Vibrio vulnificus. Iron deposition in the thyroid gland causes hypothyroidism. Iron deposition in the adrenal and parathyroid glands rarely results in clinical manifestations.  Hemochromatosis - evaluation The investigation should start with the measurement of serum transferrin saturation or serum ferritin concentration. The ferritin specificity can be affected by inflammatory conditions. Ferritin level above 200 mcg/L in women or 300 mcg/L in men or transferrin saturation of more than 40% in women or 50% in men should lead to further testing. Genetic testing for mutations will confirm the diagnosis in over 90% of cases. Radiography can be utilized in diagnosing organ involvement. Liver biopsy is the test that is most sensitive and specific for measuring liver iron content and can also assess liver damage. A liver biopsy is indicated in the following situations: 1. Elevated liver enzymes in a diagnosed case of hemochromatosis 2. Serum ferritin levels more than 1000 mcg/L Liver enzymes are usually elevated, with most patients having elevated aminotransferase levels, but the liver enzymes are usually not higher than twice the normal levels. Fasting blood glucose levels need to be checked for diabetes. Glycosylated hemoglobin levels might not be reliable in patients with high red cell turnover. Other tests that need to be done in patients with high ferritin levels are echocardiogram for cardiomyopathy, hormone levels to evaluate hypogonadism, and bone densitometry to evaluate for osteoporosis. First-degree relatives of patients with hemochromatosis should undergo screening with genetic testing.  Hemochromatosis - Treatment/Management The conventional therapy for primary hemochromatosis is phlebotomy. By drawing off red blood cells, the major mobilizer of iron in the body, iron toxicity, can be minimized. Patients may require 50 to 100 phlebotomies of 500 mL each to reduce iron levels to normal. Phlebotomy is usually performed once or twice a week. Once iron levels have normalized, lifelong, but less frequent, phlebotomy (typically 3-4 times a year) is required. The objective is to obtain a ferritin level of less than 50 mcg/L Iron removal through phlebotomy improves insulin sensitivity, skin pigmentation, and fatigue; however, cirrhosis, hypogonadism, and arthropathy remain unchanged. Alcohol should be strictly prohibited in this condition because it can accelerate liver and pancreatic toxicity. Preexisting end-organ damage is rarely reversed by phlebotomy. Treatment for associated end-organ dysfunction, such as insulin for pancreatic dysfunction, is indicated. If hemochromatosis is detected early, treatment prevents end-organ dysfunction, and there is little mortality or morbidity associated with it. However, patients rarely live more than two years after the diagnosis if severe end-organ damage has occurred. Patients who have end-stage liver disease may be candidates for liver transplantation.  Hepatosteatosis Fatty liver (also reffered to as hepatic steatosis or hepatosteatosis), is an accumulation of fat in the liver. While the term is attributed to numerous conditions, it's most commonly used in reference to fatty liver disease. Primary: insuline resistance, obesity, metabolic syndrome, diabetes melitus, dyslipidaimia Secondary:  NAFLD Terminology Prevalence of NAFLD Non-alcoholic fatty liver disease (NAFLD) incidence is rapidly increasing, especially in western countries, which is around 20 to 30%. Rising obesity levels, increasing incidence of childhood obesity, sedentary lifestyles, consumption of unhealthy quick eats, and a longer lifespan are some of the likely contributors. The incidence and prevalence of NAFLD are underestimated as ultrasonography is commonly used to screen for fatty liver disease. The prevalence of NAFLD is 80% to 90% in obese adults, 30% to 50% in patients with diabetes mellitus, 90% or more in patients with hyperlipidemia, 3 to 10% in children, and as high as 40% to 70% among obese children. Progression of NAFLD `  NAFLD Pathophysiology MFLD: an “old” new disease. Metabolic associated fatty liver disease (MAFLD) is present if hepatic steatosis is accompanied by either obesity or overweight (BMI >25 kg/m2 in white and >23 kg/m2 in Asian individuals), type 2 diabetes mellitus or evidence of metabolic dysregulation. At least two metabolic risk factors should be present for definition of metabolic dysregulation: waist circumference ≥102/88 cm in white men and women or ≥90/80 cm in Asian men and women; prediabetes; inflammation with elevated high-sensitive serum C- reactive protein level; elevated blood pressure or specific drug treatment; decreased HDL-cholesterol levels; increased plasma triglycerides levels; and homeostasis model assessment (HOMA)-insulin resistance score ≥2.5. Heterogenous factors lead to MAFLD, including ethnicity , sex, dietary habits, genetic predisposition, age, gut microbiota and metabolic status. NAFLD NAFLD is associated with an increased risk of developing chronic kidney disease, cardiovascular disease, and type 2 diabetes mellitus.  NAFLD – Evaluation/Diagnosis Mildly elevated serum aminotransferases are the primary abnormality in non- alcoholic fatty liver disease (NAFLD), although the liver enzymes are normal in the majority of patients. The ratio of aspartate aminotransferase (AST) to alanine aminotransferase (ALT) is less than 1. Gamma-glutamyl transferase (GGT), when elevated in non-alcoholic fatty liver disease (NAFLD), can be a marker of increased mortality. With the progression of the disease hypoalbuminemia, hyperbilirubinemia, thrombocytopenia, and prolonged prothrombin time present due to hepatic synthetic dysfunction. Ultrasound of the abdomen is routinely used to evaluate fatty liver, but a liver biopsy is considered the gold standard for the diagnosis of NAFLD. A non-invasive clinical scoring system called NAFLD in metabolic syndrome (MS) score was developed to predict the development of NAFLD in patients with metabolic syndrome. The clinical predictors included are BMI greater than or equal to 25, AST/ALT greater than or equal to 1, type 2 diabetes mellitus, and obesity. The positive likelihood ratio of developing NAFLD is 2.32 (low when the score is less than 3), and the risk is 7.77 (high when the five or more). Some of the other scoring systems are NAFLD fibrosis score (NFS), FIB-4 (fibrosis- 4) index, original ELF (enhanced liver fibrosis) test, AST-to-platelet ratio index (APRI), AAR, fibrometer, NAFLD-MS score. NAFLD – Treatment  NAFLD Dietary recommemdations NALFD – Dietary recommendations NALFD – Proposed mechanisms NALFD – Proposed mechanisms NALFD – Proposed mechanisms  NAFLD Dietary recommemdations NAFLD – Rapid weight loss Rapid weight loss/malnutrition (>2 kg/w) has been reported to induce hepatic inflammation and exacerbate steatohepatitis with progression to liver failure within a relatively short timeframe. Possible mechanism: increase in lipolysis and enhanced release of endogenous free fatty acid from adipose deposits. Fat is rapidly mobilized from visceral adipose tissue and free fatty acids flood the portal circulation in rapid weight loss and may perhaps overwhelm hepatic parenchyma.  Alcoholic Fatty Liver or Steatosis The alcoholic liver disease covers a spectrum of disorders beginning from the fatty liver, progressing at times to alcoholic hepatitis and culminating in alcoholic cirrhosis, which is the most advanced and irreversible form of liver injury related to the consumption of alcohol. There are three histologic stages of alcoholic liver disease: 1.Alcoholic Fatty Liver or Steatosis - At this stage, fat accumulates in the liver parenchyma. 2.Alcoholic Hepatitis - Inflammation of liver cells takes place at this stage, and the outcome depends on the severity of the damage. Alcohol abstinence, nutritional support, treatment of infection, and prednisolone therapy in severe cases can help in the treatment of alcoholic hepatitis, but more severe cases lead to liver failure. 3.Alcoholic Cirrhosis - Liver damage at this stage is irreversible and leads to complications of cirrhosis and portal hypertension.  Alcoholic Fatty Liver or Steatosis - Etiology Different factors, such as metabolic, genetic, environmental, and immunological, collectively play a role in alcoholic liver disease. The liver tolerates mild alcohol consumption, but as the consumption of alcohol increases, it leads to disorders of the metabolic functioning of the liver. The initial stage involves the accumulation of fat in the liver cells, commonly known as fatty liver or steatosis. If the consumption of alcohol does not stop at this stage, it sometimes leads to alcoholic hepatitis. With continued alcohol consumption, the alcoholic liver disease progresses to severe damage to liver cells known as "alcoholic cirrhosis." Alcoholic cirrhosis is the stage described by progressive hepatic fibrosis and nodules. Quantity and duration of the patient's alcohol intake are the highest risk factors for the development of liver disease. The beverage type plays a minimal role. Women are more susceptible than men. Obesity and high-fat diet also increase the risk of alcoholic liver disease. Concurrent hepatitis C infection is associated with younger age of onset, more advanced histological damage, and decreased survival.  Alcoholic Fatty Liver or Steatosis - Epidemiology Alcohol is the most frequently misused drug throughout the entire world and in the United States of America. In the United States, it is the leading cause of liver disease. It involves 61 percent of the American population, and among the 61 percent, 10 to 12 percent are heavy drinkers. The prevalence of alcoholic liver disease is highest in European countries. Daily consumption of 30 to 50 grams of alcohol for over five years can cause alcoholic liver disease. Steatosis can occur in 90% of patients who drink over 60 g/day, and cirrhosis occurs in 30% of individuals with long-standing consumption of more than 40 g/day. Definition of one alcohol drink as per the Centers for Disease Control and Prevention (CDC) is a half-ounce or 13.7 g pure alcohol which is the amount of alcohol present in: 340 ml beer (5% alcohol)/ 227 ml malt liquor (7% alcohol)/ 142 ml wine (12% alcohol)/ 43 ml “hard-liquor” (40% alcohol) At-risk drinking definitions are below: Men: over 14 drinks per week or more than four drinks per occasion Women and those over 65 years: over 7 drinks per week or greater than three drinks per occasion Definitions of significant drinking from a liver toxicity standpoint are as below (this history is essential to differentiate non-alcoholic fatty liver disease (NAFLD) from alcoholic fatty liver disease (AFLD) → Men: more than 21 drinks per week/ Women: over 14 drinks per week  Alcoholic Fatty Liver or Steatosis - Pathophysiology Alcohol metabolism by the liver is primarily via two enzymes: 1.Alcohol dehydrogenase 2.Aldehyde dehydrogenase Alcohol dehydrogenase converts alcohol into acetaldehyde, and aldehyde dehydrogenase converts acetaldehyde into acetate. The metabolism of alcohol increases the production of NADH by reducing NAD in the body. This shifting of metabolic balance toward the production of NADH leads to the formation of glycerol phosphate, which combines with the fatty acids and becomes triglycerides, which accumulate within the liver. When lipid oxidation (lipolysis) stops due to alcohol consumption, fats accumulate in the liver and lead to "fatty liver disease." Continued alcohol consumption brings the immune system into play. Interleukins with the help of neutrophils attack the hepatocytes, and swelling of the hepatocytes known as the "alcoholic hepatitis" takes place. Ongoing liver injury leads to irreversible liver damage, the cirrhosis of the liver.  AFLD – Clinical presentation Alcoholic steatosis (fatty liver) Alcoholic cirrhosis Asymptomatic Fatigue, malaise Weight loss May have vague abdominal discomfort Jaundice and scleral icterus (from hyperbilirubinemia) Hepatomegaly on examination Pruritus (bile salt deposition in the skin) Hepatic encephalopathy: Asterixis/ Lethargy/ Confusion/ Coma Alcoholic hepatitis Ascites (due to portal hypertension and decreased albumin) Low-grade fever Upper GI bleeding (esophageal varices from portal hypertension) Loss of appetite, nausea Skin changes: Telangiectasias / Caput medusae (dilation of Jaundice periumbilical veins) / Peripheral palmar erythema/ Clubbed nails Hepatomegaly Dupuytren’s contracture (flexion deformities of fingers from Portal hypertension → ascites thickening and shortening of palmar fascia) Hyperestrogenism: Lethargy, confusion (from Gynecomastia/ Hypogonadism (testicular atrophy) hepatic encephalopathy) Reduced libido/ Erectile dysfunction Infertility/ Amenorrhea Alopecia Smooth tongue due to 1 or more nutritional deficiencies (iron, folate, vitamin B12)  Jaundice Jaundice, also known as hyperbilirubinemia, is a yellow discoloration of the body tissue resulting from the accumulation of an excess of bilirubin. Deposition of bilirubin happens only when there is an excess of bilirubin, a sign of increased production or impaired excretion. The normal serum levels of bilirubin are less than 1mg/dl; however, the clinical presentation of jaundice as scleral icterus (peripheral yellowing of the eye sclera), is best appreciated only when the levels reach more than 3 mg/dl. Sclerae have a high affinity for bilirubin due to their high elastin content. With further increase in serum bilirubin levels, the skin will progressively discolor ranging from lemon yellow to apple green, especially if the process is long-standing. Icterus acts as an essential clinical indicator for liver disease, apart from various other insults. Yellowing of skin sparing the sclerae is indicative of carotenoderma which occurs in healthy individuals who consume excessive carotene-rich foods. Jaundice Treatment / Management: Treatment of choice for jaundice is the correction of the underlying hepatobiliary or hematological disease, when possible.  Ascites Ascites is the pathologic accumulation of fluid within the peritoneal cavity. It is the most common complication of cirrhosis and occurs in about 50% of patient with decompensated cirrhosis in 10 years. The development of ascites denotes the transition from compensated to decompensated cirrhosis. Mortality increases from complications such as spontaneous bacterial peritonitis and hepatorenal syndrome. Mortality ranges from 15% in a year to 44% in 5 years. In most healthy individuals, there is very little free intraperitoneal fluid; some women may have about 20 ml during the menstrual cycle. Ascites – Causes Ascites – Treatment Weight adjustment according to grading of ascites Weight adjustment according to peripheral oedema  AFLD – Management/treatment Management of alcohol liver disease depends on the extent of the disease. Medical Treatment Alcohol abstinence, enrollment to detoxification programs Nutritional support Screening for hepatocellular carcinoma with ultrasonography every six months and screening for esophageal varices in those with cirrhosis Chronic alcoholics are more prone to develop hepatotoxicity from acetaminophen, so dosing should not exceed more than 2000 mg per day. An average person can tolerate up to 4000 mg of acetaminophen per day. Treatment of co-existing liver diseases such as Hepatitis B and C viral infections Surgical Treatment If liver damage is irreversible, definitive treatment is a liver transplant in those who have shown a commitment to continued alcohol abstinence  Nutritional disorders and liver disease in heavy alcohol drinkers AFLD Deficiency or surplus of vitamins, major minerals, and trace elements in ALD  Assessment and management of malnutrition across the stages of alcohol-related liver disease  Hepatic cirrhosis Cirrhosis is characterized by fibrosis and nodule formation of the liver, secondary to a chronic injury, which leads to alteration of the normal lobular organization of the liver. Various insults can injure the liver, including viral infections, toxins, hereditary conditions, or autoimmune processes. With each injury, the liver forms scar tissue (fibrosis), initially without losing its function. After a long-standing injury, most of the liver tissue gets fibrosed, leading to loss of function and the development of cirrhosis.  Hepatic cirrhosis Etiology - Epidemiology Chronic liver diseases usually progress to cirrhosis. In the developed world, the most common causes of cirrhosis are hepatitis C virus (HCV), alcoholic liver disease, and nonalcoholic steatohepatitis (NASH), while hepatitis B virus (HBV) and HCV are the most common causes in the developing world. Other causes of cirrhosis include autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis, hemochromatosis, Wilson disease, alpha-1 antitrypsin deficiency, Budd-Chiari syndrome, drug- induced liver cirrhosis, and chronic right-sided heart failure. Cryptogenic cirrhosis is defined as cirrhosis of unclear etiology. The worldwide prevalence of cirrhosis is unknown; however, it has been estimated to be between 0.15% and 0.27% in the United States.  Hepatic cirrhosis - Classification Morphology classification Etiology classification This classification is not as clinically useful as Based on the cause of cirrhosis which is sub- etiologic classification. classified as follows: Micronodular cirrhosis (uniform nodules less Viral - hepatitis B, C, and D than 3 mm in diameter): Cirrhosis due to alcohol, hemochromatosis, hepatic venous Toxins - alcohol, drugs outflow obstruction, chronic biliary Autoimmune - autoimmune hepatitis obstruction, jejunoileal bypass, and Indian childhood cirrhosis. Cholestatic - primary biliary cholangitis, primary sclerosing cholangitis Macronodular cirrhosis (irregular nodules with a variation greater than 3 mm in Vascular - Budd-Chiari syndrome, sinusoidal diameter): Cirrhosis due to hepatitis B and C, obstruction syndrome, cardiac cirrhosis alpha-1 antitrypsin deficiency, and primary Metabolic - hemochromatosis, NASH, Wilson biliary cholangitis. disease, alpha-1 antitrypsin deficiency, Mixed cirrhosis (when features of both cryptogenic cirrhosis. micronodular and macronodular cirrhosis are present): Usually, micronodular cirrhosis progresses into macronodular cirrhosis over time.  Hepatic cirrhosis – Treatment/Management Damage to the liver is permanent. Further injury to the liver should be avoided to halt the progression of the disease. General management to prevent chronic liver disease includes avoidance of alcohol, vaccination for HBV and HCV, good nutrition with a balanced diet, weight reduction, and early treatment of precipitating factors like dehydration, hypotension, and infections. This is achieved by routine monitoring of volume status, kidney function, varices development, and progression to HCC. Specific therapy usually targets the etiology, including antiviral medications in viral hepatitis, steroids, and immunosuppressant agents in autoimmune hepatitis, ursodeoxycholic acid and obeticholic acid in primary biliary cholangitis, copper chelation in Wilson disease, and iron chelation and phlebotomy in hemochromatosis. Weight loss of at least 7% is beneficial in NASH, and alcohol abstinence is crucial in alcoholic cirrhosis.  Hepatic cirrhosis – Prognosis Predictive models for the prognosis of cirrhosis estimate the ten-year survival in patients with compensated cirrhosis at 47%, but this drops to 16% once a decompensating event occurs. The Child-Turcotte-Pugh (CTP) scoring or classification uses serum albumin, bilirubin, PT, ascites, and hepatic encephalopathy to classify patients with cirrhosis into classes A, B, and C. One- and two-year survival rates for these classes are 100% and 85% (A), 80% and 60% (B), and 45% and 35% (C). The model for end-stage liver disease (MELD) score is another model used to predict the short- term mortality of patients with cirrhosis. It uses serum bilirubin, creatinine, and INR to predict mortality within the next three months. Based on the MELD score (more recently the MELDNa score), the priority of organ allocation for liver transplantation for patients with cirrhosis is adjudicated in the US. Liver transplantation is indicated in decompensated cirrhosis that does not respond to medical treatment. The one-year and five-year survival rates after liver transplantation are approximately 85% and 72%, respectively. Recurrence of the underlying liver disease can occur after a transplant. Long-term side effects of immunosuppressant drugs is another cause of morbidity in transplant patients.  Cirrhotic sarcopenia  Nutritional screening and assessment in patients with cirrhosis Assessment and management of malnutrition in liver cirrhosis Nutritional screening and assessment in patients with cirrhosis Nutritional approach and management in patients with cirrhosis Micronutrients in patients with cirrhosis  Nutritional treatment in cirrhotic patients with bone diseases  Hepatic Encephalopathy Hepatic encephalopathy (HE) is a hallmark of liver failure and affects up to 40% of patients with liver cirrhosis. It is defined as a multifactorial neuropsychiatric disorder presenting with a broad spectrum of cognitive impairment and neuromuscular dysfunction. HE is a significant contributor to repeated hospitalizations for patients with liver cirrhosis and severely impacts on the quality of life of both patients and caregivers. It is a marker of poor prognosis in cirrhotic patients, with reported rates of survival of only 36% at 1 year from its first presentation.  Hepatic Encephalopathy - Pathopysiology HE can be classified as three separate clinical entities. Type A HE is due to acute liver failure Type B due to portosystemic shunting (e.g., transjugular intrahepatic portosystemic shunting procedures) Type C results as a complication of liver cirrhosis. Type A HE is associated with an increased intracranial pressure that progresses rapidly and may lead to brain herniation. The pathophysiology of Type B and C HE is complex and remains under investigation. The main hypothesis involves the limited ability of the liver to effectively remove nitrogenous waste products, resulting in their accumulation and the deleterious effects on the brain due to portosystemic shunting  HE – Pathophysiology Ammonia is produced from nitrogenous products by bacterial metabolism of urea and proteins in the gut and from deamination of glutamine in the small intestine. Normally, ammonia is cleared by liver and kidneys and metabolized in skeletal muscle. However, as a result of liver dysfunction and portosystemic shunting, ammonia cannot be cleared adequately. **Increased ammonia levels in the plasma increases metabolism to glutamine (via glutamine synthetase) in astrocytes, which subsequently causes intracellular swelling and edema.  HE – Diagnosis & clinical features →The onset of disorientation and asterixis is described as overt encephalopathy. → Arterial or venous ammonia levels can be helpful, but should not be used alone in diagnosis as they are often inconsistent. → Differential diagnosis? The American and European Associations for the Study of the Liver 2014 practice guidelines recommend that HE be classified according to four factors: 1. the underlying etiology as described previously – Type A, B or C; 2. severity – using grading system such as West Haven Criteria; 3. time course – episodic, recurrent (>1 episode in 6 months) or persistent (symptoms always present and can have episodes of acute exacerbations); and 4. nonprecipitated or precipitated by factors such as infections, medications or electrolyte disorders  Hepatic Encephalopathy – Treatment/management Treatment for HE involves proper identification and treatment of the underlying cause. Antibiotics (e.g., rifaximin, neomycin/paromomycin/metronidazole, or vancomycin) are often given empirically due to the frequency of infection as an underlying cause. Additional treatment measures include lactulose/lactitol (a non-absorbable osmotic laxative that also helps convert ammonia to non-absorbable ammonium in the gastrointestinal tract), LOLA (L-ornithine and L- aspartate preparation - increases the use of ammonia in the urea cycle to produce urea), zinc (to correct underlying deficiency common in cirrhotic patients) either alone or in combination with each other and/or antibiotics. Nutritional treatment for Hepatic Encephalopathy Branch-chained Amino Acids supplementation BCAAs (leucine, isoleucine and valine) do not require the liver for metabolism, and thus are preferentially used in liver failure. On the other hand, aromatic amino acids (AAAs) (phenylalanine, tryptophan and tyrosine) are not metabolized effectively in liver failure and thus accumulate. The expected ratio, the so-called Fisher’s ratio, or the BCAAs/tyrosine ratio (BTR) should be 3.5:1; however, this ratio falls to 1:1 in patients with ESLD, allowing preferential transport of the AAAs to occur across the blood-brain barrier. These are metabolized to octopamine, phenylethylamine, and phenylethanolamine, which are weak false neurotransmitters that compete with endogenous neurotransmitters, inhibit excitatory stimulation of the brain, competing with endogenous neurotransmitters, thus aggravating HE. In addition, tryptophan is metabolized to 5-hydroxytryptophan (serotonin), which can produce further lethargy. There is a debate on the use of BCAA-enriched versus standard amino acid formulas based on the hypothesis that decreased BTR contributes to HE. However, ESPEN guidelines do not recommend using specialized formulas. Etiology of Malnutrition in End Stage Liver Disease  Assessment of nutritional status in End Stage Liver Disease Patients Nutritional interventions before and after liver transplantation Malnutrition in patients undergoing liver transplantation: preoperative nutrition Malnutrition in patients undergoing liver transplantation: postoperative nutrition