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Portal hypertension

Current Management of Portal hypertension

by: DR AMANULLAH SHAMS

Introduction
Portal hypertension is the increase in porto-systmic pressure gradient in any part of the portal venous system. It can result from pre-hepatic, intrahepatic and post-hepatic abnormalities. By far the commonest cause is chronic liver disease and liver cirrhosis. The prevalence of liver disease continues to rise, especially with the epidemic of viral hepatitis and obesity. The main complication of liver cirrhosis is portal hypertension, which causes significant morbidity and mortality. Despite current advances in the management of chronic liver disease, mortality from portal hypertension remains high. In this review we summarize the current advances in the management of portal hypertension.

Definition
Portal hypertension is defined as hepatic venous pressure gradient (HVPG) of more then 5 mmHg, which essentially means a pathological increase in the pressure gradient between inferior vena cava and portal vein. However, clinically significant portal hypertension develops with HVPG of 10 mmHg and greater [1]. Portal hypertension can result from pre-hepatic abnormalities (e.g portal or splenic vein thrombosis), intrahepatic (e.g cirrhosis, schistosomiasis) and post-hepatic such as (e.g Budd-Chiari syndrome and inferior vena cava obstruction). It is associated with the most severe complications of cirrhosis, including ascites, hepatic encephalopathy, and bleeding from gastro-esophageal varices [2].

Pathogenesis
Increased resistance to portal venous blood outflow initiates portal hypertension. It then get worsens by changes in the systemic and splanchic circulation, which increases portal inflow. In patients with liver cirrhosis the main site of resistance is within the liver itself, which is caused by two major factors. 1) Disruption of the liver architecture and mechanical obstruction principally due to fibrosis and regenerative nodules and 2) dynamic and circulatory changes mediated by active contraction of vascular smooth muscle cells and stellate cells. The dynamic part, that has been demonstrated to be reversible, accounts for almost 30% of increased intrahepatic resistance and has been the focus of much research.

Mechanical or structural factors
Mechanical factors which is principally caused by hepatic fibrosis and regenerative nodules cause distortion of the intrahepatic vascular architecture. It is a major component of the intrahepatic vascular resistance. The so-called “fixed anatomical factors” of fibrosis and nodularity could be improved with treatment of the underlying causative agent and subsequently result in improvement of portal pressure. Roberts et al [3] observed that patients with hepatitis C and compensated cirrhosis that were treated with antiviral therapy and had sustained response showed a drop in their HVPG by 20%. They found that histologic response and sustained viral response was associated with clinically relevant HVPG reduction. Disease stabilization and improvement of underlying cause of liver disease (e.g. Hepatitis C treatment and alcohol abstinence) can improve fibrosis, which may result in improvement of mechanical component of intrahepatic vascular resistance [4].

Intrahepatic circulation and endothelial dysfunction
Intrahepatic endothelial dysfunction is associated with portal hypertension. It causes intrahepatic vasoconstriction, mediated by insufficient synthesis of Nitric Oxide (NO), which is a powerful vasodilator [5, 7].

The decrease activity of eNOS [14, 15, 16], which primarily produce NO and the reduced bioavailability of NO due to oxidative stress [12], results in decrease levels of NO and subsequent intrahepatic vasoconstriction. Carbone monoxide (CO) which promotes smooth muscle relaxation, is considered as an important modulator in intrahepatic vasoconstriction [6,17].

Other factors which are considered to modulate vascular tone in cirrhotic patients are Endothelins [9], Angiotensin 2 [10] and Norepinephrine [11, 12] which could be potential areas for further research.

Splanchnic and systemic circulation; and endothelial dysfunction
An increase in portal pressure is first sensed in intestinal microcirculation then splanchnic and subsequently by systemic circulation [18]. This process trigger vasodilatation, which results into increase portal venous inflow and hyperdynamic circulation (low mean arterial pressure, high cardiac output and decrease peripheral resistance). Arterial vasodilation is mediated primarily by increased production of nitric oxide (NO) by splanchnic and systemic endothelial cells. Other important vasomodulators also play a role such as carbon monoxide, prostacyclin and endocannabiniods [18, 19].

Variceal Haemmorrhage
Variceal haemmorrhage is one of the major complications of portal hypertension and despite current advances it still carries a 6-week mortality of 15-20%. Almost 50% of patient with cirrhosis will have gastroesophageal varices at the time of their diagnosis and the risk of 1-year rate of variceal haemorrhage is almost 12% [20]. Hence, prevention and effective management of variceal haemorrhage is an important clinical goal.

Pre-primary prophylaxis (prevention of variceal formation)
Patients who have been diagnosed with cirrhosis should be screened for varices. Those who do not have varices will not benefit from non-selective Beta Blockers. A multi-centre randomized control trial did not show non-selective Beta-Blockers to prevent the development of varices and in fact they were associated with more adverse events [21].

Primary prophylaxis
First variceal haemorrhage occurs at an annual rate of about 12% [20]. It carries a significant risk of morbidity and mortality; therefore, prevention of first variceal bleed is an essential part of the management of portal hypertension.

In patients with medium/large varices, quality trials have shown that NSBB (Carvedilol, propranolol, Nadolol) and EBL are all effective in preventing first variceal haemorrhage [22, 23, 24]. Though carvedilol as with added vasodilatory effect has been shown to be more effective than EBL [22]. In those with small and low-risk varices, there is limited evidence that NSBB may delay the progression of varices [25]. However, at present it is considered optional, given the low risk, lack of adequate data and wide availability of regular endoscopic surveillance of varices.

Treatment of acute variceal haemorrhage
Acute variceal haemorrage is a major medical emergency and despite recent advances in its management, it remains a lethal complication of portal hypertension with a 6-week mortality of 15-20%. The primary aim of acute variceal haemmorrage management is; patient resuscitation, haemostasis and preventing early re-bleed.

Current standard management includes early therapeutic endoscopy (

Secondary prophylaxis
Those who survive their first variceal haemorrhage are at a very high risk of rebleed. The median risk of further bleed stands as high as 60% with a mortality rate of up to 33%. Hence, prevention of rebleeding is a crucial part of the management of variceal haemorrhage, which should be initiated before patient is discharged for hospital.

NSBB has been shown to reduce the risk of rebleeding significantly [34]. Combination therapy of NSBB and ISMN has been reported to have considerable portal-pressure reducing effect [35], however, a recent meta-analysis did not show any reduction in rebleeding episodes or survival advantage as appose to NSBB alone [36]. Sclerotherapy has been replaced by EBL due its improved efficacy and better outcome and it has been shown that sclerotherapy is more effective than NSBB in preventing the rebleeding, however, there was no survival difference between the two groups [37]. Lo et al, reports in their study of comparing EBL with NSBB+ISMN that there EBL was superior to NSBB+ISMN in preventing rebleeding, howere, in the longterm survival was better in pharmacological group [38]. A recent meta-analysis suggested that combination of NSBB and EBL was better than endoscopic therapy alone, however, sclerotherapy trials were included in the study, which has been shown to be inferior to EBL (39).

Patients who received TIPSS during their first bleed will require regular TIPSS check and those patient who has recurrent variceal haemorrhage despite secondary prophylaxis will require TIPSS which has been shown to be superior to EBL in preventing rebleeding [40]. Patient with recurrent variceal bleed should be considered for a referral to the transplant unit.

Ascites
Management of uncomplicated ascites
Ascites as a marker of hepatic decompensation and is associated with poor prognosis. The 5-year survival of cirrhotic patients with ascites is 50% [41]. In those with refractory ascites, 6-month mortality is as high as 50% [42]. Ascites can be classified as mild (grade 1, detectable by USS), moderate (grade 2) and severe (grade 3, tense) ascites. Patients with first presentation of ascites require paracentesis to evaluate ascetic fluid. A SAAG of >11 gr/L is consistent with portal-hypertension related ascites. Neutrophil count more then 250/mm3 is diagnostic of SBP [43-45]. Ascetic protein of less than 1.5mg/dl indicates primary prophylaxis of SBP [46]. A stepwise approach is recommended while treating ascites, and the aim should be alleviation of symptoms, creating negative sodium balance and preventing complications of ascites.

Dietary sodium restriction
Dietary salt restriction should be advised to patients. Negative sodium balance can be achieved by dietary salt restriction and 10-15% of patients may respond with loss of ascites in the early stages [47]. A dietary review involving, low sodium diet advice (60-90 mEq/day which equivalent to 1.5-2gr salt/day) adequate calorie and protein intake is recommended as part of the management of patients with ascites [19].

Diuretics
Spironolactone as an aldosterone antagonist should be started at a dose of 100mg daily, which could be increased gradually up to 400mg on weekly basis [48]. Loop-acting diuretics such as frusemide has synergistic effect with spironolactone, though it is less effective as a single agent in cirrhotic ascites [49]. It is advisable to use them as a combination therapy, whenever possible. Whenever possible they should be used in combination [50,51]. One of the side effects of spironolactone is painful gynaecomastia and in such scenario it can be switched to amiloride (5-20mg once daily), which is less effective than spironolactone.

Large Volume Paracentesis (LVP)
Large volume paracentesis (>5L), which is used in tense ascites for symptom relief and brisk mobilization of ascites is safe and more effective than isolated diuretics therapy. Although It is associated with post-paracentesis circulatory dysfunction (PPCD), it can still be safely performed by concomitant use of albumin (6-8gr/L ascites removed) [52,53]. PPCD, which is associated with increased risk of mortality, involves fall in systemic vascular resistance, hyponatraemia, a rise in serum renin and aldosterone [52,53].

Management of refractory ascites
Refractroy ascites is defined by international ascites club, as ascites that could not be mobilized or its recurrence which could not be prevented by medical therapy [54]. 5-10% may develop this type of ascites [55]. It has been subdivided by two subgroups 1) diuretics resistant ascites (no response to high dose diuretics therapy; 2) diuretics intractable ascites (could not tolerate high dose diuretics) [56]. In patients with refractory ascites and no contraindication to liver transplant, they should be referred for transplant assessment [57].

Regular LVP and TIPSS are the most commonly used treatment options for patients with refractory ascites. TIPSS is superior to LVP for long-term control of ascites. Although up until recently there was no evidence that TIPSS has any survival benefits [58], a recent metanalysis of individual patients data suggests survival advantage [59].

The role of using vasoconstrictors such as terlipressin, vasopressin V2 antagonists and ALFApump system to treat refractory ascites are currently under investigation. Two new studies shown that the use of NSBB in patients with refractory ascites may have a poor outcome, which may be associated with PICD [60, 61]. However, the results should be interpreted with caution given the design and sample size of the studies. Clearly further studies are needed to evaluate this.

SBP
Spontaneous bacterial peritonitis is one of the most severe complications of patients with cirrhosis and ascites. It is defined by the presence of >250 PMN in the ascetic fluid in absence of any other source of intra-abdominal infection and malignancy. It is a common infection in cirrhotic patients and accounting for almost 10-30% of hospitalized patients [62-66]. Bacterial translocation is the most common cause of SBP though transient bacteraemia due to invasive procedure may also lead to SBP [67, 68].

Treatment of SBP
Empirical antibiotics should be started immediately after the diagnosis of SBP and before the result of the culture is known. Patients who presents with community acquired SBP can be treated with third generation cephalosporin, amoxicillin-calvulanic acid or oral quinolones in less complicated cases [69]. In nosocomial SBP with associated increased risk of bacterial resistance such as previous hospitalization, prior antibiotics therapy including prophylaxis, carbapenems as a broad-spectrum antibiotic should be considered as first line empirical antibiotics therapy [69].

The concomitant use of albumin is recommended as it has been shown to improve survival and prevent worsening of renal function [70, 71].

Primary and secondary prophylaxis of SBP
Patient with cirrhosis and ascites who have previous episode of SBP, those with GI bleed or who have low opsonic activity of their ascites (ascites protein <15mg/L) are at high risk of SBP [78]. Patients with low ascites protein (<15mg/L), together with one of the following: serum creatinine ≥1.2 mg/dL, blood urea nitrogen ≥25 mg/dL, serum sodium ≤130 mEq/L or Child-Pugh ≥9 points with bilirubin ≥3 mg/dL should be considered for primary prophylaxis with norflixacin 400mg/ day or alternatively trimethoprim-sulfamethoxazole [72-77].

In those who survive their first episode of SBP the use of norfloxacin at a dose of 400mg/ day (alternatively trimethoprim-sulfamethoxazole) are recommended as a secondary prophylaxis [72-77].

Hepatorenal Syndrome
Patient with advanced liver disease and ascites who develop renal failure in the absence of any other identifiable cause of kidney injury is called Hepatorenal syndrome. It has a circulatory origion where splenchic vasodilation trigger marked disturbance in the systemic circulation, which ultimately leads to renal arterial constriction and renal failure [79]. Type one HRS is defined by rapidly progressive renal failure within two weeks and has a poor prognosis. Type two HRS is charcterised by moderate renal failure with a steady progress and is generally associated with refractory ascites.

Treatment
Vasoconstrictors and albumin
The use of Terlipressin as a vasopressin analogue to reduce splenchic vasodilation and subsequently improve renal perfusion is recommended. Albumin at a dose of 1mg/Kg by day one followed by 20-40gr/day should be used together with terlipressin [81,82].

Noradrenaline infusion with albumin and midodrine with octreotide have been shown to be effective and improve renal function [83,84].

TIPSS
TIPSS has been shown to be effective in the management of HRS [85,86]. A recent study with a long-term follow up of 7 years demonstrated a significant improvement in renal function after placement of TIPSS and patients with worse renal function benefited the most [87]. However, TIPSS creation may be a choice in selected patients with who do not have contraindications.

Liver Transplantation
Liver transplantation remains the treatment of choice in patients with HRS who are generally considered to have advanced liver disease [87,88]. Where access to liver transplantation is available, medical therapy and TIPSS should be considered as bridge for transplantation [89].

Encephalopathy
Hepatic encephalopathy encompasses a broad spectrum of neuropsychological dysfunctions in patients with acute and chronic liver failure. Hepatocellular failure and portal-systemic shunting are the anatomic whole mark, and ammonia is the key factor in the pathogenesis of hepatic encephalopathy [90]. Ammonia reduction remains the core therapeutic strategy [91].

Low protein diet does not have beneficial effects in patients with cirrhosis and encephalopathy and this practice has been abandoned [92]. The use of purgatives, which, cleanses the bowels and subsequently reduces the production of ammonia in the colon remains a widely used therapeutic option despite paucity of evidence. Nonabsorbable disaccharides (i.e. lactulose) with its various mechanisms have been used and a more recent study suggested beneficial effects in hepatic encephalopathy [93]. Other purgatives such as enema has also been suggested to be effective [94]. Nonabsorbable antibiotics such as neomycin and rifaxamine are used in conjunction of nonabsorbable disaccharides to treat HE. A meta-analysis found that antibiotics were more effective than nonabsorbable disaccharides [95]. A more recent meta-analysis found rifaxamine to be as effective as any other conventional oral treatment of HE [96]. A more pragmatic approach may involve starting dissachride as initial therapy while adding antibiotics as a second line. The use of probiotics and other agents which increases ureagensis are also suggested to help.

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