Cirrhosis is the pathological replacement of functional liver tissue with scarred, fibrous, nonfunctional tissue (Bohm 2010). Most forms of late-stage chronic liver disease often manifest cirrhosis (Liou 2014).

Cirrhosis can progress for years before the patient experiences any symptoms (Liou 2014). In this phase, which is called "compensated cirrhosis," enough healthy liver tissue remains to carry out the important functions of the liver (UMMC 2013; BLT 2011). As the disease progresses to the point where there is not enough functional liver tissue remaining to support metabolic demands, "decompensated cirrhosis" emerges. A cirrhotic patient is deemed "decompensated" upon the emergence of symptoms such as ascites (fluid accumulation in the abdominal cavity), variceal bleeding (hemorrhage of dilated blood vessels, usually in the esophagus or stomach), hepatic encephalopathy (altered mental state due to the diseased liver's inability to remove toxins from the blood), or jaundice (yellowing of the whites of the eyes and skin) (MedicineNet 2014; Garcia-Tsao 2012).

Worldwide, cirrhosis prevalence is increasing in tandem with rising incidence of its primary risk factors: hepatitis virus infection, alcoholism, and non-alcoholic fatty liver disease (NAFLD) (Sirli 2012; Schuppan 2013). As of 2014, cirrhosis was the 12^th most common cause of death in the United States (National Center for Health Statistics 2013; Fox 2014; Garcia-Tsao 2012).

Owing to its myriad and diverse responsibilities within the body, functional liver loss leads to repercussions in several areas, including digestion, detoxification, circulation, energy production, and immune function, which can ultimately lead to the potentially life-threatening complications seen in decompensated cirrhosis: cardiovascular and pulmonary compromise; kidney failure; serious infection; gastrointestinal hemorrhage; and neurological, endocrine, and skeletal disorders (Liou 2014; Schuppan 2008).

Currently, the only definitive cure for cirrhosis is liver transplant (Manns 2013). However, awareness of modifiable risks such as alcohol consumption and obesity may help prevent the disease; early detection and treatment of underlying conditions may help slow its progression; and dietary and lifestyle changes may further improve quality of life in patients with cirrhosis (Liou 2014; Schwartz 2012; Plauth 2006; Amodio 2013; Purnak 2013).

This protocol will discuss the nature, causes, and outcomes of cirrhosis; outline current and emerging methods of diagnosis and treatment; and summarize state of the art nutritional support for the cirrhotic patient.

The liver has a vast array of metabolic responsibilities; as the largest organ of the digestive system, it (Marieb 2010):

• secretes bile to emulsify and absorb dietary fats (Nicolaou 2012)
• receives fatty acids and lipoproteins from circulation and repackages them for distribution throughout the body (McGillicuddy 2011)
• stores the bulk of excess glucose as glycogen to fuel the nervous system during periods of starvation
• processes most excess amino acids into glucose and detoxifies their byproduct (ammonia) into urea to be removed from the body (Kaloyianni 1990; Jungas 1992)
• stores vitamins (B₁₂, A, D, K) and minerals (iron, copper) (Loew 1999; Higashi, Sato, 2005; Shearer 1996; Anderson 2005; Roberts 2008)
• synthesizes albumin, the principal protein of the blood and a factor responsible for maintaining blood volume for proper circulation and oxygen transfer to peripheral tissues (Busher 1990)
• synthesizes most of the clotting factors, which are necessary for proper hemostasis during vascular damage (Mammen 1992)

The liver also functions as a biological filter, detoxifying foreign molecules and endogenous metabolites. The liver receives blood from the intestines (via the portal vein) and from the systemic circulation (through the common hepatic artery). The liver consists of several types of cells; of these, hepatocytes occupy almost 80% of the total liver volume and participate in most functions of the liver (Kmiec 2001). These extremely metabolically active cells are responsible for most of the liver’s detoxification, synthetic, and storage activities. Blood and its contents that have been filtered and metabolized by the hepatocytes exit the liver through the hepatic vein and enter the systemic circulation. Waste (excess hormones, foreign toxins, metabolites from dead cells) is excreted from the liver through its bile canaliculi and ducts, and along with bile, is stored in the gallbladder then poured into the intestines for ultimate excretion. In this way, the liver acts to constantly surveil the contents of circulating blood, and clear it of waste and toxins, while also providing a first-pass filtration of ingested foodstuffs from the intestines before they enter the general circulation (Marieb 2010).

Given its diversity of functions, it becomes apparent how stress on the liver (such as from excessive detoxification demanded during chronic alcoholism, infection by hepatitis viruses, or during storage of excessive amounts of fat) has the potential to affect several major processes simultaneously (eg, circulation, clotting, digestion, energy production, detoxification, waste elimination) and presents a serious health threat (Marieb 2010).

Cirrhosis can be the end stage of any chronic liver disease (Garcia-Tsao 2009). It begins with chronic inflammation, triggering the wound healing process and initiating tissue destruction and its replacement with new fibrous tissue. As the chronic disease persists, low level “wound healing“ and deposition of fibrous tissue continues, eventually building scar tissue with decreasing probability of being reversed and remodeled into functional tissue (Schuppan 2013).

Cirrhosis can be classified as compensated or decompensated. Compensated (where liver function is maintained) cirrhosis can remain asymptomatic for many years. Decompensated (marked by deteriorating liver function) cirrhosis is characterized by the development of a serious complication; once a complication of cirrhosis develops, the 5-year survival rate decreases to less than 20% (Liou 2014; Schuppan 2013; Garcia-Tsao 2009; D'Amico 2006).

There are many possible complications of cirrhosis:

Portal hypertension (high blood pressure in the liver). During cirrhosis, deposition of fibrous tissue increases resistance to the flow of blood through the portal vein of the liver; this increases portal blood pressure and causes portal hypertension. To alleviate the excessive pressure, new collateral blood vessels are generated, which bypass the liver and deliver intestinal blood to the other organs. Portal hypertension leads to dramatic changes in circulation, with detrimental consequences for kidney, lung, gastrointestinal, and cardiovascular function (Iwakiri 2014; Busk 2013; Biecker 2013; Aprile 2002). Portal hypertension is the cause of a majority of complications associated with cirrhosis (Tsochatzis 2014; Procopet 2013).

Ascites. Ascites is the the most common complication of cirrhosis; 50% of patients will develop ascites within 10 years (Liou 2014). Ascites is associated with a 50% increased risk of mortality over two years (Moore 2006). Ascites, an increase in free fluid in the abdomen, is due to increased pressure of hepatic circulation that forces blood plasma (the clear, fluid portion of the blood) out of blood vessels and into the body cavity (Chung 2013; Gatta 2012; Moore 2006).

Bacterial peritonitis. Infection of the ascitic fluid in the abdominal cavity occurs in about 30% of patients with cirrhosis and ascites; it has an in-hospital mortality rate of about 20% (Liou 2014; A.D.A.M. 2014). Decompensated liver cirrhosis delays intestinal motility and increases intestinal permeability, both of which facilitate the translocation of harmful bacteria out of the intestines (Bruns 2014).

Coagulopathy. The majority of protein factors responsible for blood clotting, as well as those that prevent clotting, are synthesized in the liver. In patients with severe liver disease, the ability to synthesize these factors is reduced, and clotting disorders (coagulopathies) are possible. These often manifest as increased bleeding (hemorrhagic coagulopathies), although increased clotting (thrombosis) is also possible. The liver also manufactures protein factors that stimulate blood platelet production, and cirrhotic patients can have low platelet counts (thrombocytopenia) that further increase bleeding risk. Additionally, liver disease can result in malabsorption of fat-soluble vitamin K, a cofactor for the activity of multiple enzymes in the clotting cascade. A variety of tests can be used to monitor changes in clotting in patients with cirrhosis-related coagulopathies (see Life Extension’s Blood Clot Prevention protocol for detailed descriptions of these tests). Severe bleeding episodes are treated by a number of methods, including vitamin K injection, plasma or platelet transfusion, blood protein transfusion (cryoprecipitate), or clot-forming drugs; thromboses and embolisms are treated with injectable anticoagulants (Amarapurkar 2011).

Gastroesophageal varices. Esophageal varices are abnormal, enlarged veins in the lower part of the esophagus. Gastric varices are enlarged veins in the stomach. Both result from portal hypertension (Garcia-Tsao 2007). Rupture and hemorrhage is a major complication of varices, with a 15-20% risk of mortality from each bleeding episode (Albillos 2014). Varices are present in 30-40% of patients with compensated cirrhosis and about 60% of patients with decompensated cirrhosis at the time of diagnosis (Liou 2014; Henry 2014).

Hepatocellular carcinoma. As of 2013, hepatocellular carcinoma was the fifth most common cancer in men and the seventh in women worldwide (Kmiec 2001). The chronic inflammatory environment of cirrhosis plays an essential role in the development of hepatocellular carcinoma (Ding 2014; Berasain 2009).

Hepatopulmonary syndrome. Hepatopulmonary syndrome, a serious complication of liver cirrhosis, is present in 10-17% of patients with liver cirrhosis and is associated with a poor prognosis (Nusrat 2014). In hepatopulmonary syndrome, portal hypertension causes bacteria to cross from the intestines into the bloodstream. The body responds by secreting a vast number of different cellular messengers, which cause blood vessels, particularly those of the lungs, to dilate, which then causes inadequate blood oxygenation. Thus, a symptom of hepatopulmonary syndrome is dyspnea, or breathing difficulty (Tumgor 2014).

Hepatic encephalopathy. A failing or cirrhotic liver is not able to effectively metabolize ammonia into urea, which results in a buildup of this toxin in the blood and in the brain, causing hepatic encephalopathy (Siegel 2006; Garcia-Tsao 2012; Rivera-Mancia 2012; Krieger 1995). Patients can exhibit various neuropsychiatric signs and symptoms: confusion, sleep disruption, cognitive and intellectual dysfunction, impaired motor activity, slowed or slurred speech, and incoordination. Coma and even death are possible in severe cases.

Hepatorenal syndrome. Approximately 20% of hospitalized cirrhosis patients with ascites will develop kidney dysfunction (Liou 2014). Hepatorenal syndrome is a functional renal failure that develops as less blood is available to circulate to the kidneys (Angeli 2012). This is a result of alterations in systemic circulation that accompany portal hypertension. Hepatorenal syndrome is almost always accompanied by ascites and can lead to rapid (type I hepatorenal syndrome) or slowly progressing (type II hepatorenal syndrome) kidney failure (Lata 2012). Signs and symptoms can be non-specific and may parallel those of liver disease (nausea, weight gain, dark urine), although low blood pressure, increased heart rate, low blood sodium, and sustained increases of nitrogenous compounds such as creatinine and urea in the blood (azotemia) are warning signs for the disease (Ng 2007; A.D.A.M. 2012; Lata 2012).

Immune dysfunction. Cirrhosis is associated with various levels of immune dysfunction, referred to as cirrhosis-associated immune dysfunction syndrome. Cirrhosis reduces production of immune-signaling molecules in the liver, depresses activity and abundance of innate immune cells, and increases production of antibacterial antibodies that may also have autoimmune activity (Sipeki 2014).

Malnutrition and hepatic cachexia. Malnutrition in cirrhotic patients is characterized by the loss of skeletal muscle and lean body mass (sarcopenia), adipose (fat) tissue (adipopenia), or both (hepatic cachexia), and does not respond to adequate dietary intake of fats or protein. Malnutrition, especially protein malnutrition, is associated with an increased incidence of several major complications of cirrhosis (including sepsis, ascites, and hepatic encephalopathy), increased mortality, and reduced quality of life (Periyalwar 2012). Malnutrition in cirrhosis patients may also include micronutrient deficiencies (Periyalwar 2012); cirrhotic patients are often deficient in water-soluble vitamins (especially thiamine) and minerals (Amodio 2013), and those with cholestatic liver disease (a disease that affects bile flow) may have difficulty absorbing fat-soluble vitamins (A, D, E and K) (Purnak 2013; Jaurigue 2014).

Other complications of cirrhosis include:

• Hepatic hydrothorax. Hepatic hydrothorax is a relatively uncommon complication (5-10% of patients with cirrhosis and ascites) in which fluid accumulates in the compartment around the lungs, potentially leading to breathing difficulties (Liou 2014; Norvell 2014).
• Endocrine disorders. Testicular atrophy and low testosterone levels are frequent in men with cirrhosis, and this can be associated with signs of feminization and gynecomastia. The liver and adrenal glands have a complex interrelationship, and adrenal insufficiency is common in patients with stable and decompensated cirrhosis (Burra 2013; Trifan 2013).
• Hepatic osteodystrophy. A metabolic bone disease that can occur in patients with chronic liver disease, hepatic osteodystrophy can result in osteoporosis (loss of bone density and mass) and/or osteomalacia (softening of bones).

Almost any chronic liver disease can develop into cirrhosis. One of the most common causes of cirrhosis globally is chronic viral hepatitis, with 30% attributed to chronic hepatitis B virus (HBV) infection and 27% to chronic hepatitis C virus (HCV) infection (Nishioka 2002; Dwyre 2011). Risk factors for infection include intravenous drug use, unprotected intercourse, blood transfusions, and tattoos (Perz 2006). Alcoholic liver disease is the second major worldwide contributor to cirrhosis incidence, accounting for almost one-third of cases (NIDDK 2014a). Non-alcoholic fatty liver disease (NAFLD) and its more severe form, nonalcoholic steatohepatitis (NASH), are common causes of cirrhosis in the United States and are highly associated with obesity and metabolic syndrome (Armstrong 2014). NASH currently affects 2-5% of Americans; NAFLD is present in an additional 10-20% in the United States (NIDDK 2014c; Ferri 2014). NASH is now the third most common cause of cirrhosis after viral hepatitis and alcoholic liver disease (NIDDK 2014a).

Of these, hepatitis C deserves special attention because it is often asymptomatic and may not be detected until cirrhosis is already present, which can be many years after the virus is contracted (NIDDK 2012b). It is a common infection in the United States, affecting over 3 million people. The most common cause of transmission today is the use of shared drug injection needles or equipment. Before 1992, when the blood supply was not tested for it, hepatitis C was transmitted through blood transfusions and organ transplants. Maternal-fetal transmission is also possible (CDC 2014). Hepatitis C viral infection is detectable with blood tests (NIDDK 2012b), and hepatitis C can be treated before it progresses to cirrhosis (Keating 2014; FDA 2013).

Aside from these top causes, there are several other less common chronic liver diseases that can lead to cirrhosis (Baertling 2013; Welty 2014; Haafiz 2010; Liou 2014; Moyer 2009; NIDDK 2012a; Fairbanks 2008):

Autoimmune hepatitis: an autoimmune disease in which the immune system attacks the body’s own hepatocytes

Cholestatic liver diseases (diseases that interfere with the production or flow of bile), such as:

• Primary biliary cirrhosis: a chronic and slowly progressive inflammatory liver disease that is thought to be autoimmune in origin and results from damage to the small bile ducts
• Primary sclerosing cholangitis: a condition often associated with inflammatory bowel disease that results in inflammation and fibrosis, which causes narrowing and dilation of the intrahepatic and extrahepatic bile ducts
• Cystic fibrosis: an inherited condition characterized by thick secretions that mainly affect the lungs, pancreas, intestines, and liver
• Biliary atresia: congenital malformation of bile ducts

Inherited metabolic disorders, such as:

• Alpha-1 antitrypsin deficiency: a genetic disease that can cause chronic liver disease, cirrhosis, and hepatocellular carcinoma
• Wilson’s disease: an inherited copper storage disease
• Hereditary hemochromatosis: iron storage disease
• Glycogen storage diseases: excessive liver storage of glycogen
• Abetalipoproteinemia: inability to synthesize certain lipoproteins and to absorb fats and fat-soluble vitamins

Budd-Chiari syndrome: thrombosis (clotting) of liver blood vessels

Clinical Signs and Symptoms

Clinical signs and symptoms of cirrhosis include (NIDDK 2014a; A.D.A.M. 2013):

• Fatigue/weakness, loss of appetite, weight loss, nausea, abdominal pain, and pruritus (itching), which are common symptoms of cirrhosis, although not specific to cirrhosis
• Splenomegaly, a palpably enlarged spleen, which can sometimes be felt on physical exam
• Spider angioma (spider veins) are occasionally seen

The consequences (sequelae) of cirrhosis can also result in distinctive associated symptoms in individuals with advanced disease (Park 2013; NIDDK 2014a; Elwell 2003; Cavanaugh 1990; Yurci, Yucesoy 2011; Stillman 1990; Nayak 2012).

• Abdominal distention due to the abdomen filling with ascitic fluid
• Jaundice (Icterus), a yellowing of the skin and sclera (whites of eyes) can be seen in advanced stages of cirrhosis. This is due to the buildup of bilirubin, a yellow waste pigment from the normal breakdown of old red blood cells that is usually removed from the blood by the liver
• Bruising or excessive bleeding from loss of coagulation (clotting) protein production
• Melena, or dark stools resulting from digested blood in feces, and “coffee ground” emesis, which is vomiting of digested blood, may result from a combination of coagulopathy and disordered gastrointestinal hemodynamics proceeding from portal hypertension
• Pale or clay-colored stools that result from lack of bile secretion
• Altered mental state, including confusion, personality change, slowed or slurred speech, memory loss, trouble concentrating, and changes in sleep habits can result from hepatic encephalopathy
• Asterixis (flapping tremors), intermittent involuntary muscle contractions, usually of the wrists and hips, can also be caused by hepatic encephalopathy
• Lower extremity swelling/peripheral edema due to low albumin in the blood leading to abnormal fluid collection in tissues
• Recurrent infections due to immune dysfunction
• Dyspnea (difficulty breathing) from hepatopulmonary syndrome
• Hypogonadism, a syndrome of low testosterone and libido, impotence, and shrinkage of the testes, may also cause gynecomastia (male breast enlargement)
• Bone loss or fracture from metabolic bone disease

Testing

Several tests, both non-invasive and invasive, can aid in confirming a diagnosis of cirrhosis (Kim 2014).

Biochemical tests. Multiple markers of liver function can be measured from blood samples. Alanine transaminase (ALT or SGPT) and aspartate transaminase (AST or SGOT) are released by damaged or inflamed hepatocytes; gamma-glutamyl transferase (GGT) and bilirubin are indicators of cholestasis (failure of the liver to excrete bile). All four can become elevated during liver disease. Patients with cirrhosis also show increased alkaline phosphatase (ALP) activity. Several compounds synthesized by a healthy liver (haptoglobin, apolipoprotein-A1, albumin, alpha-2-macroglobulin) may fall with the onset of liver damage. Panels that test several markers concurrently (eg, Fibrotest, APRI, or the European Liver Fibrosis Panel) are widely validated and are good predictors of fibrosis and cirrhosis, but are insufficient for evaluating dynamic changes (Kim 2014; Ohkubo 1994).

Diagnostic imaging. Ultrasound (US) is an inexpensive, non-invasive imaging modality that constructs dynamic 2D images using high-frequency sound waves. It can be used to assess several liver parameters (eg, size, bluntness of edges, coarseness of liver tissue, presence of surface nodules) that may be consistent with hepatic fibrosis. Doppler ultrasound can additionally measure velocity of blood flow in the liver, and may detect changes in portal vein volume and velocity and arterial resistance in the liver, which may be evident in portal hypertension. Contrast-enhanced ultrasound is a more recent technique that involves the injection of “microbubbles” intravenously prior to imaging, which enhances the ultrasound signals and allows for more detailed measurements of blood flow. Computed tomography (CT) is a three-dimensional x-ray imaging technique for visualizing internal structures; magnetic resonance imaging (MRI) is an imaging technique that produces cross-sectional images using radio waves in powerful magnetic fields. Both are useful methods for visualizing advanced liver disease and are standard methods for diagnosing hepatocellular carcinoma in cirrhosis patients. Both are suitable for imaging the anatomical features of advanced cirrhosis (surface nodules, prominent fibrous bands, shrinkage of liver volume, and an enlarged portal venous system), but are not as useful for diagnosing early stages of cirrhosis where these features may be absent (Kim 2014).

Elastography. Elastography is a newer ultrasound-based method that measures liver stiffness as a marker for fibrosis, enabling diagnosis of liver fibrosis in earlier stages before obvious changes in liver architecture like surface nodules may be present (Adebajo 2012; Sirli 2012). Two newer technologies, transient elastography and acoustic radiation force impulse elastography, utilize different ultrasonic strategies to obtain stiffness measurements; both have similar sensitivity and specificity for the diagnoses of liver fibrosis and cirrhosis (Bota 2013; Sirli 2012).

Liver biopsy. Biopsy remains the gold standard for assessing liver fibrosis. It allows direct examination of inflammatory and architectural changes due to fibrosis, and allows staging of the liver disease, which may guide treatment. Biopsies are not without limitations, however, as they are invasive and have potential for complications. Because the biopsied sample is representative of only a very small fraction of liver tissue, biopsies are subject to sampling error (Kim 2014). Three biopsy approaches are used. Percutaneous biopsies use a hollow cutting needle inserted through skin and into the liver to take one or more samples. Laparoscopic biopsy is a minimally invasive surgical technique used to obtain samples from a specific area of the liver or to avoid disrupting a tumor or site of infection (NIDDK 2014b).

For patients with ascites or a clotting disorder, a transjugular biopsy may be taken; here the biopsy needle is threaded down the neck through the jugular vein into the liver, and samples are taken under x-ray guidance. Transjugular biopsy allows measurement of the hepatic venous pressure gradient, which is a good predictor of portal hypertension and thus of clinical prognosis. Because it is an accurate prognostic test but invasive and not widely available, attempts have been made to use ultrasound measurements of liver stiffness (such as elastography) as a proxy to estimate hepatic venous pressure gradient (Tsochatzis 2014).

Other diagnostic techniques. Other techniques may also be used in liver disease or related pathology:

• Upper GI endoscopy. Direct visualization of dilated or ruptured blood vessels in the esophagus or stomach by a flexible camera (endoscope) is the gold standard for identifying varices, a common, serious complication of portal hypertension and cirrhosis (Berzigotti 2013).
• Autoantibody testing. Anti-mitochondrial antibody (AMA) is found in the blood of 90-95% of patients with primary biliary cirrhosis, a condition that creates a chronic obstruction of bile ducts, which can lead to cirrhosis (Tanaka 2002).
• Molecular analysis. Genomic analysis is available for inherited disorders of metabolism that increase cirrhosis risk. These include tests for Wilson’s disease (copper storage disease); HFE gene mutations, the most common cause of hereditary hemochromatosis (iron overload); alpha-1 antitrypsin deficiency; and cystic fibrosis (Santos 2012; Zarrilli 2013).
• Ferritin and transferrin saturation (TSAT) testing. Both of these iron transport proteins are elevated in individuals with hereditary hemochromatosis, a risk factor for cirrhosis (Zarrilli 2013).

Prognostic Scores

Prognostic scoring combines laboratory and qualitative measurements of liver function to estimate the survival of a cirrhosis patient within a given time period (Durand 2008). Two systems are in use. An older system, the Child-Pugh (or Child-Turcotte-Pugh) score considers albumin and bilirubin levels, clotting (international normalized ratio; INR) time, and the degree of ascites and encephalopathy in its scoring system. The Child-Pugh score ranges from 5-15, with the lowest scores of 5-6 (class A) indicating a better rate of survival after one year (81%) than the highest scores of 10-15 (class C), which indicate a one-year survival rate of 45% (Huo 2006; Fox 2014). Child-Pugh has largely been replaced by the Model for End-Stage Liver Disease (MELD) score, as MELD is a more accurate predictor of survival (Lee 2013). It is derived from an equation that accounts for the biomarkers creatinine, bilirubin, and prothrombin time (international normalized ratio; INR). It is used to predict short-term (3-month) survival in patients with liver disease. MELD scores range from 6 to 40 on a continuous scale, with higher scores indicating greater risk of mortality within a three-month period (a MELD score of 40 indicates a 71.3% risk of mortality, while a score <9 indicates a 1.9% risk) (Wiesner 2003; Fox 2014). The MELD system is used in the United States for ranking patients for liver transplants (Durand 2005). Other permutations of the MELD score are also in use, including MELD-Na (which incorporates blood sodium levels into the MELD equation to prioritize patients with low blood sodium for transplants), MELDNa (which further refines MELD-Na), and DeltaMELD (which monitors MELD changes over time and is useful in predicting intermediate outcomes in patients with advanced cirrhosis) (Lee 2013).

The first goal of cirrhosis management is preventing progression of the underlying chronic liver disease to reduce risk of decompensated cirrhosis. Once a decompensation event occurs, the focus becomes treatment of cirrhosis complications and the option of liver transplantation. The definitive treatment for decompensated cirrhosis is liver transplant (Ferri 2014).

Management of cirrhosis complications includes (Liou 2014):

• Ascites. Therapy for ascites includes treatment of the underlying disorder (eg, cessation of alcohol use, treatment of hepatitis), sodium restriction (≤2g/day), and diuretics (“water pills;” a combination of spironolactone and furosemide has been recommended) (Liou 2014; Garcia-Tsao 2012). Patients with refractory ascites may require additional treatment with large volume paracentesis, the direct removal of ascitic fluid from the abdomen through a catheter. Correction of albumin deficiency can improve circulatory function following paracentesis, and albumin administration (6 – 8 g/L of ascitic fluid removed) is recommended when the volume of ascites fluid removed by paracentesis exceeds 5 liters (Bernardi 2012; Garcia-Tsao 2012). Paracentesis fluid can also function as a diagnostic technique for bacterial infection (spontaneous bacterial peritonitis) in hospitalized cirrhotic patients and may improve short-term survival (Orman 2014).
  
  
• Portal hypertension. Options for the conservative management of portal hypertension are limited. Beta-blockers and nitrates may sometimes be recommended, along with diuretics in cases of ascites. However, surgical treatment involving the installation of shunts can be performed for serious cases (NIDDK 2014a; Anand 2012).
  
  Portal hypertension, and refractory cases of ascites, can be treated surgically with placement of a transjugular intrahepatic portosystemic shunt (TIPS). This method is less invasive than traditional surgery. In TIPS placement, artificial channels are installed that directly connect the flow of the portal vein and hepatic veins.
  
  In a 2014 meta-analysis of trials in which TIPS was compared to paracentesis in 390 patients, TIPS significantly reduced the need for liver transplants (39%); the incidence of recurrent ascites (85%) and hepatorenal syndrome (68%); and reduced deaths from liver disease (38%). However, in this study population, TIPS more than doubled the risk of severe hepatoencephalopathy and nearly tripled the risk of hepatoencephalopathy overall (Bai 2014).
  
  
• Spontaneous bacterial peritonitis. Treatment with broad-spectrum oral or intravenous antibiotics (Liou 2014).
  
  
• Hepatorenal syndrome. Therapy includes vasoconstrictors (eg, octreotide [Sandostatin] or terlipressin [Glypressin]) and albumin (to increase circulation and oxygenation of the kidneys) (Arroyo 2014; Garcia-Tsao 2012).
  
  
• Hepatic hydrothorax. Typical treatment includes dietary sodium restriction and diuretics (Liou 2014).
  
  
• Esophageal and gastrointestinal varices. Screening by endoscopy is recommended to check for varices. Non-selective beta-blockers (propranolol [Inderal], nadolol [Corgard]) do not prevent varices, but may reduce the risk of rupture and hemorrhage of fragile varices (Liou 2014). Endoscopic ligation of varices may also be effective.
  
  
• Hepatic encephalopathy. Hepatic encephalopathy can be treated with non-absorbable carbohydrates (lactulose), which are fermented by colonic bacteria and help to reduce excess ammonia. Rifaximin (Xifaxan), a non-absorbable antibiotic, is effective against ammonia-producing bacteria and appears to be as effective as lactulose in the treatment of symptoms related to mild-to-moderate encephalopathy (Zullo 2012; Kimer 2014).
  
  
• Hepatocellular carcinoma. Surgical excision of hepatocellular carcinoma is indicated when the tumor is a more important clinical concern than cirrhosis. Often only part of the tumor can be removed (Graf 2014). Even then, hepatocellular carcinoma recurs within 5 years more than 50% of the time (Liou 2014). Ablation (local destruction of the tumor) is an option in patients who are not suitable for resection. Common treatment techniques include ethanol injection and radiofrequency ablation (Graf 2014).
  
  
• Hepatic osteodystrophy. Calcium, vitamin D, and vitamin K may be used for osteopenia; alendronate (Fosomax) is often prescribed for osteoporosis. Calcitonin has also been studied for this purpose (Lipkin 2002; Liou 2014; Yurci, Kalkan 2011; Goel 2010).

Transplantation. Liver transplantation surgery has become the standard treatment for end-stage cirrhosis and chronic liver disease over the past two decades, resulting in a marked reduction in deaths from chronic liver disease (Fox 2014; Silva Santos 2012). Liver transplantation survival rates in the United States are now greater than 74% after 5 years post-surgery (Liou 2014). There are several medical contraindications to liver transplantation: cardiac and pulmonary diseases, sepsis or active infection, cancer outside the liver, poorly-controlled HIV infection, insufficient social support or psychiatric disorders that would prevent post-transplant medical compliance, and active substance abuse. Advanced age, obesity, HIV infection, malnutrition, and a history of poor medication compliance are relative contraindications to liver transplant surgery (Fox 2014). Although transplantation can be curative for cirrhosis (and a number of chronic liver diseases), it typically requires a lifetime of immunosuppressive drug therapy to prevent “rejection” of the transplanted organ by the immune system.

Emerging therapies for cirrhosis mostly target the pathways that initiate hepatic fibrosis (Rockey 2013).

PPAR Activators

PPAR-γ is a nuclear receptor that is predominantly found in liver and adipose tissue. It becomes active when it senses fatty acids (and some anti-diabetic drugs) within cells, and responds in turn by activating genes that regulate lipid metabolism and fat cell growth (Zhang, Kong 2013). While it is a target for medications that restore insulin sensitivity in diabetics and promote fatty acid metabolism in high cholesterol, PPAR-γ also plays an important role in liver repair. During liver damage, specialized storage cells in the liver called hepatic stellate cells become active, multiplying and producing large amounts of fibrous matrix, which is a central event in hepatic fibrogenesis and cirrhosis. PPAR-γ inhibits this fibrosis, making it an attractive target for anti-fibrotic therapies (Zhang, Kong 2013; Deng 2012). Thiazolidinediones, originally developed as anti-diabetic drugs, activate PPAR-γ and have shown mixed results for hepatic fibrosis in animal investigations and early clinical trials; multiple larger trials of several candidates (pioglitazone [Actos], Rosiglitazone [Avandia], GFT505) for use in the treatment of fibrosis from NASH are underway or have recently been completed (Schuppan 2013).

Ursodeoxycholic Acid

Ursodeoxycholic acid (UDCA; Ursodiol), a natural constituent of bile, is the only approved pharmacological treatment for primary biliary cirrhosis, a disease that can cause liver cirrhosis (Corpechot 2000; Intercept Pharmaceuticals 2014). However, UDCA has broader pharmaceutical applications that are rarely appreciated or even understood. It is a promising therapy that deserves, and is indeed the subject of, further trials for chronic liver disease.

In a long-term (1-2 year) placebo-controlled trial evaluating UDCA (with or without vitamin E) in patients with NASH, those who received UDCA and vitamin E experienced a statistically significant reduction in the liver enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as well as significant improvements in liver tissue structure including steatosis, cellular injury, and inflammation (Dufour 2006). A two-week, double-blind, crossover study compared UDCA to placebo for 10 cirrhotic patients with indigestion and excess fat in their stools. During the trial, both groups ate an identical controlled diet. The treatment reduced indigestion symptoms common in cirrhosis; lowered the amount of fat in the stool, a sign of improved fat digestion; and significantly reduced AST levels in the blood (Salvioli 1990). Another uncontrolled trial using UDCA significantly lowered ALT in cirrhotic patients during a 15-month trial (Buongiorno 1994). In an uncontrolled trial that followed 100 patients over more than five years, UDCA was used as a hepatic anti-inflammatory in an attempt to prevent progression from early hepatitis C-associated cirrhosis to hepatocellular carcinoma. Subjects not taking UDCA had two and a half times the risk of developing hepatocellular carcinoma as did those taking placebo (Tarao 2005).

Pentoxifylline

By inhibiting the pro-inflammatory mediator tumor necrosis factor-alpha (TNF-α), pentoxifylline may attenuate liver inflammation, one of the initiators of liver fibrosis (Jaurigue 2014). In an animal model of cirrhosis, it prevented the development of hepatopulmonary syndrome; it also decreased the risk of hepatorenal syndrome in cirrhosis patients in several studies (Sztrymf 2004; Parker 2013). A systematic review of pentoxifylline trials has shown conflicting data on survival of patients with chronic liver diseases (Jaurigue 2014). Pentoxifylline has also shown mixed results on reducing liver fibrosis in patients with hepatitis C infection or NASH, with several trials underway or recently completed (Schuppan 2013).

Current evidence points to pentoxifylline as an effective therapy to reduce the risk of severe hepatorenal syndrome in alcoholic hepatitis, but without apparent improvement in overall survival. It is recommended by several major gastroenterology organizations as a second-line therapy for severe alcoholic hepatitis for those in whom corticosteroids are contraindicated (Jaurigue 2014).

Angiotensin II Receptor Blockers

The renin-angiotensin system, which is central to the regulation of blood volume and pressure, has long been a therapeutic target for the treatment of hypertension and congestive heart failure (Li 2004; Volpe 2002). It may also represent a target for novel anti-fibrotic drugs. During chronic liver injury, overproduction of the hypertensive hormone angiotensin II can stimulate the activation of hepatic stellate cells and their overproduction of fibrous tissue in the liver (Kim 2012). Angiotensin II receptor blockers (ARBs) may block this interaction. Several ARBs (losartan [Cozaar], telmisartan [Micardis], olmesartan [Benicar], candesartan [Atacand], and valsartan [Diovan]) have been shown to reduce fibrosis in multiple animal studies and human trials of NASH and NAFLD (Georgescu 2008). A trial of a combination of candesartan and UDCA (a prescription isolated and concentrated bile acid) versus UDCA alone reduced measures of fibrosis in subjects with compensated alcoholic liver fibrosis (Kim 2012). Of the several available ARBs, telmisartan appears most intriguing because in addition to having demonstrated beneficial effects in various animal cirrhosis or fibrosis models (Tamaki 2013; Mende 2013; Jin 2007), it also activates an important modulator of metabolic activity called PPAR-gamma (Benson 2004). The PPAR-gamma signaling pathway is important for optimal mitochondrial function and the formation of new mitochondria, and this pathway appears to be downregulated among people with insulin resistance compared to healthy individuals (Patti 2003; Din 2014). Moreover, PPAR-gamma and associated metabolic pathways are thought to mediate some of the beneficial effects of caloric restriction and help promote cellular stress resistance and longevity; thus, agents that activate PPAR-gamma, like telmisartan, have gained the attention of longevity researchers as potential anti-aging interventions (Corton 2005; Scalera 2008).

As a word of caution, it is worth noting that the combination of an ARB with an angiotensin converting enzyme (ACE) inhibitor caused severe hepatic encephalopathy in a patient with cirrhosis, portal hypertension, and kidney disease in one case study, which reversed when the combination was discontinued (Oertelt-Prigione 2010).

Lysyl Oxidase Inhibitors

Lysyl oxidase is an enzyme responsible for cross-linking collagen fibrils, one of the final steps in the maturation of the fibrous matrix produced during liver fibrosis. Additionally, lysyl oxidase is also thought to inhibit the breakdown of fibrous matrix, preventing the reversal of fibrosis. A humanized antibody (simtuzumab) against LOXL2 (one of the lysyl oxidase enzymes) is the subject of two trials for liver fibrosis at the time of this writing (Schuppan 2013).

Stem-Cell Therapy

Liver transplant remains the only definitive cure for end-stage, fibrotic liver disease. Given the shortage of donor livers, stem cell therapy may prove a useful alternative for replenishing hepatocytes, reducing inflammation, and reversing liver fibrosis in patients with cirrhosis or liver failure. Several human trials have investigated the use of mesenchymal (connective tissue), bone marrow-derived, or hematopoietic (blood-derived) stem cells in patients with liver failure or cirrhosis, and have revealed improvements in liver function, liver volume, and MELD or Child-Pugh score (Zhang, Wang 2013); several more trials are underway (Schuppan 2013).

Liver Dialysis

Liver dialysis has similarities to kidney dialysis; aiming to filter blood through an external device to provide short-term support to the liver (extracorporeal liver support therapy) (Stange 2011). Since many blood toxins are tightly bound to albumin molecules in circulation, liver dialysis devices must selectively separate these toxins from the albumin, while preserving albumin levels in the blood. The use of this therapy is more prevalent outside the United States, though multiple reviews have reached varying conclusions about its degree of improvement to mortality and avoidance of liver transplant. Its primary indication is as a “bridge to transplant” – a palliative treatment that can be used while waiting for a liver transplant (Nevens 2012; Zheng 2013; Krisper 2011). Several different methodologies are in use: molecular adsorbent recirculating system (MARS); Prometheus dialysis; plasma exchange combined with hemodialysis (PE/HD); and single-pass albumin dialysis (SPAD) (Schaefer 2013).

Abstain From Alcohol

Alcoholism is the second most common cause of cirrhosis in the United States (NIDDK 2014a; Orman 2013; Perz 2006). Five-year survival amongst all cirrhotic patients is 70%, but is only 30% in drinkers with decompensated cirrhosis. In contrast, prognosis improves with abstinence; after alcohol cessation, the 5-year survival of patients with compensated and decompensated cirrhosis can climb as high as 90% and 60%, respectively (Schwartz 2012).

Avoid Tobacco Use

In one population-based study, smoking >10 g tobacco/day nearly quadrupled the risk of alcoholic cirrhosis and more than doubled the risk of other types of cirrhosis in women. In men, the corresponding increases were 60% and 40%, though the latter results fell just shy of statistical significance. Tobacco smoke contains chemical substances with cytotoxic properties that can activate stellate cells and induce fibrosis. In addition, smoking increases pro-inflammatory chemical messengers (eg, TNF-α, IL-1, IL-6) and decreases anti-inflammatory messengers (eg, IL-10) (Dam, Flensborg-Madsen 2013).

Adjust Prescription Drug Doses

Many drugs depend on the liver for metabolism, or require albumin, synthesized by the liver, for their pharmacokinetics and distribution. Cirrhosis alters these processes, making reduced dosages, or in some cases, avoidance, necessary. Recommendations for safe prescribing include (Lewis 2013):

• Reduce medication dosages in general (consult your healthcare professional before making a change)
• Opioid analgesics, anxiolytics, and sedatives can cause or worsen hepatic encephalopathy symptoms and should be used cautiously
• Non-steroidal anti-inflammatory drugs (NSAIDs) can more readily cause renal failure and gastrointestinal bleeding in patients with cirrhosis and should generally be avoided
• Anticancer and immunomodulating drugs; lower doses are recommended for some agents
• Antimicrobials; some types (macrolides, tetracyclines, aminoglycosides) should generally be avoided
• Proton pump inhibitors and histamine blockers can lead to serious infections
• Antidepressants; half-lives and clearances may be altered
• Cardiovascular drugs; dose adjustments may be needed for anti-arrhythmic drugs and beta-blockers

Coffee

Coffee consumption has been associated with a lower incidence of cirrhosis in several observational studies (Muriel 2010). In one study, 4 or more cups of coffee per day reduced the risk of alcoholic cirrhosis by 80% compared to non-coffee drinkers. For one to three cups, the associated protection was 40%. The same study found that for non-alcoholic cirrhosis, 4 or more cups per day conferred a 30% reduced risk of cirrhosis (Klatsky 2006). Coffee may reduce the risk of fibrosis by lowering blood levels of growth factors associated with liver damage and fibrosis (Arauz 2013). Coffee consumption has also been associated with reduced risk of liver cancer in several European and Japanese studies, especially among heavy drinkers (consumption of over 3 cups of coffee per day reduced hepatocellular carcinoma risk by an average of 55% over 12 observational studies) (Bravi 2007; Larsson 2007).

Some benefit of coffee may be due to its antioxidant content (Arauz 2013). There is no definitive indication of exactly which coffee compounds are responsible for its health benefits. However, chlorogenic acids (a member of the group of antioxidant compounds known as polyphenols) have been shown in animal models to reduce liver inflammation and fibrosis (Shi 2009; Shi 2013).

Maintain Adequate Nutrient Intake

Liver disease in general, and cirrhosis especially, increases the likelihood of malnutrition, which is not surprising given the vital role of the liver in maintaining nutrient levels and energy balance (Purnak 2013). The European Society for Clinical Nutrition and Metabolism (ESPEN), the International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus, and other groups have developed recommendations for avoiding malnutrition in individuals with cirrhosis or hepatic encephalopathy (Plauth 2006; Amodio 2013; Purnak 2013):

• Calories. Patients should strive for an energy intake of 35-40 kcal/kg/day (Plauth 2006; Amodio 2013). Moderate, gradual weight loss is indicated for many individuals with NAFLD or NASH. Dietary fructose has been associated with metabolic syndrome and diabetes, two conditions associated with NAFLD and NASH (Purnak 2013).
• Protein. Restriction of dietary protein is not recommended, unless it is not tolerated due to hepatic encephalopathy. The diet should include 1.2-1.5 g/kg/day of whole protein to avoid muscle wasting (Plauth 2006).
• Vitamins. Patients with both alcohol and non-alcohol-related cirrhosis may be deficient in water-soluble vitamins, especially thiamine, and supplementation is warranted in patients with decompensated cirrhosis (Amodio 2013). Vitamin B₁₂ and folate deficiencies have been reported in HBV and HCV infection (Purnak 2013); folate deficiency was present in one study of obese patients with NAFLD (Hirsch 2005). Low folate concentrations were associated with elevated levels of the vasculotoxic compound homocysteine in cirrhosis patients in an observational study (Kazimierska 2003). Patients with cholestatic liver disease may have reduced absorption of fat-soluble vitamins (A, D, E, and K) (Purnak 2013; Jaurigue 2014). Vitamin A deficiency is also a common problem in HCV infection (Purnak 2013), and vitamin K may be useful in the treatment of bone loss in patients with cirrhosis and chronic liver disease (Shiomi 2002; Lipkin 2002).
• Minerals. Tissue zinc levels are decreased in patients with cirrhosis and hepatic encephalopathy, though trials of zinc supplementation have had conflicting results (Amodio 2013). Hepatic osteodystrophy, a common consequence of cirrhosis, can lead to calcium/magnesium imbalances. One study found that untreated hepatitis C patients presented with lower levels of plasma and red blood cell zinc and selenium than did healthy control subjects (Ko 2005).

Nutrients for Viral Hepatitis

Viral hepatitis (B and C) is the leading risk factor for the development of cirrhosis and liver failure. Several nutrients have been studied in human trials for their effects on minimizing risks or improving outcomes of hepatitis B viral infection, either alone or as adjuncts to antiviral drugs. These include green tea extract, selenium, coffee/chlorogenic acid, zinc, phyllanthus, whey protein, astragalus, schizandra, and milk thistle. These are reviewed in Life Extension’s Hepatitis B protocol. The nutrients S-adenosylmethionine (SAMe), N-acetyl cysteine (NAC), alpha lipoic acid, whey protein, milk thistle, licorice, schizandra, vitamin D, coffee, zinc, curcumin, and L-carnitine have each been investigated in human trials as potential adjuncts to hepatitis C treatments. See Life Extension’s Hepatitis C protocol for more details on these studies.

Nutrients for Non-Alcoholic Fatty Liver Disease and Non-Alcoholic Steatohepatitis

In the United States and developing world, NAFLD and NASH together are the third most common cause of cirrhosis. Vitamin E, omega-3 fatty acids, and N-acetyl cysteine plus metformin have each been studied as possible adjuncts to treatment of NAFLD and NASH in human trials.

Further nutritional strategies are reviewed in Life Extension’s Non-Alcoholic Fatty Liver Disease (NAFLD) protocol.

Nutrients for Iron Overload

High iron stores are a risk factor for the development of liver disease (Fargion 2011; Valenti 2012), and patients with hereditary hemochromatosis are at increased risk for cirrhosis (Crownover 2013). Nutrients that have been investigated in human clinical trials for their ability to reduce iron load include pectin, milk thistle, and green tea (reviewed in Life Extension’s Hemochromatosis protocol).

Nutrients specifically investigated in the context of cirrhosis or its complications include:

Milk Thistle/Silymarin

Milk thistle and its principal flavonoid mixture silymarin have shown remarkable hepatoprotective and antioxidant effects against several types of liver damage (including chemical, viral, inflammatory, and poisoning) in laboratory, rodent, and human settings (Vargas-Mendoza 2014; Polyak 2013; Jia 2001). They have been investigated for a number of chronic liver conditions that can precede cirrhosis, including viral hepatitis (Hawke 2010), alcoholic liver disease (Habib-ur-Rehman 2009; Ferenci 1989), and NAFLD (Loguercio 2012). Studies in cirrhotic patients have shown mixed results. In a study of patients with alcoholic and non-alcoholic cirrhosis, 4-year survival rates were higher in patients on silymarin (140 mg, three times daily) compared to control subjects (58% vs. 39%, respectively) (Ferenci 1989). A similar study, however, failed to show any survival benefit at 6 years in patients taking 450 mg silymarin per day. It is important to note that all the patients in this second study had alcoholic cirrhosis, and many significantly reduced their alcohol intake over the course of the study, possibly obscuring any effects of silymarin (Parés 1998). In patients with alcoholic cirrhosis, silymarin reduced markers of oxidative damage and improved antioxidant status (Lucena 2002).

Branched-Chain Amino Acids

Branched-chain amino acids (BCAAs) (leucine, isoleucine, and valine), nutritionally essential amino acids not metabolized into energy in the liver, are taken up by skeletal muscle where they serve multiple purposes. The breakdown products of BCAAs can be used to form the amino acid glutamate, which can scavenge toxic ammonia in skeletal muscles and convert it into glutamine (Dam, Ott 2013; Amodio 2013). A systematic review of 8 trials (382 cirrhosis patients) on the use of BCAAs for symptoms of hepatic encephalopathy demonstrated a clear benefit in reducing manifestations of the disease in patients with both minimal and overt forms of encephalopathy (Gluud 2013). The effect was independent of the cause of cirrhosis (alcoholic or viral), and the average dose was 0.25g/kg/day. Other authors believe that the effect of BCAAs is entirely a result of their leucine content, and that while BCAAs may eventually be proven to have nutritional benefits for cirrhosis patients, including regeneration of liver cells, they are not effective for hepatic encephalopathy (Amodio 2013).

Vitamin D

About 66% of patients with moderately severe cirrhosis, and 96% of people waiting for liver transplants, have vitamin D deficiency. In individuals with chronic liver disease, the rate of osteoporotic fractures is approximately twice that of age-matched controls. For these reasons, calcium and vitamin D supplementation have been recommended for patients with cirrhosis and low bone density (Crawford 2006). In a study of over 324 subjects with alcoholic liver disease compared to controls, severe vitamin D deficiency was significantly associated with higher liver enzymes, increased hepatic venous pressure gradient, and worse MELD and Child-Pugh scores. Further analysis showed that low vitamin D was associated with cirrhosis and mortality after one year (Trepo 2013). An analysis of chronic liver disease patients admitted to an outpatient liver clinic found that vitamin D deficiency predicted worse Child-Pugh and MELD scores, and may predict decompensation and mortality in chronic liver failure patients (Putz-Bankuti 2012). A study on 88 hospitalized patients in the hepatology unit of a hospital revealed that low levels of vitamin D were independently associated with bacterial infection in patients with cirrhosis; another similar study found that low vitamin D was associated with increased mortality in patients with severe liver disease (Anty 2014; Stokes 2013). A laboratory study using a special form of vitamin D along with a novel chemotherapeutic agent inhibited proliferation of hepatic stellate cells (Neeman 2014).

Vitamin C

Patients with cirrhosis show endothelial dysfunction within the vessels of the liver, and this is associated with lower circulating levels of vitamin C. In an uncontrolled study of cirrhosis patients, intravenous injection of 3 g vitamin C lowered markers of oxidative stress and venous pressure within the liver (Hernández-Guerra 2006). Vitamin C mitigated the increase in liver fat and globulins (blood proteins) caused by experimentally induced cholestasis (decreased bile flow) in rats (Matos 2008) and reduced alcohol-induced small-intestinal bacterial overgrowth in a model of alcoholic liver fibrosis in guinea pigs (Abhilash 2014).

Vitamin E

Liver cirrhosis patients generally have low blood levels of vitamin E; liver biopsies from people with alcoholic cirrhosis typically show lower hepatic alpha-tocopherol content than individuals with normal livers, and lower blood alpha-tocopherol levels than individuals with alcoholic fatty liver or those with normal liver histology (Bell 1992; Lu 2003). These lower levels of vitamin E were associated with an increased susceptibility of the plasma component of blood to oxidative stress (Ferre 2002; Lu 2003). In patients with primary biliary cirrhosis, one author concluded that vitamin E supplementation should be considered not only in individuals with overt vitamin E deficiency, but also in individuals who meet certain additional criteria, such as total serum bilirubin over 3 mg/dL, serum cholylglycine (a crystalline bile acid involved in emulsification of fat) over 600 mcg/dL, or serum alkaline phosphatase over 1000 IU/L (Sokol 1989). In a study that enrolled women with primary biliary cirrhosis, serum vitamin E levels were significantly decreased in patients who had psychomotor impairment (Arria 1990).

Patients with liver cirrhosis show marked increases in oxidative stress levels. In patients with hepatitis C-related cirrhosis, vitamin E normalized levels of the liver enzyme alanine aminotransferase (ALT), while vitamin E and fermented papaya extract each improved glutathione levels, which were significantly lower in patients with cirrhosis (Marotta 2007). A study on patients with liver cirrhosis and a history of hepatitis C infection revealed that participants treated with alpha-tocopherol lived longer without the development of hepatocellular carcinoma as compared to participants who were not treated, but the difference was not statistically significant (Takagi 2003). A study on 80 prospective liver transplantation recipients showed that oral tocotrienols lowered MELD scores by 50%, whereas supplementation with 200 mg alpha-tocopherol lowered it by only 20%. The authors concluded that further studies are needed to examine the effects of tocotrienols in end-stage liver disease (Patel 2012).

Probiotics

The wrong kind of intestinal bacteria play a role in several complications of cirrhosis; urease-producing bacteria in the gut increase ammonia production, which contributes to hepatic encephalopathy, and migration of bacteria across the intestinal wall has been implicated in both spontaneous bacterial peritonitis and bleeding due to esophageal varices (Pereg 2011). Use of probiotics to address these complications has had mixed results. In some studies, supplementation of cirrhosis patients with probiotic bacteria (including species of Lactobacilli, Bifidobacteria, Pediococcus, and Leuconostoc) combined with fermentable fiber prebiotics reduced blood ammonia levels and urease-producing colonic bacteria (Malaguarnera 2010; Liu 2004). Two studies that used a slightly different combination of probiotics without prebiotics found no effect (Saji 2011; Pereg 2011). There was a trend toward reduced Child-Pugh scores (suggesting an improvement in liver function) in some studies (Lata 2007; Liu 2004), mixed results on portal venous pressure (Gupta 2013; Tandon 2009), and no reduction in the incidence of spontaneous bacterial peritonitis (Pande 2012).

Prebiotics

Hepatic encephalopathy, a complication of cirrhosis, is currently treated by the nondigestible, fermentable disaccharide lactulose, a synthetic prebiotic (Wang 2013; Amodio 2013). Combinations of fermentable natural fibers (beta-glucan, inulin, pectin, and resistant starch) (Liu 2004) or fructooligosaccharides (Malaguarnera 2010) with probiotic bacteria showed reductions in blood ammonia levels in cirrhosis patients with minimal or mild hepatic encephalopathy.

Zinc

In a meta-analysis of 4 randomized controlled trials of oral zinc supplementation (zinc acetate, sulfate, or carnosate) in 223 patients with hepatic encephalopathy resulting from cirrhosis, three trials showed improvements in cognitive function compared to baseline measurements (Chavez-Tapia 2013). In the fourth study using zinc carnosate, cirrhosis patients experienced reductions in blood ammonia levels, improved quality of life scores, and reduced Child-Pugh scores (measurements of cirrhosis severity) after six months of supplementation.

S-Adenosylmethionine

S-adenosylmethionine (SAMe) participates in the synthesis of the important liver-protectant antioxidant glutathione, which is lower in patients with cirrhosis (Bianchi 1997; Mato 1999). Although SAMe has been studied as an innovative therapy for fibrosis (Czaja 2014), one systematic review of the literature was unable to confirm a statistically significant benefit in alcoholic liver disease, perhaps partially as a result of variable quality across studies (Rambaldi 2006). In a large clinical trial of SAMe (Mato 1999), patients with alcoholic cirrhosis on SAMe (1.2 g/day for 2 years) demonstrated a non-significant trend towards improvement in 2-year survival compared to control patients. When only patients with mild-to-moderate disease were included in the analysis, however, survival was significantly improved, and progression to liver transplantation was significantly reduced in the SAMe group (88%) versus the control group (71%). Differences in survival between the groups only became apparent after 1 year. Many of the subjects in this trial had hepatitis B or C infection in addition to alcoholic cirrhosis. While several other smaller studies have shown encouraging results for the use of SAMe to improve liver biochemical parameters (such as liver enzyme values) in alcoholic cirrhosis patients, they have shown mixed results for its ability to improve survival in patients with the disease and have had no apparent effect on steatosis, fibrosis, or inflammation (Rambaldi 2006; Medici 2011; Le 2013).

Polyenylphosphatidylcholine (PPC)

Soybeans contain a lipid mixture called polyenylphosphatidylcholine (PPC) that has been shown to help protect the integrity of cellular membranes, especially in the liver. One of the mechanisms by which toxicants like alcohol lead to liver dysfunction is by damaging liver cell membranes in a process called lipid peroxidation. PPC helps prevent lipid peroxidation in liver cells. The lipid mixture prevented cirrhosis in animal experiments, and it opposed fibrosis and improved liver function tests among heavy-drinking human clinical trial participants (Lieber 2004; Lieber 2003).

Curcumin

In animal models, curcumin has mitigated liver injury from hepatitis B and C infection, alcoholic liver disease, NAFLD, hepatocellular carcinoma, primary biliary cirrhosis, and primary sclerosing cholangitis; all chronic liver diseases with cirrhosis as their potential endpoint (Nabavi 2013). It may also have a protective effect against chemically-induced cirrhosis in animal livers (Ali 2014). In these models, curcumin inhibits metabolic pathways (such as NF-κB signaling) that produce the inflammatory cytokines that stimulate fibrosis (Nabavi 2013). In addition, laboratory and animal studies have shown that curcumin reduces β-catenin, a protein that promotes liver stellate cell activation and fibrosis (Cui 2014).

Glycyrrhizic Acid

Glycyrrhizic acid, also known as glycyrrhizin, is an extract from the roots of the licorice plant Glycyrrhiza glabra. It has been studied and found effective in many conditions (Li 2014), but its most common application is in liver disease, where it has pronounced anti-inflammatory (Ming 2013) and anti-viral (Pu 2013) effects.

A trial compared intravenous (IV) glycyrrhizic acid in 17 patients to IV glycyrrhizic acid plus corticosteroids in 14 patients for the treatment of autoimmune hepatitis. Recovery rate was significantly higher in the glycyrrhizic acid alone group (Yasui 2011). A trial in 379 patients who failed interferon plus ribavirin treatment for hepatitis C found that a twelve-week course of IV glycyrrhizic acid, compared to placebo, dramatically lowered the liver enzyme ALT. A subsequent 40-week uncontrolled trial of IV glycyrrhizic acid found a trend towards reduction of inflammation and fibrosis that barely missed the cutoff for statistical significance (Manns 2012). An uncontrolled study of long-term (average 10 years) oral glycyrrhizic acid administration in hepatitis C found that those in the treatment group had 2.5 times less chance of developing hepatocellular carcinoma, a common outcome of hepatitis C (Arase 1997). In a rodent model, glycyrrhizic acid was found to have hepatoprotective effects similar to silymarin (Rasool 2014).

Coenzyme Q₁₀

Coenzyme Q₁₀ (CoQ₁₀) acts as a scavenger of free radicals in cell membranes. One study found that CoQ₁₀ levels were 70% lower in subjects with liver cirrhosis compared to healthy controls; the authors speculated that this may be a result of low dietary intake of this important nutrient, or due to decreased synthesis in the cells (Bianchi 1994). Reduced CoQ₁₀ levels are also seen in patients with NAFLD (Yesilova 2005). CoQ₁₀ (10 or 30 mg/kg) inhibited fibrosis induced by the liver toxin dimethylnitrosamine in mice (Choi 2009).

Berberine

Berberine is a plant alkaloid that has been studied primarily for its bacteriostatic and bactericidal properties (Sun 1988). In patients with hepatic encephalopathy, oral berberine (600-800 mg/day) reduced blood concentrations of tyramine, an indirect neurotransmitter that is elevated in hepatic encephalopathy and can lead to some of its cardiovascular and neurological complications (Watanabe 1982). In a small trial of patients with chronic hepatitis B, C, or cirrhosis, berberine (1 g/day for 3 months) reduced circulating LDL and total cholesterol levels and liver enzymes (Zhao 2008).

Although berberine has been studied in human clinical trials and shown to have several metabolic benefits, concerns about long-term use of berberine have been raised on the basis of certain preclinical studies (Kysenius 2014; Mikes 1985; Mikes 1983). Some evidence suggests that long-term berberine use, especially at high doses, may impair particular aspects of cellular metabolism in specific types of cells. The implications of this preclinical research are yet to be determined by long-term human clinical trials, therefore Life Extension currently recommends short-term use of berberine.

Green Tea Extract/Epigallocatechin-3-gallate

Epigallocatechin-3-gallate (EGCG) is the most potent and abundant catechin in green tea extract, usually comprising approximately 40% of green tea’s polyphenol content. The anti-inflammatory, antioxidant, and anti-fibrotic properties of EGCG make it a candidate as a natural therapy for hepatitis and liver fibrosis (Halegoua-De Marzio 2012). In a laboratory study, EGCG inhibited entry of the HCV into liver cells (Ciesek 2011). An experiment with hepatic stellate cells, which are key in the development of liver fibrosis, revealed that EGCG can regulate the growth and structure of these cells, such that EGCG may turn out to be a therapeutic agent for liver fibrosis (Higashi, Kohjima 2005). In a rat model of NASH, which is characterized by liver inflammation and fibrosis, and is associated with liver cancer, oral administration of EGCG (0.1% in tap water) was shown to prevent liver fibrosis and tumorigenesis (Kochi 2014). In a mouse model of chemically-induced liver injury and fibrosis, EGCG was able to attenuate the progression of liver fibrosis, possibly as a result of its ability to reduce oxidative stress and inflammatory response (Tipoe 2010).