Courtney Reynolds, MD/PhD1 Emily Law, MD1 Duminda Suraweera, MD1 Gaurav Singhvi, MD2 1Department of Medicine, Olive View-UCLA Medical Center, Sylmar, CA 2David Geffen School of Medicine at UCLA, Los Angeles, CA
Worldwide, the etiology of portal hypertension is divided between Western and non-Western countries, where 90% of cases in the former are caused by cirrhosis. In the latter, non-cirrhotic conditions such as schistosomiasis or portal vein thrombosis predominate.1 In some cases, the exact cause of portal hypertension is unclear. Globally, idiopathic non-cirrhotic portal hypertension (INCPH) is a rare disorder associated with infections such as human immunodeficiency virus (HIV) and an array of autoimmune and immunodeficiency disorders ranging from combined variable immunodeficiency to Crohn’s disease.2 Here, we will review portal hypertension focusing upon the etiology of cirrhosis. In the US, the prevalence of cirrhosis has been calculated between 0.15% and 0.27% of the population (roughly 400,000 to 660,000 people).3-4 Among those with cirrhosis, it is estimated that 80-90% have portal hypertension, even if they are otherwise asymptomatic.1 In 2013, the Center for Disease Control (CDC) reported that chronic liver disease and cirrhosis caused approximately 36,000 deaths in the United States.5 In other words, there is a 5-9% annual mortality associated with cirrhosis; this high mortality is largely attributed to complications of portal hypertension.
Alterations in the Circulatory System
The pathophysiology of portal hypertension involves alteration of both the splanchnic and the systemic circulatory systems (Figure 1). While portal hypertension had previously been conceptualized as the result simply of increased resistance within the portal system, there is mounting evidence that elevated pressure is also the consequence of increased blood volume or hyperemia, particularly in later stages. It is thought that early hypoxia due to resistance to blood flow triggers the development of collateral blood supply and a local hyperdynamic state characterized by vasodilation. This vasodilation is driven primarily by increased splanchnic production of nitrous oxide (which also contributes to the collateral angiogenesis), leading to decreased responsiveness to vasoconstrictors and overall increased blood volume within the portal system. These changes lead to decreased blood volume and pressure sensed at carotid and renal baroreceptors, leading to similar neurohumoral activation as seen in heart failure (i.e., upregulation of the renin-angiotensin system and anti- diuretic hormone). Thus, portal hypertension spurs a hyperdynamic response in the systemic circulation characterized by increased cardiac output, expansion of plasma volume and reduced systemic vascular resistance.6-15
Alterations in Liver Structure and Function
In the setting of cirrhosis, there are characteristic structural and vascular changes within the liver that contribute to portal hypertension. It is well known that hepatic stellate cells (HSC), which function as quiescent lipid and vitamin storage cells in normal liver, become activated as a result of ongoing hepatic injury. This activation results in altered gene activity thought to produce the characteristic fibrotic changes of cirrhosis. However, preceding this development there are substantial changes to the sinusoid endothelial cells as well. The sinusoids ordinarily allow passage of macromolecules to the liver parenchyma through large fenestrations. Capillarization, or loss of endothelial cell fenestration, is an early response to liver injury that appears to occur prior to HSC activation and leads to increased vascular resistance. Interestingly, animal models suggest that reversal of the capillarization process can restore HSC quiescence and reverse fibrosis.6,16 Thus, cirrhosis triggers alterations in liver architecture that contribute to portal hypertension by increased mechanical and vascular resistance.
Pathophysiology of Ascites In the Setting of Portal Hypertension
While the etiologies of ascites are diverse-including malignancy, infection, hypoalbuminemia and lymphatic obstruction-the overwhelming majority of cases are due to portal hypertension from cirrhosis.17 In the US in particular, an estimated 80% of patients with ascites are due to cirrhosis. Ascites is the most common complication of portal hypertension. The development of ascites is a poor prognostic indicator; median survival for patients with refractory ascites is six months.18 The formation of ascites is similar to edema developing in other parts of the body: ascites emerges when there is a gradient in the hydraulic and oncotic pressures within blood vessels versus the interstitial space. With portal hypertension, ascites is partly the result of the arterial vasodilation that occurs as mentioned above; this vasodilation and the resulting increased blood volume render increased hydraulic pressure within the vascular bed causing ascites. On the other hand, decreased oncotic pressure, which also contributes to ascites, is primarily due to decreased synthetic function of the cirrhotic liver rather than from portal hypertension directly.
The development of ascites exacerbates the neurohumoral responses activated by portal hypertension. Venous return and renal perfusion are further compromised by ascites and lead to water and sodium retention. It is believed that the presence of ascites corresponds to a decrease in liver function of 60% or less, according to perfused hepatic mass imaging.19 Renal hypoperfusion may initially be countered by increased production of nitric oxide and prostaglandins, however long-standing decompensated cirrhosis usually leads to chronic kidney disease and in some cases the often fatal hepatorenal syndrome. Clinically, patients with ascites develop volume overload and dilutional hyponatremia despite increased total body sodium. Hyponatremia is associated with a poor prognosis and has been shown to predict the development of hepatic encephalopathy, the hepatorenal syndrome and mortality both from cirrhosis and in the short term following liver transplantation.20
Complications of Portal Hypertension
Portal hypertension can result in several severe complications leading to significant morbidity and mortality. Generally these complications manifest when hepatic venous pressure gradient exceeds 10 to 12 mm Hg.21 Ascites is the most common complication of portal hypertension as discussed above.
It is estimated that 5-15% of cirrhotic patients develop gastroesophageal (GE) varices per year, with the development of GE varices correlating with the degree of severity of cirrhosis. About 40% of Child-Pugh A patients have varices as compared to 85% of Child- Pugh C patients.22 Approximately 50% of patients with cirrhosis have gastroesophageal varices at any given time, while the majority of patients with cirrhosis develop GE varices at some point during their lifetime.
Esophageal variceal bleeding occurs at a yearly rate of 5-15%.23 Risk factors for esophageal variceal hemorrhage include size of varices, severity of cirrhosis, variceal pressure and endoscopic presence of variceal red spots. An acute episode of variceal hemorrhage carries a six week mortality rate in excess of 20%.24
Gastric varices are present in 5-44% of patients with portal hypertension.25 Risk factors for gastric variceal hemorrhage include the size of fundal varices, Child- Pugh class and endoscopic presence of variceal red spots.26 Gastric varices can be subdivided into two groups:27 those associated with esophageal varices (gastroesophageal varices) and those not associated with esophageal varices (isolated gastric varices). Gastroesophgeal varices can be further subdivided into two groups depending on their distribution. Type 1 extend along the lesser curvature, and Type 2 extend along the fundus. Isolated gastric varices can also be subdivided into two types by distribution: Type 1 are located in the fundus while Type 2 are located in the body, antrum or around the pylorus (Figure 2).
Esophagogastroduodenoscopy (EGD) is the gold standard for the diagnosis of gastroesophageal varices. Varices can be classified as small, medium or large. Small varices are minimally elevated veins above the mucosal surface, medium varices are tortuous veins occupying less than one-third of the esophageal lumen while large varices occupy greater than one-third of the lumen. It is recommended by the American College of Gastroenterology that patients undergo screening for varices at the time of diagnosis of cirrhosis.27-29
Hepatorenal syndrome (HRS) is a manifestation of acute renal dysfunction that is seen in severe cirrhosis.30 Risk of developing hepatorenal syndrome from cirrhosis is estimated at 20% after one year and 40% after five years with an incidence of 10% among hospitalized patients with cirrhosis and ascites.31 While the exact mechanism is unknown, it is likely due to a decrease in peripheral arterial circulation from arterial vasodilation in the splanchnic circulation.32 A reduction in cardiac output may also play a concurrent role.33 Patients often present with profound volume overload and electrolyte abnormalities. The diagnosis of hepatorenal syndrome is one of exclusion. Criteria include a plasma creatinine concentration of greater than 1.5 mg/dL, presence of liver disease and portal hypertension, absence of apparent other causes of kidney injury and lack of improvement in renal function after volume expansion with intravenous albumin.34 There are two described types of hepatorenal syndrome. Type 1 is a rapidly developing renal failure defined as a doubling of the serum creatinine to above 2.5 mg/dL or a decrease in glomerular filtration by more than 50% in less than two weeks.35 In contrast, Type 2 hepatorenal syndrome is a gradually developing renal failure with creatinine above 1.5 mg/dL (Table 1).34
Ideally, hepatorenal syndrome is treated with recovery of liver function either through treatment of the underlying cause (abstinence from alcohol, antiviral therapy, etc.) or through liver transplantation. One study of liver transplantation for Type 1 hepatorenal syndrome found 75% of patients had complete recovery of kidney function after transplant; non-response was associated with prolonged courses of dialysis proceeding transplant, suggesting that prompt referral is key.36 Medical therapy targeted at HRS itself aims to increase perfusion to the kidneys by increasing arterial pressure. In the United States, a combination of octreotide, midodrine and albumin is most frequently used, and the usual course of treatment is two weeks. Alternatives include norephinephrine and vasopressin. Although small studies suggest the effectiveness of vasoconstrictors in this setting, the mortality of HRS remains high.37-38 Patients who fail medical therapy but are either expected to recover liver function or await liver transplantation can transition to dialysis.
Hepatic encephalopathy is a neurologic dysfunction seen in patients with liver disease and portal hypertension. The pathogenesis of hepatic encephalopathy is likely multifactorial. Ammonia produced by gut bacteria is typically processed in the liver. However, in the setting of portal hypertension, portosystemic shunts result in ammonia bypassing the liver and accumulating in the systemic circulation and crossing the blood-brain barrier.39 Patients can present with a wide spectrum of neurocognitive manifestations. Hepatic encephalopathy can be divided into minimal hepatic encephalopathy- patients with abnormal psychometric tests but no obvious clinical changes-and overt hepatic encephalopathy, in which patients have obvious clinical manifestations. These manifestations include personality changes, irritability and disinhibition. The West Haven Criteria is used to grade hepatic encephalopathy.40 Grade 1 is considered minimal hepatic encephalopathy, grades 2-3 are intermediate, and grade 4 is a comatose patient. Management of encephalopathy is primarily with non- absorbable disaccharides, such as lactulose and non- absorbable antibiotics, such as rifaximin.41-42 Probiotics, polyethylene glycol, flumazenil ammonia scavengers and zinc have also been shown to be of benefit in the management of hepatic encephalopathy.43-47
Hepatopulmonary syndrome (HPS) is a syndrome defined by liver disease, increased alveolar-arterial oxygen gradient and intrapulmonary vascular dilatations.48 It is more common than portopulmonary hypertension, but both can occur in the same patient. Prevalence ranges from 4 to 34% of patients with liver disease.49-50 While the development of HPS does not require the presence of cirrhosis, it is more common in this setting.51-53 Still, HPS does not correlate with the severity of liver disease.54 The proposed pathophysiology of HPS involves pulmonary production of excess vasoactive mediators, nitric oxide (NO) and carbon monoxide (CO). Arterial hypoxemia is then caused by intrapulmonary vascular dilatation. Other mechanisms or pathways are under investigation, however some studies suggest that there may be increased pulmonary angiogenesis, resulting from greater macrophage production of vascular endothelial growth factor (VEGF)-A.55-56 Screening for HPS with an arterial blood gas is recommended in liver transplant candidates and patients with liver disease who have shortness of breath. The ABG then directs whether the patient needs a contrast-enhanced echocardiography (CEE) which is diagnostic.48
Clinical features of HPS include dyspnea, cyanosis and progressive hypoxemia.57-59 A hallmark finding is platypnea or increased dyspnea with upright positioning that is relieved by lying down; quantitatively platypnea corresponds with orthodeoxia or a decrease in arterial oxygenation by more than 4mmHg moving from recumbency to sitting. A variety of medical therapies exist for HPS but there is a dearth of evidence on their efficacy in improving oxygenation or dyspnea; these agents include somatostatin analogues, beta- blockers, cyclooxygenase inhibitors, glucocorticoids, immunosuppression, pulmonary vasoconstrictors, NO inhibitors, inhaled NO, antimicrobials and garlic.60-77 Supplemental oxygen is often used for symptom relief. Case reports suggest a benefit from TIPS, however this is not routinely recommended due to otherwise variable outcomes and theoretical risk of worsening HPS.78-81 Definitive treatment of HPS is liver transplantation, which results in complete resolution of HPS in greater than 80% of patients.82-88
Pulmonary hypertension is a complication of portal hypertension, with or without cirrhosis, and is considered to be a type of pulmonary arterial hypertension.89 Portopulmonary hypertension (POPH) is more commonly found in females and in patients with autoimmune liver diseases, namely primary biliary cholangitis and autoimmune hepatitis.90 It is not, however, found to be related to the severity of liver dysfunction, whether by Child Turcotte Pugh (CTP) classification or model for endstage liver disease (MELD) score.91 The pathophysiology of POPH is not clearly defined, however current research has shown remodeling of the pulmonary arterial wall which causes an obstructive thickening and fibrosis of the arteries.92-93 The remodeling is a consequence of the hyperdynamic state caused by splanchnic vasodilation, and the dysfunctional imbalance of mediators such as endothelin-1, prostacyclin and nitric oxide.
Right heart catheterization is required to establish the diagnosis of POPH. According to the criteria established by the 2004 European/US Consensus Study Group, the diagnosis requires 1) portal hypertension with or without hepatic cirrhosis and 2) pulmonary arterial hypertension by right heart catheterization (RHC) with mPAP > 25 mmHg, PVR > 240 dynes.s.cm^-5 and PAWP < 15 mmHg. The severity of portopulmonary hypertension depends on the mPAP: mild is mPAP 25-34 mmHg, moderate is mPAP 35-44 mmHg, and severe is 45 mmHg and greater. In terms of screening, the American Association for the Study of Liver Disease (AASLD) recommends patients being evaluated for liver transplant undergo echocardiogram followed by right heart cardiac catheterization if the RVSP is greater than or equal to 45 mmHg. There is currently no screening recommendation regarding patients with portal hypertension not undergoing liver transplant.48
Medical therapies for POPH include agents used for pulmonary arterial hypertension: endothelin receptor antagonists, prostanoids, phosphodiesterase-5 inhibitors and soluble guanylate cyclase stimulators. Liver transplantation is the only potentially curative option; after transplant, about half of patients can be weaned from POPH medications.94-95
Hepatic hydrothorax (HH) is an uncommon complication in patients with liver disease, found in only 5-10% of patients.96-98 It is defined as a transudative pleural effusion greater than 500 mL in a patient with portal hypertension without any other etiology of the effusion.99-101 The pathologic process is presumed to result from translocation of peritoneal ascetic fluid into the pleural cavity through small diaphragmatic defects.102 This occurs more frequently on the right side than the left, possibly due to embryogenic defects.103-104 Subsequently, the hydrothorax can cause an acute tension hydrothorax or infection, namely spontaneous bacterial empyema. The diagnosis is often clinical, and symptoms include shortness of breath, nonproductive cough, chest discomfort and hypoxia. Thoracentesis is performed mainly to exclude other causes, whereas treatment options for HH include medical management with dietary sodium restriction and combined loop diuretic and aldosterone receptor antagonist therapy.105 When HH is refractory to medications, therapeutic thoracentesis can be pursued but it has a high rate of recurrence. Similarly, pleurodesis has a limited role in the management of non-malignant pleural effusions and has been associated with recurrence and significant morbidity such as infection.106 Other options available are transjugular intrahepatic portosystemic shunt (TIPS) and liver transplantation, although due to high associated morbidity TIPS is reserved for patients with relatively preserved liver function (Child-Pugh score <13 or MELD <15).107-108
Diagnosis and Management of Portal Hypertension and Ascites
Diagnosis of Portal Hypertension and Ascites
The gold standard for diagnosis of portal hypertension is hepatic venous pressure gradient testing (HVPG), which indirectly measures portal pressure as the difference between the wedged and free hepatic venous pressures. Normal values for HVPG are 1-5mmHg. Any pressure above this range is considered portal hypertension, however HVPG of >10mmHg has been termed “clinically significant” as this level is predictive of the development of ascites and varices. Variceal bleeding becomes more likely with HVPG of 12 or more.109 While less invasive diagnostic techniques are being investigated, such as contrast enhanced ultrasound, in practice, most patients with cirrhosis (or other conditions known to cause portal hypertension) who develop complications such as ascites or varices are presumed to have portal hypertension without further testing.110 The diagnosis of ascites is usually prompted by patient presentation of increased abdominal girth, weight gain and dyspnea. Free fluid within the abdomen can be visualized and graded by imaging, most often ultrasound, while paracentesis allows sample collection to analyze the fluid. The range of tests performed on ascitic fluid depends on clinical suspicion, however one essential test for diagnostic paracentesis is to calculate the serum ascites albumin gradient (SAAG) comparing the serum and ascites albumin levels. A high gradient indicates ascites with a low protein content, consistent with cirrhosis or heart failure. Low gradients occur in the setting of malignancy or infection.111 Beyond this, it is standard to obtain cytology, cell count, culture and Gram stain on an initial, diagnostic paracentesis and to evaluate for the presence of spontaneous bacterial peritonitis (SBP), which is heralded by the presence of >250 polymorphonuclear cells/mm3.
Primary Management of Portal Hypertension
While management of portal hypertension most often focuses upon its complications, there is evidence to support treating the underlying cause as well. In the case of portal hypertension caused by cirrhosis, the regression of cirrhosis after stopping the offending agent or treating the underlying cause has been demonstrated for several disparate etiologies (autoimmune hepatitis, biliary obstruction, iron overload, NASH and hepatitis B and C).112-118 Treatment response to antiviral therapy in patients with Hepatitis C has been correlated with improvement in hepatic fibrosis.119-121 Similar findings have been demonstrated in chronic hepatitis B, where regression of cirrhosis is feasible with long-term suppression with tenofovir.122 The evidence is more limited for improvement of fibrosis following treatment of alcoholic cirrhosis, however abstinence from alcohol has been shown to lead to improved liver function and decreased inflammation and is associated with significantly improved survival compared to cirrhotic patients who continue to drink.123 Nonetheless, although there is evidence to suggest regression in fibrosis, the degree of regression is highly variable, and an actual reversal of cirrhosis has not been demonstrated in humans.124
Management of Gastroesophageal Varices
Management of varices consists of primary prevention, acute treatment of variceal bleeding and secondary prevention. In patients newly diagnosed with cirrhosis, it is currently a Class IIa recommendation from the American College of Gastroenterology (ACG) to perform a baseline upper endoscopy to assess for gastroesophageal varices.125 On the initial EGD screening, varices should be graded as small, medium or large as mentioned above, and evaluated for the presence or absence of red signs (wale marks or red spot). In patients with compensated cirrhosis and no varices on the initial EGD, an EGD screening should be repeated in three years. In patients with decompensated cirrhosis and no varices, EGD should be repeated annually.126
In patients with small varices that have not bled and who are not on a non-selective beta-blocker (NSBB), an EGD should be repeated in 2 years. However, in patients with small varices who are on a NSBB, no follow-up EGD is needed. In patients with medium/large varices who are on a NSBB, the dose should be adjusted to the maximum tolerated and a follow-up or surveillance EGD is not needed.125 NSBB is an accepted therapy for primary prophylaxis of variceal hemorrhage. Through blockade of beta-1 receptors, these agents reduce cardiac output and thereby portal pressure. Through blockade of beta-2 receptors, they reduce portal blood inflow from splanchnic vasoconstriction. Propranolol and nadolol are NSBBs that have demonstrated efficacy in much of the literature. They can decrease the incidence of a first variceal hemorrhage from 25 to 15% in a median follow-up of 24 months.127 There is also a lower mortality in patients on NSBBs (propranolol or nadolol) versus placebo.128 In addition to propranolol and nadolol, there are recent studies on carvedilol, a non-selective beta-blocker with a vasodilatory effect through anti- alpha adrenergic activity. In a randomized placebo- controlled trial, carvedilol was effective in preventing the progression of small to large esophageal varices in patients with cirrhosis.129 Some trials have shown that carvedilol can lower HVPG130-131 and in a systematic review with meta-analysis, reduce HVPG more than propranolol.132-135 In a randomized controlled trial, in comparison to endoscopic variceal ligation (EVL), carvedilol has lower rates of a first variceal bleed but with no significant difference in overall mortality and bleeding-related mortality.136 There are limited studies on carvedilol and its comparison to other therapies in regards to their side effect profiles. However, other studies have failed to show that NSBB agents affect the natural history of varices. A recent meta-analysis of cirrhotic patients with no or small varices showed that patients started on a NSBB experienced no difference in rates of development of large varices, first occurrence of upper gastrointestinal bleeding or death.137 The use of NSBB in patients with Child’s class C cirrhosis or renal dysfunction has become controversial, as some studies have associated their use in this setting with higher mortality.138-139 One theory is that since NSBB reduce cardiac output, there is reduced renal perfusion and thus increased risk for hepatorenal syndrome.140
If patients with medium or large varices undergo endoscopic variceal ligation, then EVL should be repeated every 1 to 2 weeks until obliteration of varices is acchieved. The first surveillance EGD should be performed 1 to 3 months after obliteration, and then every 6 to 12 months to check for recurrent varices.125 Two recent meta-analyses comparing EVL and NSBB use in the preventive setting showed that while EVL did result in significantly lower occurrence of variceal bleeding, there was no difference in mortality.141-142 Further, episodes of bleeding tended to be more severe after EVL, which has been attributed to post-ligation ulceration.
Although EVL can be used in the primary prevention setting as mentioned, it is most often used for treatment of acute variceal bleeding or prevention of re-bleeding. In an episode of acute variceal bleeding, specific measures (vs general management of gastrointestinal bleeding) are divided into pharmacologic management and endoscopic therapy (mainly sclerotherapy and EVL). Pharmacologic agents include vasopressin, somatostatin and their analogues (most commonly terlipressin and octreotide, respectively) that function as splanchnic vasoconstrictors, reducing blood flow and thus pressure within the portal system. In practice, somatostatin analogues have a more favorable safety profile for extended use, and of these octreotide is most widely used in the US. For endoscopic therapy, EVL has been shown to achieve better initial control of bleeding and is also superior for secondary prophylaxis vs sclerotherapy.143 In the acute setting, combined use of pharmacologic and endoscopic measures has been shown to improve both initial and five-day control of hemostasis without a significant impact on mortality or increase in adverse events.144 In the event of persistent uncontrolled bleeding, balloon tamponade or expedited TIPS can be performed; other indications for TIPS will be discussed later in this section. The one-year rate of recurrent variceal hemorrhage is roughly 60%.145 Recurrent variceal bleeding in patients on appropriate medical therapy should prompt consideration for referral to liver transplantation.
While the management of Type 1 gastric varices (gastroesophageal) is similar to that outlined above, the treatment of isolated gastric varices, which occur most often in the fundus, differs greatly. During an acute bleed, gastric varices can be temporized with injection of cyanoacrylate (“glue”), a safe and well- tolerated procedure that may also prevent future bleeding. Band ligation has not proven as effective for acute treatment of gastric varices, while NSBB have not been shown to decrease the risk of future bleeding events.146-148 Balloon-occluded retrograde transvenous obliteration (BRTO) is a relatively new procedure that occludes gastric varices using a sclerosing agent. A recent meta-analysis determined that BRTO resulted in lower rates of re-bleeding compared to TIPS, without any differences in procedure-related complications.149 However, BRTO can worsen esophageal varices and ascites, leading some to combine TIPS with BRTO.
Management of Ascites
The development of ascites is also associated with a poor prognosis and high mortality, chiefly due to the resulting risk of spontaneous bacterial peritonitis and hepatorenal syndrome. However, unlike with varices there is no standard for primary prevention, and treatment is usually reserved for development of clinically apparent fluid accumulation. Initial management includes sodium restriction and diuretic medications. Of note, sodium restriction (to less than two grams daily) is most effective in patients with relatively intact renal function, as sodium excretion becomes more impaired with disease progression. Concomitant fluid restriction is usually only implemented if severe hyponatremia has developed (i.e., serum sodium less than 120 mEq/L).150 In one randomized controlled trial, cirrhotic patients with ascites on diuretics were randomized to a low sodium diet versus unrestricted sodium intake. There was no significant difference between the two groups among the endpoints measured (mortality, time for complete resolution of ascites, hospital stays and cost).151 However, in patients with no previous history of gastrointestinal bleeding, there was a higher survival rate in those on a low sodium diet. In practice, the effectiveness of sodium restriction is limited by patient compliance.
Diuretic therapy is a complement to, rather than a replacement for, sodium restriction and is usually instituted concurrently. The diuretic of choice is spironolactone, as it works to combat the renin- angiotensin system activation triggered by portal hypertension and ascites.152 Patients who do not respond to an adequate dose of spironolactone (200 to 400mg daily), may also receive oral furosemide; the ratio of spironolactone to furosemide dosing is generally 100mg: 40mg respectively. Rapid fluid or weight loss from diuretics should be avoided, and patients in the dose titration phase need to be monitored closely for complications of diuretic treatment including hyponatremia, hyperkalemia, encephalopathy and renal failure. The additional benefit of albumin to diuretic therapy has been controversial. In one randomized controlled trial, cirrhotic patients in an outpatient setting received either diuretics alone versus diuretics with albumin. They found a higher clinical response rate in those who received diuretics with albumin compared to diuretics alone, resulting in shorter hospital stays, lower probability of re-developing ascites and lower probability of readmission to the hospital.153 Practically, the routine use of albumin is limited by expense and patient adherence. Finally, therapeutic paracentesis is often used in the setting of severe or tense ascites. Refractory ascites is defined as ascites that fails the above measures or recurs rapidly after therapeutic paracentesis; it occurs in approximately 5-10% of patients with ascites. Treatment options include large volume paracentesis (up to 5L), liver transplantation or TIPS.
Transjugular Intrahepatic Portosystemic Shunting for Refractory Bleeding or Ascites
TIPS, which creates a shunt from the portal vein to the hepatic vein, has emerged as a second line treatment for severe complications of portal hypertension including recurrent variceal bleeding and refractory ascites. Before TIPS is performed, the patient must be evaluated to determine if they are an appropriate candidate. Risk factors for poor outcome and complications from the procedure include prior encephalopathy, hyperbilirubinemia and cardiopulmonary disease. These risks must be considered, along with the possibility of referral for definitive treatment with liver transplant. Absolute contraindications to TIPS include congestive heart failure, multiple hepatic cysts, uncontrolled sepsis, biliary obstruction and severe pulmonary hypertension. For variceal bleeding, TIPS has been shown to be superior to NSBB plus sclerotherapy in preventing recurrence in one meta-analysis; despite this, no difference in mortality has been proven.154 One retrospective study comparing TIPS with EVL did find a survival benefit, however this has yet to be demonstrated in controlled prospective trials.155 For refractory ascites, there is conflicting evidence from randomized controlled trials (and meta-analyses of these trials) about whether TIPS confers a survival benefit compared to large volume paracentesis. Available trials are limited by small sample size and heterogeneous patient selection, however there may be an advantage for using TIPS in patients with ascites and relatively preserved renal function.156-158 In one retrospective study, patients who had MELD scores greater than 15 were evaluated in two groups, those who received TIPS and whose who did not. In the first two months post-TIPS, patients had increased mortality compared to their counterparts, however this was not statistically significant. After two months, TIPS was associated with lower mortality and need for liver transplantation versus cirrhotic patients who did not undergo TIPS.159 Further, prospective, controlled studies are needed to confirm this result.
Portal hypertension is an important cause of mortality globally and a frequent consequence of end stage liver disease in the United States. If untreated, portal hypertension results in the associated conditions of ascites, variceal bleeding, hepatorenal syndrome and cardiopulmonary disease. Effort should be focused upon the prevention of these outcomes, by screening and treating the common etiologies of cirrhosis including alcohol, Hepatitis B and C. Further studies are needed to guide the management of portal hypertension and its complications, which continues to present many challenges.