Relationship of portal hypertension and cirrhosis

Complication of Cirrhosis Portal Hypertension: A Review | OMICS International

relationship of portal hypertension and cirrhosis

Cirrhosis is a form of liver disease. It can cause portal hypertension and other side effects that can be life threatening. The most common cause of portal hypertension is cirrhosis. Vascular resistance . Location of resistance in relation to the liver and sinusoids. In patients with chronic liver disease, portal hypertension is driven by progressive fibrosis .. European Association For The Study Of The Liver.

It is difficult to predict which of these approaches, if any, will reach the stage of evidence-based clinical routine in humans, since any such treatment is incomplete and much more complex than interruption of the main cause which initiates and perpetuates liver disease. Established substances, proven in the treatment of other indications for many years, are the primary candidates and include statins, AT-1 receptor blockers, and farnesoid-X receptor FXR agonists [ 415784 — 86 ].

Additionally, statins improve endothelial dysfunction and blunt a general inflammatory response, both present in patients with liver cirrhosis [ 8486 ].

Therefore, early administration of these substances should be tested mainly in those patients in whom interruption of liver injury leading to liver fibrosis and portal hypertension has failed.

This could apply to patients with autoimmune chronic liver disease who respond incompletely to ursodesoxycholic acid UDC in primary biliary cirrhosis PBCpatients with primary sclerosing cholangitis PSCpatients unable to abstain from alcohol, and patients with late-stage NAFLD or genetic liver disease.

Renin-angiotensin system and portal hypertension The systemic renin-angiotensin system RAS plays a major role in the regulation of the blood pressure and aldosterone secretion, both of which are deranged in patients with liver cirrhosis and portal hypertension. High renin levels in serum can be found in patients with compensated liver cirrhosis [ 87 ] and increase considerably with decompensation of liver cirrhosis [ 88 ].

In addition, local RAS activation in different tissues, especially the liver and kidney, occurs [ 8990 ].

One major reason for systemic activation of RAS and secretion of other vasoconstrictors is the response to a decrease of the intrathoracic effective arterial blood volume caused by splanchnic pooling [ 291 ]. It has been repeatedly shown that myofibroblasts express AT1 receptors [ 589293 ]. This explains why blockade of AT1 receptors decreases intrahepatic resistance and blunts fibrogenesis, especially in animal models [ 9394 ].

This is in agreement with AT1 receptor-induced intracellular downstream signaling [ 58 ]. Accordingly, AT1 knockout mice show less fibrosis, whereas genetic overexpression of RAS or long-term angiotensin II infusion enhances fibrosis and portal pressure Research group J Trebicka and T Sauerbruch, unpublished data in rodents [ 94 — 96 ]. Although upregulation of intrahepatic RAS has also been demonstrated in human cirrhotic tissue, clinical trials showed only a trend toward reduction of portal pressure and fibrosis compared with placebo [ 9798 ] after earlier very promising reports [ 99 ].

In some trials, systemic application was burdened by hemodynamic side effects [ ]. This can be explained by deleterious effects of AT1 receptor blockade in patients with decompensated cirrhosis in whom high activation of RAS is necessary to maintain adequate blood pressure [ 3 ].

Thus, RAS blockade to modulate fibrosis and lower portal hypertension probably requires early and long-term treatment with low dosages [ 63], at a time when patients have compensated disease, or require specific targeting of intrahepatic myofibroblasts. Systemic application of low doses may be the most promising [ 63, ]. There are indications that—at least in patients with low renin values—sodium retention of the kidney may also be positively influenced by AT1 receptor blockade [ 63, ].

A future therapy of portal hypertension by chronic application of AT1 receptor blockers is reasonable only in patients in whom interruption of the baseline cause of chronic liver cirrhosis cannot be achieved or only partially.

Treatment may be combined with propranolol [ ] or statins as in cardiovascular disease [ 86 ]. Blockade of the AT1 receptor leads to a rebound increase of renin [ ] and angiotensin II, which is not only the substrate for cleavage to angiotensin I via angiotensin-converting enzyme ACE but also the precursor for the formation of angiotensin 1—7 via ACE2 and ACE [ 97].

More recent findings show that angiotensin 1—7 induces vasodilation and blunts fibrosis via stimulation of the Mas-receptor, counteracting deleterious intrahepatic effects in chronic liver disease [ 97 ].

At the same time, Mas-receptor stimulation augments extrahepatic splanchnic vasodilation [ ], which may increase portal tributary blood flow and portal pressure. This underlines how complex and double-edged manipulation of the RAS in chronic liver cirrhosis can be. Intestine and portal hypertension A complex interaction exists in humans and other mammals between microbes that colonize different organs by a factor of 10 compared with the eukaryotic cells of their own body [ ].

The intestinal tract is by far the most heavily colonized compartment. If the composition of the intestinal microorganisms or the intestinal barrier together with its immune system or both are deranged, the liver is the first organ to encounter microbial products in the sinusoidal delta entered via the portal vein.

Portal Hypertension

Such pathogen-associated molecular patterns PAMPs or other small molecules may liberate inflammatory cytokines or reactive oxygen species ROS via sensing proteins such as inflammasomes [] or Toll-like receptors TLRs and elicit intrahepatic vasoconstriction as well as HSC activation [ ]. Changes of the intestinal microbiome are believed to contribute decisively to the generation of hepatic inflammation and fibrogenesis [ ], especially in overweight patients and patients with alcohol abuse and hepatic steatosis.

Currently, more statistical, rather than functional, associations have been generated with the help of the rapidly growing options of high-throughput techniques [ ].

With better understanding of how and why gut microbiota change and which key molecules perpetuate intrahepatic cell activation and vasoconstriction, specific interventions in the gut-liver axis may become a future tool for modulation of portal pressure. Thus, it has been shown that intake of rifaximin, a poorly absorbed antibiotic with broad-spectrum antimicrobial activity, reduces systemic lipopolysaccharide LPS levels LPS leads to induction of tumor necrosis factor production via TLR4decreases portal pressure, and improves systemic hemodynamics [ — ].

However, the other way around, portal decompression using TIPS does not impede the inflammatory influx and its effect on mortality [ 7879 ]. This may be one explanation for the minor impact of shunt procedures on survival [].

The enterohepatic circulation of the bile acids and its influence on portal pressure, the gut, and the respective immune system have been underestimated for a long time. However, now the potential therapeutic role of FXR agonists in blunting bacterial translocation has been demonstrated in recent experimental studies [ — ]. Shunts Shunts were introduced for prevention of variceal bleeding in the s through open surgery [] and since the early s through a TIPS, creating a direct bridge between an intrahepatic branch of the portal vein and the hepatic vein [].

It has been shown in numerous controlled trials that shunts decrease portal hypertension more effectively than any other method and that they guarantee the best prophylaxis from variceal bleeding. Furthermore, excellent studies have shown that TIPS is the optimum approach to blunt RAS activation and treat refractory ascites by improving renal sodium excretion []. Yet despite these beneficial effects, it is still doubtful whether elective TIPS prolongs survival [].

In fact, reduction of portal venous perfusion of the liver may even deteriorate liver function and shorten time to liver failure in patients with marginal liver function. Interestingly, signs of intrahepatic inflammatory response persist after TIPS as mentioned above [ 77 — 79 ], suggesting that the mere interruption of portal hypertension improves disease-associated cardiovascular changes but not the chronic inflammatory response found in liver cirrhosis. Although elective or rescue shunts for variceal bleeding have not been shown to convincingly improve survival, there is new evidence from small controlled trials that very early shunting—within less than 2 days after a variceal bleeding episode—using TIPS [ — ] prolongs long-term survival compared with standard non-shunt therapy in high-risk patients.

Although they lack some basal requirements for clinical trials, data from one very experienced center suggest that an immediate open surgical side-to-side shunt is superior to endoscopic hemostasis and even to TIPS with respect to long-term survival and rebleeding [ ].

One may hypothesize from these few studies that there is a subgroup of patients with portal hypertension in whom bleeding is the prime problem and who are therefore candidates for early shunt treatment. Future management will need more input to define these patients. Infection and portal hypertension Acute infections worsen portal hypertension in patients with liver cirrhosis and may induce bleeding [].

In contrast, variceal hemorrhage itself is less often a precipitating event for acute-on-chronic liver failure [ ]. Nevertheless, if patients bleed because of portal hypertension, antibiotic therapy is paramount and one of the most important steps to prevent death [].

In regard to primary prophylaxis of complications due to portal hypertension, more information is required on the individual response to infections [ — ], especially to stimuli coming from the gut in order to investigate whether antibiotics can reduce portal pressure and prevent bleeding in selected patients [ ].

Adrenergic system and nitric oxide There exists the paradox of an enhanced vasoconstrictive response within the liver and a decrease outside the liver. Both phenomena contribute to the pathogenesis of portal hypertension and the generalized vascular dysfunction in patients with liver cirrhosis [].

According to current knowledge, they reduce portal pressure by lowering portal tributary blood flow []. Personalized treatment of portal hypertension A common catchword for future treatment approaches in medicine is personalized treatment.

In regard to portal hypertension and liver cirrhosis, several aspects have to be taken into consideration: All of these require different interventions.

In the future, genetic, metabolomics, or proteomic information, as well as an integration of all of these, may help to better assign patients to the right therapies.

The genetic information may include genes that make patients prone to alcoholism as well as genes involved in alcohol metabolism, the natural immune response, the steatotic reaction of the liver, fibrogenesis, or drug metabolism [— ]. However, it may also include genes which do not fall into biological pathways known to be involved in liver disease, identified through systematic genome-wide approaches such as genome-wide association studies or, ultimately, genome sequencing.

In any case, before such information can be used in a clinical setting, its clinical value has to be demonstrated in adequate clinical studies. However, first studies have suggested that common genetic variation in NOD2 nucleotide-binding oligomerization domain-containing protein 2 or TLR2 may predispose cirrhotic patients to infectious complications and that patients with certain PNPLA3 variants may be more prone to rapid fibrosis [— ].

It remains to be seen whether decoding of the genome as well as of the microbiome or metabolome with respect to pathways leading to end-stage liver disease will actually enable the definition of targets for timely intervention. This may not work for the treatment of multiple interacting mechanisms.

Here, the question arises how this complex information can be integrated in a meaningful way. The major challenge in the realization of the concept of systems biology will require the development of complex computational models. The hope is that by these means disease complications, which in our case is portal hypertension, can be prevented in the future. If this becomes true, there will be a change of paradigms in medicine because judgment of physicians and clinical research will be replaced by computer algorithms.

Other approaches It has been shown that inflammation and fibrosis of the liver are influenced by the endocannabinoid system []. CBR2 has protective properties, whereas in different models of liver injury in rodents, upregulation of the CBR1 has been shown to enhance fibrogenesis and steatosis [].

Thus, the respective specific ligands might be suitable for targeting portal hypertension in chronic liver disease as shown in animal studies [], provided that these drugs do not enter the central nervous system where they can cause psychotropic side effects.

Portal hypertension together with liver inflammation induces angiogenesis [], which supports splanchnic hyperemia and formation of collaterals [ — ]. Antiangiogenetic therapy for example, with multikinase inhibitorsalready established for treatment of hepatocellular carcinoma [ ], reduced portal hypertension in animal models [, ] and in very preliminary pilot studies in humans [ ]. However, side effects have to be considered [,].

relationship of portal hypertension and cirrhosis

Yet according to animal studies, doses lower than those applied in cancer treatment may effectively blunt portal hypertension in the future. At the cirrhosis stage, the liver has obviously lost its enormous ability of proper and differentiated renewal.

Yet hemodynamic studies were not included in these studies, and infarction of liver areas by infused cells might even augment portal hypertension. Considerable progress has been made in the characterization of cells, which activate HSCs and stimulate the formation of myofibroblasts [ 4961].

The resulting deposition of collagen is the fixed structural cause of portal hypertension. However, fibrosis generally divided into a perisinusoidal and septal form is not synonymous with cirrhosis, the definition of which comprises not only an increase in collagen tissue but also abnormal nodules, neovascularization, and intrahepatic vascular shunts [ ], leading to hemodynamic alterations, especially portal hypertension.

Cirrhosis: Ascites, Hyponatremia and Spontaneous Bacterial Peritonitis

The possibility of whether full-blown cirrhosis is reversible, which would be the optimal treatment of portal hypertension, has been questioned. However, a few decades ago [], anecdotal reports were published on the disappearance of varices in patients with liver cirrhosis after longer periods of abstinence and on continuous phlebotomy in patients with hemochromatosis or loss of hepatitis B surface antigen. Further reports showed that correction of mechanical cholestasis in patients with chronic pancreatitis [ ] or bariatric surgery in patients with NAFLD [ ], venesection therapy in genetically proven hemochromatosis [ ], or treatment of autoimmune hepatitis [ ] led to reduction of different fibrosis scores as assessed by follow-up biopsies.

relationship of portal hypertension and cirrhosis

In most of these studies, a change in portal pressure was not systematically determined. One study on a limited number of patients with compensated hepatitis C-related cirrhosis [ ], in which interruption of the underlying cause decreased portal hypertension within 12 months after interruption of viremia even without a change in the histological stageshowed that portal pressure reacts early to reduced inflammation but not necessarily combined with regression of the fibrotic stage.

Non-invasive techniques, such as elastography, demonstrated even higher response rates [ ]. However, it has to be kept in mind that the vast majority of these patients had compensated cirrhosis and that the observed reversal required many years. Furthermore, cirrhosis may even progress in a small number of patients [ ] despite a lack of viremia.

Pathogenesis and pathology of cirrhotic portal hypertension Portal venous pressure is directly related to the volume of portal blood flow as well as the vascular resistance to portal flow. R — Venous resistance. In cirrhotic portal hypertension, the portal blood flow as well as the intrahepatic vascular resistance is increased. The increased intrahepatic vascular resistance has two components, a fixed components and a functional component.

The fixed component is secondary to sinusoidal fibrosis and compression by regenerative nodules and relative obstruction to the terminal portal venules. This resistance at the level of the hepatic microcirculation sinusoidal portal hypertension results from architectural distortion of the liver due to fibrous tissue, regenerative nodules, and collagen deposition in the space of Disse [ 34 ].

A functional component also exists due to vasoconstriction secondary to a deficiency in intrahepatic NO and enhanced activity of vasoconstrictors [ 34 ]. The increased intrahepatic vascular tone is mediated by the increased activity of endogenous vasoconstrictors, viz endothelin, alpha-adrenergic activity, leukotrienes, thromboxane A2, angiotensin II, etc [ 34 ]. The vascular tone is reduced by nitric oxide, prostacyclin and by various drugs nitrates, adrenolytic agents, and calcium channel blockers.

In cirrhotics with portal hypertension, the hepatic vascular resistance is increased because of an imbalance between vasodilatory and vasoconstrictor stimuli [ 3 ]. Hydrogen sulphide H2Sa gas neurotransmitter with vasodilator activity, was found to be altered in cirrhosis, and there is abrogation of the relaxation produced by l-cysteine thru H2S production [ 3 ].

Neutral endopeptidase, in cirrhotics, degrades atrial natriuretic peptide and bradykinin and generates endothelin-1, which contributes to increased intrahepatic resistance [ 5 ]. The increase in portal blood flow is caused by splanchnic arteriolar vasodilatation. Splanchnic vasodilatation and hyperdynamic circulation may be the eventual result of bacterial translocation from the gutwhich results in an increase in circulating levels of tumor necrosis factor and NO [ 5 ].

VEGF mediated angiogenesis may play a role in the increased splanchnic arterial flow as well as in the development of porto-systemic collaterals [ 5 ]. Earlier research focused on circulating vasodilator substances of splanchnic origin such as glucagonvasoactive intestinal peptide, bile salts, platelet-activating factor, substance P, calcitonin gene-related peptide, atrial natriuretic peptide, etc.

Impaired activation of eNOS endothelial NO synthetase found in cirrhotic livers may be due to multiple defects in several interconnected signaling cascades that regulate intrahepatic eNOS activity [ 6 ], and also leads to down regulation of specific receptors for adrenomedullin, atrial natriuretic peptide and VEGF. Thus there is resultant vasoconstriction in the intrahepatic portal vasculature. An important role in the up regulation of eNOS has been attributed to a chronic increase in the shear stress in endothelial cells as a result of the increased portal blood flow and hyperdynamic circulationon [ 6 ].

The pathogenetic relationship between shear stress and arterial vasodilation has been further reinforced in other animal experiments.

In addition, other factors like vascular endothelial growth factor [ 6 ] and pro-inflammatory cytokines have been associated with enhanced eNOS activity. CO has also been suggested to participate in the mesenteric arterial vasodilatation of portal hypertensive rats through the activity of heme oxygenase isoenzymes [ 6 ].

Complications of portal hypertension Chronic portal hypertension leads to multiple effects as a result of congestion and venous obstruction in the organs drained by the portal vein and the development of multiple porto-systemic collaterals.

relationship of portal hypertension and cirrhosis

The most significant among these is the development of esophageal varices i. Similar changes may lead to the development of varices in other parts of the gut, like duodenal varices and rectal varices, which may manifest as hemorrhoids. Such collateral vessels may also be seen as caput medusa around the umbilicus, peri-stomal varices which may bleed, or may be seen in and around the bile duct manifesting as portal biliopathy.

Although ectopic varices can occur at several sites, they are most commonly found in the duodenum and at sites of previous bowel surgery including stomas. Dilatation of veins in the peri-choledochal plexus of Petren and para-choledochal plexus of Saint may give rise to portal biliopathy in patients with cirrhosis, though this is far more commonly seen in patients with EHPVO and non-cirrhotic causes of PHT [ 7 ].

Congestion in the organs having portal drainage leads to splenomegaly with hypersplenism usually manifest as thrombocytopeniaportal gastropathy, portal hypertensive enteropathy and portal colopathy. Gut congestion may also reflect in the reduced delivery of hepatotrophic factors to the liverand relative growth hormone insensitivity may also be seen. These findings correlate better with the extent of hepatic dysfunction, though the presence of portal hypertension or malnutrition is also required [ 7 ].

Portal hypertension leads to the development of porto-systemic collaterals and diversion of portal flow from the gut to the systemic circulation. The delivery of venous blood from the intestines to the systemic circulation has its attendant effects with the development of porto-systemic encephalopathy. With the development of portal hypertension, most cirrhotics will go on to develop a hyperdynamic circulation with increased cardiac output. Shear stress in the portal circulation results in the upregulation of eNOS in systemic circulation resulting in increased vascular capacitance and a hyperdynamic circulation.

Portal hypertension seems to be the common denominator in the circulatory disturbances seen in cirrhotics [ 7 ], and the resulting relative hypovolemia plays a significant role in renin-angiotensin activation and water retention. States of homeostasis and anti-natriuresis are activated, which results in sodium and water retention. In addition, a combination of portal hypertension and splanchnic arterial vasodilation alters splanchnic microcirculation and intestinal permeability, facilitating the leakage of fluid into the abdominal cavity and hence ascites.

Sodium retention and ascites develop and decreased free water excretion leads to dilutional hyponatremia and eventually to impaired renal perfusion and hepatorenal syndrome. Portal hypertension also seems to be pathogenetically closely linked to the development of pulmonary complications seen in liver disease: Although commonly seen in Childs C cirrhotics, both have been described in isolated portal hypertension without cirrosis [ 278 ].

The Management of Portal Hypertension Varices and Variceal Bleeding The natural history and prognosis is quite different in patients who have never bled, patients having acute variceal bleed, and patients who have survived a bleeding episode. The efficacy of available treatments in controlling or preventing bleeding is inversely proportional to invasiveness and the adverse effects Table 1.

The predictive value of noninvasive methods such as fibroscan, spleen size, portal vein diameter, and transient elastography in the diagnosis of esophageal varices remains to be established [ 7 ]. The size and variceal wall thickness, the presence of endoscopic stigmata such as red signs an area where the variceal wall is thin and weakenedthe severity of the liver disease, and the portal pressure are determinants of risk of variceal bleeding [ 78 ].

Other local factors that increase variceal wall tension and cause mucosal injury play a role. The wall tension is defined by Frank's modification of Laplace's law: Surveillance endoscopy may be repeated every two years in patients without varices. In those with small varices and a high risk factor like alcoholic cirrhosis, decompensated cirrhosis or those with red signs at baseline endoscopy may warrant yearly endoscopic surveillance.

The APASL guidelines for primary prophylaxis of screening and surveillance of varices are as follows: Endoscopic screening should be carried out on all cirrhotic patients at diagnosis. Patients with no varices should have an endoscopic surveillance every 2 years. The frequency of endoscopic surveillance depends on the severity of liver disease.

Prophylactic VBL to prevent variceal bleeding should be used in patients with high-risk varices at the time of initial screening.

Preprimary prophylaxis There is no effective treatment to prevent development of varices preprimary prophylaxis and available prophylactic measures have been disappointing with unacceptable adverse effects and limited efficacy [ 7 ]. There does not seem to be any role for endoscopic therapy in early primary prophylaxis as yet. It may be therefore wise to advise patients to avoid activities that cause increase in the IAP. Total volume paracentesis may decrease variceal pressure and may improve portal hemodynamics by reducing the intra-abdominal pressure [ 7 ].

Beta blockers may help protect against the effect of moderate physical exercise at the expense of reducing blood flow to the liver [ 7 ]. Post prandial hyperemia is reduced by octreotide [ 2 ] and isosorbide mononitrate, whereas propranolol only reduces basal HVPG. Propranolol may protect against the effects of a moderate physical exercise on portal hemodynamics. Postprandial hyperemia might be blunted by octreotide and ISMN. Propranolol decreases only the baseline HVPG.

Acute ethanol consumption may cause variceal bleeding. It is wise to abstain from alcohol. Nonselective beta-blockers reduce the rate of variceal bleeding and also bleeding related mortality. EST is effective in preventing variceal bleeding, but has been superseded by VBL due to a better safety profile.

VBL is effective primary prophylaxis with a very low incidence of adverse effects and significantly reduces the risk of first variceal bleed. A meta-analysis concluded that VBL reduces first variceal bleed, bleeding related mortality and overall mortality [ 8 ].

Simple measures like proton pump inhibitors and sucralfate reduce esophageal ulceration [ 8 ]. Other measures like using multi-banders and increasing the interval between banding sessions [ 8 ] may improve the results of VBL and increase its safety and efficacy compared with those of beta-blockers.

Nitrates, short-acting nitroglycerin or long-acting isosorbide mononitrates reduce portal blood flow, but the effect on intrahepatic resistance is not impressive, and nitrates are no longer recommended for primary prophylaxis due to discrepant results of clinical trials [ 8 ].

Combination therapy with beta blockers and nitrates cannot be recommended yet for primary prophylaxis, due to limited and conflicting evidence.

Two trials in the last decade showed that beta-blockers with VBL was better than VBL alone in primary prophylaxis [ 89 ], suggesting that treatment with VBL alone should be restricted to patients with contraindications to beta-adrenergic blockers. However, Sarin et al. However, the recurrence of varices seems to be lower if propranolol is added to VBL [ 89 ]. TIPS transjugular intrahepatic portosystemic shunt may be more effective in reducing portal pressure and primary variceal bleeding that endoscopic or pharmacotherapy.

However, it does not prolong survival and has its own disadvantages of cost and encephalopathy. Endothelin receptor blockers and liver-selective NO donors that target intrahepatic vascular resistance are promising investigational therapies. APASL recommendations Beta-blockers and VBL, both reduce the risk of primary variceal hemorrhage and bleeding-related mortality compared with no treatment.

Cirrhosis and Portal Hypertension -

ISMN monotherapy has no role in primary prophylaxis, alone or in combination. Management of Acute Variceal Bleeding The management of acute variceal bleeding includes hemodynamic resuscitation, general treatments, prevention of complications, and achievement of hemostasis.

Transfusion of packed RBC to replace the blood loss is indicated, but over-transfusion can cause a rebound increase in portal pressure and should be avoided [ 8 ]. Transfusion of FFP and platelets is commonly used to correct the coagulopathy. However the usual amounts of FFP and platelets used may be inadequate in correcting the coagulopathy and cause volume overload and rebound portal hypertension [ 9 ].

Antibiotic prophylaxis is indicated as it significantly reduces episodes of infective complications, which are common and gravely affect prognosis [ 8 ]. Pharmacotherapy Terlipressin is the only drug shown to improve survival in patients with acute variceal bleeding and therefore should be the drug of choice [ 8 ]. Somatostatin, octreotide, and vapreotide are the next option [ 89 ]. If these drugs are not available, then vasopressin with transdermal nitroglycerin may be used.

Terlipressin results in splanchnic vasoconstriction resulting in reduction in portal inflow and thereby reducing portal and variceal pressure. Terlipressin is the only drug that has been shown to have a beneficial on control of bleeding and survival. It is probably as effective as other therapies like EST and VBL, it protects against renal failure that may develop after a variceal bleed [ 8 ] and is safer than vasopressin with nitroprusside.

Somatostatin has been compared to terlipressin in efficacy, and no differences were found for failure to control bleeding, rebleeding, and mortality [ 8 ]. In a landmark article published by Bosch et al. WHVP decreased by