Cirrhosis

Cirrhosis is a condition of diffuse hepatic fibrosis with replacement of the normal liver architecture by nodules. It is the final pathway for a wide variety of chronic liver diseases.

Progression of chronic liver disease to cirrhosis can take anywhere from weeks to years, depending on the disease etiology. Cirrhosis is a leading cause of mortality during the most productive years of life. There is no treatment to reverse cirrhosis.

A wide variety of chronic liver diseases lead to cirrhosis. The most common are toxic/metabolic (alcohol, non-alcoholic fatty liver disease, hemochromatosis), viral (hepatitis B and C), and autoimmune (autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis). Less common etiologies include biliary (atresia, stone, tumor), vascular (Budd-Chiari, cardiac), genetic (cystic fibrosis, lysosomal acid lipase deficiency), metabolic (alpha-1-antitrypsin deficiency, galactosemia, Wilson’s disease) and iatrogenic (biliary injury, drugs) conditions.

Cirrhosis can be classified as compensated or decompensated. Patients with compensated cirrhosis are often asymptomatic and may have no abnormalities on physical examination, laboratory tests, or imaging. Cirrhosis is called decompensated in the presence of hepatic encephalopathy, variceal bleeding, ascites, or jaundice.

Hepatic encephalopathy can result in lethargy, confusion, slurred speech, hallucinations, asterixis, obtundation, and coma. Hemorrhage from esophageal varices is not uncommon and can result in massive hematemesis and high mortality.

Patients with decompensated disease may also develop complications involving other organ systems, including renal failure due to hepatorenal syndrome, hypoxia caused by hepatopulmonary syndrome, pulmonary hypertension secondary to portopulmonary hypertension, or heart failure secondary to cirrhotic cardiomyopathy. The risk of liver cancer in patients with cirrhosis is estimated at about 1-2% per year.

Treatment of the underlying etiology of disease can occasionally revert decompensated cirrhosis back to a compensated state. However, those who do not improve with treatment should be considered for liver transplantation.

Risk Factors

Alcohol-related disease. Alcohol-use disorder is one of the main causes of liver disease and associated mortality. Approximately 1 in 12 adults have alcohol-use disorder defined as consumption of > 3 drinks per day in men and > 2 drinks in women, or binge drinking (defined as > 5 drinks in males and > 4 drinks in females, consumed over a 2-hour period). One drink is defined as a beverage containing 14 g of alcohol, which is approximately 12 oz. of beer, 5 oz. of wine, or 1.5 oz. of hard liquor.

Viral hepatitis. Established risk factors for the acquisition of chronic hepatitis B (HBV) and C (HCV) include intravenous drug use, chronic hemodialysis, blood transfusion or transplantation prior to 1992 (HCV), receipt of blood (including needle stick) from a person with HCV, receipt of clotting factor concentrates products before 1987, Asian ancestry (HBV), lack of vaccination (for health care workers) (HBV), and childbirth from a mother with chronic HBV or HCV. Possible risk factors include body piercing or tattoos, multiple sexual partners, sexually transmitted diseases, work in health care (HCV), and contact with HCV-positive persons.


Non-alcoholc fatty liver disease (NAFLD). Risk factors for the development of NAFLD include features of the metabolic syndrome, including type 2 diabetes, hyperlipidemia, hypertriglyceridemia, obesity (body mass index > 30 kg/m2), increased waist circumference ( > 89 cm in women and > 102 cm in men) and reduced high-density lipoprotein (HDL) cholesterol ( < 40 mg/dL in men and < 50 mg/dL in women). Other conditions associated with NAFLD include polycystic ovarian syndrome, obstructive sleep apnea, hypothyroidism, and hypopituitarism.

Medications. Long-term use of methotrexate, amiodarone, and tamoxifen can cause hepatic fibrosis and cirrhosis in certain patients.

Diagnosis

The diagnosis of cirrhosis is based on a combination of clinical, laboratory, and radiologic features. Generally, once a patient develops decompensated disease, the diagnosis is obvious and does not require further confirmation. Patients with compensated cirrhosis may lack obvious features. All patients with chronic liver disease should have an assessment of hepatic fibrosis to determine if cirrhosis is present.

Although more common in patients with decompensated disease, abnormal physical findings in cirrhosis can include spider nevi, palmar erythema, terry nails, gynecomastia, and caput medusa. Laboratory and imaging abnormalities are also more common in decompensated patients, including thrombocytopenia, hypoalbuminemia, coagulopathy, nodular appearing liver, collateral formation, splenomegaly, and ascites. Upper endoscopy may reveal esophageal and/or gastric varices, portal hypertensive gastropathy, or gastric antral vascular ectasia.

Liver function tests can be normal early in the disease, but they become abnormal as the liver is destroyed. Transaminase levels reflect hepatocellular injury; alkaline phosphatase reflects cholestasis; and albumin reflects hepatic synthetic activity. These levels may normalize in the late stages of cirrhosis as the liver will no longer produce transaminases. The prothrombin time will become elevated as the liver is no longer able to produce adequate amounts of coagulation factors. Thrombocytopenia (platelet count < 160 x 103/μL) is a sensitive marker of hypersplenism induced by portal hypertension.

Liver biopsy remains the most definitive means for assessment of hepatic fibrosis at this time, but suffers from sampling error, intra- and inter-observer variability, and lack of hepatopathology experience in many community settings. Noninvasive methods are increasingly popular but are not without limitations.

Noninvasive laboratory-based scoring systems include the aspartate aminotransferase-to-platelet ratio index (APRI), fibrosis-4 (FIB-4), and the NAFLD fibrosis score (NFS), among others.[1],[2]

Noninvasive imaging-based techniques for the assessment of fibrosis are constantly evolving, but currently include ultrasound and magnetic resonance- based elastography.[3] Patients with NAFLD as well as non-viral, non-alcohol-based etiologies of disease require liver biopsy for assessment of fibrosis.

Treatment

Management goals in cirrhosis patients are to treat underlying diseases and prevent complications. Treatment should be directed by a hepatologist and will vary based on disease etiology but may include alcohol abstinence, antiviral therapy, weight loss, and immunosuppression.

Complications that require screening include variceal hemorrhage, hepatocellular carcinoma, and acute viral hepatitis. Screening for varices is performed with upper endoscopy to determine the presence and size of varices and the need for primary prophylaxis with either variceal band ligation or non-selective beta-blocker therapy. Hepatocellular carcinoma screening is performed with abdominal ultrasound and serum alpha-fetoprotein levels every 6 months. Immunity to hepatitis A and B can be evaluated with serum laboratory testing and vaccination against both viruses is recommended if immunity is not present.

In decompensated disease, treatment is based on the presence of complications. Ascites is managed with diuretics and/or abdominal paracentesis, in addition to sodium restriction in the diet. Hepatic encephalopathy is treated with a combination of ammonia-lowering agents including lactulose and rifaximin. Variceal bleeding is managed with routine upper endoscopy for variceal surveillance and possible band ligation, as well as non-selective beta-blocker therapy.

Prognosis in cirrhosis can be estimated using the Child-Turcotte-Pugh (CTP) score as well as the Model for End-Stage Liver Disease (MELD) Score. MELD scores ≤ 9 are associated with a 1.9% mortality at 3 months. For MELD scores between 30-39, 3-month mortality has been estimated at 52.6%.[4],[5] Once a patient with cirrhosis has a decompensating event, liver transplantation should be considered by the treating hepatologist. Priority for liver transplantation is determined by calculation of the MELD score, with referral for transplant evaluation recommended at scores > 15.

Nutritional Considerations

Malnutrition can be present in up to 20% of patients with compensated cirrhosis and 50% of patients with decompensated cirrhosis and is associated with increased morbidity and mortality.[6],[7],[8] There is no universally accepted definition of malnutrition, but it is often defined as loss of skeletal muscle mass and strength, in addition to diminished subcutaneous and visceral fat mass (adipopenia), due to reduced protein and energy consumption.[9]

There are many contributing factors to malnutrition in cirrhosis. Decreased oral intake can occur due to anorexia, dysgeusia (often caused by zinc deficiency), and early satiety due to ascites as well as during hospitalizations due to procedures or hepatic encephalopathy.[10],[11] Malabsorption of nutrients can also occur due to decreased synthesis of luminal bile acids, coexisting chronic pancreatitis in patients with chronic alcohol use, portal hypertensive gastropathy and/or enteropathy, intestinal dysbiosis, and chronic lactulose use.[6],[10]

Patients with cirrhosis also have decreased hepatocyte mass and thereby decreased glycogen stores, which promotes gluconeogenesis. Aromatic amino acids and branched-chain amino acids are released from skeletal muscle via proteolysis for gluconeogenesis. Decrease in circulating branched-chain amino acids, as well as increased skeletal muscle ammonia production, endotoxemia, and low testosterone levels, all promote increased protein catabolism and decreased protein synthesis.[9],[11],[12],[13]

A comprehensive nutritional assessment in cirrhosis includes subjective global assessment (SGA), in addition to anthropometric and biochemical measurements.[14],[15],[16] The SGA is a questionnaire with both a history and physical examination component which can be used to classify patients into one of three stages: well nourished (Stage A); moderately malnourished (Stage B); or severely malnourished (Stage C).[17] The SGA can predict complications during liver transplantation in addition to post-operative outcomes.[18] Biochemical assessment should include hemoglobin, albumin, white blood cell count, retinol-binding protein, transferrin, liver function tests, glucose, cholesterol, urea nitrogen, C-reactive protein, pre-albumin, nitrogen balance, creatinine, sodium, magnesium, zinc, potassium, and others.[15],[19]

Anthropometric testing (height, weight, mid-arm circumference, triceps skin fold thickness, and biceps skinfold thickness), and body mass index (BMI) are important for assessing skeletal muscle mass and adipose deposit levels.[15],[16],[20]Given that edema and ascites can falsely elevate the BMI, corrective measures have been developed to subtract five, ten, or fifteen percent of the measured weight for mild, moderate or severe ascites, respectively, with an additional five percent subtracted for pedal edema.[21],[22] A state of malnutrition in cirrhosis has also been defined as a BMI ≤ 22 kg/m2 with no ascites, ≤ 23 kg/m2 with mild ascites, or ≤ 25 kg/m2 with tense ascites.[23] Functional testing using hand-grip strength as a tool to assess muscle strength has been shown to have the highest accuracy for detecting nutritional compromise in chronic liver disease.[24]

In addition to overall malnutrition, patients with cirrhosis often have micronutrient deficiencies. Fat-soluble vitamin deficiencies (vitamins A, D, E and K) are common, especially in patients with cholestatic liver disease, due to malabsorption, decreased intake, and reduced production of carrier proteins.[20],[25] Vitamin D deficiency has been independently associated with mortality in patients with cirrhosis and hepatocellular carcinoma.[26],[27] All patients should take 2,000 IU of vitamin D daily, with deficient patients requiring 50,000 IU weekly for 8-12 weeks, with a target 25-hydroxyvitamin D level ≥ 30 ng/mL.[11],[28] Patients may also be deficient in water-soluble vitamins, including thiamine (B1), and, less commonly, pyridoxine (B6), folate (B9), and cobalamin (B12) due to reduced hepatic storage.[11] Zinc and magnesium deficiencies are also common.[29] Zinc is needed for conversion of ammonia to urea and glutamic acid, and blood concentrations of this mineral are inversely associated with ammonia levels.[30],[31]

Supplementation with 150-175 mg/day can lower ammonia levels when used as monotherapy or when combined with vitamin A, C, and E supplementation.[32],[33] A daily multivitamin with minerals can address most of these deficiencies.

Malnourished cirrhosis patients should consume 35-40 kcal/kg/day (using body weight corrected for ascites) to promote anabolism.[23],[34] Macronutrient recommendations are for 1.2-1.5 g/kg/day of protein, 50-70% of calories from carbohydrates, and 10-20% of calories from fat.[35] With regard to protein, there is an increase in aromatic amino acids (AAA) and decrease in BCAAs in cirrhosis, which can promote hepatic encephalopathy and other neurologic complications.[20] Supplementation with 4 g of oral branched-chain amino acids daily can increase albumin and protein synthesis and decrease risk for hepatic decompensation.[36],[37],[38] The optimal timing, route of administration and preparation are still not entirely clear.[39]

Several studies have shown benefit in hepatic encephalopathy when meat protein is replaced with vegetable protein. A randomized clinical trial in patients with cirrhosis using a nutritional intervention with 1.0-1.5 g vegetable protein/kg/day for 6 months improved neuropsychiatric performance in patients with minimal hepatic encephalopathy and decreased the risk for development of overt hepatic encephalopathy, compared with no nutritional intervention.[40] In addition, a 14-day casein-vegetable, high-protein, high-calorie diet was shown to improve mental performance and decrease ammonia levels in 150 patients with overt hepatic encephalopathy.[41]

Vegetable protein may be preferable to animal protein for multiple reasons. Plant protein has fewer sulfur-containing amino acids and more arginine and ornithine than animal-based proteins. Sulfur-containing amino acids have been implicated in hepatic encephalopathy, due to the formation of indole compounds and mercaptans during digestion.[42] Arginine and ornithine facilitate ammonia disposal by way of the urea cycle.[42],[43]

The high fiber content of a plant-based diet can also help clear nitrogen waste products from the gastrointestinal tract.[44] Multiple uncontrolled studies have shown that vegetable and dairy protein is better tolerated than meat protein in patients with cirrhosis.[45],[46],[47] Both the European Association for the Study of Liver Disease and the International Society for Hepatic Encephalopathy and Nitrogen Metabolism recommend diets rich in vegetable and dairy protein.[11],[48] Studies directly comparing vegetable to dairy protein in cirrhosis have not been performed.

Fewer data are available for guidelines regarding carbohydrate and fat intake in cirrhosis. Current recommendations are for 50-70% of daily calories to come from carbohydrates, with the avoidance of simple sugars, particularly fructose.[49],[50] 10-20% of calories should come from fat, with an emphasis on intake of mono- and polyunsaturated fat and minimization of trans and saturated fat.[49],[51]

Sodium restriction is also an important part of dietary guidelines in patients with cirrhosis and ascites.[52] A 2 g sodium-restricted diet, when combined with diuretic therapy, is effective for controlling fluid overload in 90% of these patients.[53] High-sodium processed foods, specifically deli meats, canned soups, frozen meals, and packaged snacks, should be avoided. Fruits, vegetables, legumes, raw nuts, and whole grains are naturally low in sodium and should be encouraged.

In patients with cirrhosis and obesity, a hypocaloric diet (500-800 kcal below daily requirement) in combination with a high protein diet ~ 1.5 g/kg/day has been used to promote weight loss while preventing muscle loss.[54]

Other interventions with limited data include oral and enteral nutritional supplementation, probiotic supplementation, and coffee consumption. Reducing prolonged fasting in cirrhosis is critical to reduce sarcopenia and malnutrition. Patients with cirrhosis have increased fat oxidation, increased gluconeogenesis and decreased glycogenolysis after an overnight fast, comparable to 2-3 days of fasting in healthy subjects.[55] In patients with CTP class A cirrhosis, a nighttime nutritional supplement led to an increase in total body protein stores compared with the same supplement given during the day.[56] Although enteral feeding is occasionally used in malnourished cirrhotic patients admitted to the hospital, systematic meta-analyses have yet to show benefit in survival.[57],[58] Probiotic data are limited to very small clinical trials, but when probiotic VSL #3 was given to patients with alcohol and NAFLD-related cirrhosis for 6 months, there was reduced risk of hospitalization for hepatic encephalopathy, and improved CTP and MELD scores.[59]

Coffee consumption was shown, in a large systematic review, to be associated with a decreased risk of progression to cirrhosis, lower mortality rate in patients with cirrhosis, and lower rate of hepatocellular carcinoma development.[60]

There are no current guidelines recommending the use of any of these interventions at this time.

Orders

See Basic Diet Orders chapter.

Provide small, frequent meals with adequate energy, protein, and fluid.

Sodium less than 2 g daily.

Nutrition assessment by a registered dietitian.

Daily multivitamin with minerals.

What to Tell the Family

Cirrhosis of the liver is a life-threatening chronic illness, which is ultimately terminal without transplantation. However, the management of some cirrhosis cases may be improved with diet, thorough compliance with prescribed medications, and abstinence from alcohol.

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