Portal de Periódicos da CAPES

Portal Hypertension and Cirrhosis: From Evolving Concepts to Better Therapies

2020; Lippincott Williams & Wilkins; Volume: 15; Issue: S1 Linguagem: Inglês

10.1002/cld.844

2046-2484

Jaime Bosch,

Organ Transplantation Techniques and Outcomes

Watch an interview with the author Watch a video presentation of this article Portal hypertension, defined as an increase in pressure gradient between the portal venous system and the hepatic veins, is a major consequence of the progression of chronic liver disease, because it gives rise to most of the complications that lead to death or to listing for liver transplantation in patients with cirrhosis. The prognosis of these patients has improved dramatically in the past three decades, as illustrated by the observation that short-term mortality rates after variceal bleeding have declined from 50% in the 1980s1 to values of ~10% in current series,2, 3 which leads to the suggestion that a mortality rate greater than 20% should be considered excessive nowadays.2, 3 This marked improvement in prognosis reflects advances in management that would have not been possible without a better understanding of the pathogenesis of portal hypertension. As with many concepts in medicine, advances in our knowledge of the underlying basic mechanisms explain why our view on the pathogenesis of portal hypertension has evolved over time (Fig. 1). The traditional view in the early 20th century was that the hard cirrhotic liver "blocks" portal blood flow, leading to "congestion" of the portal system,4 which was based on the pioneering hepatic perfusion experiments at Mayo Clinic by the future legendary plastic surgeon Archibald McIndoe.5 The results of McIndoe's studies refuted the fin de siècle hypothesis of Guido Banti that increased portal inflow came from a diseased spleen, to which cirrhosis was a secondary phenomenon. "Portal congestion" implied increased pressure with slow and decreased flow. Accordingly, therapy was based on creating surgical shunts that could bypass the cirrhotic liver, or on local therapies aimed at mechanically arresting variceal bleeding by means of a balloon tamponade or on eradicating varices by means of endoscopic injection sclerotherapy; ascites was relieved by paracentesis (Fig. 1A). This was the situation in 1981 at the time of publication of the landmark paper by Graham and Smith,1 which reported a 50% mortality rate in variceal bleeding. This concept was challenged mainly through a series of clinical and translational studies by Roberto Groszmann and colleagues6, 7 indicating that rather than being "congested," the portal circulation was actually "hyperdynamic" in advanced cirrhosis, a concept that implied that there is increased blood flow and shortened transit time in the portal circulation caused by splanchnic vasodilation. Many subsequent studies analyzed the molecular mechanisms involved in this hyperdynamic splanchnic circulation and ascertained its role in determining an increased cardiac index and decreased peripheral resistance leading to "effective hypovolemia" (or reduced central blood volume) that in turn plays a central role in aggravating sodium retention and causing renal dysfunction in patients with ascites. Fig.2 illustrates a key moment in the history of modern portal hypertension, when the concept of the hyperdynamic portal circulation raised by the experimental studies by Groszmann6, 7 inspired Didier Lebrec to propose the continued administration of propranolol for the long-term pharmacological treatment of portal hypertension,8 which was yet another landmark discovery of modern hepatology in which I could contribute from the very beginning. The fact that propranolol is still the mainstay in the treatment of portal hypertension, more than 35 years after its introduction,9, 10 illustrates the importance, relevance, and prescience of Lebrec's contribution. The same rationale applied to the introduction of intravenous vasoactive drugs (vasopressin, somatostatin, and its long-acting derivatives terlipressin and octreotide)11, 12 in the treatment of acute variceal bleeding (Fig. 1B). These treatments were then combined with more advanced endoscopic therapies such as endoscopic band ligation,13 cautious use of blood transfusion,14 and prophylactic broad-spectrum antibiotic therapy that together are responsible for reducing the mortality from acute variceal bleeding to current values.9 The last major breakthrough in this story of evolving concepts comes with the demonstration by Bathal15 that the increased hepatic vascular resistance that gives rise to portal hypertension in cirrhosis is not a fixed, irreversible consequence of the structural damage caused by fibrosis, nodular regeneration, vascular remodeling, and parenchymal collapse after venous obstruction, but that it can be modulated over time, for instance, by successful etiological treatment or intensive lifestyle intervention, and that this structural element is accompanied by a dynamic component because of increased hepatic vascular tone, mainly determined by endothelial dysfunction and decreased nitric oxide availability in the context of increased vasoconstrictor stimuli (Fig. 1C). This has led to intensive research of the underlying mechanisms and for potentially therapeutic targets. Even now this has resulted in the introduction of simvastatin for portal hypertension16 derived, on the one hand, from its capacity to improve endothelial dysfunction and downregulate fibrogenesis,17-19 and on the other from its liver-protective effects against injury caused by endotoxemia, hypovolemic shock, and acute-on-chronic liver failure.20, 21 Many other drugs are being explored, which may be expected to result in further improvements in the prognosis of chronic liver diseases. The benefits of traditional nonselective beta-blockers (NSBBs) such as propranolol or nadolol have been improved by the advent of carvedilol, a new-generation NSBB that has an intrinsic vasodilatory effect22 due to anti-alpha-adrenergic activity and by inducing the release of nitric oxide. These activities confer on carvedilol a greater portal pressure–lowering effect than that of propranolol, even at the recommended low dosages of 6.25 to 12.5 mg/day.23 Carvedilol is better tolerated than propranolol, probably because at recommended doses it causes less beta-blockade than regular doses of propranolol and hence allows better exercise tolerance. Carvedilol is increasingly demonstrating its safety in advanced cirrhosis and is becoming the NSBB of choice. This short review would not be complete without acknowledging other technological advances that may impact prognosis, ranging from better methods for noninvasive evaluation to new therapies, best exemplified by the introduction of transjugular intrahepatic portosystemic shunts (TIPSs) using polytetrafluorethylene-covered stents,24 which have obviated almost entirely the use of surgical shunts. Also, the early use of TIPSs in high-risk patients further decreases mortality from variceal hemorrhage to less than 20% at 1 year, even in patients with Child-Turcotte-Pugh class C.25 TIPSs have also been shown to be the best treatment option for patients with refractory or difficult-to-treat ascites.26 Other noteworthy technological innovations include the use of dedicated covered esophageal stents as a safer alternative to balloon tamponade27 and the use of balloon-occluded retrograde transvenous obliteration (BRTO) and its variants for the treatment of gastric varices in patients who are not candidates for TIPS. Finally, a pathogenesis-based approach to the treatment of portal hypertension based on effectively reducing the increased portal pressure has the advantage of preventing not only variceal bleeding and rebleeding, but also other complications of portal hypertension. This is of great relevance in early stages of cirrhosis, such as compensated cirrhosis with portal hypertension but without varices requiring treatment. In this stage, results of recent studies have shown that continued treatment with propranolol or carvedilol significantly decreases the incidence of decompensation28 mainly through a marked decrease of the risk for development of ascites, for which no preventive therapy was previously available and which is a much more frequent decompensating event than variceal bleeding. Looking at the future is hazardous, or as the humorous aphorism goes (attributed to Danish Nobel Laureate Niels Bohr but probably an old Danish proverb), "Det er vanskeligt at spa, især naar det gælder Fremtiden" (It is difficult to make predictions, especially about the future.), but in this field the sky is not covered by stormy clouds; on the contrary, it looks like a clear summer night with a myriad of brilliant stars illuminating the dreams of the young investigators who are accepting the challenge of continuing to improve the prognosis of patients with cirrhosis. If, for one fanciful moment, one had to choose a never-ending tale to illustrate the history of hepatology and a skilled raconteur to relate it, then the story of the evolution of our understanding of the pathophysiology of portal hypertension and Dr. Jaume Bosch, respectively, would be the choices of a skilled series editor—as you see. This "bloody" tale of the liver, so to speak, begins in Paleolithic times, as witnessed in the remarkable cave art of prehistoric hunters and the practice of ancient Egyptian mummifiers who preserved the liver in a Canopic jar of its own. The existence of low-resistance intrahepatic vascular channels between the portal and hepatic veins, which the great Galen derided, was brilliantly demonstrated by the portal perfusion experiment of Glisson and the landmark microscopic examination by Malpighi. Ironically, a millennium later, intrahepatic resistance in cirrhosis, an early step in the pathophysiology of portal hypertension, was demonstrated by perfusion and microscopy. The complex evolution of the yin and yang of resistance and increased blood flow, and their therapeutic implications that are summarized in Fig. 2, are lucidly developed here by the talented scion of the Barcelona–West Haven, Connecticut portal hypertension axis.