Liver Cirrhosis
Diseases

Author: anna rivetti
Date: 20/02/2013

Description

Anna Rivetti

Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis , scar tissue and regenerative nodules (lumps that occur as a result of a process in which damaged tissue is regenerated), leading to loss of liver function.
After heart disease and cancer, cirrhosis is the third most common cause of death in people aged 45-65 years.
This peculiar transformation of the liver was identified by the first anatomic pathologist, Gianbattista Morgagni in his 500 autopsies published in 1761 but the name of "cirrhosis" (greek=orange color) was given by Laennec in 1826 because of the yellowish-tan color of the cirrhotic liver. Only in 1930, one hundred years later, however, the first theory as to the pathogenesis of this disorder was advanced by Roessle: parenchymal degeneration, regeneration and scarring which is now understood according to the following sequence:
  1. INJURY
  2. DEGENERATION
  3. FIBROSIS
  4. FORMATION OF FIBRO-VASCULAR MEMBRANES
  5. DISSECTION INTO NODULES
  6. REARRANGEMENT OF BLOOD CIRCULATION
  7. CIRRHOSIS
which is considered by most experts as a self-perpetuating irreversible process.


The definition of cirrhosis remains morphological, described by a working party for the World Health Organization (WHO) in 1978 as: “ a diffuse process characterized by fibrosis and the conversion of normal liver architectures into structurally abnormal nodules ”.
Cirrhosis is scarring of the liver and poor liver function. It is the final phase of chronic liver disease, October 2011

Classification of cirrhosis
According to World Health Organization

1) MORPHOLOGIC: Macronodular   Micronodular   Mixed

MICRONDULAR CIRRHOSIS: Small rather uniform 2cm nodules seperated by thin fibroussepta usually due to a chemicalagent as alcohol which diffuseuniformly throught the liver.

MACRONODULAR CIRRHOSIS: Larger nodules separated by wider scars and irregularly distributed throughout the liver usually due to an infectious agent such as viral hepatitis which does not diffuse uniformly throughout the liver.

REGENERATIVE NODULES:
  • these occur in micro and macro nodular cirrhosis.
  • they arise in the midst of scars favored by the rich arterial blood of scar tissue.
  • they are round nodules with a fibrous pseudocapsule with bile ductules due to obstruction of bile flow.
  • they have embryonal type of cell plates, two cells thick, "twinning of cell plates".
  • nuclei are aligned at the sinusoidal pole of the plates.
  • they often show focal cholestasis.
  • they may undergo dysplastic and malignant changes.
  • they compress the vessels of the capsule contributing to the perpetuation of the cirrhosis.
Nodular regenerative hyperplasia: Evolving concepts on underdiagnosed cause of portal hypertension,World J Gastroenterol. 2011 March 21

2) ETIOLOGIC AGENTS :

Alcoholism
Chronic alcoholism particularly endangers the liver by causing alcoholic liver disease (also called alcohol-induced liver disease). Alcoholic liver disease includes fatty liver (build-up of fat cells in the liver), alcoholic hepatitis (inflammation of the liver caused by chronic drinking), and alcoholic cirrhosis. Alcoholic cirrhosis is the primary type of cirrhosis in the U.S. It develops in 10 - 20% of heavy drinkers, usually after 10 - 15 years of heavy alcohol consumption. People who drink heavily and who also have hepatitis C are at particular risk of developing cirrhosis. In the liver, alcohol converts to toxic chemicals that trigger inflammation and tissue injury, which lead to cirrhosis.
Chronic Hepatitis Chronic hepatitis, both hepatitis B and hepatitis C, is another primary cause of cirrhosis. Chronic hepatitis C is a more common cause of cirrhosis in developed countries, while hepatitis B is a more common cause of cirrhosis worldwide, especially in sub-Saharan Africa and parts of Asia. People with chronic hepatitis B who are co-infected with hepatitis D are especially at risk for cirrhosis. The longer a patient has had chronic hepatitis, the greater the risk for eventually developing cirrhosis. The hepatitis virus can produce inflammation in liver cells, causing injury or destruction. If the condition is severe enough, the cell damage becomes progressive, building a layer of scar tissue over the liver. In advanced cases, as with alcoholic cirrhosis, the liver shrivels in size, a condition called postnecrotic or posthepatic cirrhosis.
Alcoholic Liver Disease: Pathogenesis and New Therapeutic Targets,Gastroenterology. 2011 November

Autoimmune Hepatitis
Autoimmune hepatitis, like other autoimmune disorders, develops when a misdirected immune system attacks the body's own cells and organs. People who have autoimmune hepatitis also often have other autoimmune conditions, including systemic lupus erythematosus, rheumatoid arthritis, Sjgren syndrome, scleroderma, inflammatory bowel disease, glomerulonephritis, and hemolytic anemia. Autoimmune hepatitis typically occurs in women ages 15 - 40.
Hepatocellular carcinoma in patients with autoimmune hepatitis,World J Gastroenterol. 2009 February 7

Bile Ducts Disorders
Disorders that block or damage the bile ducts can cause bile to back up in the liver, leading to inflammation and cirrhosis. These diseases include primary biliary cirrhosis and primary sclerosing chlorangitis.
  • Primary Biliary Cirrhosis. Up to 95% of primary biliary cirrhosis (PBC) cases occur in women, usually around age 50. In people with PBC, the immune system attacks and destroys cells in the livers bile ducts. Like many autoimmune disorders, the causes of PBC are unknown.
  • Primary sclerosing cholangitis (PSC) is a chronic disease that mostly affects men, usually around age 40. The cause is unknown, but immune system defects, genetics, and infections may play a role.

Nonalcoholic Fatty Liver Disease (NAFLD) and Nonalcoholic Steatohepatitis (NASH)
Nonalcoholic fatty liver disease (NAFLD) resembles alcoholic liver disease, but it occurs in people who do not drink a lot of alcohol. Obesity and type 2 diabetes are the two main causes of a fatty liver. Some evidence suggests that insulin resistance (the primary problem in type 2 diabetes) is a major factor in development of a fatty liver. A diet high in fatty foods may also be a risk factor, as dietary fat accumulates in the liver. Due to the recent rise in childhood obesity, NAFLD is increasingly occurring in children. In fact, NAFLD is now the most common liver disease in American children. Nonalcoholic fatty liver disease is usually benign and very slowly progressive. But, in certain patients, it can lead to cirrhosis, liver failure, or liver cancer. About 8 - 20% of people with nonalcoholic steatohepatitis go on to develop cirrhosis.
Nonalcoholic fatty liver disease and the metabolic syndrome: clinical implications and treatment,Nutr Clin Pract. 2013 Feb

Hereditary Disorders
  • Hemochromatosis is a disorder of iron metabolism. This disease interferes with the way the body normally handles iron. People with hemochromatosis absorb too much iron from the food that they eat. The iron overload accumulates in organs in the body. When excess iron deposits accumulate in the liver, they can cause cirrhosis.
  • Wilsons disease (which causes an accumulation of copper in the body), alpha-1 antitrypsin deficiency (a genetic disorder caused by defective production of a particular enzyme).
  • Glycogen storage diseases (a group of disorders that cause abnormal amounts of glycogen to be stored in the liver).
  • Alpha 1-antitrypsin deficiency (A1AD). Autosomal recessive disorder. Patients may also have COPD, especially if they have a history of tobacco smoking . Serum AAT levels are low. Recombinant AAT is used to prevent lung disease due to AAT deficiency.
  • Lysosomal acid lipase deficiency (LAL Deficiency) is a rare autosomal recessive genetic condition and is characterized by hepatomegaly, persistently abnormal LFTs and type II hyperlipidemia. Splenomegaly and evidence of mild hypersplenism may affect some patients. Untreated, LAL Deficiency may lead to fibrosis, cirrhosis, liver failure and death. Cardiac cirrhosis Due to chronic right sided heart failure which leads to liver congestion.

Galactosemia

Glycogen storage disease type IV

Cystic fibrosis

Hepatotoxic drugs or toxins

PATHOPHYSIOLOGY

The liver plays a vital role in synthesis of proteins (e.g., albumin, clotting factors and complement), detoxification and storage (e.g., vitamin A). In addition, it participates in the metabolism of lipids and carbohydrates.
Cirrhosis is often preceded by hepatitis and fatty liver (**steatosis**), independent of the cause. If the cause is removed at this stage, the changes are still fully reversible.
The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma, blocking the portal flow of blood through the organ and disturbing normal function. Recent research shows the pivotal role of the stellate cell, a cell type that normally stores vitamin A, in the development of cirrhosis. Damage to the hepatic parenchyma leads to activation of the stellate cell, which becomes contractile (called myofibroblast) and obstructs blood flow in the circulation. In addition, it secretes TGF-β, which leads to a fibrotic response and proliferation of connective tissue. Furthermore, it secretes TIMP 1 and 2, naturally occurring inhibitors of matrix metalloproteinases, which prevents them from breaking down fibrotic material in the extracellular matrix.
The fibrous tissue bands (septa) separate hepatocyte nodules, which eventually replace the entire liver architecture, leading to decreased blood flow throughout. The spleen becomes congested, which leads to hypersplenism and increased sequestration of platelets. Portal hypertension is responsible for most severe complications of cirrhosis.
The pathological hallmark of cirrhosis is the development of scar tissue that replaces normal parenchyma

COMPLICATIONS
Cirrhosis can cause many serious complications including:

Portal hypertention is a state in which the pressure within the hepatic portal vein is increased, causing enlargement of the spleen, enlargement of the veins in the oesophagus (gullet) (which may rupture to cause severe bleeding), and accumulation of fluid in the peritoneal cavity (ascites). The commonest cause is cirrhosis, but other diseases of the liver or thrombosis of the portal vein can also produce it.
Treatment is :
-by diuretic drugs
-by surgery to join the portal vein to the inferior vena cava (bypassing the liver)
-implanting a stent within the liver to join portal tract veins to a hepatic vein tributary ( TIPS – transjugular intrahepatic porto-systemic shunt)
Treatment of portal hypertension,World J Gastroenterol. 2012 March 21
Transjugular Intrahepatic Portosystemic Shunt (TIPS),ACR(American College of Radiology

Ascites is fluid buildup in the abdominal cavity. It is uncomfortable and can impair breathing and other functions. Ascites is caused by a combination of portal hypertension (high pressure in the blood vessels of the liver) and low albumin levels. Albumin is a protein produced by the liver. Although ascites itself is not fatal, it is a marker for severe progression.
Guidelines on the management of ascites in cirrhosis

Hepatorenal syndrome occurs if the kidneys drastically reduce their own blood flow in response to the altered blood flow in the liver. It is a life-threatening complication of late-stage liver disease that occurs in patients with ascites. Symptoms include dark colored urine and a reduction in volume, yellowish skin, abdominal swelling, mental changes (such as delirium and confusion), jerking or coarse muscle movement, nausea, and vomiting.
Clinical Guidelines for the management of Hepatorenal syndrome

Variceal Bleeding one of the most serious consequences of portal hypertension is the development of varices, veins that enlarge to provide an alternative pathway for blood diverted from the liver. In most patients, they form in the esophagus. They can also form in the upper stomach. Varices pose a high risk for rupture and bleeding because they are thin-walled, twisted, and subject to high pressure. Variceal intestinal bleeding is a life-threatening event. Symptoms include vomiting blood or black and tarry stools.
UK guidelines on the management of variceal haemorrhage in cirrhotic patients,Gut 2000

Spontaneous bacterial peritonitis is a life-threatening bacterial infection of the ascitic fluid.The main symptoms include confusion and altered mental status, fever, chills, and abdominal pain.

Hepatic Encephalopathy. Mental impairment is a common event in advanced cirrhosis. In severe cases, the disease causes encephalopathy (impaired brain function), with mental symptoms that range from confusion to coma and death. Hepatic encephalopathy is caused by a buildup in the blood of harmful intestinal toxins, particularly ammonia, which then accumulate in the brain. Encephalopathy can be triggered by many different conditions including internal bleeding, infection, constipation, and dehydration.Early symptoms of hepatic encephalopathy include forgetfulness, unresponsiveness, and trouble concentrating. Sudden changes in the patient's mental state, including agitation or confusion, may indicate an emergency condition. Other symptoms include bad fruity-smelling breath and tremor. Late-stage symptoms of encephalopathy are stupor and eventually coma.
PRACTICE GUIDELINES Hepatic Encephalopathy,THE AMERICAN JOURNAL OF GASTROENTEROLOGY

Liver Cancer. People with cirrhosis have an increased risk for hepatocellular carcinoma, a type of liver cancer. Hepatitis B and C, alcoholism, hemochromatosis, and primary biliary cirrhosis -- all causes of cirrhosis -- are some of the major risk factors for liver cancer. Cirrhosis due to hepatitis C is the leading cause of hepatocellular carcinoma, while cirrhosis due to hepatitis B is the leading cause of deaths related to liver cancer
Kidney Failure. Portal hypertension can cause several secondary complications, including kidney failure (severe cirrhosis )
Chronic Ingestion of Ethanol Induces Hepatocellular Carcinoma in Mice Without Additional Hepatic Insult,Nutr Clin Pract. 2013 Feb

Osteoporosis. Many patients with cirrhosis develop osteoporosis, a bone-thinning disease.

THE CHILD-PUGH CLASSIFICATION SYSTEM
The Child-Pugh classification is a scoring system used to determine the prognosis with cirrhosis.
Scoring is based upon several factors: albumin, ascites, total bilirubin, prothrombin time, and encephalopathy, as follows:
 

>3 means higher than 3
<3 means lower than 3 The three classes and their scores are: **Class A** is score 5 - 6 **Class B** is score 7 - 9 **Class C** is score >9

Patients with a score of 10 or more (in the Class C category) have a prognosis with 1-year survival being about 50%. Patients with Class A or B have a better prognosis of 5-years, with a survival rate of 70%- 80%.
Additional poor prognistic indices include refractory ascites, albumin < 3.2 gm/l, and a recent episode of SBP (spontaneous bacterial peritonitis). All individually are associated with a one-year survival of 50% or less.
Improvement of prognostic power of the Child-Pugh classification of liver cirrhosis by hyaluronan,J Hepatol. 2003 Dec.

Rules
Comments
2014-06-24T08:48:24 - Lorenzo Gaiero

HEPATORENAL SYNDROME

Hepatorenal syndrome ( HRS ) is functional, reversible renal failure that occurs in patients with advanced liver cirrhosis or acute hepatic failure. It is a frequent complication in this patients and is characterized by an intense renal vasoconstriction, witch leads to very low renal perfusion and glomerular filtration rate (GFR). Renal histology shows no significant lesion sufficient to justify the impairment in renal function, so HRS is the extreme expression of the circulatory dysfunction of cirrhosis that has been traditionally considered to be the consequence of an arterial vasodilatation in the splanchnic circulation. However, recent data indicate that an important role is played by the reduction in cardiac output and the increased activity of both the renin-angiotensin and sympathetic nervous system.

EPIDEMIOLOGY

HRS is not uncommon. It occurs in 39% of patient within five years of the diagnosis of cirrhotic ascites and in 18% within 1 years. Because 50% of patient develop ascites within 10 years of the diagnosis of cirrhosis, a substantial percentage of these will develop HRS. The 10-week mortality rate approaches 90% and the median survival is 1,7 week.

CLINICAL PRESENTATION

HRS occurs almost esclusively in patient with ascites is divided into two tipes:

- type I: rapidly progressive, where the serum creatinine doubles in 2 week (values of 2,5 mg/dL are usually achieved) or the glomerular filtration rate below 20 ml/min, and is followed by death. It frequently occurs in close relationship with a precipitating factor, such as severe bacterial infection, gastrointestinal hemorrhage, major surgical procedure or acute hepatitis superimposed to cirrhosis. The 25% of patients with spontaneous bacterial peritonitis develop HRS despite a rapid resolution of the infection with non-nephrotoxic antibiotics.

- type II: slowly progressive, it is quite stable. Serum creatinine rises slowly or not at all and it usually does not exceed 1,3 mg/dL. The clinical record is dominated by refractory ascites and relatively stable liver function. Median survival is about 4-6 months. It probabily represents the genuine functional renal failure of cirrhosis, expression of the impairment in circulatory function that spontaneously develops during the course of the disease.

Hepatorenal syndrome. 2012

PATHOGENESIS

The occurrence of HRS is better predicted by presence of circulatory dysfunction and renal function abnormalities than by the presence of hepatic dysfunction. The factor associated to HRS are:

- SPLANCHNIC ARTERIAL VASODILATATION : the portal hypertension is associated to arterial vasodilatation in the splanchnic circulation due to the local release of nitric oxide and other vasodilatory substances. Early the decrease in systemic vascular resistance is compensated by the development of a hyperdynamic circulation(increased heart rate and cardiac output). However it is insufficient to correct the effective arterial hypovolemia and the hypotension develops, leading to activation of high pressure baroceptors, reflex stimulation of the renin-angiotensin and sympathetic nervous system, sodium and water retention and the formation of ascites. Since the splanchnic circulation is resistant to the effect of angiotensin-II, noradrenaline and vasopressin due to the local release of nitric oxide and other vasodilatator, the maintenance of arterial pressure is due to vasoconstriction in extra-splanchnic vascular territories such as the kidneys and brain. So HRS develop at the latest phase of the disease when there is an extreme deterioration in effective arterial blood volume and severe arterial hypotension. The homeostatic stimulation of the renin-angiotensin system, the sympathetic nervous system and the antidiuretic hormone is very intense leading to extreme renal vasoconstriction, a marked decrease in renal perfusion and GFR, azotemia and increased serum creatinine concentration.

- REDUCTION IN CARDIAC OUTPUT: in studies assessing cardiovascular function in patient with HRS or refractory ascites, cardiac output was found to be significantly reduced compared to patients without HRS. In some cases it was even lower than in normal subjects, suggesting that circulatory dysfunction associated with HRS is due not only to arterial vasodilatation but also to a decrease in cardiac function.

- RENAL IMPAIRMENT: the mechanism of the renal vasoconstriction that causes HRS is complex. Renal perfusion in decompensated cirrhosis correlates inversely with the activity of the renin-angiotensin and sympathetic nervous system, HRS is thought to be related to the extreme stimulation of these system. The urinary excretion of prostaglandin E2 and kallikrein is decreased in patient with HRS, which is compatible with a reduced renal production of these vasodilatory substances. So renal failure can be the consequence of an imbalance between the activity of the vasoconstrictors systems and the renal production of vasodilatators. Finally the renal hypoperfusion could be modified by the stimulation of intrarenal vasoconstrictors such as adenosine, leukotrienes and F2-isoprostanes. Renal vasoconstriction is, therefore, the consequence of the simultaneous effect of numerous vasoactive mechanism on the intrarenal circulation.

- ADRENAL DYSFUNCTION IN PATIENTS WITH SEPSIS AND SEVERE CIRCULATORY DYSFUNCTION :Adrenal dysfunction in patients with sepsis and severe circulatory dysfunction: in patient with cirrhosis, adrenal insufficiency was detected in 80% of patients with HRS but only in 34% with serum creatinine below 1,5 mg/dL. It exist a close relationship between adrenal insufficiency and HRS in patient with severe infection, severe liver failure and arterial hypotension. Normal adrenal function is essential for an adequate response of the arterial circulation to endogenous vasoconstrictors, so its insufficiency could be an important contributory mechanism of circulatory disfuction associated with HRS in patients with severe infections. The mechanism of this adrenal disfuction related to severe sepsis has not been explored. It may be related to a reduction in adrenal blood flow secondary to regional vasoconstriction. Moreover, very high levels of inflammatory cytokines directly inhibit adrenal cortisol synthesis. Treatment with hydrocortisone in cirrhotic patient with severe sepsis and adrenal isufficiency is associated with rapid improvement in systemic hemodynamics, reduction in vasoconstrictor requirements and high hospital survival.

So the vasodilatation, which occurs mainly in the splanchnic region, induces a decreased effective arterial blood volume and an increased activity of vasoconstrictor system. In the early stages of the disease the increased activity of vasoconstrictors is enough to compensate the arterial vasodilatation. As the disease progresses the activation of the vasoconstrictor system further increases leading to sodium and water retention and ascites formation, followed by severe renal vasoconstriction with HRS in the late stage of the disease.

Advances in the pathogenesis and treatment of type-1 and type-2 hepatorenal syndrome. 2007

DIAGNOSIS

the diagnosis of HRS is based on the exclusion of other possible causes of renal failure.

Major criteria: all the following major criteria must be present to make the diagnosis:

1-Chronic or acute liver disease with advanced hepatic failure and portal hypertension
2- Low glomerular filtration rate, as indicated by serum creatinine higher than 1,5mg/dL or 24h creatinine clearance less than 40mL/min.
3- Absence of shock, ongoing bacterial infection, fluid loss and current or recent treatment with nephrotoxic drugs.
4- No sustained improvement in renal function following diuretic withdrawal and expansion of plasma volume with 1.5 L of isotonic saline
5-Proteinuria less than 500 mg/day
6-No ultrasonographic evidence of obstructive urophaty or parenchymal renal disease.

Additional criteria: are frequently present but are not necessary for the diagnosis

1-Urine volume less than 500 ml/24h
2-Urine sodium less than 10Meq/L
3-Urine osmolality major than plasma osmolality
4-Red blood cells in urine less than 50 X high-power field
5-Serum sodium concentration less than 130 Meq/L

Hepatorenal syndrome, 2004

TREATMENT

Available treatments for type 1 HRS:

- LIVER TRANSPLANTATION: is the treatment of choice of HRS. Immediately after transplantation a further impairment in GFR may be observed and many patients require hemodialysis(35%, compared with 5% of patients without HRS). Because cyclosporine or tacrolimus may contribute to this, it has been suggested to delay the administration of these drugs until a recovery of renal function is noted, usually 48-72 h after transplantation. After this GFR starts to improve and reaches an average of 30-40ml/min by 1-2 months postoperatively. The hemodynamic and neurohormonal abnormalities associated with HRS disappear within the first month after the operation and the patient regain a normal ability to excrete sodium and free water even if persist a moderate renal failure probability due to a great nephrotoxicity of the immunosuppressur drugs. The long term survival is good, with 3-years probability of survival of 60% that is only slightly reduced compared to that of transplantation in patient without HRS. The main problem is the applicability of transplantation because most patients die before transplantation even if they are generally allocated in the first places of waiting list.

- VASOCONSTRICTOR AND ALBUMINE : several studies have shown that the administration of vasoconstrictor drugs, analogues of vasopressin and albumin are effective in patient with HRS. The mechanism of action of terlipressin is vasoconstriction of the splanchnic circulation, wich is associated with an improvement in systemic hemodynamics and a decrease in the activity of vasoconstrictor system with the consequent enhancement in renal hemodynamics. Terlipressin is the most widely used vasoconstrictor and is very effective and is associated to low incidence of side effect. Noradrenaline has also been shown to be effective and safe and is less expensive than terlipressin however has been used in only few studies. Albumine is an important component in the treatment not only for the expansion of the plasma volume but also for a direct vasoconstrictor effect on the peripheral arterial circulation. Also the combination of oral midodrine(an alpha-agonistic agent) and subcutaneous octreotide is an effective treatment.

- TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT : TIPS reduced sympathetic and RAAS activity and has a positive effect on renal function demonstrated by a rapid increase of urinary sodium excretion, urinary volume and improvement in plasma creatinine concentration. It can be applied either as a bridge treatment extending the waiting period for a liver transplant. The curative effect only comes after several days or weeks after intervention.

Avaible treatments for type 2 HRS : the main clinical problem is refractory ascites, therefore we should consider not only survival but also the control of ascites.

- TRANSJUGULAR INTRAHEPATIC PORTOSYSTEMIC SHUNT: it is associated with a significant improvement in the control of ascites.

- VASOCONSTRICTORS AND ALBUMINE: reversal of HRS is obtained in most cases.

Hepatorenal syndrome: pathogenesis and novel pharmacological targets, 2004

PREVENTION

In the last years two randomized studies in large series of patient have shown that HRS can be prevented in specifical clinical settings. In the first study with administration of albumin together with cefotaxime in patients with spontaneous bacterial peritonitis markedly reduced the incidence of HRS. In a second study the administration of the tumoral necrosis factor inhibitor pentoxyfilline to patients with severe acute alcoholic hepatitis reduced the occurence of HRS. Pentoxyfilline is a methylated xanthine derivatives, it is a competitive nonselective phosphodiesterase inhibitor which raises intracellular cAMP, activates PKA, inhibits TNF and leukotriene synthesis, and reduces inflammation and innate immunity. In addition, pentoxifylline improves red blood cell deformability , reduces blood viscosity and decreases the potential for platelet aggregation and thrombus formation and it is also an antagonist at adenosine 2 receptors.

Advances in the management of patients with cirrhosis and portal hypertension-related renal dysfunction.2014

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