Cirrhosis is the pathological replacement of functional liver tissue with scarred, fibrous, dysfunctional tissue, which can affect many of the liver’s metabolic processes and present a serious health threat. Most forms of late-stage chronic liver disease often exhibit cirrhosis. Alcoholism prognosis.
Integrative interventions like silymarin, vitamin E, and S-adenosylmethionine (SAMe) can be helpful in protecting liver cells and improving survival rates.
Complications of Cirrhosis
Ascites, an increase in free fluid in the abdomen, is the most common complication of cirrhosis
Portal hypertension (high blood pressure in the liver) can lead to consequences for kidney, lung, gastrointestinal, and cardiovascular function
Gastroesophageal varices, which are abnormal, enlarged veins in the lower part of the esophagus or stomach that can rupture and hemorrhage
Hepatic encephalopathy occurs when the dysfunctional liver can no longer metabolize toxins, which build up in the brain, causing cognitive dysfunction, memory problems, mood changes, poor decision making, or delirium; coma and death are possible in severe cases.
Causes and Risk Factors
Chronic viral hepatitis is the most common cause, usually either hepatitis B or hepatitis C
Alcoholic liver disease is the second major contributor to cirrhosis incidence in the United States
Non-alcoholic fatty liver disease and its more severe form, nonalcoholic steatohepatitis, are common causes of cirrhosis and are highly associated with obesity and metabolic syndrome
Note: Proper management and treatment of existing liver disease improves outcomes and may lead to regression of liver fibrosis in some cases.
Diagnosis is based on signs and symptoms (which can sometimes take years to show up) and clinical testing.
Signs and symptoms include:
Fatigue/weakness, loss of appetite, weight loss, nausea, abdominal pain, and pruritus (itching)
Enlarged spleen when palpated
Distended abdomen from ascites
Jaundice (yellowing of the skin and whites of the eyes)
Bruising or excessive bleeding
Dark stools resulting from blood in the feces, or pale-colored stools from lack of bile secretion
Biochemical tests for compounds released by damaged hepatocytes, including alanine transaminase and aspartate transaminase
Diagnostic imaging including ultrasound
Liver biopsy, which is the gold standard for assessing the extent of liver damage
Prevent progression of the underlying chronic liver disease and manage complications of cirrhosis
Liver transplantation surgery is the standard treatment for end-stage cirrhosis
Novel and Emerging Therapies
These therapies mostly target the pathways that initiate the liver damage, including:
PPAR activators, which inhibit liver fibrosis
Ursodeoxycholic acid, approved for treatment of primary biliary cirrhosis
Metformin, an anti-diabetic drug that may increase survival time in diabetics with cirrhosis
Dietary and Lifestyle Management
Abstain from alcohol use and avoid smoking
Under physician supervision, adjust prescription drug doses as cirrhosis alters liver metabolism of many drugs
Coffee consumption has been associated with a lower incidence of cirrhosis and may reduce the risk of liver damage
Milk thistle/silymarin: Milk thistle and its principal flavonoid mixture silymarin have shown remarkable protective and antioxidant effects against several types of liver damage, including cirrhosis.
Branched-chain amino acids (BCAAs): A systematic review on the use of BCAAs for symptoms of hepatic encephalopathy, a complication of cirrhosis, demonstrated a clear benefit in reducing manifestations of the disease. The effect was independent of the cause of cirrhosis (alcoholic or viral).
Vitamin D: In a study of subjects with alcoholic liver disease compared with controls, severe vitamin D deficiency was significantly associated with higher liver enzymes, increased liver venous pressure gradient, and worse Model for End-Stage Liver Disease (MELD) scores. Low vitamin D was also associated with cirrhosis and mortality after one year.
Vitamin E: A study on prospective liver transplantation recipients showed that oral tocotrienols lowered MELD scores (higher scores predict a worse outcome) in 50% of recipients and supplementation with alpha-tocopherol lowered them in 20%.
S-adenosylmethionine (SAMe): In a large clinical trial of patients with alcoholic cirrhosis on SAMe, those with mild-to-moderate disease were found to have significantly improved survival and significantly reduced progression to liver transplantation in the SAMe group (88%) versus the control group (71%).
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
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.
Complications of Cirrhosis
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).
Causes and Risk Factors
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
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 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).
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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.
Novel and Emerging Therapies
Emerging therapies for cirrhosis mostly target the pathways that initiate hepatic fibrosis (Rockey 2013).
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).
Ursodeoxych olic 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 ).
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).
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 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).
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 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).
Dietary and Lifestyle Management
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).
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).
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 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 B
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).
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.
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 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 (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).
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).
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).
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).
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).
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.
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 (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).
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).
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, 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).
) acts as a scavenger of free radicals in cell membranes. One study found that CoQ
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 CoQ
levels are also seen in patients with NAFLD (Yesilova 2005). CoQ
(10 or 30 mg/kg) inhibited fibrosis induced by the liver toxin dimethylnitrosamine in mice (Choi 2009).
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).
Disclaimer and Safety Information
This information (and any accompanying material) is not intended to replace the attention or advice of a physician or other qualified health care professional. Anyone who wishes to embark on any dietary, drug, exercise, or other lifestyle change intended to prevent or treat a specific disease or condition should first consult with and seek clearance from a physician or other qualified health care professional. Pregnant women in particular should seek the advice of a physician before using any protocol listed on this website. The protocols described on this website are for adults only, unless otherwise specified. Product labels may contain important safety information and the most recent product information provided by the product manufacturers should be carefully reviewed prior to use to verify the dose, administration, and contraindications. National, state, and local laws may vary regarding the use and application of many of the treatments discussed. The reader assumes the risk of any injuries. The authors and publishers, their affiliates and assigns are not liable for any injury and/or damage to persons arising from this protocol and expressly disclaim responsibility for any adverse effects resulting from the use of the information contained herein.
The protocols raise many issues that are subject to change as new data emerge. None of our suggested protocol regimens can guarantee health benefits. The publisher has not performed independent verification of the data contained herein, and expressly disclaim responsibility for any error in literature.
Abhilash, P. A., Harikrishnan, R., and Indira, M. Ascorbic acid suppresses endotoxemia and NF-κB signaling cascade in alcoholic liver fibrosis in guinea pigs: a mechanistic approach. Toxicol. Appl. Pharmacol. 2014;274(2):215–24
A.D.A.M. PubMed Health. Diseases and Conditions page. Hepatorenal syndrome. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001519/. 5/1/2012. Accessed 7/2/2014.
A.D.A.M. PubMed Health. Cirrhosis: Liver cirrhosis; Cryptogenic chronic liver disease. Available at: http://www.ncbi.nlm.nih.gov/pubmedhealth/PMH0001301/. 10/13/2013. Accessed 7/2/2014.
A.D.A.M. MedlinePlus. Peritonitis. Available at: http://www.nlm.nih.gov/medlineplus/ency/article/001335.htm. Last updated 4/9/2014. Accessed 7/28/2014.
Adebajo CO, Talwalkar JA, Poterucha JJ, Kim WR, Charlton MR. Ultrasound-based transient elastography for the detection of hepatic fibrosis in patients with recurrent hepatitis C virus after liver transplantation: a systematic review and meta-analysis. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Mar 2012;18(3):323-331.
Amarapurkar, P. D., and Amarapurkar, D. N. Management of Coagulopathy in Patients with Decompensated Liver Cirrhosis. International Journal of Hepatology. 2011;2011(5):1–5
Albillos A and Tejedor M. Secondary Prophylaxis for Esophageal Variceal Bleeding. Clin Liver Dis. 2014;18(2):359–70
Ali SO, Darwish HA, Ismail NA. Modulatory effects of curcumin, silybin-phytosome and alpha-R-lipoic acid against thioacetamide-induced liver cirrhosis in rats. Chem Biol Interact. 2014;216C:26–33
Amodio P, Bemeur C, Butterworth R. The nutritional management of hepatic encephalopathy in patients with cirrhosis: International Society for Hepatic Encephalopathy and Nitrogen Metabolism Consensus. Hepatology. 2013;58:325–36.
Anand B, Melcher ML, Schleyer AM. Cirrhosis. First Consult. Available at: www.clinicalkey.com. Last updated 3/2/2012. Accessed 8/25/2014.
Anderson GJ, Frazer DM. Hepatic iron metabolism. Seminars in liver disease. Nov 2005;25(4):420-432.
Angeli P and Gines P. Hepatorenal syndrome, MELD score and liver transplantation: an evolving issue with relevant implications for clinical practice. J Hepatol. 2012;57(5):1135–40
Anty R, Tonohouan M, Ferrari-Panaia P, Piche T, Pariente A, Anstee QM,... Tran A. Low Levels of 25-Hydroxy Vitamin D are Independently Associated with the Risk of Bacterial Infection in Cirrhotic Patients. Clinical and translational gastroenterology. 2014;5:e56.
Aprile LR, Meneghelli UG, Martinelli AL, Monteiro CR. Gastric motility in patients with presinusoidal portal hypertension. The American journal of gastroenterology. Dec 2002;97(12):3038-3044.
Arase Y, Ikeda K, Murashima N, et al. The long term efficacy of glycyrrhizin in chronic hepatitis C patients. Cancer. 1997;79(8):1494-500.
Arauz, J., Moreno, M. G., Cortés-Reynosa, P., Salazar, E. P., and Muriel, P. Coffee attenuates fibrosis by decreasing the expression of TGF-β and CTGF in a murine model of liver damage. J Appl Toxicol. 2013;33(9):970–9
Armstrong MJ, Adams LA, Canbay A, et al. Extrahepatic complications of nonalcoholic fatty liver disease. Hepatology. 2014;59(3):1174-97.
Arria AM, Tarter RE, Warty V, Van Thiel DH. Vitamin E deficiency and psychomotor dysfunction in adults with primary biliary cirrhosis. The American journal of clinical nutrition. Aug 1990;52(2):383-390.
Arroyo V, García-Martinez R, Salvatella X. Human Serum Albumin, Systemic Inflammation And Cirrhosis. J Hepatol. 2014. [Epub ahead of print]
Baertling F, Mayatepek E, Gerner P, Baba HA, Franzel J, Schlune A, Meissner T. Liver cirrhosis in glycogen storage disease Ib. Molecular genetics and metabolism. Mar 2013;108(3):198-200.
Bai M, Qi XS, Yang ZP, et al. TIPS improves liver transplantation-free survival in cirrhotic patients with refractory ascites: an updated meta-analysis. World J Gastroenterol. 2014;20(10):2704–14
Bell H, Bjorneboe A, Eidsvoll B, Norum KR, Raknerud N, Try K,... Drevon CA. Reduced concentration of hepatic alpha-tocopherol in patients with alcoholic liver cirrhosis. Alcohol and alcoholism (Oxford, Oxfordshire). Jan 1992;27(1):39-46.
Benson SC, Pershadsingh HA, Ho CI, Chittiboyina A, Desai P, Pravenec M,... Kurtz TW. Identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma-modulating activity. Hypertension. May 2004;43(5):993-1002.
Berasain C, Castillo J, Perugorria MJ, Latasa MU, Prieto J, Avila MA. Inflammation and liver cancer: new molecular links. Annals of the New York Academy of Sciences. Feb 2009;1155:206-221.
Bernardi, M., Caraceni, P., Navickis, R. J., and Wilkes, M. M. Albumin infusion in patients undergoing large-volume paracentesis: A meta-analysis of randomized trials. Hepatology. 2012;55(4):1172–81
Berzigotti A, Seijo S, Reverter E, et al. Assessing portal hypertension in liver diseases. Expert Rev Gastroenterol Hepatol. 2013;7(2):141–55
Bianchi, G. P., Fiorella, P. L., Bargossi, A. M., Grossi, G., and Marchesini, G. Reduced ubiquinone plasma levels in patients with liver cirrhosis and in chronic alcoholics. Liver. 1994;14(3):138–40
Bianchi G, Bugianesi E, Ronchi M, Fabbri A, Zoli M, Marchesini G. Glutathione kinetics in normal man and in patients with liver cirrhosis. Journal of hepatology. Mar 1997;26(3):606-613.
Biecker E. Portal hypertension and gastrointestinal bleeding: diagnosis, prevention and management. World journal of gastroenterology: WJG. Aug 21 2013;19(31):5035-5050.
BLT. British Liver Trust. Cirrhosis. Available at: http://www.britishlivertrust.org.uk/liver-information/liver-conditions/cirrhosis/. Last updated March 2011. Accessed 7/28/2014.
Bohm F, Kohler UA, Speicher T, Werner S. Regulation of liver regeneration by growth factors and cytokines. EMBO molecular medicine. Aug 2010;2(8):294-305.
Bota S, Herkner H, Sporea I. Meta-analysis: ARFI elastography versus transient elastography for the evaluation of liver fibrosis. Liver Int. 2013;33(8):1138–47
Bravi F, Bosetti C, Tavani A, et al. Coffee drinking in hepatocellular carcinoma risk: a meta-analysis. Hepatology. 2007;46(2):430-5.
Bruns T, Zimmermann HW, Stallmach A. Risk factors and outcome of bacterial infections in cirrhosis. World J Gastroenterol. 2014;20(10):2542–54
Buongiorno G, Quaranta GM, Penna A, et al. [The effect of ursodeoxycholic acid in patients with liver cirrhosis and chronic hypertransaminasemia]. Minerva gastroenterological e dietologica. 1994;40(1):31-36.
Burra P. Liver abnormalities and endocrine diseases. Best Pract Res Clin Gastroenterol. 2013;27(4):553–63
Busher JT. Serum Albumin and Globulin. In: Clinical Methods: The History, Physical, and Laboratory Examinations. 3
ed. Walker HK, Hall WD, Hurst JW, eds. Boston: Butterworths; 1990. Available at: http://www.ncbi.nlm.nih.gov/books/NBK024/.
Busk TM, Bendtsen F, Moller S. Cardiac and renal effects of a transjugular intrahepatic portosystemic shunt in cirrhosis. European journal of gastroenterology & hepatology. May 2013;25(5):523-530.
Cavanaugh J, Niewoehner CB, Nuttall FQ. Gynecomastia and cirrhosis of the liver. Archives of internal medicine. Mar 1990;150(3):563-565.
CDC. Centers for Disease Control and Prevention. Hepatitis C Information for the Public: Hepatitis C FAQs for the Public. Available at: http://www.cdc.gov/hepatitis/c/cfaq.htm#cFAQ31. Accessed 7/14/2014.
Chavez-Tapia NC, Cesar-Arce A, Barrientos-Gutiérrez T, et al. A systematic review and meta-analysis of the use of oral zinc in the treatment of hepatic encephalopathy. Nutr J. 2013;12:74
Alcoholism prognosis statistics Alcoholism prognosis scale Chronic alcoholism prognosis Neuropathy alcoholism prognosis Bipolar alcoholism prognosis Alcoholism recovery prognosis Peripheral neuropathy alcoholism prognosis End stage alcoholism prognosis Li
Chen S, Zhou J, Xi M, Jia Y, Wong Y, Zhao J,... Wen A. Pharmacogenetic variation and metformin response. Current drug metabolism. Dec 2013;14(10):1070-1082.
Choi, H.-K., Pokharel, Y. R., Lim, S. C., et al. Inhibition of liver fibrosis by solubilized coenzyme Q10: Role of Nrf2 activation in inhibiting transforming growth factor-beta1 expression. Toxicol. Appl. Pharmacol. 2009;240(3):377–84
Chung C and Iwakiri Y. The lymphatic vascular system in liver diseases: its role in ascites formation. Clin Mol Hepatol. 2013;19(2):99–104
Ciesek S, von Hahn T, Colpitts CC, Schang LM, Friesland M, Steinmann J,... Steinmann E. The green tea polyphenol, epigallocatechin-3-gallate, inhibits hepatitis C virus entry. Hepatology (Baltimore, Md.). Dec 2011;54(6):1947-1955.
Corpechot C, Carrat F, Bonnand AM, Poupon RE, Poupon R. The effect of ursodeoxycholic acid therapy on liver fibrosis progression in primary biliary cirrhosis. Hepatology (Baltimore, Md.). Dec 2000;32(6):1196-1199.
Corton JC, Brown-Borg HM. Peroxisome proliferator-activated receptor gamma coactivator 1 in caloric restriction and other models of longevity. The journals of gerontology. Series A, Biological sciences and medical sciences. Dec 2005;60(12):1494-1509.
Crawford BA, Labio ED, Strasser SI, McCaughan GW. Vitamin D replacement for cirrhosis-related bone disease. Nature clinical practice. Gastroenterology & hepatology. Dec 2006;3(12):689-699.
Craxi A, Cooksley WG. Pegylated interferons for chronic hepatitis B. Antiviral research. Oct 2003;60(2):87-89.
Cui L, Jai X, Zhou Q, et al. Curcumin affects β-catenin pathway in hepatic stellate cell in vitro and in vivo. J Pharm Pharmacol. 2014 Jun 19. [Epub ahead of print]
Crownover BK, Covey CJ. Hereditary hemochromatosis. American family physician. Feb 1 2013;87(3):183-190.
Czaja AJ. Drug choices in autoimmune hepatitis: part A--Steroids. Expert review of gastroenterology & hepatology. Sep 2012;6(5):603-615.
Czaja AJ. Hepatic inflammation and progressive liver fibrosis in chronic liver disease. World J Gastroenterol. 2014;20(10):2515–32
D'Amico G, Garcia-Tsao G, Pagliaro L. Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies. Journal of hepatology. Jan 2006;44(1):217-231.
Dam G, Ott P, Aagaard NK, et al. Branched-chain amino acids and muscle ammonia detoxification in cirrhosis. Metab Brain Dis. 2013;28(2):217–20
Dam MK, Flensborg-Madsen T, Eliasen M, et al. Smoking and risk of liver cirrhosis: a population-based cohort study. Scand. J. Gastroenterol. 2013;48(5):585–91
Degasperi E, Aghemo A. Sofosbuvir for the treatment of chronic hepatitis C: between current evidence and future perspectives. Hepatic medicine: evidence and research. 2014;6:25-33.
Delangle P and Mintz E. Chelation therapy in Wilson's disease: from D-penicillamine to the design of selective bioinspired intracellular Cu(I) chelators. Dalton Trans. 2012;41(21):6359–70
Delgado JS, Vodonos A, Malnick S, Kriger O, Wilkof-Segev R, Delgado B,... Fich A. Autoimmune hepatitis in southern Israel: a 15-year multicenter study. Journal of digestive diseases. Nov 2013;14(11):611-618.
Deng YL, Xiong XZ, Cheng NS. Organ fibrosis inhibited by blocking transforming growth factor-β signaling via peroxisome proliferator-activated receptor γ agonists. HBPD INT. 2012;11(5):467–78
Din S, Konstandin MH, Johnson B, Emathinger J, Volkers M, Toko H,... Sussman MA. Metabolic dysfunction consistent with premature aging results from deletion of pim kinases. Circulation research. Jul 18 2014;115(3):376-387.
Ding J and Wang H. Multiple interactive factors in hepatocarcinogenesis. Cancer Lett. 2014;346(1):17–23
Dufour JF, Oneta CM, Gonvers JJ, et al. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin e in nonalcoholic steatohepatitis. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association. 2006;4(12):1537-1543.
Durand F and Valla D. Assessment of the prognosis of cirrhosis: Child-Pugh versus MELD. J Hepatol. 2005;42 Suppl(1):S100–7
Durand F, Valla D. Assessment of Prognosis of Cirrhosis. Semin Liver Dis. 2008;28(1):110-122.
Dwyre DM, Fernando LP, Holland PV. Hepatitis B, hepatitis C and HIV transfusion-transmitted infections in the 21st century. Vox sanguinis. Jan 2011;100(1):92-98.
Elwell RJ, Spencer AP, Eisele G. Combined furosemide and human albumin treatment for diuretic-resistant edema. The Annals of pharmacotherapy. May 2003;37(5):695-700.
Enweluzo C, Aziz F, Mori A. Comparing efficacy between regimens in the initial treatment of autoimmune hepatitis. Journal of clinical medicine research. Aug 2013;5(4):281-285.
European Association for the Study of Liver. EASL clinical practical guidelines: management of alcoholic liver disease. J Hepatol. 2012;57(2):399–420
Fabio G, Minonzio F, Delbini P, Bianchi A, Cappellini MD. Reversal of cardiac complications by deferiprone and deferoxamine combination therapy in a patient affected by a severe type of juvenile hemochromatosis (JH). Blood. Jan 1 2007;109(1):362-364.
Fairbanks KD, Tavill AS. Liver Disease in Alpha 1-Antitrypsin Deficiency: A Review. Am J Gastroenterology. 2008;103:2136-2141.
Fargion S, Valenti L, Fracanzani AL. Beyond hereditary hemochromatotis: new insights into the relationship between iron overload and chronic liver diseases. Dig Liver Dis. 2011;43(2):89-95.
FDA. U.S. Food and Drug Administration. News & Events: FDA News Release. FDA approves Sovaldi for chronic hepatitis C. Available at:. Last updated 12/9/2013. Accessed 7/7/2014.
Ferenci P, Dragosics B, Dittrich H. Randomized controlled trial of silymarin treatment in patients with cirrhosis of the liver. J Hepatol. 1989;9(1):105–13
Ferre N, Camps J, Prats E, Girona J, Gomez F, Heras M,... Joven J. Impaired vitamin E status in patients with parenchymal liver cirrhosis: relationships with lipoprotein compositional alterations, nutritional factors, and oxidative susceptibility of plasma. Metabolism: clinical and experimental. May 2002;51(5):609-615.
Ferri FF. Ferri’s Clinical Advisor. Nonalcoholic Fatty Liver Disease. Available at: www.clinicalkey.com. Copyright 2014 by Mosby, an Imprint of Elsevier Inc. Accessed 7/23/2014.
Fox RK. When to consider liver transplant during the management of chronic liver disease. Med. Clin. North Am. 2014;98(1):153–68
Garcia-Tsao G, Lim JK, Lim J. Members of Veterans Affairs Hepatitis C Resource Center Program. Management and treatment of patients with cirrhosis and portal hypertension: recommendations from the Department of Veterans Affairs Hepatitis C Resource Center Program and the National Hepatitis C Program. Am J Gastroenterol. 2009;104(7):1802–29
Garcia-Tsao G, Sanyal AJ, Grace ND, et al. Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis. Am J Gastroenterol. 2007;102(9):2086–102
Garcia-Tsao G, Goldman L (ed.), Schafer AI (ed.). Goldman's Cecil Medicine, Twenty-Fourth Edition. Chapter 156: CIRRHOSIS AND ITS SEQUELAE; 999-107. Copyright 2012 Saunders, an imprint of Elsevier Inc. 2012.
Gatta A, Verardo A, Bolognesi M. Hypoalbuminemia. Intern Emerg Med. 2012;7 Suppl 3:S193–9
Gattermann N. The treatment of secondary hemochromatosis. Deutsches Arzteblatt international. Jul 2009;106(30):499-504, i.
Georgescu EF. Angiotensin receptor blockers in the treatment of NASH/NAFLD: could they be a first-class option? Advances in therapy. 2008;25(11):1141–74
Gluud LL, Dam G, Borre M. Oral branched-chain amino acids have a beneficial effect on manifestations of hepatic encephalopathy in a systematic review with meta-analyses of randomized controlled trials. Journal of Nutrition. 2013;143(8):1263–8
Goel V and Kar P. Hepatic osteodystrophy. Trop Gastroenterol. 2010;31(2):82–6
Graf D, Vallböhmer D, Knoefel WT. Multimodal treatment of hepatocellular carcinoma. Eur. J. Intern. Med. 2014. [Epub ahead of print]
Gupta N, Kumar A, Sharma P, et al. Effects of the adjunctive probiotic VSL#3 on portal haemodynamics in patients with cirrhosis and large varices: a randomized trial. Liver Int. 2013;33(8):1148–57
Haafiz AB. Liver fibrosis in biliary atresia. Expert review of gastroenterology & hepatology. Jun 2010;4(3):335-343.
Habib-ur-Rehman M, Mahmood T, Salim T, Afzal N, Ali N, Iqbal J,... Khan A. Affect of silymarin on serum levels of ALT and GGT in ethanol induced hepatotoxicity in albino rats. Journal of Ayub Medical College, Abbottabad: JAMC. Oct-Dec 2009;21(4):73-75.
Halegoua-De Marzio D, Kraft WK, Daskalakis C, Ying X, Hawke RL, Navarro VJ. Limited sampling estimates of epigallocatechin gallate exposures in cirrhotic and noncirrhotic patients with hepatitis C after single oral doses of green tea extract. Clinical therapeutics. Dec 2012;34(12):2279-2285.e2271.
Hawke RL, Schrieber SJ, Soule TA. Silymarin ascending multiple oral dosing phase I study in noncirrhotic patients with chronic hepatitis C. J Clin Pharmacol. 2010;50(4):434–49
Heli H, Mirtorabi S, Karimian K. Advances in iron chelation: an update. Expert Opin Ther Pat. 2011;21(6):819–56
Henry Z, Uppal D, Saad W, et al. Gastric and Ectopic Varices. Clin Liver Dis. 2014;18(2):371–88
Hernández-Guerra, M., García-Pagán, J. C., Turnes, J., et al. Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension. Hepatology. 2006;43(3):485–91
Higashi N, Kohjima M, Fukushima M, Ohta S, Kotoh K, Enjoji M,... Nakamuta M. Epigallocatechin-3-gallate, a green-tea polyphenol, suppresses Rho signaling in TWNT-4 human hepatic stellate cells. The Journal of laboratory and clinical medicine. Jun 2005;145(6):316-322.
Higashi N, Sato M, Kojima N, Irie T, Kawamura K, Mabuchi A, Senoo H. Vitamin A storage in hepatic stellate cells in the regenerating rat liver: with special reference to zonal heterogeneity. The anatomical record. Part A, Discoveries in molecular, cellular, and evolutionary biology. Oct 2005;286(2):899-907.
Hirsch, S., Poniachick, J., Avendaño, M., et al. Serum folate and homocysteine levels in obese females with non-alcoholic fatty liver. Nutrition. 2005;21(2):137–41
Hofmann WP, Herrmann E, Sarrazin C, Zeuzem S. Ribavirin mode of action in chronic hepatitis C: from clinical use back to molecular mechanisms. Liver international: official journal of the International Association for the Study of the Liver. Dec 2008;28(10):1332-1343.
Huo TI, Lin HC, Wu JC, Lee FY, Hou MC, Lee PC,... Lee SD. Proposal of a modified Child-Turcotte-Pugh scoring system and comparison with the model for end-stage liver disease for outcome prediction in patients with cirrhosis. Liver transplantation: official publication of the American Association for the Study of Liver Diseases and the International Liver Transplantation Society. Jan 2006;12(1):65-71.
Intercept Pharmaceuticals, Inc. Intercept Announces that FDA Grants Fast Track Designation to Obeticholic Acid for the Treatment of Patients with Primary Biliary Cirrhosis. 5/28/2014. Available at: http://ir.interceptpharma.com/releasedetail.cfm?releaseid=851012. Accessed 7/31/2014.
Iwakiri Y. Pathophysiology of Portal Hypertension. Clin Liver Dis. 2014;18(2):281–91
Jaurigue MM and Cappell MS. Therapy for alcoholic liver disease. World J Gastroenterol. 2014;20(9):2143–58
Jia JD, Bauer M, Cho JJ, et al. Antifibrotic effect of silymarin in rat secondary biliary fibrosis is mediated by downregulation of procollagen alpha1(I) and TIMP-1. J Hepatol. 2001;35(3):392-8.
Jin H, Yamamoto N, Uchida K, Terai S, Sakaida I. Telmisartan prevents hepatic fibrosis and enzyme-altered lesions in liver cirrhosis rat induced by a choline-deficient L-amino acid-defined diet. Biochemical and biophysical research communications. Dec 28 2007;364(4):801-807.
Jungas RL, Halperin ML, Brosnan JT. Quantitative analysis of amino acid oxidation and related gluconeogenesis in humans. Physiological reviews. Apr 1992;72(2):419-448.
Kaloyianni M, Freedland RA. Contribution of several amino acids and lactate to gluconeogenesis in hepatocytes isolated from rats fed various diets. The Journal of nutrition. Jan 1990;120(1):116-122.
Kazimierska, E., and Czestochowska, E. [Serum homocysteine, vitamin B12 and folic acid concentrations in patients with alcoholic liver cirrhosis]. Pol. Merkur. Lekarski. 2003;15(86):140–3
Keating GM. Sofosbuvir: a review of its use in patients with chronic hepatitis C. Drugs. 2014;74(10):1127-46.
Kimer, N., Krag, A., Møller, S., Bendtsen, F., and Gluud, L. L. Systematic review with meta-analysis: the effects of rifaximin in hepatic encephalopathy. Aliment. Pharmacol. Ther. 2014.
Kim MY, Cho MY, Baik SK. Beneficial effects of candesartan, an angiotensin-blocking agent, on compensated alcoholic liver fibrosis - a randomized open-label controlled study. Liver Int. 2012;32(6):977–87
Kim MY, Jeong WK, Baik SK. Invasive and non-invasive diagnosis of cirrhosis and portal hypertension. World J Gastroenterol. 2014;20(15):4300–15
Klatsky, A. L., Morton, C., Udaltsova, N., and Friedman, G. D. Coffee, cirrhosis, and transaminase enzymes. Arch Intern Med. 2006;166(11):1190–5
Kmiec Z. Cooperation of liver cells in health and disease. Advances in anatomy, embryology, and cell biology. 2001;161:Iii-xiii, 1-151.
Ko WS, Guo CH, Yeh MS, et al. Blood micronutrient, oxidative stress, and viral load in patients with chronic hepatitis C. World J Gastroenterol. 2005;11(30):4697-702.
Kochi T, Shimizu M, Terakura D, Baba A, Ohno T, Kubota M,... Moriwaki H. Non-alcoholic steatohepatitis and preneoplastic lesions develop in the liver of obese and hypertensive rats: suppressing effects of EGCG on the development of liver lesions. Cancer letters. Jan 1 2014;342(1):60-69.
Krieger D, Krieger S, Jansen O, Gass P, Theilmann L, Lichtnecker H. Manganese and chronic hepatic encephalopathy. Lancet. Jul 29 1995;346(8970):270-274.
Krisper P, Stadlbauer V, Stauber RE. Clearing of toxic substances: are there differences between the available liver support devices? Liver Int. 2011;Suppl 3:5-8.
Kysenius K, Brunello CA, Huttunen HJ. Mitochondria and NMDA receptor-dependent toxicity of berberine sensitizes neurons to glutamate and rotenone injury. PloS one. 2014;9(9):e107129.
Larsson SC and Wolk A. Coffee consumption and risk of liver cancer: a meta-analysis. Gastroenterology. 2007;132(5):1740-5.
Lata J. Hepatorenal syndrome. World J Gastroenterol. 2012;18(36):4978–84
Lata J, Novotný I, Príbramská V. The effect of probiotics on gut flora, level of endotoxin and Child-Pugh score in cirrhotic patients: results of a double-blind randomized study. Eur J Gastroenterol Hepatol. 2007;19(12):1111–3
Le MD, Enbom E, Traum PK, et al. Alcoholic liver disease patients treated with S-adenosyl-L-methionine: an in-depth look at liver morphologic data comparing pre and post treatment liver biopsies. Exp. Mol. Pathol. 2013;95(2):187–91
Lee YH, Hsu CY, Huo TI. Assessing liver dysfunction in cirrhosis: role of the model for end-stage liver disease and its derived systems. J Chin Med Assoc. 2013;76(8):419–24
Lewis JH and Stine JG. Review article: prescribing medications in patients with cirrhosis - a practical guide. Aliment. Pharmacol. Ther. 2013;37(12):1132–56
Li YC, Qiao G, Uskokovic M, Xiang W, Zheng W, Kong J. Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure. The Journal of steroid biochemistry and molecular biology. May 2004;89-90(1-5):387-392.
Li JY, Cao HY, Liu P, et al. Glycyrrhizic Acid and Treatment of Liver Diseases: Literature Review. Biomed Res Int. 2014;872139. [Epub 2014 May 13]
Lieber CS. New concepts of the pathogenesis of alcoholic liver disease lead to novel treatments. Current gastroenterology reports. Feb 2004;6(1):60-65.
Lieber CS, Weiss DG, Groszmann R, Paronetto F, Schenker S. II. Veterans Affairs Cooperative Study of polyenylphosphatidylcholine in alcoholic liver disease. Alcoholism, clinical and experimental research. Nov 2003;27(11):1765-1772.
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology. 2009;50(1):291–308
Liou IW. Management of end-stage liver disease. Med. Clin. North Am. 2014;98(1):119–52
Lipkin EW and Kowdley KV. Vitamin K replacement in osteoporosis associated with cirrhosis: another reason to "eat your vegetables"? Am J Gastroenterol. 2002;97(4):786–8
Liu Q, Duan ZP, Ha DK, et al. Synbiotic modulation of gut flora: effect on minimal hepatic encephalopathy in patients with cirrhosis. Hepatology. 2004;39(5):1441–9
Loew D, Wanitschke R, Schroedter A. Studies on vitamin B12 status in the elderly--prophylactic and therapeutic consequences. International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition. May 1999;69(3):228-233.
Loguercio C, Andreone P, Brisc C. Silybin combined with phosphatidylcholine and vitamin E in patients with nonalcoholic fatty liver disease: a randomized controlled trial. Free Radic Biol Med. 2012;52(9):1658–65
Lu XL, Zhang ZL, Zhou JF, Cai JT, Qian KD. [Plasma levels of ascorbic acid and vitamin E in patients with liver cirrhosis]. Zhejiang da xue xue bao. Yi xue ban = Journal of Zhejiang University. Medical sciences. Dec 2003;32(6):533-535.
Lucena MI, Andrade RJ, de la Cruz JP, et al. Effects of silymarin MZ-80 on oxidative stress in patients with alcoholic cirrhosis. Results of a randomized, double-blind, placebo-controlled clinical study. Int J Clin Pharmacol Ther. 2002;40(1):2–8
Malaguarnera M, Gargante MP, Malaguarnera G. Bifidobacterium combined with fructo-oligosaccharide versus lactulose in the treatment of patients with hepatic encephalopathy. Eur J Gastroenterol Hepatol. 2010;22(2):199–206
Mammen EF. Coagulation abnormalities in liver disease. Hematology/oncology clinics of North America. Dec 1992;6(6):1247-1257.
Manns MP, Wedemeyer H, Singer A, et al. Glycyrrhizin in patients who failed previous interferon alpha-based therapies: biochemical and histological effects after 52 weeks. J Viral Hepat. 2012;19(8):537-56.
Manns MP. Liver cirrhosis, transplantation and organ shortage. Deutsches Arzteblatt international. Feb 2013;110(6):83-84.
Marieb E and Hoehn K. Human anatomy & physiology. 8 ed. San Francisco: Pearson Benjamin Cummings, 2010
Marotta F, Yoshida C, Barreto R, Naito Y, Packer L. Oxidative-inflammatory damage in cirrhosis: effect of vitamin E and a fermented papaya preparation. Journal of gastroenterology and hepatology. May 2007;22(5):697-703.
Mato JM, Cámara J, Fernández de Paz J. S-adenosylmethionine in alcoholic liver cirrhosis: a randomized, placebo-controlled, double-blind, multicenter clinical trial. J Hepatol. 1999;30(6):1081–9
Matos, C. R., and Coe, C. A. R. Ascorbic acid supplementation has a cytoprotective effect on secondary biliary cirrhosis: experimental study in young rats. J Pediatr (Rio J). 2008;84(6)
McGillicuddy FC, Reilly MP, Rader DJ. Adipose modulation of high-density lipoprotein cholesterol: implications for obesity, high-density lipoprotein metabolism, and cardiovascular disease. Circulation. Oct 11 2011;124(15):1602-1605.
Medici V, Virata MC, Peerson JM. S-adenosyl-L-methionine treatment for alcoholic liver disease: a double-blinded, randomized, placebo-controlled trial. Alcohol. Clin. Exp. Res. 2011;35(11):1960–5
MedicineNet. Digestive Problems and Bleeding Varices. Available at: http://www.medicinenet.com/bleeding_varices/article.htm. 7/28/2014. Accessed 7/28/2014.
Mende S, Schulte S, Strack I, Hunt H, Odenthal M, Pryymachuck G,... Tox U. Telmisartan plus propranolol improves liver fibrosis and bile duct proliferation in the PSC-like Abcb4-/- mouse model. Digestive diseases and sciences. May 2013;58(5):1271-1281.
Mikes V, Dadak V. Berberine derivatives as cationic fluorescent probes for the investigation of the energized state of mitochondria. Biochimica et biophysica acta. 1983;723(2):231-239.
Mikes V, Yaguzhinskij LS. Interaction of fluorescent berberine alkyl derivatives with respiratory chain of rat liver mitochondria. Journal of bioenergetics and biomembranes. 1985;17(1):23-32.
Ming LJ, Yin AC. Therapeutic effects of glycyrrhizic acid. Nat Prod Commun. 2013;8(3):415-8.
Moore KP, Aithal GP. Guidelines on the management of ascites in cirrhosis. Gut. Oct 2006;55 Suppl 6:vi1-12.
Alcoholism prognosis statistics Alcoholism prognosis scale Chronic alcoholism prognosis Neuropathy alcoholism prognosis Bipolar alcoholism prognosis Alcoholism recovery prognosis Peripheral neuropathy alcoholism prognosis End stage alcoholism prognosis Li
Moyer K, Balistreri W. Hepatobiliary disease in patients with cystic fibrosis. Curr Opin Gastroenterol. 2009;25(3):272-8.
Muriel P and Arauz J. Coffee and liver diseases. Fitoterapia. 2010;81(5):297–305
Nabavi SF, Daglia M, Moghaddam AH, et al. Curcumin and Liver Disease: from Chemistry to Medicine. Comprehensive Reviews in Food Science and Food Safety. 2013;13(1):62–77
National Center for Health Statistics. National Vital Statistics Reports. 2013:1–118
Nayak, R., Pandurangi, A., Bhogale, G., Patil, N., and Chate, S. Asterixis (flapping tremors) as an outcome of complex psychotropic drug interaction. J Neuropsychiatry Clin Neurosci. 2012;24(1):E26–7
Neeman R, Abramovitch S, Sharvit E, Elad-Sfadia G, Haklai R, Kloog Y, Reif S. Vitamin D and S-Farnesylthiosalicylic Acid Have a Synergistic Effect on Hepatic Stellate Cells Proliferation. Digestive diseases and sciences. Jun 19 2014.
Nevens F, Laleman W. Artificial liver support devices as treatment option for liver failure. Best Pract Res Clin Gastroenterol. 2012;26(1):17-26.
Ng CK, Chan MH, Tai MH, Lam CW. Hepatorenal syndrome. The Clinical biochemist. Reviews / Australian Association of Clinical Biochemists. Feb 2007;28(1):11-17.
Nicolaou M, Andress EJ, Zolnerciks JK, Dixon PH, Williamson C, Linton KJ. Canalicular ABC transporters and liver disease. The Journal of pathology. Jan 2012;226(2):300-315.
NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. National Digestive Diseases Information Clearinghouse (NDDIC) webpage. Cirrhosis. Available at: http://digestive.niddk.nih.gov/ddiseases/pubs/cirrhosis/. Last updated 4/23/2014a. Accessed 5/1/2014.
NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. National Digestive Diseases Information Clearinghouse (NDDIC) webpage. Liver Biopsy. Available at: http://digestive.niddk.nih.gov/ddiseases/pubs/liverbiopsy/. Last updated 5/7/2014b. Accessed 5/1/2014.
NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. National Digestive Diseases Information Clearinghouse (NDDIC) webpage. Nonalcoholic Steatohepatitis. Available at: http://digestive.niddk.nih.gov/ddiseases/pubs/nash/index.aspx. Last updated 5/28/2014c. Accessed 7/2/2014.
NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. National Digestive Diseases Information Clearinghouse (NDDIC) webpage. Biliary Atresia. Available at: http://digestive.niddk.nih.gov/ddISeases/pubs/atresia/#1. Last updated 8/1/2012a. Accessed 7/14/2014.
NIDDK. National Institute of Diabetes and Digestive and Kidney Diseases. National Digestive Diseases Information Clearinghouse (NDDIC) webpage. What I need to know about Hepatitis C. Available at: http://digestive.niddk.nih.gov/ddiseases/pubs/hepc_ez/index.aspx. Last updated 12/19/2012b. Accessed 7/23/2014.
Nishioka SD, Gyorkos TW, Joseph L, Collet JP, Maclean JD. Tattooing and risk for transfusion-transmitted diseases: the role of the type, number and design of the tattoos, and the conditions in which they were performed. Epidemiology and infection. Feb 2002;128(1):63-71.
Norvell JP and Spivey JR. Hepatic Hydrothorax. Clin Liver Dis. 2014;18(2):439–49
Nusrat S, Khan MS, Fazili J, et al. Cirrhosis and its complications: evidence based treatment. World J Gastroenterol. 2014;14(20):5442-60.
Oertelt-Prigione, S., Crosignani, A., Gallieni, M., Vassallo, E., Podda, M., and Zuin, M. Severe hepatic encephalopathy in a patient with liver cirrhosis after administration of angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker combination therapy: a case report. J Med Case Rep. 2010;4(1):141
Ohkubo A. [Bilirubin metabolism in liver cirrhosis]. Nihon rinsho. Japanese journal of clinical medicine. Jan 1994;52(1):138-144.
Orman ES, Odena G, Bataller R. Alcoholic liver disease: pathogenesis, management, and novel targets for therapy. Journal of Gastroenterology and Hepatology. 2013;28 Suppl 1:77–84
Orman, E. S., Hayashi, P. H., Bataller, R., and Barritt, A. S., IV. Paracentesis Is Associated With Reduced Mortality in Patients Hospitalized With Cirrhosis and Ascites. Clinical Gastroenterology and Hepatology. 2014;12(3):496–503.e1
Pande C, Kumar A, Sarin SK. Addition of probiotics to norfloxacin does not improve efficacy in the prevention of spontaneous bacterial peritonitis: a double-blind placebo-controlled randomized-controlled trial. Eur J Gastroenterol Hepatol. 2012;24(7):831–9
Papatheodoridis GV, Dimou E, Papadimitropoulos V. Nucleoside analogues for chronic hepatitis B: antiviral efficacy and viral resistance. The American journal of gastroenterology. Jul 2002;97(7):1618-1628.
Parés A, Planas R, Torres M. Effects of silymarin in alcoholic patients with cirrhosis of the liver: results of a controlled, double-blind, randomized and multicenter trial. J Hepatol. 1998;28(4):615–21
Park CW, Kim SH, Yang HW, Lee YJ, Jung SH, Song HS,... Cha SW. A case of variceal bleeding from the jejunum in liver cirrhosis. Clinical and molecular hepatology. Mar 2013;19(1):78-81.
Parker R, Armstrong MJ, Corbett C, et al. Systematic review: pentoxifylline for the treatment of severe alcoholic hepatitis. Aliment. Pharmacol. Ther. 2013;37(9):845–54
Patel V, Rink C, Gordillo GM, Khanna S, Gnyawali U, Roy S,... Sen CK. Oral tocotrienols are transported to human tissues and delay the progression of the model for end-stage liver disease score in patients. The Journal of nutrition. Mar 2012;142(3):513-519.
Patti ME, Butte AJ, Crunkhorn S, Cusi K, Berria R, Kashyap S,... Mandarino LJ. Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1. Proceedings of the National Academy of Sciences of the United States of America. Jul 8 2003;100(14):8466-8471.
Pawlotsky JM, Dahari H, Neumann AU, Hezode C, Germanidis G, Lonjon I,... Dhumeaux D. Antiviral action of ribavirin in chronic hepatitis C. Gastroenterology. Mar 2004;126(3):703-714.
Pereg D, Kotliroff A, Gadoth N, et al. Probiotics for patients with compensated liver cirrhosis: a double-blind placebo-controlled study. Nutrition. 2011;27(2):177–81
Periyalwar, P., and Dasarathy, S. Malnutrition in cirrhosis: contribution and consequences of sarcopenia on metabolic and clinical responses. Clin Liver Dis. 2012;16(1):95–131
Perz JF, Armstrong GL, Farrington LA, et al. The contributions of hepatitis B virus and hepatitis C virus infections to cirrhosis and primary liver cancer worldwide. J Hepatol. 2006;45(4):529–38
Plauth M, Cabré E, Riggio O. ESPEN Guidelines on Enteral Nutrition: Liver disease. Clinical Nutrition. 2006;25:285–94.
Plessier A, Rautou PE, Valla DC. Management of hepatic vascular diseases. J Hepatol. 2012;56 Suppl 1:S25–38
Polyak SJ, Ferenci P, Pawlotsky JM. Hepatoprotective and antiviral functions of silymarin components in hepatitis C virus infection. Hepatology (Baltimore, Md.). Mar 2013;57(3):1262-1271.
Procopet B, Tantau M, Bureau C. Are there any alternative methods to hepatic venous pressure gradiant in portal hypertension assessment? J Gastrointestin Liver Dis. 2013;22(1):73-8.
Pu JY, He L, Wu SY, et al. [Anti-virus research of triterpenoids in licorice]. Bing Du Xue Bao. 2013;29(6):673-9.
Purnak T and Yilmaz Y. Liver disease and malnutrition. Best Pract Res Clin Gastroenterol. 2013;27(4):619–29
Putz-Bankuti C, Pilz S, Stojakovic T, Scharnagl H, Pieber TR, Trauner M,... Stauber RE. Association of 25-hydroxyvitamin D levels with liver dysfunction and mortality in chronic liver disease. Liver international: official journal of the International Association for the Study of the Liver. May 2012;32(5):845-851.
Rambaldi A and Gluud C. S-adenosyl-L-methionine for alcoholic liver diseases. Cochrane Database Syst Rev. 2006;(2):CD002235
Rasool M, Iqbal J, Malik A, et al. Hepatoprotective Effects of Silybum marianum (Silymarin) and Glycyrrhiza glabra (Glycyrrhizin) in Combination: A Possible Synergy. Evid Based Complement Alternat Med. 2014;641597. [Epub 2014 Mar 25]
Rivera-Mancia S, Rios C, Montes S. Manganese and ammonia interactions in the brain of cirrhotic rats: effects on brain ammonia metabolism. Neurochemical research. May 2012;37(5):1074-1084.
Roberts EA, Sarkar B. Liver as a key organ in the supply, storage, and excretion of copper. The American journal of clinical nutrition. Sep 2008;88(3):851s-854s.
Rockey DC. Translating an understanding of the pathogenesis of hepatic fibrosis to novel therapies. Clin. Gastroenterol. Hepatol. 2013;11(3):224–31.e1–5
Saji S, Kumar S, Thomas V. A randomized double blind placebo controlled trial of probiotics in minimal hepatic encephalopathy. Trop Gastroenterol. 2011;32(2):128–32
Salvioli G, Carati L, Lugli R. Steatorrhoea in cirrhosis: effect of ursodeoxycholic acid administration. The Journal of international medical research. 1990;18(4):289-297.
Santos PC, Krieger JE, Pereira AC. Molecular diagnostic and pathogenesis of hereditary hemochromatosis. Int J Mol Sci. 2012;13(2):1497–511
Sanyal AJ, Mullen KD, Bass NM. The treatment of hepatic encephalopathy in the cirrhotic patient. Gastroenterology & hepatology. Apr 2010;6(4 Suppl 8):1-12.
Scaglione SJ and Lok ASF. Effectiveness of hepatitis B treatment in clinical practice. Gastroenterology. 2012;142(6):1360–1
Scalera F, Martens-Lobenhoffer J, Bukowska A, Lendeckel U, Tager M, Bode-Boger SM. Effect of telmisartan on nitric oxide--asymmetrical dimethylarginine system: role of angiotensin II type 1 receptor gamma and peroxisome proliferator activated receptor gamma signaling during endothelial aging. Hypertension. Mar 2008;51(3):696-703.
Schaefer B, Schmitt CP. The role of molecular absorbent recirculating system dialysis for extracorporeal liver support in children. Pediatr Nephrol. 2013;28(9):1763-9.
Scheen AJ. Pharmacokinetic and toxicological considerations for the treatment of diabetes in patients with liver disease. Expert opinion on drug metabolism & toxicology. Jun 2014;10(6):839-857.
Schuppan D, Afdhal NH. Liver cirrhosis. Lancet. 2008;371(9615):838-51.
Schuppan D and Kim YO. Evolving therapies for liver fibrosis. J Clin Invest. 2013;123(5):1887–901
Schwartz JM and Reinus JF. Prevalence and natural history of alcoholic liver disease. Clin Liver Dis. 2012;16(4):659–66
Senior M. Sovaldi makes blockbuster history, ignites drug pricing unrest. Nature biotechnology. Jun 9 2014;32(6):501-502.
Shah AM, Malhotra A, Kothari S, Baddoura W, Depasquale J, Spira R. Reversal of liver cirrhosis in autoimmune hepatitis. Hepato-gastroenterology. Nov-Dec 2011;58(112):2115-2117.
Shi H., Dong, L., Bai, Y., Zhao, J., Zhang, Y., and Zhang, L. Chlorogenic acid against carbon tetrachloride-induced liver fibrosis in rats. European Journal of Pharmacology. 2009;623(1-3):119–24
Shi H., Dong, L., Jiang, J., et al. Chlorogenic acid reduces liver inflammation and fibrosis through inhibition of toll-like receptor 4 signaling pathway. Toxicology. 2013;303:107–14
Shearer MJ, Bach A, Kohlmeier M. Chemistry, nutritional sources, tissue distribution and metabolism of vitamin K with special reference to bone health. The Journal of nutrition. Apr 1996;126(4 Suppl):1181s-1186s.
Shiomi S, Nishiguchi S, Kubo S, et al. Vitamin K2 (menatetrenone) for bone loss in patients with cirrhosis of the liver. Am J Gastroenterol. 2002;97(4):978-81.
Siegel GJ, Albers RW, Brady ST, Price DL. Basic Neurochemistry - Molecular, Cellular, and Medical Aspects. Copyright 2006, American Society for Neurochemistry. Chapter 34; 596-598.
Silva Santos PS, Fernandes KS, Gallottini MH. Assessment and management of oral health in liver transplant candidates. Journal of applied oral science: revista FOB. Mar-Apr 2012;20(2):241-245.
Sipeki N, Antal-Szalmas P, Lakatos PL, et al. Immune dysfunction in cirrhosis. World J Gastroenterol. 2014;20(10):2564–77
Sirli R, Sporea I, Bota S, et al. Liver elastography for the diagnosis of portal hypertension in patients with liver cirrhosis. Med Ultrason. 2012;14(3):225–30
Sokol RJ, Kim YS, Hoofnagle JH, Heubi JE, Jones EA, Balistreri WF. Intestinal malabsorption of vitamin E in primary biliary cirrhosis. Gastroenterology. Feb 1989;96(2 Pt 1):479-486.
SRTR (Scientific Registry of Transplant Recipients). HRSA: Health Resources and Services Administration webpage. OPTN/SRTR 2012 Annual Data Report. Liver. pp. 69-96. 2012. Available at: http://srtr.transplant.hrsa.gov/annual_reports/2012/pdf/03_liver_13.pdf.
Stange, J. Extracorporeal liver support. organogenesis. 2011;7(1):64–73
Stillman AE. Jaundice. In: Clinical Methods: The History, Physical, and Laboratory Examinations. 3
ed. Walker HK, Hall WD, and Hurst JW, eds. Boston: Butterworths; 1990. Available at: http://www.ncbi.nlm.nih.gov/books/NBK413/.
Stokes CS, Krawczyk M, Reichel C, Lammert F, Grunhage F. Vitamin D deficiency is associated with mortality in patients with advanced liver cirrhosis. European journal of clinical investigation. Nov 15 2013.
Sun D, Courtney HS, Beachey EH. Berberine sulfate blocks adherence of Streptococcus pyogenes to epithelial cells, fibronectin, and hexadecane. Antimicrobial agents and chemotherapy. Sep 1988;32(9):1370-1374.
Sztrymf B, Rabiller A, Nunes H, Savale L, Lebrec D, Le Pape A,... Herve P. Prevention of hepatopulmonary syndrome and hyperdynamic state by pentoxifylline in cirrhotic rats. The European respiratory journal. May 2004;23(5):752-758.
Takagi H, Kakizaki S, Sohara N, Sato K, Tsukioka G, Tago Y,... Mori M. Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis. International journal for vitamin and nutrition research. Internationale Zeitschrift fur Vitamin- und Ernahrungsforschung. Journal international de vitaminologie et de nutrition. Nov 2003;73(6):411-415.
Tamaki Y, Nakade Y, Yamauchi T, Makino Y, Yokohama S, Okada M,... Yoneda M. Angiotensin II type 1 receptor antagonist prevents hepatic carcinoma in rats with nonalcoholic steatohepatitis. Journal of gastroenterology. Apr 2013;48(4):491-503.
Tanaka A, Miyakawa H, Luketic VA, et al. The diagnostic value of anti-mitochondrial antibodies, especially in primary biliary cirrhosis. Cell Mol Biol (Noisy-le-grand). 2002;48(3):295-9.
Tandon P, Moncrief K, Madsen K. Effects of probiotic therapy on portal pressure in patients with cirrhosis: a pilot study. Liver Int. 2009;29(7):1110–5
Tarao K, Fujiyama S, Ohkawa S, et al. Ursodiol use is possibly associated with lower incidence of hepatocellular carcinoma in hepatitis C virus-associated liver cirrhosis. Cancer epidemiology, biomarkers & prevention: a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2005;14(1):164-169.
Thakkar B, Aronis KN, Vamvini MT, Shields K, Mantzoros CS. Metformin and sulfonylureas in relation to cancer risk in type II diabetes patients: a meta-analysis using primary data of published studies. Metabolism: clinical and experimental. Jul 2013;62(7):922-934.
Tipoe GL, Leung TM, Liong EC, Lau TY, Fung ML, Nanji AA. Epigallocatechin-3-gallate (EGCG) reduces liver inflammation, oxidative stress and fibrosis in carbon tetrachloride (CCl4)-induced liver injury in mice. Toxicology. Jun 29 2010;273(1-3):45-52.
Trepo E, Ouziel R, Pradat P, Momozawa Y, Quertinmont E, Gervy C,... Moreno C. Marked 25-hydroxyvitamin D deficiency is associated with poor prognosis in patients with alcoholic liver disease. Journal of hepatology. Aug 2013;59(2):344-350.
Trifan A, Chiriac S, Stanciu C. Update on adrenal insufficiency in patients with liver cirrhosis. World journal of gastroenterology: WJG. Jan 28 2013;19(4):445-456.
Tsochatzis EA, Bosch J, Burroughs AK. Liver cirrhosis. Lancet. 2014;383(9930):1749-61.
Tumgor G. Cirrhosis and hepatopulmonary syndrome. World J Gastroenterol. 2014;20(10):2586–94
UMMC. University of Maryland Medical Center website. Cirrhosis. Available at: http://umm.edu/health/medical/reports/articles/cirrhosis. Last updated 9/18/2013. Accessed 7/23/2014.
Valenti L, Dongiovanni P, Fargion S. Diagnostic and therapeutic implications of the association between ferritin level and severity of nonalcoholic fatty liver disease. World J Gastroenterol. 2012;18(29):3782-6.
Valera JM, Smok G, Marquez S, Poniachik J, Brahm J. [Histological regression of liver fibrosis with immunosuppressive therapy in autoimmune hepatitis]. Gastroenterologia y hepatologia. Jan 2011;34(1):10-15.
Vargas-Mendoza N, Madrigal-Santillán E, Morales-González A, et al. Hepatoprotective effect of silymarin. World J Hepatol. 2014;6(3):144-9.
Volpe M, Savoia C, De Paolis P, Ostrowska B, Tarasi D, Rubattu S. The renin-angiotensin system as a risk factor and therapeutic target for cardiovascular and renal disease. Journal of the American Society of Nephrology: JASN. Nov 2002;13 Suppl 3:S173-178.
Wang H, Yang R, Hua X, Zhao W, Zhang W. Enzymatic production of lactulose and 1-lactulose: current state and perspectives. Applied microbiology and biotechnology. Jul 2013;97(14):6167-6180.
Watanabe, A., Obata, T., and Nagashima, H. Berberine therapy of hypertyraminemia in patients with liver cirrhosis. Acta Med. Okayama. 1982;36(4):277–81
Welty FK. Hypobetalipoproteinemia and abetalipoproteinemia. Current opinion in lipidology. Jun 2014;25(3):161-168.
Wiesner, R., Edwards, E., Freeman, R., et al. Model for end-stage liver disease (MELD) and allocation of donor livers. Gastroenterology. 2003;124(1):91–6
Wolf D. Cirrhosis. Medscape. 2013; Available at: http://emedicine.medscape.com/article/185856-overview [Accessed May 4, 2014].
WHO. World Health Organization. Hepatitis B vaccines. Wkly. Epidemiol. Rec. 2009;84(40):405–19
Yasui S, Fujiiwara K, Tawada A, et al. Efficacy of intravenous glycyrrhizin in the early stage of acute onset autoimmune hepatitis. Dig Dis Sci. 2011;56(12):3638-47.
Yesilova, Z., Yaman, H., Oktenli, C., et al. Systemic markers of lipid peroxidation and antioxidants in patients with nonalcoholic Fatty liver disease. Am J Gastroenterol. 2005;100(4):850–5
Yurci A, Yucesoy M, Unluhizarci K, Torun E, Gursoy S, Baskol M,... Ozbakir O. Effects of testosterone gel treatment in hypogonadal men with liver cirrhosis. Clinics and research in hepatology and gastroenterology. Dec 2011;35(12):845-854.
Yurci A, Kalkan AO, Ozbakir O, Karaman A, Torun E, Kula M,... Bayram F. Efficacy of different therapeutic regimens on hepatic osteodystrophy in chronic viral liver disease. European journal of gastroenterology & hepatology. Nov 2011;23(12):1206-1212.
Wong LL. Current status of liver transplantation for hepatocellular cancer. American journal of surgery. Mar 2002;183(3):309-316.
Zarrilli F, Elce A, Scorza M, et al. An update on laboratory diagnosis of liver inherited diseases. Biomed Res Int. 2013:697940
Zhang F, Kong D, Lu Y, et al. Peroxisome proliferator-activated receptor-γ as a therapeutic target for hepatic fibrosis: from bench to bedside. Cell. Mol. Life Sci. 2013;70(2):259–76
Zhang Z and Wang FS. Stem cell therapies for liver failure and cirrhosis. J Hepatol. 2013;59(1):183–5
Zhang P, Li H, Tan X, Chen L, Wang S. Association of metformin use with cancer incidence and mortality: a meta-analysis. Cancer epidemiology. Jun 2013;37(3):207-218.
Zhang X, Harmsen WS, Mettler TA, Kim WR, Roberts RO, Therneau TM,... Chaiteerakij R. Continuation of metformin use after a diagnosis of cirrhosis significantly improves survival of patients with diabetes. Hepatology (Baltimore, Md.). May 3 2014.
Zhao, W., Xue, R., Zhou, Z.-X., Kong, W.-J., and Jiang, J.-D. Reduction of blood lipid by berberine in hyperlipidemic patients with chronic hepatitis or liver cirrhosis. Biomed Pharmacother. 2008;62(10):730–1
Zheng Z, Li X, Ma X. Artificial and bioartificial liver support systemis for acute and acute-on-chronic hepatic failure: A meta-analysis and meta-regression. Exp Ther Med. 2013;6(4):929-936.
Zullo, A. Rifaximin therapy and hepatic encephalopathy: Pros and cons. World J Gastrointest Pharmacol Ther. 2012;3(4):62