literature review on portal hypertension

• Open access
• Published: 10 November 2017

Advances and challenges in cirrhosis and portal hypertension

• Annalisa Berzigotti 1  

BMC Medicine volume  15 , Article number:  200 ( 2017 ) Cite this article

Liver cirrhosis is the fourth cause of death in adults in Western countries, with complications of portal hypertension being responsible for most casualties. In order to reduce mortality, development of accurate diagnostic methods for early diagnosis, effective etiologic treatment, improved pharmacological therapy for portal hypertension, and effective therapies for end-stage liver failure are required.

Early detection of cirrhosis and portal hypertension is now possible using simple non-invasive methods, leading to the advancement of individualized risk stratification in clinical practice. Despite previous assumptions, cirrhosis can regress if its etiologic cause is effectively removed. Nevertheless, while this is now possible for cirrhosis caused by chronic hepatitis C, the incidence of cirrhosis due to non-alcoholic steatohepatitis has increased dramatically and effective therapies are not yet available. New drugs acting on the dynamic component of hepatic vascular resistance are being studied and will likely improve the future management of portal hypertension.

Cirrhosis is now seen as a dynamic disease able to progress and regress between the compensated and decompensated stages. This opinion article aims to provide the author’s personal view of the current major advances and challenges in this field.

Peer Review reports

Chronic liver disease (CLD) affects more than 29 million people in Europe [ 1 ] and over 300 million people worldwide. The main causes of CLD are alcohol abuse, chronic viral hepatitis, and metabolic factors (non-alcoholic fatty liver disease). Over time, extracellular fibrotic tissue develops and accumulates in the liver as a result of chronic injury, progressively leading to fibrous septa that prevent normal oxygenation and blood exchange to the liver parenchyma. This late stage, featuring marked liver anatomical changes, including hepatocyte extinction, micro- and macrovascular remodeling, neoangiogenesis, nodule formation, and development of portosystemic shunts, is termed ‘cirrhosis’ [ 2 ]. Mortality in CLD is primarily due to complications of liver cirrhosis and hepatocellular carcinoma (HCC), which is considerably more prevalent in patients with cirrhosis. The term ‘advanced chronic liver disease’ (ACLD) has been recently proposed to better mirror the late stages of CLD, which should be considered within a continuum spectrum, ranging from severe fibrosis to fully developed cirrhosis [ 3 ].

Compensated versus decompensated cirrhosis: the burden of advanced chronic liver disease (ACLD)

According to the largest study available thus far [ 4 ], cirrhosis represents the fourth cause of death due to non-communicable diseases worldwide, with the total number of deaths from cirrhosis and liver cancer having steadily risen by approximately 50 million per year over the last two decades. This large mortality rate is due, to some extent, to a late diagnosis. A decades-long asymptomatic stage during which no overt sign of the disease is noticed is characteristic of CLD. Indeed, even after the onset of cirrhosis, the disease can remain asymptomatic, or ‘compensated’, for a long time [ 5 ]. Nevertheless, during this time, portal hypertension progressively develops, usually accompanied by a decline in hepatocellular function.

Portal hypertension is the major driver in the transition from the compensated to the ‘decompensated’ stage of cirrhosis [ 5 ], defined by the presence of clinical complications, including ascites [ 6 ], bleeding from gastroesophageal varices [ 7 ], spontaneous bacterial peritonitis [ 8 ], hepatorenal syndrome [ 6 ], and hepatic encephalopathy [ 9 ]. Further decompensating episodes are often triggered by bacterial infections [ 10 ], and are associated with a very high mortality risk. From a prognostic point of view, compensated and decompensated cirrhosis are dramatically different, and can be considered as two separate diseases. Furthermore, within these two major stages, several sub-stages with varying risk of further decompensation and death can be identified [ 11 ] (Fig.  1 ). Knowledge of the pathophysiological mechanisms driving the transition within these stages is key in the current management of cirrhosis [ 7 ]. Besides its negative impact on life expectancy, cirrhosis implies several other burdens, including a marked increase in healthcare costs due to hospitalization and treatment (estimated at approximately $2.5 billion per year in the US) [ 12 ], loss of productivity (estimated at $10.6 billion per year in the US) [ 12 ], and a marked reduction in quality of life [ 13 ]. These burdens are almost exclusively caused by complications during the decompensated stage.

Clinical stages of cirrhosis. The first major classification is based on the absence or presence of complications. Cirrhosis is named ‘compensated’ in the absence of complications, and ‘decompensated’ if complications are present or have been present in the past. In patients with compensated cirrhosis, the presence of clinically significant portal hypertension (HVPG ≥ 10 mmHg) identifies a substage with higher risk of developing any complication (varices, decompensation). The decompensated stage is characterized by a high risk of progression to further decompensation, liver failure, and death. Evidence-based therapy has been developed by targeting the pathophysiological mechanisms driving the transition from a given step to the following one. The major advances in each stage are indicated within the figure

Given that chronic viral hepatitis C (HCV) is a leading etiology of CLD [ 14 ], the recent availability of direct, high efficacy oral antiviral agents against HCV represents a major breakthrough towards achieving a reduction in mortality linked to CLD. Unfortunately, despite the reduction in the incidence of HCV-related liver disease complications already observed [ 15 ] and the marked decrease further expected over the coming years, over 40% of HCV infection cases have not been identified and may be recognized at a late, decompensated stage, when treatment of the viral infection may be futile [ 16 ]. In addition, other etiologies of CLD are becoming more common or remaining steadily frequent. Cirrhosis due to non-alcoholic steatohepatitis is markedly increasing as a consequence of the obesity pandemic worldwide [ 17 ], already ranking second among the etiologies of cirrhosis in patients on the waiting list for liver transplantation in the US [ 15 ]. Furthermore, liver disease associated with alcohol use disorders is highly prevalent worldwide, and is particularly relevant in Europe, where it accounts for the highest proportion of cirrhosis cases [ 18 ]. Of note, over the past 30 years, mortality due to cirrhosis in Europe increased in areas with the highest alcohol consumption (United Kingdom, Eastern Europe, Ireland, and Finland) [ 19 ]. Nevertheless, in several countries within the EU limiting alcohol use is not yet considered an absolute priority for policy-makers [ 20 ].

Over the last decades, new knowledge on the pathophysiology, diagnostic methods, and therapy of cirrhosis and portal hypertension have significantly improved the management of this disease, with a marked reduction in mortality related to some of its complications, particularly variceal bleeding [ 21 ]. However, in a recent analysis based on over 100,000 cases, 30-day mortality following discharge for any decompensation of cirrhosis was equal to or even higher than that observed 10 years prior, suggesting that the burden of mortality was merely shifted to the immediate postdischarge period [ 22 ]. Among the major determinants of mortality are inflammation in acute-on-chronic liver failure (associated with different complications of end-stage liver disease) and HCC [ 23 ] (not discussed in the present paper), both of which have been the subject of extensive research but remain unsatisfactorily resolved.

To achieve a substantial improvement in survival, every step of the management process of patients with ACLD should be addressed and optimized (Fig.  2 ). An early diagnosis of cirrhosis, i.e., within the compensated stage, and an accurate risk stratification are key to the following steps. Indeed, in the author’s opinion, the use of resources at this initial step (e.g., initiation of HCC surveillance, endoscopic screening of varices needing treatment in patients at high risk, prevention of decompensation by appropriate non-pharmacological and pharmacological therapy) is largely justified by the expected survival benefits.

Logical steps in the clinical management of advanced chronic liver disease/cirrhosis. Improved survival can be achieved through adequate diagnosis and risk stratification, thus allowing a personalized approach to therapy. Some examples of factors to be considered, as well as the major pathophysiological factors driving the therapy of portal hypertension in patients with compensated cirrhosis, are provided

Early diagnosis and risk stratification: moving towards personalized medicine

The reference standard methods to diagnose cirrhosis, portal hypertension, and esophageal varices are liver biopsy, hepatic venous pressure gradient (HVPG) measurement, and endoscopy, respectively [ 24 ]. All of these methods are invasive, and require expertise to be correctly performed and interpreted. Undoubtedly, the availability of novel non-invasive diagnostic methods, and ultrasound elastography in particular, has enhanced the likelihood of early diagnosis of ACLD, facilitating the identification of patients with compensated disease who are at high risk of complications, prior to the occurrence of decompensation. Liver stiffness (and more recently spleen stiffness) can be measured by various ultrasound elastography methods [ 25 ], and mirrors the severity of liver disease and portal hypertension in patients with compensated ACLD [ 26 ]. The diagnosis of clinically significant portal hypertension (CSPH; HVPG ≥ 10 mmHg) is made possible by elastography, with an accuracy greater than 80% when using a binary cut-off approach [ 27 ]. As with all numerical variables holding prognostic value, liver stiffness can be modeled and calibrated, and the risk (probability) of CSPH can be calculated according to the measured values [ 28 ], thus leading to personalized medical decision-making. The vast data available regarding the relationship between liver stiffness, CSPH, and varices led the Baveno VI consensus conference on portal hypertension, held in 2015 [ 29 ], to suggest a simple combination of liver stiffness measured by transient elastography (<20 kPa) and platelet count (>150 G/L) in order to identify patients at low risk of varices needing treatment in whom endoscopic screening could be safely avoided [ 29 ]. Since 2015, these non-invasive criteria have proven robust and accurate, even if conservative (only approximately 20–25% of endoscopies spared). Recent research has proposed expanded non-invasive criteria allowing a much larger proportion of endoscopies to be spared without increasing the risk of false negative results [ 30 , 31 ].

Real-time, simple diagnostic methods, such as ultrasound and elastography, are key to achieving bedside screening and first risk stratification. However, in patients who cannot be sufficiently characterized by these simple methods or in particularly sensitive situations, such as in patients with compensated cirrhosis and potentially resectable HCC [ 23 , 32 ], HVPG measurement remains the best method to accurately stage portal hypertension. Nevertheless, recent advances in magnetic resonance imaging (magnetic resonance elastography [ 33 ], multiparametric magnetic resonance imaging [ 34 ]) hold promise and should be further investigated as surrogates of portal hypertension, particularly in patients who are not appropriate candidates for ultrasound elastography.

Despite the use of diagnostic tests being of paramount importance to achieve a correct risk stratification, the meaning of risk factors that are easily detected by physical examination and clinical history should not be disregarded. For instance, factors related to nutrition, and which are therefore potentially modifiable, should be actively investigated. Irrespective of the etiology leading to ACLD, overweight and obesity are increasingly observed in compensated patients [ 35 ], and have been consistently associated with an up to three-fold higher risk of clinical decompensation. Further, sarcopenia [ 36 ] and vitamin D deficiency [ 37 ] are frequent in cirrhosis (including in obese patients), almost invariably present in decompensated patients, and associated with higher mortality. Research in the field of nutritional factors modulating the natural history of cirrhosis is insufficient and represents a field for future investigation. For example, while alcohol intake is a well-known negative prognostic factor, coffee consumption has only recently been proven protective [ 38 , 39 ].

Future research should also focus on providing accurate and individualized prediction of ‘hard’ endpoints, such as clinical decompensation and death, by non-invasive diagnostic methods. In the author’s opinion, the development of risk algorithms similar to those used in cardiovascular medicine (e.g., Framingham risk score [ 40 ]) would be advisable and feasible in the field of compensated cirrhosis to predict and stratify the risk of complications of portal hypertension.

Advances in therapy

Several studies have demonstrated that, in portal hypertensive patients, if portal pressure is reduced enough (i.e., by at least 20%) by applying pharmacological and/or non-pharmacological therapies, the risk of decompensation or further decompensation and death is markedly reduced [ 7 , 41 , 42 , 43 ] – this constitutes the rationale of treatment of portal hypertension. To achieve the highest efficacy, treatment should be aimed at correcting the main pathophysiological target in each stage of cirrhosis. In the early, compensated stages of cirrhosis, increased hepatic resistance plays a pivotal role in the development of portal hypertension (Pressure = Resistance × Flow) [ 2 ]. Therefore, in compensated cirrhosis, correction of increased intrahepatic resistance should be addressed [ 7 , 44 ]. This can be achieved by ameliorating the mechanical component of resistance mostly represented by fibrosis and/or by acting on the functional component represented by active vasoconstriction and sinusoidal endothelial dysfunction [ 45 ]. Etiologic treatments have been shown effective in improving fibrosis and can lead to cirrhosis regression in the long term [ 46 ]; thus, they should be considered central at this stage of the disease.

Short-term (4 months) lifestyle changes consisting of diet and exercise combinations are able to improve obesity in compensated cirrhosis and are associated with a significant reduction in HVPG [ 47 ], likely mirroring a decrease in intrahepatic resistance (e.g., mediated by a decrease in insulin resistance). While supplementing vitamin D deficiency and correcting sarcopenia is likely to positively influence prognosis, the mechanisms driving the interaction between nutritional factors and portal hypertension remain to be elucidated.

Pure antifibrotic drugs are currently lacking [ 48 ]. However, statins, which improve the phenotype of sinusoidal endothelial cells by restoring nitric oxide production, are able to decrease intrahepatic fibrogenesis and angiogenesis in experimental models [ 49 ] and ameliorate portal hypertension by decreasing both the dynamic and structural components of intrahepatic resistance [ 50 ]. Interestingly, this is accompanied by an amelioration in hepatic function and perfusion in patients with cirrhosis [ 51 ]. Statins have proven effective in preventing hepatic decompensation in large epidemiological surveys in patients with HCV and hepatitis B virus cirrhosis [ 52 , 53 ]. In addition, their use has been associated with a decreased risk of HCC [ 54 ] and, most recently, addition of simvastatin to standard medical and endoscopic therapy has been shown to improve survival in a double-blind randomized multicenter clinical trial in patients who survived an episode of bleeding from esophageal varices [ 55 ]. Thus, statins constitute the most promising class of drugs to be added to the standard therapy armamentarium for ACLD and portal hypertension.

Once CSPH has developed, and even more so following the formation of varices, the resulting hyperdynamic circulatory state leads to an increased portocollateral flow, which aggravates portal hypertension [ 2 , 56 ]. At this stage, drugs acting to reduce blood flow are effective in reducing portal pressure. Non-selective beta-blockers (NSBBs; propranolol, nadolol, or carvedilol) are the mainstay of therapy in this clinical scenario [ 7 ], and recent data from a randomized controlled trial (RCT) suggest that they effectively reduce the risk of ascites and clinical decompensation in patients with small varices [ 57 ].

Given the abovementioned data, it has been suggested that NSBBs, statins, and oral antibiotics (rifaximin [ 58 ] or norfloxacin) could be used in combination to prevent clinical decompensation in patients with cirrhosis [ 59 ]. In a recent study, patients treated with rifaximin added to propranolol showed a more marked decreased in HVPG as compared to patients on propranolol alone [ 60 ].

A further group of drugs showing promising results is represented by anticoagulants. Contrarily to what was previously thought, cirrhosis can be considered a pro-coagulant state, and experimental data suggest that low molecular weight heparin [ 61 ] and direct oral anticoagulants [ 62 ] inhibit fibrogenesis and decrease portal pressure in cirrhosis. A small RCT using enoxaparin to prevent portal vein thrombosis in patients in the waiting list for liver transplantation showed a reduction in mortality [ 63 ].

Given the increased susceptibility to life-threatening bacterial infections observed in patients with decompensated cirrhosis [ 8 ], the reduction of intestinal bacterial translocation by antibiotic therapy is another potential treatment able to reduce the risk of spontaneous bacterial peritonitis and mortality in patients with decompensated cirrhosis and ascites. In a recent RCT [ 64 ], norfloxacin combined to standard medical therapy improved survival compared with standard medical therapy alone in patients with decompensated alcoholic cirrhosis and severe liver failure. In addition, a further strategy aimed at improving effective intravascular volemia by using weekly administration of intravenous albumin in addition to standard medical therapy improved survival in patients with ascites versus standard medical therapy alone [ 65 ]. Nevertheless, these results are not yet published in full and require validation.

Transjugular intrahepatic portosystemic shunt (TIPS) is a well-accepted therapy to prevent rebleeding in patients experiencing more than one episode of variceal bleeding, in patients with refractory ascites it demonstrated a survival benefit vs. large volume paracentesis. Recent data suggest that TIPS may also be applied to other clinical scenarios in cirrhosis to improve outcomes. In a RCT of TIPS versus standard medical plus endoscopic therapy in patients presenting with variceal bleeding and poor liver function (Child–Pugh score B9 to C12 points), the early use of TIPS (within 72 hours with the aim of preventing early rebleeding) reduced mortality by 25% [ 66 ]; these results have been validated in a second multicentric study [ 67 ]. In the setting of patients with recurrent (not refractory) ascites, TIPS improved survival by over 40% in comparison to standard medical therapy [ 68 ].

A major gap remains regarding the ability to non-invasively monitor the effect of therapy on portal pressure. None of the currently available non-invasive tests holds sufficient accuracy in mirroring the HVPG response. A recent study suggested that changes in spleen stiffness (measured by point shear wave elastography) might parallel changes in HVPG and portal pressure gradient after NSBB and TIPS [ 69 ]; however, these results require validation. The development of other non-invasive tests, such as subharmonic aided pressure estimation on contrast-enhanced ultrasound [ 70 ], as well as non-invasive measurements derived by parameters from contrast-enhanced ultrasound [ 71 ] or magnetic resonance imaging [ 34 ] are urgently needed in this field.

Finally, a novel challenge has resulted with regards to the population of patients with HCV cirrhosis in whom the virus was successfully cured by direct acting antivirals. A minority of these patients will improve after treatment, but a substantial proportion (over 70%) of those who had CSPH at the time of therapy remains at risk of developing complications of portal hypertension [ 72 ]. Unfortunately, we currently lack non-invasive surrogates of HVPG in this population, and it remains unknown whether cirrhosis will successfully revert in the long term. The ‘point of no return’ in the natural history of cirrhosis is currently unknown, and certainly represents a major field for future research as well as a potential endpoint for novel therapies.

Conclusions and future perspectives

Currently, cirrhosis is considered a dynamic disease able to progress and regress. In this new way of understanding the spectrum of changes characterizing ACLD, early diagnosis, prior to the occurrence of decompensation, is an important step to achieve a reduction in mortality due to CLD since several different pharmacological and non-pharmacological approaches can be used during this phase to prevent decompensation (an ominous step in the natural history of this disease). Ultrasound elastography of the liver allows an accurate non-invasive identification of patients with ACLD, with the additional advantage of providing a numerical surrogate of the risk of portal hypertension and complications. Prevention of decompensation is possible by reducing portal pressure through measures aimed at eliminating all the possible sources of injury (etiology and cofactors), at reducing intrahepatic resistance (e.g., by correcting intrahepatic endothelial dysfunction), and at reducing portocollateral flow. Long-standing drugs, such as NSBBs, remain the mainstay for portal pressure reduction and are able to prevent not only variceal bleeding, but also other more frequent decompensating events such as ascites. After decompensation, therapy should be aimed towards avoiding further decompensation and death, with statins being promising in these cases. TIPS is effective in decreasing the risk of variceal rebleeding and improves mortality in patients with recurrent and refractory ascites. The extent to which modulating the gut microbiota impacts the natural history of decompensated cirrhosis remains unknown, yet antibiotics already play an important role in the prevention and treatment of severe bacterial infection in decompensated patients. Unfortunately, despite the indubitable improvement in the management of portal hypertension, severe liver failure cannot be reversed.

Effective artificial liver support remains a major unmet need in patients with end-stage liver disease, with liver transplantation representing the only available curative option to date (in those who have no contraindications). Indeed, research in the field of regenerative medicine represents a major expected breakthrough of the 21st century, holding great promise [ 73 ] for a reduction in the need of liver transplantation in the future.

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Berzigotti, A. Advances and challenges in cirrhosis and portal hypertension. BMC Med 15 , 200 (2017). https://doi.org/10.1186/s12916-017-0966-6

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REVIEW article

Pathophysiology and management of liver cirrhosis: from portal hypertension to acute-on-chronic liver failure.

• 1 Department of Hepatology, Gastroenterology and Liver Transplant Medicine, Metro Hospital, Noida, India
• 2 Department of Gastroenterology, Institute of Gastrosciences and Liver Transplantation, Apollo Hospitals, Kolkata, India
• 3 Department of Hepatology, Mahatma Gandhi Medical College and Hospital, Jaipur, India
• 4 Department of Hepatology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India
• 5 Department of Hepatology, Asian Institute of Gastroenterology (AIG) Hospitals, Hyderabad, India

Cirrhosis transcends various progressive stages from compensation to decompensation driven by the severity of portal hypertension. The downstream effect of increasing portal hypertension severity leads to various pathophysiological pathways, which result in the cardinal complications of cirrhosis, including ascites, variceal hemorrhage, and hepatic encephalopathy. Additionally, the severity of portal hypertension is the central driver for further advanced complications of hyperdynamic circulation, hepatorenal syndrome, and cirrhotic cardiomyopathy. The management of these individual complications has specific nuances which have undergone significant developments. In contrast to the classical natural history of cirrhosis and its complications which follows an insidious trajectory, acute-on-chronic failure (ACLF) leads to a rapidly downhill course with high short-term mortality unless intervened at the early stages. The management of ACLF involves specific interventions, which have quickly evolved in recent years. In this review, we focus on complications of portal hypertension and delve into an approach toward ACLF.

1. Introduction

Cirrhosis is a major cause of morbimortality, constituting around 2.4% of global deaths ( 1 ). The natural history of cirrhosis has a progressive and dynamic course transitioning from a relatively stable state of compensated cirrhosis to an advanced stage of decompensated cirrhosis ( 2 ). Central to the dynamics of the transition is the degree of portal hypertension (PH) which serves as the primary driver of complications like the development of varices, ascites, renal dysfunction, hepatic encephalopathy (HE), hyperdynamic circulation, and cardiomyopathy ( 3 , 4 ). While on the one hand, the stagewise progression of cirrhosis with worsening of PH delineates the conventional natural history of cirrhosis, another distinct syndrome marked by an acute deterioration of liver function with or without extrahepatic organ failures known as acute-on-chronic liver failure (ACLF) has opened up newer paradigms in PH over the last decade ( 5 ). This review explores newer insights into the pathophysiology of PH in cirrhosis and ACLF.

2. Basic pathophysiological mechanisms of development of PH

Central to the development of PH is the occurrence of resistance at any point in the portal venous system, leading to the effect of a pressure gradient. In patients with cirrhosis, this resistance level is at the level of hepatic sinusoids, which arises from a combination of structural (fibrosis, nodule formation) and functional alterations ( 6 ). The static or architectural changes behind the development of PH are driven by alterations in the interplay between hepatic stellate cells (HSCs) and liver sinusoidal endothelial cells (LSECs). In response to any injury or insult, HSCs are activated and lead to extracellular matrix formation and fibrogenesis, while LSECs undergo a phenotypic remodeling leading to capillarization of the sinusoids, thereby increasing intrahepatic resistance. Coupled with this, a dynamic component arising from myofibroblast contraction and decreased vasodilators like nitric oxide further accentuate the resistance pathway ( 6 , 7 ). These two fundamental mechanisms lead to the progressive development of PH, leading to splanchnic vasodilation, neurohormonal disturbances, systemic vasodilatation, decreased mean arterial pressures (MAP), and an overall hyperdynamic state ( 8 ) ( Figure 1 ). In combination with these, gut microbial alterations, increased intestinal permeability, and systemic inflammation act as both precipitants and perpetrators of worsening PH and further downstream complications ( 8 ) ( Figure 2 ). In the following sections, we elaborate on the individual consequences of PH and their management.

Figure 1 . Mechanism of portal hypertension in cirrhosis. HE, hepatic encephalopathy; RAAS, renin-angiotensin-aldosterone system; SNS, sympathetic nervous system; HRS, hepatorenal syndrome.

Figure 2 . Effects of portal hypertension: migration from compensated stage to decompensated stage. HE, hepatic encephalopathy; HRS, hepatorenal syndrome.

3. Variceal hemorrhage

3.1. development of varices and importance of hepatic venous pressure gradient.

Resistance to portal blood flow and increased portal venous blood inflow result in the reversal of flow and formation of alternate blood flow channels between the portal and systemic circulation, which result in varices. The development of varices acts as a surrogate marker of PH and signifies clinically significant portal hypertension (CSPH). HVPG is the closest surrogate marker of actual portal pressure and PH, with the presence of PH being defined as an HVPG > 5 mm Hg, while a value of >10 mmHg signifies CSPH ( 9 ) ( Table 1 ). In patients with VH, an HVPG > 20 mmHg (measured within 24 h after admission) is the best predictor of a poor outcome. A reduction in the HVPG < 12 mm Hg or a reduction of more than 20% from the baseline value has been associated with a decreased risk of VH and improved survival ( 10 ). HVPG > 20 mm Hg has been associated with a 5.21-fold likelihood of rebleeding, and reducing HVPG below this threshold using a vasoactive drug improves outcomes. Patients with HVPG > 20 mmHg or < 10% decline in HVPG (non-responders) on vasoactive medications increases the risk of rebleeding and have higher mortality ( 10 ). All patients presenting with VH should ideally undergo HVPG measurement, although access to the procedure at all centers is limited ( 11 , 12 ). Patients with VH who have an HVPG > 20 mmHg should be evaluated for an early transjugular portosystemic shunt (TIPSS) ( 13 ).

Table 1 . Hepatic venous pressure gradient and esophageal varices.

3.2. Risk factors for VH and risks associated with re-bleeding

VH from esophageal varices or gastric varices can result in high mortality (10–20% at 6 weeks) ( 3 , 14 ). Other rare ectopic sites for VH (< 5% of VH) are the rectum, duodenum, and post-surgical stomas. There are multiple risk factors for VH, including the larger size of varices (>5 mm), higher HVPG, higher grade of the child class, presence of red color signs (RCS) markings, active alcohol consumption, and presence of sepsis. There are also certain high-risk factors for re-bleeding, including a pressure gradient measured within 24 h of bleeding more than 20 mmHg, presence of large varices, age ≥ 60 years, renal failure, and severe initial bleeding (on admission, hemoglobin < 8 g/dL) ( 11 , 15 ).

3.3. Management of acute variceal bleeding

The management consists of controlling acute bleeding to prevent death and prevention of re-bleeding. Hemodynamic resuscitation is the initial treatment considering patient age, co-morbidities, ongoing blood loss, hemodynamic status, and other parameters. Fluid resuscitation should be cautious and restrictive to keep hemoglobin between 7 and 9 gm/dl, as overaggressive resuscitation can worsen PH and bleeding ( 16 ). INR-based corrections with fresh frozen plasma, factor VII transfusion, platelet, cryoprecipitate, or other blood products are not warranted ( 17 , 18 ). Moreover, overzealous use of these products can be harmful due to the increase in PH due to volume overload or transfusion-related lung injury ( 14 , 19 ). After gastrointestinal (GI) bleeding, blood acts as a culture media to grow infections; therefore, adequate purging should be done to prevent post-bleed sepsis, HE, ascites, or other complications of PH. Post-bleed sepsis can increase mortality; thus mandating the use of antibiotics during bleeding events as per local antibiograms. Currently, third-generation cephalosporins are recommended ( ceftriaxone 1 gm IV every 24 h for 7 days) ( 20 , 21 ). Vasoconstrictors should be started as early as possible in VH, along with proton-pump inhibitors. Vasoconstrictors should be continued for at least 2–5 days ( 15 ). Somatostatin, octreotide, and terlipressin are the recommended agents with comparable efficacy and safety ( 22 ).

Endoscopy-based endotherapy is definitive in managing VH and should be done within 12 h after hemodynamic resuscitation ( 23 ). Prokinetics (intravenous erythromycin) and anti-emetics should be given before the endoscopy for better visualization ( 24 ). Patients with altered mentation, severe sepsis, shock, and acidosis should be electively intubated before endoscopy. Endoscopic band ligation (EBL) is the definitive therapy for esophageal varices and gastro-esophageal varices (GOV) type 1. Endoscopic glue injection with cyanoacrylate glue remains the most used therapy for treating bleeding from isolated gastric varices (IGV) and GOV type 2 ( Figure 3 ). Tamponade with Sengastaken–Blakemore (SB tube) or Minnesota tube is usually considered a salvage modality in cases of refractory bleeding, often serving as a bridge to more definitive therapy such as TIPSS. The role of TIPSS in VH has been advocated as a pre-emptive modality (pre-emptive TIPSS) and a salvage modality (rescue TIPSS) ( 25 ). After stabilization, imaging studies (ultrasonography/computed tomographic scan) to rule out acute causes of PH like portal vein thrombosis (PVT) and hepatocellular carcinoma (HCC) should be performed ( 26 ).

Figure 3 . Treatment of variceal hemorrhage. HE, hepatic encephalopathy; IV, intravenous.

3.4. Newer perspectives

An emerging concept proposed is identifying risk factors and possible avoidance of antibiotics in patients with well-preserved liver functions presenting with VH, however, prospective validation is needed ( 27 , 28 ). Although the model for end-stage liver disease (MELD) is reasonable in predicting outcomes of patients with VH, a recent study reported MELD-Lactate to be superior in predicting mortality after VH ( 29 , 30 ).

3.5. Primary prophylaxis of VH

Non-selective beta-blockers (NSBBs) or EBL are the treatments of choice to prevent VH ( 31 ). The use of NSBBs in PH is well-studied and has a pleiotropic mechanism. In addition to being economical to use, recent studies have demonstrated their pleiotropic effects, like preventing bacterial translocation, antioxidant properties, containing further non-bleed decompensations, and portal hypertensive gastropathy progression, as well as improving survival in ACLF ( 32 – 35 ). Adding another rate-controlling agent, ivabradine, to NSBB has shown some promising results, achieving better hemodynamics, reducing the incidence of acute kidney injury (AKI) and HE, and achieving a target heart rate ( 36 ). However, external validation of this merits consideration.

Gastric variceal bleeds account for ~20% of total variceal bleeds, are more profuse, are predominantly flow-related rather than pressure-related, and have higher mortality. Primary prophylaxis for GOV-1 is similar to EV: with either NSBB or balloon/coil/plug-assisted retrograde transvenous obliteration (BRTO/PARTO/CARTO) of gastrorenal/lienorenal shunt for patients with a history of HE. For patients with high-risk (size > 20 mm or severe PHG or MELD > 17) GOV2/IGV1, it may be preferable to perform CARTO/PARTO if there is a gastro renal shunt. Otherwise, an endoscopic ultrasonography-guided coil with or without NSBB or prophylactic cyanoacrylate injection is suggested in addition to NSBB. For patients with low-risk GOV2/IGV1 (< 10 mm), NSBBs would be sufficient ( 37 ).

3.6. Newer perspectives

Emerging data have frequently advocated BRTO to be effective in managing gastric variceal bleeding. A recent Korean study shows that BRTO and endoscopic obliteration are equivalent in preventing gastric variceal bleeds compared to placebo ( 38 ). This retrospective study needs further validation.

3.7. Secondary prophylaxis

Propranolol first demonstrated its effectiveness in preventing recurrent esophageal variceal bleeding in 1980 ( 39 ). Later, carvedilol was introduced, which has a better profile than propranolol. The addition of carvedilol to EBL than propranolol to EBL can lead to better HVPG response ( 40 ). NSBB reduces and prevents death while waiting for liver transplantation (LT) in patients with refractory ascites (RA) and/or VH, but controversies in advanced decompensated patients with ascites remain ( 41 ). TIPSS is traditionally performed for patients with refractory bleeding who fail EBL + NSBB. A recent study on early TIPSS (stent placement within 5 days of variceal bleed) has shown significant mortality benefits with a substantial reduction in the recurrence of variceal bleeding without increasing the risk of HE ( 42 ). In gastric variceal bleeding, TIPSS has been shown to prevent gastric variceal re-bleeding in patients with high HVPG ( 43 , 44 ). BRTO, where the target flow is selectively occluded, is more effective than TIPSS in preventing re-bleeding from fundal varices as the bleed is flow-related than pressure-related and is associated with improved survival ( 45 ).

3.8. Newer perspectives

EUS-guided glue injection with or without coiling is safe and effective in primary and secondary prophylaxis of gastric varices bleeds ( 46 , 47 ). Recent studies suggest performing TIPSS with BRTO in patients with recurrent variceal bleeding and spontaneous portosystemic shunts (SPSS) to prevent HE ( 48 ). The feasibility and cost-effective analysis of such procedures require further evaluation.

Ascites is the most common complication of cirrhosis, and PH develops in ~85% of the cases ( 49 , 50 ). To differentiate from other causes of ascites, ascitic fluid analysis is recommended, including serum-ascites albumin gradient (SAAG). SAAG value ≥ 1.1 g/dL has 97% sensitivity for PH as a cause of ascites ( 51 ). As discussed earlier, hepatic resistance and PH result in backflow and accumulation of vasodilatory substances, which results in intrahepatic vasoconstriction and peripheral vasodilation, including splanchnic vasodilation, which results in hypoperfusion of the renal system, even when the patient is euvolemic or hypervolemic ( 52 ). This state of relative hypovolemia due to vasodilation results in the activation of the renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS), leading to salt and fluid retention ( 50 ). This leads to the retention of blood and a significant rise in blood volume leading to filtration from the liver surface and the mesenteric vessels. High hydrostatic pressure, low oncotic pressure (hypoalbuminemia), and increased vascular permeability contribute to increasing filtration through mesenteric vessels. The resorptive capacity of the peritoneum and lymphatics cannot counteract these mechanisms ( 53 ). Any inflammation or infection of the peritoneum can affect peritoneal resorption. Dysregulation of these can lead to an increase in ascitic fluid formation.

4.1. Management of ascites

The foremost important part of the treatment of ascites is sodium restriction (salt intake of < 5 g) and the judicious use of diuretics. A combination of two diuretic classes (aldosterone antagonists and loop diuretics) is better tolerated and more effective than sequential treatment (i.e., first aldosterone antagonists followed by loop diuretics) ( 54 ). Use of albumin replacement and increased oral protein intake helps ascites mobilization. A recent pilot study has shown that early use of midodrine for a short course can control ascites better than diuretics alone, with a lesser occurrence of diuretic complications ( 55 ).

RA: A weight loss of < 0.8 kg over 4 days in a patient with cirrhosis on intensive diuretic therapy for at least 1 week is termed diuretic-resistant ascites, provided the urinary sodium is less than the sodium intake/day ( 56 ). Furosemide 160 mg/day and spironolactone 400 mg/day are considered for intensive diuretic therapy. Diuretic-resistant ascites is a rare event, especially in Asian countries, as the recommended full dose of diuretics (160 mg of furosemide and 400 mg of spironolactone) is rarely reached as most patients develop adverse events with higher recommended doses, which is called diuretic-intractable ascites ( 4 , 55 ). This diuretic intolerance in the Asian population is due to a higher incidence of sarcopenia, poor muscle reserve, and a higher occurrence of diuretic-related complications, including renal injury and electrolyte imbalances ( 4 ). Before labeling a patient as refractory to therapy, hepatocellular carcinoma, portal vein thrombosis, and infection of the peritoneum [sepsis, spontaneous bacterial peritonitis (SBP)/Non-SBP/tuberculosis] should be ruled out. An elevated ascitic fluid protein content of more than 2–2.5 g/dl is suggestive of tuberculous ascites ( 57 ). Moreover, the higher incidence of tuberculosis in Asian countries can occur in immuno-compromised cirrhosis patients without manifesting classical signs and symptoms. Therefore, adenosine deaminase (ADA) and gene x-pert (tuberculosis nucleic acid testing) analysis of ascitic fluid is suggested in all patients with cirrhosis with difficulty uncontrolled ascites before labeling them as RA, especially in tuberculosis-endemic countries ( 4 ). LT is the best and ideal treatment option for patients with RA. Large-volume paracentesis (LVP > 5 L) with albumin infusion (8 gm/L of ascites removed) is the recommended therapy to relieve the symptoms. However, LVP is associated with the risk of paracentesis-induced circulatory dysfunction (PICD), which is mitigated with concomitant albumin usage. In a network meta-analysis, midodrine was reported as superior to albumin in preventing PICD ( 55 , 58 , 59 ). NSBBs are contraindicated in patients with RA requiring LVP due to compromised cardiac performance ( 60 ). Midodrine, an alpha-1 agonist, is beneficial in RA as it increases urine sodium loss and urinary volume ( 61 , 62 ). By reducing endotoxemia, rifaximin may offer an additional benefit in RA ( 63 ). Tolvaptan is beneficial in ascites control with survival benefit ( 64 ). However, tolvaptan has a black box warning as it can cause or precipitate bleeding episodes by platelet aggregation inhibition and depleting vitamin-K-dependent clotting factors and has a risk of liver injury ( 65 ). Therefore, its use should be cautious and restrictive to patients of grade 3 ascites/RA with refractory hyponatremia and should be used for the shortest duration possible ( 51 ). Terlipressin, the most used drug in hepatorenal syndrome (HRS) and RA, helps in ascites control by mobilizing ascites and increasing renal perfusion, glomerular filtration rate (GFR), and urinary sodium excretion ( 66 ). Long-term albumin administration in patients with ascites improves survival, decreases hospitalization, and reduces overt HE, ascites, SBP, and non-SBP infections ( 67 ). TIPSS is a valuable therapy in RA and has been found to increase transplant-free survival ( 68 ). Careful selection of patients for TIPSS after a proper cardiac evaluation is recommended. A patient with age < 70 years with preserved liver function tests and low severity scores (MELD < 18 and Child score < 8) without any history of HE in the preceding 6 months are candidates suitable for TIPSS ( Figure 4 ).

Figure 4 . Treatment of ascites. SGLTA2I, Sodium-Glucose Co-transporter 2 inhibitors; MELD, model for end-stage liver disease; HE, hepatic encephalopathy; PAH, pulmonary arterial hypertension; TIPSS, transjugular intrahepatic portosystemic shunts; CPAP, continuous positive airway pressure; LVP, large volume paracentesis; LT, liver transplantation.

4.2. Newer perspectives

The automated low-flow ascites pump (ALFA) system, a novel device that transfers ascites from the peritoneal cavity to the urinary bladder, is effective in patients with RA ( 69 ). However, it is not universally available, complicated to use, and has higher adverse events; therefore, its use is currently limited ( 69 ). ANSWER trial reported the beneficial effects in terms of survival of long-term albumin infusions in patients with decompensated cirrhosis ( 70 ). Although results have been contradictory from two recent large trials, future research with more clearly defined selection criteria and endpoints may streamline the use of long-term albumin in ascites ( 70 , 71 ). Sodium-glucose co-transporter 2 inhibitors (SGLT2I) increase sodium and glucose excretion in the urine and decrease renin secretion, showing significant improvement in ascites besides glycemic control in a few small studies ( 72 , 73 ). Major side effect is an increased risk of urinary infections. Further prospective studies are needed in cirrhosis patients with RA for SGLT2I. Patients with RA and poor quality of life required long-term abdominal drains/catheters as a palliative measure. Although deemed to have an increased risk of infections, preliminary studies have shown good technical success and low rates of life-threatening infections providing options for home-based care ( 74 , 75 ).

5. Renal dysfunction: acute kidney injury and hepatorenal syndrome

HRS, a functional renal failure, is a potentially reversible renal injury in patients with cirrhosis and ascites due to decreased renal blood flow ( 76 ). An increase in serum creatinine by ≥0.3 mg/dl within 48 h or an increase of >50% from baseline value with or without a decrease in urinary output < 0.5 ml/kg for >6 h in patients with cirrhosis and ascites in the absence of other evident cause for acute renal injuries such as proteinuria, shock, or nephrotoxins is termed HRS-AKI ( 76 ).

Recently, there has been a suggestion for a change in terminology, with previous terms like HRS-1 and HRS-2 being replaced by more physiologic HRS-AKI, HRS-acute kidney disease (AKD), and HRS-chronic kidney disease (CKD). The estimated incidence of HRS is around 18% at 1 year and 39% at 5 years and is associated with an inferior median survival of ≤ 3 months without a transplant ( 51 , 56 ).

Although several medical management options remain in HRS, LT is the definitive therapy. Vasoconstrictors (terlipressin, octreotide in combination with midodrine and noradrenaline) and albumin infusion are the cornerstones of the treatment of HRS. The crux of HRS therapy still revolves around an attempt to rule out other causes (infections, glomerular disease, shock, and acute tubular necrosis) concomitant with volume expansion with albumin for 48 h followed by initiation of vasoconstrictors. Terlipressin remains the most effective vasoconstrictor, with an infusion strategy of administration associated with lesser adverse events ( 77 , 78 ). Patients with HRS who have not responded to therapy and have persistently low GFR (i.e., < 25 ml/min) for more than 1.5 months and/or dialysis dependence are candidates for simultaneous liver-kidney transplantation (SLKT) ( 56 ). Recurrent episodes of HRS or renal insult lead to the development of HRS–CKD. The development of CKD in cirrhosis is a poor prognostic marker in both pre- and post-transplant settings ( 79 ). Risk factors of HRS-AKI progression to HRS-CKD are terlipressin non-response, high MELD score, albuminuria, recurrent AKI episodes, and high baseline serum cystatin ( 80 ). Management of HRS-CKD is unclear and needs further studies. Although treatment with terlipressin, diuretics in case of fluid overload, vaptans in case of hyponatremia, midodrine, and TIPSS with a high risk of HE are some options, SLKT is the definitive treatment ( 81 , 82 ).

5.1. Newer perspectives

The use of TIPSS in patients with HRS-CKD has been recently shown to improve renal function with excellent control of ascites across stages of CKD ( 83 ). Recent studies suggest frailty as a predictor of HRS-AKI ( 84 ). It is unknown whether branched-chain amino acid (BCAA) supplementation reduces the development of HRS-AKI. With the approval of terlipressin in the US setting, exciting research is expected, with initial data advocating early initiation of terlipressin at lower grades of AKI being associated with improved survival ( 85 ).

6. Hepatic encephalopathy

HE is a neuropsychiatric manifestation related to severe liver disease. HE in a patient with acute liver failure is termed type A, while those related to shunts are termed type B, and those with cirrhosis are termed type C. HE is graded as per West-Haven criteria. HE can be covert [minimal HE (MHE) and Grade I HE], which needs to be identified with the help of specialized neuropsychological tests. Covert HE is reported among 80% of patients with advanced liver disease, while overt HE is reported among 40% ( 86 ). Overt HE can be new onset, episodic, with an interval between episodes of >6 months, or recurrent, where further episode occurs within 6 months. Persistent HE refers to an uncommon entity with no resolution of HE. Refractory HE (lack of response after treatment of precipitants and on treatment with lactulose and rifaximin for 48 h) is an uncommon but serious condition and requires active investigation into hidden precipitating events (i.e., portosystemic shunt) and requires alternative diagnosis to be ruled out ( 87 ). Important alternative causes include septic encephalopathy (23%), alcohol withdrawal, seizure, dyselectrolytemia, metabolic disorders, drugs/toxins (7%), intracranial structural lesions (5%), psychiatric disorders (1%), and multiple causes together (8%) ( 88 ).

6.1. Pathophysiology of HE and effect of ammonia

Alterations in neurotransmission and brain–blood barrier coupled with persistent neuroinflammation and oxidative stress, apart from GABA-ergic or benzodiazepine pathway abnormalities, lead to disruptions in brain energy and blood flow, causing HE. Disturbed ammonia metabolism is the central and most studied event in HE, with complex multimodality mechanisms. In brief, as liver failure progresses, concentrations of ammonia increase which exerts its systemic effects and neurotoxicity through multiple pathways, including astrocyte swelling, inflammation, oxidative stress, mitochondrial permeability alterations, alteration in energy kinetics, and membrane potential alterations ( 89 ). Despite this implicating pathophysiological basis, no direct correlation has been established between the severity of HE and ammonia concentrations. However, it is imperative to state that in the presence of a normal ammonia level, the diagnosis of HE is almost always an exclusion.

A venous ammonia level of >55 μmol/L is 47% sensitive and 78.3% specific to diagnose HE ( 90 ). Other studies have identified a blood ammonia level cutoff of >133 μg/dl as a diagnostic of HE. Arterial ammonia is an excellent surrogate marker for the severity of HE in ACLF in advanced stages, and an ammonia level above 140 μg/dl at baseline or at any time point in first week with grades III–IV HE serves as a poor prognostic marker for 28- and 90-day survival ( 91 ). Venous NH3 is more variable; therefore, arterial ammonia measurements are used ( 91 , 92 ).

Spontaneous portosystemic shunts (SPSS) should be actively looked for, especially in recurrent/refractory HE and where liver diseases are not advanced (e.g., MELD < 15). SPSS shunts are noted in 10–20% of patients with cirrhosis and PH. SPSS is a “release valve,” a compensatory mechanism to reduce the portal pressure and bypass normal liver flow. More than 90% of patients with large SPSS have enlarged spleen, hepatic atrophy, and thrombocytopenia ( 93 ). Identification of these shunts is essential as these need to be ligated at the time of liver transplant, or else the patient can have persistent HE, even after liver transplant.

6.2. Management strategies in HE

Correct identification of the precipitant is the key to the management of HE. Non-absorbable disaccharidases (lactulose/lactitol) are the first-line therapy. Adding polyethylene glycol to non-absorbable disaccharidases leads to earlier, sustainable improvement in HE with survival benefits ( 94 ). Studies have shown a positive role of rifaximin and intravenous L-ornithine L-aspartate (LOLA) in overt HE management ( 95 , 96 ).

Diet and calorie requirements must be met, especially for patients with altered mentation who cannot take orally. Adequate calories (35–45 kcal/kg/day) and protein (1–1.5 gm/kg/day) are essential to improve overall nutritional status. BCAA may be beneficial as they are metabolized in muscle and brain and promote protein synthesis, suppress protein catabolism, and act as gluconeogenesis substrates ( 97 ). Rifaximin is an oral antibiotic with minimal absorption (< 0.4%), broad-spectrum activity against enteric bacteria, excellent tolerability, no significant drug interactions, and no dose adjustment requirement in hepatic or renal dysfunction ( 98 ). The evidence for using rifaximin in HE needs close attention. The most robust evidence for rifaximin is as an add-on agent to lactulose in HE recurrence. However, high-quality evidence does not support its use as monotherapy for treating an episode of HE and direct comparative trials with non-absorbable disaccharides.

When used in conjunction with lactulose, rifaximin is effective in HE improvement, mortality reduction, and reduction in length of hospital stay ( 99 ). Zinc is a co-factor of urea cycle enzymes, and zinc deficiency has been reported to precipitate HE, thereby mandating the use of zinc supplements in HE ( 100 ). Although few studies have reported improvement in HE with probiotics, it is currently not FDA-approved ( 101 ).

6.3. Newer perspectives

Ammonia-lowering agents (Phenylacetate, Phenylbutyrate, and Sodium Benzoate) and drugs affecting neurotransmission (flumazenil and bromocriptine) have been reported to be effective but are rarely used. Recent trials have demonstrated the efficacy of L-ornithine L-aspartate in critically ill patients with HE ( 102 , 103 ). CARTO/PARTO of SPSS is an excellent modality for patients with HE ( 104 ). The side effects of shunt occlusion include worsening of esophageal varices (19–46%), new onset varices in 6%, and new/worsening ascites in 14% of cases. Fecal microbiota transplantation (FMT) or intestinal microbiota transplantation is a feasible and safe option for patients with recurrent or persistent HE ( 105 ). By modulating the gut flora favorably, FMT restores the altered gut–liver–brain axis. The role of human albumin infusions in the management of HE has been controversial. However, in a recent randomized controlled trial, of outpatients with cirrhosis, prior HE, and current MHE, albumin infusions improved cognitive function and quality of life ( 106 ). Along similar lines, a systematic review indicates a possible beneficial effect of albumin in overt HE ( 107 ).

7. Hyper-dynamic circulation

As discussed earlier, an imbalance between vasodilators and vasoconstrictor occurs in PH and leads to hepatic vasoconstriction and peripheral vasodilation, which leads to hyperdynamic circulation, which is a very close mimic of the septic state. This is also known as “Hepsis” ( 108 ). In cirrhosis, immunological mechanisms are compromised, leading to a state of cirrhosis-associated immune dysfunction (CAID), predisposing patients with cirrhosis to the development of sepsis, which leads to an increase in pathogen-associated molecular patterns (PAMPs) and cytokines (tumor necrosis factor-α, interleukin-1β) and other vasodilators including nitric oxide. Consequently, a cycle of preferential splanchnic vasodilatation leading to the activation of vasoconstrictive systems along with central hypovolemia and cardiovascular dysfunction leads to a gradual development of the hyperdynamic syndrome and multiple organ dysfunctions ( 50 , 109 , 110 ). Treatment is targeted on these fundamental mechanisms. Still, so far, no single agent has been found to take care of all these aspects, and multimodality management addressing underlying pathophysiology is advocated.

7.1. Newer perspectives

Obeticholic acid (OCA) has been used in several liver diseases, including non-alcoholic steatohepatitis, primary biliary cholangitis, and primary sclerosing cholangitis ( 111 ). OCA has been reported to effectively reduce intrahepatic vascular resistance and improve PH in pre-clinical models ( 112 ). A recent study showed the beneficial effects of curcumin in cirrhotic rats with PH due to its antifibrotic, vasoactive, and anti-angiogenesis actions ( 113 ). Curcumin counteracts the hyperdynamic circulation of cirrhosis by inhibiting endothelial nitric oxide synthetase (eNOS) activation and reducing mesenteric angiogenesis by blocking the vascular endothelial growth factor (VEGF) pathway. However, the current evidence is too premature to recommend these drugs.

8. Cirrhotic cardiomyopathy

Hyperdynamic syndrome in patients with cirrhosis and PH leads to persistently activated compensatory mechanisms, activation of RAAS, and SNS, which results in tachycardia, increase in cardiac output, and reduction in systemic vascular resistance and MAP. This phenomenon, over time, results in cardiac dysfunction, described as “cirrhotic cardiomyopathy (CCM).” Altered contractile response to stress, abnormalities in electrophysiologic transmission, and diastolic dysfunction are the characteristic features of CCM in the absence of any evident cardiac disease ( 114 ). These can be in compensated form and result in symptoms only in case of stress (e.g., volume overload and post-TIPSS). Dyspnea and exertional fatigue due to pulmonary edema is the most common manifestation. Some other complications include overt heart failure, pulmonary hypertension, arrhythmias, pericardial effusion, and cardiac thrombus formation. The proposed pathophysiological mechanisms include aberrant beta-adrenergic signaling, increased endocannabinoid activity, alterations in Na + /Ca 2+ exchanger, and the negative inotropic effect of nitric oxide and carbon monoxide ( 115 , 116 ).

CCM is associated with an increased risk of complications (including RA, HRS, and impaired response to stressors), leading to poor quality of life, increased morbidity, and mortality. A targeted heart rate reduction using ivabradine can improve cardiac filling and output ( 114 ). CCM is potentially reversible with LT, provided other pathological diseases of cardia are ruled out ( 114 ). There have been some contradictory viewpoints about the effect of CCM on disease severity, with one study showing the lack of association of CCM with the severity of PH or liver dysfunction and age being the predominant determinant of CCM ( 117 ). Further studies resolve the contradictory observations that are required. Treatment of CCM is non-specific and supportive and rests on minimizing the treatment and interventions which can aggravate CCM ( 118 ). LT should be considered for well-optimized stable CCM patients and good performance status ( 119 ). Management of heart failure is similar to non-cirrhotic patients, including salt and fluid restriction, use of diuretics, and afterload reduction. Cardiac glycosides are not effective in cirrhotic patients ( 120 ). The studies on NSBB are conflicting. β-blocker can reduce prolonged QT intervals with some improvement in electromechanical uncoupling but with a reduction in cardiac output, which can be detrimental ( 121 , 122 ).

8.1. Newer perspectives

Targeted heart rate reduction to improve cardiac filling and thereby improve the cardiac output with ivabradine can be tried in sinus rhythm patients ( 114 ). Potassium-Canrenoate can reduce the left ventricular wall thickness and left ventricular diastolic dysfunction (LVDD) in patients with Child A cirrhosis ( 122 ). These require further randomized controlled trials before universal recommendation.

9.1. Basic pathophysiological mechanisms and clinical outcomes in ACLF

Decompensation in cirrhosis is a dynamic process, and patients can transition in the Child stage between A and C, depending upon the type and number of decompensation. Therefore, decompensation can be an index/first event or a recurrent event after recovery from the first event. In some cases, it becomes very severe to cause hepatic or extrahepatic organ failures/organ dysfunctions and is identified as ACLF, which heralds high short-term mortality of over 15% at 28 days with organ dysfunctions/organ failures ( 123 ). It is a state of dysregulated inflammation with a potential for reversibility, and it is different from acute liver failure and acutely decompensated cirrhosis ( 91 , 124 ).

Controversies exist between the definition and diagnostic criteria between east and west, but the central theme of the disease revolves around high short-term mortality ( Figure 5 ). The two prominent definitions for ACLF are the Canonic by the European Association for the Study of Liver (EASL) and the Asian Pacific Association for Study of Liver (APASL) definition ( Table 2 ). A large electronic database study reported significant discordance between APASL and EASL definitions ( 125 ). The incidence rate of ACLF as per APASL definition was 5.7 per 1,000 person-years, and the incidence rate of ACLF as per EASL definition was 20.1. Mortality was higher in EASL-identified ACLF than APASL identified ( 125 ). The median bilirubin level in the EASL-ACLF cohort was 2.0 mg/dL implying preserved liver function in EASL-ACLF. EASL and APASL criteria do not measure the same entity, and there is no uniformity in the ACLF definition. However, APASL ACLF is easier to use in clinical practice as it requires very few liver-specific laboratory variables (INR and bilirubin) and clinical history of ascites and/or encephalopathy.

Figure 5 . Definition of acute-on-chronic liver failure. APASL, Asian pacific association for the study of liver; EASL, European association for the study of the liver; NACSELD, North American Association for Study of Liver Diseases; INR, international normalized ratio; DILI, drug-induced liver injury.

Table 2 . Differentiating two major definitions of acute on chronic liver failure (ACLF).

9.2. Key pathophysiological interplays in ACLF

Systemic Inflammatory Response Syndrome (SIRS) and sepsis are the keys to the development of ACLF, which is caused by gut dysbiosis, leaky gut, increased intestinal translocation of viable bacteria, and PAMPs ( 110 ). In the initial phases of cirrhosis, lamina propria is the predominant site of inflammation in the gut, where it is contained with localized vasodilation, but as the disease progresses, there is the involvement of deeper structures leading to a leaky gut. Inflammation becomes pronounced as bacterial translocation occurs, along with products of bacterial metabolism and damage-associated molecular patterns (DAMPs) from the diseased liver. These changes occur rapidly and mostly coincide with a burst of systemic inflammation, SIRS, which is usually triggered by a precipitating event ( 126 ). Prostaglandin (PG) E2 and PGE2-EP4 pathway-mediated monocyte dysfunction are the predominant factors for immunosuppression in ACLF and lead to inflammation-related mitochondrial dysfunction ( 127 , 128 ). Therefore, the overall pathogenesis is characterized by an initial cytokine burst presenting as SIRS, progression to compensatory anti-inflammatory response system (CARS), and associated immune paralysis, which leads to sepsis and multi-organ failure ( Figure 6 ).

Figure 6 . Pathophysiological derangements in acute-on-chronic liver failure. AIH, autoimmune hepatitis; SIRS, systemic inflammatory response syndrome; DAMPS, damage-associated molecular patterns; PAMPS, pathogen-associated molecular patterns; TLR, toll-like receptors; NLR, neutrophil-to-lymphocyte ratio.

9.3. ACLF and acute decompensation

Acute decompensation (AD) of chronic liver disease refers to a sudden worsening of the condition of a previously compensated or decompensated cirrhotic patient due to an acute event that may present with hepatic (jaundice, ascites, and HE) or non-hepatic (VH, AKI, or sepsis) failure, up to 3 months of acute insult ( 91 ). ACLF is a distinct syndrome from “AD” due to intense systemic inflammation in ACLF. The precipitant for AD can be hepatic or non-hepatic ( 129 ). Mortality in patients with AD (< 30% at 3 months) is lower than in those with ACLF ( 91 ). Management of AD and ACLF is quite similar, and LT would be the treatment of choice.

9.4. Precipitating events in ACLF

Since ACLF is triggered by an acute insult and has a potential for reversibility, identifying precipitating events is crucial so that targeted treatment can be instituted for better outcomes. Bacterial infections and active alcohol intake are the most common precipitating event in the west. In contrast, hepatitis B reactivation, followed by active sepsis and alcohol intake, is the most frequent precipitating event in the eastern world. However, no precipitating event may be found in about 40% of cases ( 129 ). In Asia, 1.8–5.7% of precipitating events are drugs related, which present as drug-induced liver injury (DILI) ( 130 , 131 ). Acute viral hepatitis like hepatitis A, E, and other hepatotropic viruses can cause AD in ACLF. In addition, the flare of autoimmune hepatitis (AIH) can frequently be the precipitating event in female patients. Patients with AIH-related ACLF present histological features typical of AIH, including perivenulitis, lymphoid aggregates, and massive hepatic necrosis ( 132 ). The development of VH in patients with ACLF is an independent predictor of mortality ( 133 ). Acute hepatic venous outflow tract obstruction (HVOTO) or PVT can present as ACLF as per APASL guidelines ( 91 ). The underlying etiology of cirrhosis needs to be established in patients with ACLF presenting for the first time for appropriate management and prognostication.

9.5. Grade of ACLF

Organ failure (OF) includes both liver and extrahepatic organs. OF/organ dysfunction is the diagnostic hallmark of ACLF. CLIF-EASL grade is defined based on OF. Grade-1 ACLF: only organ failure (renal, liver, coagulation, circulatory, or lung) that is associated with a serum creatinine level of 1.5–1.9 mg/dL; Grade-2 ACLF: a combination of any 2 OFs. Grade-3 ACLF: a combination of any 3 or more OFs ( 134 ). Conversely, the APASL definition is based on a dynamic score calculation known as the AARC score ( 91 ). AARC score between 5 and 7 is considered as APASL ACLF grade-1; 8–10 as AARC-2; and those with scores between 11 and 15 are AARC grade-3. Prognosis between the grades varies significantly, with grade 1 being a potentially recoverable group with a 28-day mortality of only 12.7%, and grade 3 needs immediate interventions to improve outcomes, with mortality at 28 days at around 85.9%.

9.6. SIRS, sepsis, ACLF, and LT

Liver failure predisposes to infections, and bacterial infections remain the most common cause of diseases in ACLF ( 135 , 136 ). Infections are associated with severe inflammatory storms, high morbidity, cost, poor clinical course, and 4-fold high mortality ( 137 ). Sepsis is more likely associated with concomitant multi-organ involvement and poor prognosis ( 137 ). Frequency of infections in hospitalized cirrhotic patients ranges from 32 to 34% and increases with hospitalized cirrhotic patients with GI bleeding to 45%. The most common sites of first infections are SBP in 22–25%, urinary tract infection (UTI) in 20–28%, and pneumonia in 8–15% ( 137 – 139 ). Among pathogens, gram-negative ( E. coli and Klebsiella spp.) are most frequent, followed by gram-positive ( Streptococcus pneumonia and Staphylococcus aureus ) and fungi ( 135 ).

Sepsis is an exaggerated inflammatory response to infection. SIRS in a patient with infection was required to identify sepsis ( 140 ). It is challenging to differentiate SIRS from sepsis due to the pre-existing hyperdynamic circulation in patients with cirrhosis and ACLF. Sepsis-3 criteria (rise of sofa score by 2 points) has been reported to be accurate in identifying sepsis in patients with cirrhosis. Furthermore, recent studies have suggested using fever and qSOFA scores to identify sepsis at the bedside ( 110 , 141 , 142 ). LT is the definitive therapy for ACLF. Early identification of those requiring LT or those who will have the resolution is the key to prolonging the survival of a patient with ACLF. Most hospitalized patients with ACLF have a clear prognosis between 3 and 7 days in either direction ( 143 ). Therefore, the concept of a transplant window period has been proposed by APASL and EASL ( 143 , 144 ). Although early LT is associated with improved survival, such strategies are difficult in Asian settings where living donor liver transplantation is frequent, and the acceptance of LT is poor ( 145 ). In a large multination study of more than 1,000 patients who required LT, only 4% underwent LT ( 144 ).

9.7. Mechanisms of infections and organ failure

Damaged hepatocytes in liver diseases become dysfunctional and cause impaired protein synthesis, which leads to immune dysfunction. Disruption of gut homeostasis with altered gut permeability increases the translocation of bacterial products, and persistent low-grade inflammation leads to non-response of the immune cells leading to immune exhaustion ( 146 ). Hepatocyte damage generates more DAMPs and PAMPs, which activate pattern recognition receptors and cytokine burst and hepatocyte death ( 147 ). OF results from simultaneous ongoing processes such as immune dysfunction, hemodynamic derangement, excessive CARS, and the exhaustion and dysfunction of critical innate and adaptive immune system cells. According to previous studies, one of the theories advocates both pro-inflammatory and anti-inflammatory responses occurring early and simultaneously, manifesting initially by an early, dominant, hyperinflammatory phase of fever, shock, and hypermetabolism, which then evolves over several days into a more protracted immunosuppressive late stage ( 148 , 149 ). According to the second theory, there is an upregulation of genes of the innate immune response and a downregulation of genes of the adaptive immune response, leading to inflammation driven by the innate immune system with resultant organ dysfunction and failure ( 150 ).

9.8. Management options in ACLF

Nutritional rehabilitation is one of the cornerstones of the management of ACLF. A target of 1.5–2.0 g protein/kg per day and 35–40 kcal/kg per day with carbohydrate-predominant late-evening snacks is recommended for patients with advanced cirrhosis. Regular screening and clinical examination of patients with ACLF may help identify the infection and organ failures early. Antibiotics should be part of ACLF management irrespective of sepsis/SIRS status due to the high risk of infection-related complications, which can mimic liver failure. Albumin infusions can prevent organ dysfunction in patients with SBP. However, the evidence to support its use in non-SBP infections and ACLF is limited. Terlipressin and albumin have been demonstrated to be beneficial in patients with ACLF ( 151 , 152 ). FDA has recently approved terlipressin for HRS-AKI but has restricted its use in patients with ACLF-grade 3 due to the risk of pulmonary overload and ischemic adverse events ( 152 – 154 ). Specific treatments are available as antiviral strategies in HBV reactivation, steroids for severe alcoholic hepatitis and AIH, withdrawal of offending drugs for DILI, and chelators and plasma exchange (PE) for Wilson's disease. PE has been shown to improve systemic inflammation and reduce OF development in ACLF ( 155 ). It offers significant survival benefits over other liver support systems and could be a preferred modality of liver support for ACLF patients. FMT is safe in a small study and was associated with improved short-term and medium-term survival of alcohol-related ACLF ( 156 ). LT has been shown to have excellent results in ACLF except in patients with high grades of respiratory or circulatory failure ( 157 ). The survival benefits of LT in ACLF have been shown convincingly in a large systematic review involving 22238 LT recipients, with worse outcomes only being reported in the subgroup of ACLF 3 when compared to 30791 non-ACLF recipients ( 158 ). The grade of ACLF on days 3–7 determines the outcomes of patients, and as such, patients, particularly those with advanced grades, merit early transplant consideration and listing of potentially viable candidates ( 143 ). However, such an early listing (< 7 days) is impractical in resource-limited settings, while LT remains the therapy of choice as non-transplanted patients with ACLF have dismal survival of 8% at 1 year compared to 80% in those who undergo LT ( 159 ). Determination of timely access to LT facilities within the “window to transplant” is essential, beyond which LT is possibly a futile effort. Several areas need further research, including uniformity in definition and non-transplant measures to improve outcomes. Identifying futility is an important aspect of listing ACLF patients for LT. Some of the indicators of futility include patients with ≥4 organ failures, CLIF-C score > 64 at day 3–7, ACLF grade 2/3 patients with either active GI bleed, controlled sepsis for < 24 h, high vasopressor support (3 mg/h), PaO2/FiO2 (P/F) ratio < 150, active drug abuse; infections by MDROs or invasive fungal infections, high cardiac risk, and significant comorbidities ( 143 , 159 – 161 ).

9.9. Newer perspectives

9.9.1. acute event and aclf.

Since the central concept of ACLF revolves around acute precipitation, the identification of acute precipitants is of key importance in the management of ACLF. There remain differences between the east and the west regarding the type of precipitants, with bacterial infections being the most common in the West while alcohol and hepatotropic viruses are common in Asia. In ~2–16% of the patients, no precipitant is identified ( 162 ). In this context, there has been recent interest in the identification of uncommon precipitants like cytomegalovirus as potential acute precipitants in ACLF in the background of a state of immune dysfunction in ACLF with CMV positivity in up to 24% of the cases ( 163 ). Similarly, drug-induced liver injury has been more frequently recognized with a large cohort of 3,132 patients with ACLF, having DILI as the precipitating event in 10.5% out of which the most common were complementary and alternative medications (71.7%) ( 164 ). However, therapeutic treatment of DILI is elusive and serves as an important area for future research. Recently, coronavirus disease (COVID-19) has been added to the list of precipitants of ACLF, which can be modified by vaccination ( 165 – 169 ). Surgical interventions (hepatic and non-hepatic) have also been investigated as precipitants of ACLF, with 24.5% developing ACLF in a cohort of 369 patients, with potential determinants being advanced age, hyponatremia, baseline bacterial infection, and abdominal non-hepatic surgery ( 170 ). Patients undergoing TIPSS, if sarcopenic, are at an increased risk of developing ACLF and consequent increased risk of hepatic encephalopathy and mortality ( 171 ). Interestingly, surgical interventions in patients who already have ACLF has also been studied and propensity-matched against TIPSS, with elective surgery being an independent predictor of worse outcomes and a recommendation to avoid elective surgery in those with ACLF and CLIF-C AD score of ≥50 ( 172 ).

9.9.2. Sarcopenia and ACLF

The impact of sarcopenia as an independent predictor for mortality in patients with decompensated cirrhosis has been well-studied. The reported prevalence of sarcopenia in ACLF based on CT skeletal muscle index is 55.6% but was not found to be an independent predictor of mortality after adjusting for inherent liver dysfunction ( 173 ). However, it is important to note that based on a preliminary retrospective analysis, sarcopenia appears to co-relate with the severity or grade of ACLF as well as is an important predictor of post-transplant 1-year survival ( 174 ). Use of novel bedside methods of sarcopenia assessment, like muscle ultrasound techniques in this critically ill cohort of ACLF, appears a promising research subject ( 175 ).

9.9.3. Therapeutics, transplantation, and ACLF

Even a modest volume of paracentesis (< 5 L) is associated with an increased risk of PICD in patients with ACLF, wherein midodrine is comparable to albumin in preventing PICD ( 176 ). While prophylaxis with norfloxacin effectively prevents infection in recovering patients of ACLF, a combination of low-dose corticosteroids with low-volume PE has been shown to improve short-term survival in ACLF in a small trial ( 135 , 177 ).

Identification of prognostic models for predicting outcomes for LT in ACLF, especially in those with the highest grade of ACLF, is the need of the hour. Mortality prediction systems are central to ACLF, with artificial intelligence-based models being shown to be better than standard prognostic scores ( 178 ). A simplified prognostic model comprising age, pretransplant arterial lactate, leucocyte count, and respiratory failure and referred to as the TAM model (transplantation for ACLF-3 model) has been proposed. The model classifies a cutoff at 2 points to distinguish between a high-risk group (score > 2) and a low-risk group (score ≤ 2) with a 1-year survival of 8.3 vs. 83.9%, respectively ( 179 ). The score has been further validated to stress the importance of downstaging and stabilizing patients with ACLF before transplant, with those with a downstaged favorable TAM score having a significantly higher post-LT survival rate than those with static or incremental TAM score (88 vs. 70%) ( 180 ). Despite evolving data on the success of LT in ACLF, there remain variations and inequalities in both prioritization and access to LT in this subgroup which calls for increasing interdisciplinary interactions and awareness ( 181 ). Establishing a balance adjusting for the success of LT and resource utilization is imperative as LT in ACLF has also been shown to be highly resource-consuming with regard to healthcare use and costs ( 182 ).

9.9.4. Prevention of ACLF and recompensation in ACLF

The field of ACLF has seen rapid developments and a plethora of research in the recent past. On the preventive aspect, exposure to statins and a decrease in von Willebrand factor (after NSBB therapy) have been shown to prevent subsequent ACLF development ( 183 , 184 ). Rifaximin, in a recent retrospective study, has been shown to reduce clinical complications and progression to ACLF in patients with severe AH ( 185 ). Sepsis is a common precipitant of ACLF through the LPS-TLR4 pathway ( 186 ). Recombinant alkaline phosphatase (recAP), may reduce the risk of organ dysfunction by dephosphorylating the endotoxins and containing hepatic TLR4 expression ( 186 , 187 ). Resatorvid (TAK-242) is a small-molecule inhibitor of TLR4 and is being utilized for the prevention of organ failures. Yak-001, an orally administered, non-absorbable, synthetic microporous carbon, has a high adsorptive capacity for bacterial products, lipopolysaccharides, and pro-inflammatory cytokines. Yak-001 was found to be safe and effective in reducing endotoxemia and inflammatory mediators ( 188 ). DIALIVE, a novel liver dialysis device that replaces dysfunctional albumin and removes pathogen-associated and damage-associated molecular patterns, has been shown to improve outcomes in patients with ACLF ( 189 , 190 ).

10. Conclusion

Early identification of the severity of PH and addressing downstream complications is central to the management of cirrhosis. Each complication merits detailed redressal, and overall management demands a holistic approach. ACLF needs to be identified early in the course with the institution of specific therapies. Newer modalities such as plasmapheresis and FMT have promising results. LT remains the definitive care in both advanced cirrhosis and ACLF.

Author contributions

AK and RJ made the study design and concept. RJ, AK, and AR prepared the initial draft. Figures by MP and KK. MS, PR, and DR provided the technical support. AK and MP critically reviewed and edited the final manuscript. All authors approved the final version.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher's note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: portal hypertension, liver cirrhosis, HVPG, acute-on-chronic liver failure, chronic liver disease

Citation: Jagdish RK, Roy A, Kumar K, Premkumar M, Sharma M, Rao PN, Reddy DN and Kulkarni AV (2023) Pathophysiology and management of liver cirrhosis: from portal hypertension to acute-on-chronic liver failure. Front. Med. 10:1060073. doi: 10.3389/fmed.2023.1060073

Received: 02 October 2022; Accepted: 19 May 2023; Published: 15 June 2023.

Reviewed by:

Copyright © 2023 Jagdish, Roy, Kumar, Premkumar, Sharma, Rao, Reddy and Kulkarni. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Anand V. Kulkarni, anandvk90@gmail.com

† These authors share first authorship

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

• Open access
• Published: 26 August 2024

Predictive factors of portal hypertensive enteropathy exacerbations based on long-term outcomes

• Yuka Matsubara 1 ,
• Akiyoshi Tsuboi 1 , 2 ,
• Issei Hirata 1 ,
• Akihiko Sumioka 1 ,
• Takeshi Takasago 1 ,
• Hidenori Tanaka 1 ,
• Ken Yamashita 1 ,
• Yuichi Hiyama 1 ,
• Hidehiko Takigawa 1 ,
• Eisuke Murakami 1 ,
• Masataka Tsuge 1 ,
• Yuji Urabe 1 &
• Shiro Oka 1  

BMC Gastroenterology volume  24 , Article number:  287 ( 2024 ) Cite this article

Portal hypertensive enteropathy (PHE) is a small-bowel lesion observed in patients with portal hypertension. The clinical significance of endoscopic findings in PHE remains unclear. We aimed to clarify the clinical significance and predictive factors of capsule endoscopic findings in patients with PHE based on long-term outcomes.

This retrospective study enrolled 55 patients with PHE (33 males and 22 females; median age, 64 years; range, 23–87) followed for > 3 years using capsule endoscopy (CE) between February 2009 and May 2023. We evaluated the clinical factors affecting PHE exacerbations and the effects of PHE exacerbations on gastrointestinal bleeding by comparing exacerbated and unchanged PHE groups.

Overall, 3 (5%) patients showed improvement, 33 (60%) remained unchanged, and 19 (35%) showed exacerbation on follow-up CE. In the exacerbated group, the rates of worsened fibrosis-4 index, exacerbated esophageal varices, and exacerbated portal hypertensive gastropathy were significantly higher than those in the unchanged group (21%, 32%, and 42% vs. 3%, 6%, and 12%, respectively; P  < 0.05), and the rate of splenectomy was significantly lower in the exacerbated group than in the unchanged group (5% vs. 39%, respectively; P  < 0.01). In multivariate analysis, exacerbation of esophageal varices and absence of splenectomy were significantly associated with PHE exacerbation. The rate of gastrointestinal bleeding after follow-up CE was significantly high in the exacerbated group (log-rank, P  = 0.037).

Conclusions

Exacerbation of esophageal varices and splenectomy were significantly associated with exacerbation of PHE. Exacerbated PHE requires specific attention to prevent gastrointestinal bleeding.

Peer Review reports

Portal hypertension, a common complication of liver cirrhosis (LC), is defined as increased pressure in the portal circulation, as estimated by the measurement of the hepatic venous pressure gradient (HVPG) [ 1 ]. HVPG does not exceed 5 mmHg in the absence of significant liver disease, and complications of portal hypertension are known to develop when the HVPG exceeds 10 mmHg [ 2 ]. Portal hypertension causes various changes in the entire gastrointestinal tract. Esophageal varices (EVs), gastric varices (GVs), and portal hypertensive gastropathy (PHG) are well-known gastrointestinal lesions in patients with portal hypertension [ 3 , 4 ]. Moreover, rectal varices and portal hypertensive colopathy (PHC) are known as lower gastrointestinal lesions in patients with portal hypertension [ 3 , 5 ].

Capsule endoscopy (CE) was first developed in 2000 [ 6 ], and recent advances in endoscopic equipment have made various CE models available worldwide. CE can be performed by swallowing a capsule-type endoscope, has a high diagnostic ability comparable to device-assisted enteroscopy [ 7 , 8 ], and has high safety profiles [ 9 ]. Thus, CE is positioned as the first-line modality of small-bowel endoscopy in guidelines in Japan [ 10 ], Europe [ 11 ], and the United States [ 12 ], owing to its low invasiveness and high diagnostic yield. The widespread use of CE in recent years has revealed the presence of small-bowel lesions in patients with portal hypertension [ 13 ]. Portal hypertensive enteropathy (PHE) is defined as mucosal inflammatory-like abnormalities (edema, erythema, granularity, brittle lesions) or vascular lesions (cherry red spots, telangiectasias, or angiodysplasia-like lesions and varices) [ 14 ].

The presence of PHE findings is associated with Child–Pugh classification, portosystemic shunts, ascites, portal vein thrombus, EVs, PHG, and a history of endoscopic injection sclerotherapy (EIS)/ endoscopic variceal ligation (EVL) [ 15 , 16 ]. We reported that exacerbations of PHE were associated with exacerbated EVs and PHG based on short-term outcomes [ 17 ]. However, there are no reports on the clinical factors associated with the exacerbation of PHE in long-term outcomes. Additionally, the clinical significance of the changes in endoscopic findings due to PHE remains unclear. Thus, we aimed to clarify the clinical significance and predictive factors of capsule endoscopic findings of PHE based on long-term outcomes.

Study design and participants

This retrospective study included 55 patients with PHE (33 males and 22 females; median age, 64 years; range, 23–87) diagnosed and followed up for PHE findings using CE for > 3 years at Hiroshima University Hospital between February 2009 and May 2023. CE was performed using a video capsule with a PillCam™ SB2 or SB3 (Covidien, Mansfield, MA, USA). Images were analyzed using a RAPID™ 8 workstation (Covidien, Mansfield, MA, USA). A flowchart of this study is shown in Fig.  1 . CE was mainly performed when the outpatient physician indicated that evaluation of PHE was necessary, such as when patients with LC had suspected bleeding in the small-bowel, when evaluation of small-bowel mucosal damage was required before the introduction of chemotherapy for hepatocellular carcinoma (HCC), or thrombolytic therapy for portal vein thrombosis. The causes of portal hypertension included LC and idiopathic portal hypertension, which were diagnosed based on the patient’s medical history, laboratory findings (impaired synthetic liver function, thrombocytopenia, hepatitis B surface antigen, antibodies against Hepatitis C virus, autoimmune markers, and immunoglobulin), computed tomography (CT) imaging findings of the upper abdomen (nodules, irregular liver contours, splenomegaly, and ascites), transabdominal ultrasound findings, or liver biopsy findings.

Flowchart of this study. CE, capsule endoscopy; PHE, portal hypertensive enteropathy

All patients underwent periodic dynamic CT in a 1.25-mm slice thickness high-quality scanning mode to check for the presence of HCC, ascites, collateral veins, and portal vein thrombosis during the follow-up for portal hypertension. Additionally, they underwent esophagogastroduodenoscopy (EGD) to evaluate the presence of EVs, GVs, and PHG. This study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of our institution (approval number: E2022-0186). All patients provided written informed consent.

Study outcome measures

In this study, we evaluated the clinical factors affecting PHE exacerbation and their effects on gastrointestinal bleeding. The images captured via CE were reviewed and interpreted independently by two experienced experts who had reviewed more than 100 examinations, and no patient information was provided to the examiners. The CE images of the patients with portal hypertension are shown in Fig.  2 . PHE was diagnosed if lesions were observed on CE scans. The appearance of new lesions or increase in existing lesions of PHE by CE was defined as “exacerbation” (Fig.  3 ), and the disappearance of lesions or decrease of existing lesions by CE was defined as “improvement.” The severity of villous edema was evaluated based on the inability to identify the lumen of the small-bowel with edema. No villous edema was defined when the small-bowel lumen was visible, with no mucosal edema (Fig.  2 a). Mild villous edema was defined as when the lumen was visible with edematous mucosal change (Fig.  2 b), and severe villous edema was defined as when the lumen was not visible owing to edema (Fig.  2 c) [ 18 ]. Patients were divided into two groups: those with PHE exacerbation and those with unchanged PHE. We evaluated the relationships between the two groups with respect to patient clinical characteristics, including sex, age, observation period, liver function (Child–Pugh classification, FIB-4 index), etiology of portal hypertension, albumin, platelet count, prothrombin activity, HCC, EVs, GVs, PHG, portal diameter, splenomegaly, portal thrombosis, ascites, splenectomy, EIS, and EVL. We analyzed the data obtained from the most recent CT and EGD conducted when the CE was performed. HCC, portal diameter, splenomegaly, portal thrombosis, and ascites were evaluated using dynamic CT. EVs, GVs, and PHG were evaluated using EGD images. Exacerbation of EVs and GVs was defined as worsening of the degree of form or new appearance of a red color sign [ 19 ]. Exacerbation of PHG was defined as a progression from mild to severe as defined by the McCormack classification system [ 20 ]. Exacerbation of portal diameter was defined as a dilatation of 5 mm or more on follow-up CT, compared to initial CT. Exacerbation of portal thrombosis was defined as the appearance of new portal thrombosis or extension thrombosis on follow-up CT compared to the initial CT. Additionally, exacerbation of ascites was defined as an increase in the thickness of the ascites surrounding the liver on follow-up CT compared to the initial CT. The FIB-4 index was divided into three levels based on the literature [ 21 ]: low, ≤ 1.3; intermediate, 1.3–2.67; and high, ≥ 2.67, and an increase in the level was considered an exacerbation. We also evaluated the rate of gastrointestinal bleeding after follow-up CE. In this study, gastrointestinal bleeding was defined as episodes of overt bleeding characterized by hematemesis, melena, hematochezia, or a drop in hemoglobin levels > 2 g/dL [ 22 ].

Capsule endoscopic images of patients with portal hypertension. ( a ) Normal, ( b ) Mild villous edema, ( c ) Severe villous edema, ( d ) Erythema, ( e ) Erosion, ( f ) Angioectasia

Representative images of the case with exacerbated PHE findings. CE images of initial ( a , b ) and followed-up ( c , d ). New angioectasia emerging at follow-up CE (yellow circle). CE, capsule endoscopy; PHE, portal hypertensive enteropathy

Statistical analysis

Comparisons were made using the Student’s t-test for quantitative data and the chi-square test for categorical data. Fisher’s exact test was also used as appropriate. All tests were two-sided, and a P -value < 0.05 was considered statistically significant. Predictors found to be significant in the univariate analysis were included in the multivariate analysis using the stepwise method. Logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) to estimate the impact of clinical variables on the long-term outcomes of PHE. The cumulative gastrointestinal bleeding rate after follow-up CE was estimated using the Kaplan–Meier method. Statistical analyses were performed using JMP15 (SAS Institute Inc., Cary, NC, USA).

The baseline characteristics of the enrolled patients are shown in Table  1 . LC was the predominant cause of pulmonary hypertension in 52 patients (95%).

All patients were observed in the entire small-bowel during both initial and follow-up CE. Of the 55 patients, 3 (5%) showed improvement in PHE findings, 33 (60%) remained unchanged in PHE findings, and 19 (35%) experienced exacerbation of PHE findings. In this study, 33 patients (22 males; median age: 61 years; median observation period: 71 months) were compared with 19 who experienced exacerbations (10 males; median age: 64 years; median observation period: 69 months). A comparison of the CE findings at the initial time points between the unchanged and exacerbated groups is shown in Table  2 . Villous edema was the most common initial finding of PHE in both groups. There were no significant differences in the PHE findings on CE between the two groups. The breakdown of the PHE findings at follow-up in the exacerbated group was as follows: 17 patients (89%) had villous edema, 13 (68%) had erythema, 6 (32%) had erosions, and 5 (26%) had angioectasia. The breakdown of the exacerbated PHE findings on follow-up CE is shown in Table  3 . The most frequently exacerbated CE findings were villous edema (88%) and angioectasia (80%). The clinical factors associated with PHE exacerbation based on CE findings are shown in Table  4 . Regarding liver function, the rate of worsening of the FIB-4 index was significantly higher in the exacerbated group than in the unchanged group (21% vs. 3%, P  = 0.03). On EGD, the rates of exacerbations in EVs and PHG were significantly higher in the exacerbated group than in the unchanged group (32% and 42% vs. 3% and 12%; P  = 0.007, 0.014). Regarding the treatment of portal hypertension, the rate of splenectomy was significantly higher in the unchanged group than in the exacerbated group (13% vs. 5%, P  < 0.01). In the multivariate analysis of the predictors of exacerbated PHE, EV exacerbation, and no splenectomy were significantly associated with the exacerbation of PHE (Table  5 ).

Additionally, we analyzed the occurrence of gastrointestinal bleeding after follow-up CE. The Kaplan–Meier curve of the cumulative gastrointestinal bleeding rate after follow-up CE is shown in Fig.  4 . The PHE exacerbated group had a significantly higher rate of gastrointestinal bleeding events than the PHE unchanged group (log-rank, P  = 0.037).

Cumulative gastrointestinal bleeding rate after follow-up CE. The PHE exacerbation group has significantly more gastrointestinal bleeding events than the PHE unchanged group (log-rank P  = 0.037). CE, capsule endoscopy; PHE, portal hypertensive enteropathy

A list of patients with improved PHE findings is presented in Table  6 . Representative images of patients with improved PHE are shown in Fig.  5 . All three patients had LC due to HCV infection (all achieved a sustained virological response [SVR]), and the Child–Pugh classification was grade A, B, or C, one case each. Concerning changes in the FIB-4 index, two patients remained unchanged, and one showed improvement. None of these three patients had EVs or PHG exacerbation, and two of them had undergone splenectomy.

Representative images of the case with improved PHE findings. The presented patient is Case No. 3 in Table  6 . CE images of initial ( a , b ) and follow-up ( c , d ). The patient undergoes splenectomy 12 months after the initial CE. This patient then undergoes follow-up CE 54 months after splenectomy. Although erythema ( a ) and villous edema ( b ) are observed at initial CE, there is no edematous change of small-bowel mucosa at follow-up CE ( c , d ). CE, capsule endoscopy; PHE, portal hypertensive enteropathy

The present study revealed a significant association between the exacerbation of EVs and the absence of splenectomy with exacerbation of PHE findings through CE. Additionally, the exacerbation of PHE findings on CE was clinically associated with the occurrence of gastrointestinal bleeding. In previous reports, PHE findings, prevalence, and predictors of the presence of PHE have been reported [ 1 , 14 , 15 , 23 ]. However, the clinical significance of PHE remains unclear. The effects of PHE on long-term outcomes are unknown, with only one report on changes in PHE [ 17 ], which was based on short-term outcomes at 6 months. Furthermore, based on short-term results, we reported that PHE exacerbations were associated with exacerbations of EVs and PHG [ 17 ]. Our findings using long-term outcomes further revealed that exacerbation of EVs was significantly associated with exacerbation of PHE. The present study indicates that splenectomy maintained a long-term reduction in portal pressure and controlled PHE.

Portal pressure above 10 mmHg, clinically termed “portal hypertension,” is associated with the formation of varices; meanwhile, portal pressure above 12 mmHg is associated with variceal bleeding. EVs and GVs are complications of portal hypertension, present in approximately 50% and 20% of patients with LC, respectively [ 24 , 25 , 26 , 27 ]. Ido et al. [ 28 ] reported that the mean portal pressure with EVs was significantly higher than that without EVs. They also reported that EVs tended to extend their localization and intensify their features, such as engorgement and tortuosity, by increasing portal pressure. Previous reports have revealed that EVs are correlated with the presence and exacerbation of PHE [ 16 , 17 ]. The results of the present study are similar to those of previous reports. The exacerbation of EVs suggests elevated portal pressure and exacerbation of PHE.

Splenectomy effectively decreased portal pressure in models of LC and non-LC portal hypertension in animals and humans [ 29 , 30 , 31 ]. It has been reported that a decrease in splanchnic blood flow by eliminating splenic blood flow and a reduction in intrahepatic vascular resistance by normalizing hepatic concentrations of endothelin-1 and nitric oxide metabolites may have jointly contributed to decreasing portal pressure by splenectomy [ 30 ]. Moreover, splenic hyperplasia produces mediators that promote liver fibrosis and inhibit liver regeneration, such as transforming growth factor-β1, tumor necrosis factor-α, and hepatocyte growth factor activity inhibitory factor, all of which are eliminated by splenectomy [ 32 , 33 , 34 ]. This study revealed an association between splenectomy and the stabilization of PHE. Splenectomy appeared to effectively lower or prevent an increase in portal pressure, which in turn prevents the exacerbation of PHE. This suggests an indirect relationship between portal pressure and the progression of PHE. Takashi et al. [ 35 ] reported a correlation between the presence and severity of small-bowel mucosal edema and HVPG. In this study, exacerbations of PHE were more frequent in patients with villous edema. This result may reflect an elevated portal pressure. We posit that the absence of PHE exacerbations suggests the maintenance of portal pressure. The measurement of portal pressure is invasive and difficult to perform regularly. However, evaluation of PHE using CE is relatively easy. Follow-up of PHE using CE may have potential utility owing to its minimal invasiveness and ease of CE with portal hypertension.

Patients with portal hypertension are known to have a variety of gastrointestinal lesions, such as PHG and PHC, resulting in gastrointestinal bleeding [ 19 , 36 , 37 , 38 ]. The prevalence of acute gastrointestinal bleeding due to PHG has been reported to be 2–12%, and the bleeding rate due to PHC is estimated to be 0–9% [ 3 , 39 ]. Chronic gastrointestinal bleeding and active bleeding have occasionally been reported in some patients with PHE, with active ileal bleeding observed in 5–10% of patients with cirrhosis [ 14 , 40 ]. Small-bowel angioectasia is the major bleeding source for small-bowel bleeding [ 41 , 42 ], and LC has been reported as a risk factor for the presence of small-bowel angioectasia [ 43 , 44 ]. In the present study, 6 of the 52 enrolled patients (12%) had small-bowel angioectasia. Additionally, 4 of the 19 patients (22%) with exacerbated PHE had increased size or number of small-bowel angioectasias. These factors may have contributed to the increase in gastrointestinal bleeding observed in the PHE-exacerbated group. The results of the present study suggest that evaluating the small-bowel mucosa through CE is important in addition to EGD and CS in patients with PHE because exacerbation of PHE findings contributes to gastrointestinal bleeding.

Moreover, three patients showed improvement in PHE. All of these three patients had type C cirrhosis and achieved SVR. In other words, the cause of accelerated liver fibrosis disappeared, and portal hypertension was controlled. Additionally, splenectomy was performed in two of the three patients. Pezzoli et al. [ 45 ] reported that a transjugular intrahepatic portosystemic shunt improved small-bowel mucosal damage caused by portal hypertension. We hypothesize that PHE can be improved by decreasing portal pressure. However, there are few cases of improvement in PHE, and the cause remains unclear. With the advent of direct-acting antivirals for HCV, the number of long-term follow-up patients who achieve SVR is expected to increase [ 46 ]. The number of patients with PHE improvement may increase in the future. Therefore, it is necessary to accumulate data from patients with improved PHE for further analysis.

Our study has some limitations. First, the sample size was relatively small, and our study group was retrospectively recruited from a single center. Second, there was a possibility of selection bias because not all patients with portal hypertension underwent CE. Third, treatment approaches for LC have evolved over time, and we were unable to account for all these changes. Fourth, the follow-up periods varied. Thus, a prospective trial is required to resolve these issues. Fifth, the diagnosis was based solely on CE findings, and the possibility of other factors, such as drugs being the cause of the lesion, could not be ruled out because of the lack of histological evaluation. Sixth, various findings were encompassed by the PHE findings. De Palma et al. [ 14 ] categorized PHE findings into two groups: inflammatory and vascular lesions, which differ in clinical significance. Additionally, challenges such as risk stratification of the severity of PHE findings remain unresolved. Finally, we used two different CEs (PillCam™ SB2 and SB3), which may have led to an over-assessment of PHE exacerbations. Moreover, CE is a relatively expensive and burdensome procedure for physicians. Thus, it is necessary to identify a marker that can determine PHE exacerbations more easily.

In conclusion, the exacerbation of EVs and splenectomy were significantly associated with the exacerbation of PHE. Splenectomy was associated with a long-term improvement in portal pressure and a reduction in PHE exacerbation.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Portal hypertensive enteropathy

Capsule endoscopy

Liver cirrhosis

Hepatic venous pressure gradient

• Esophageal varices

Gastric varices

Portal hypertensive gastropathy

Portal hypertensive colopathy

Endoscopic injection sclerotherapy

Endoscopic variceal ligation

Hepatocellular carcinoma

Computed tomography

Esophagogastroduodenoscopy

Odds ratios

Confidence intervals

Sustained virological response

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Yuka Matsubara, Akiyoshi Tsuboi, Issei Hirata, Akihiko Sumioka, Takeshi Takasago, Hidenori Tanaka, Ken Yamashita, Yuichi Hiyama, Hidehiko Takigawa, Eisuke Murakami, Masataka Tsuge, Yuji Urabe & Shiro Oka

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Conception and design: A.T. and S.O. Clinical data collection: Y.M., A.T., I.H., A.S., T.T., H.T., K.Y.,Y.H., H.T., E.M., M.T., Y.U., S.O. Analysis and interpretation of data: Y.M. and A.T. Drafting and critical revision of the article for important intellectual content: Y.M., A.T., and S.O. All authors reviewed the manuscript. Final approval of the article: All authors.

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Matsubara, Y., Tsuboi, A., Hirata, I. et al. Predictive factors of portal hypertensive enteropathy exacerbations based on long-term outcomes. BMC Gastroenterol 24 , 287 (2024). https://doi.org/10.1186/s12876-024-03377-7

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Knowledge Transfer

Portal hypertension in chronic liver disease.

September 2, 2024

What Is the Main Idea?

High blood pressure in the portal vein, known as portal hypertension, can cause serious complications and early detection is a priority. In the open-access review article “Non-Invasive versus Invasive Assessment of Portal Hypertension in Chronic Liver Disease” , published in the journal GE – Portuguese Journal of Gastroenterology , the authors review research published to date regarding different methods used to assess and measure portal hypertension in patients with liver cirrhosis.

What Else Can You Learn?

In this blog post, different methods that are used to detect and assess portal hypertension are discussed. The role of the liver and different stages in the progression of chronic liver disease are also described.

Take-Home Message

Although hepatic vein catheterization is currently considered the most effective way to assess portal hypertension, research is being conducted to develop non-invasive methods with the aim of detecting it earlier and slowing the progression of chronic liver disease.

What Does the Liver Do?

The liver is the largest solid organ in the body and plays many essential roles that keep it healthy. These include making a fluid called bile (which helps the body to break down fats in the food we eat), processing digested food from the intestine by breaking down proteins and carbohydrates so that the body can use them, storing vitamins and iron, and fighting infections.

The liver also cleans the blood to remove harmful substances and microbes that can cause infections. As a result, the liver has about 13% of the body’s total volume of blood in it at any one time. It enters the liver via two major blood vessels called the hepatic artery (which supplies oxygen-rich blood to the liver) and the portal vein (which carries blood from the digestive tract and spleen to the liver). This is to ensure that molecules from digestion are taken up into the blood and processed or checked before they start to circulate the body in the bloodstream.

What Is Chronic Liver Disease?

Because the liver filters toxins from the blood, it is vulnerable to becoming damaged and its ability to function reducing if it is exposed to high levels of toxins. Although the liver is able to produce new cells and regenerate itself, its ability to regenerate becomes reduced over time if it keeps having to work too hard. Eventually, chronic liver disease can develop, in which damage to the liver progresses (gets worse) over a long period of time (at least 6 months). This damage cannot be reversed.

Chronic liver disease develops in four stages:

• The first (called “hepatitis”) means that there is inflammation in the liver tissue. In the short term, this means that the liver can deal with infections and start the healing process. However, if it continues for a long time, hyperactive healing can take place.
• This eventually causes the second stage, known as “fibrosis” (scarring). During this stage, thin bands of scar tissue build up over time, leading to the liver gradually becoming stiffer and the blood flow through it becoming reduced. Some of this damage can be reversed.
• If it continues, though, the third stage is eventually reached. This is called “cirrhosis” and is characterized by severe, permanent scarring that is no longer reversible.
• When the damage becomes so extensive that the fourth stage, “liver failure” (also known as “decompensated cirrhosis”), is reached the liver can no longer function properly.

What Are the Symptoms of Cirrhosis?

Early on in the development of cirrhosis, signs and symptoms may not be noticeable. The first signs can include feeling generally ill, weak or tired; loss of appetite; nausea; pain in the upper abdomen (tummy); and red patches on the palms of the hands or spider-like, visible blood vessels. As cirrhosis progresses, symptoms can include jaundice (yellowing of the whites of the eyes and skin), itchy skin, swollen legs, and bleeding or bruising easily.

Although cirrhosis cannot be reversed, treatment may be able to stop it from getting worse or slow its progression. This is important because cirrhosis is associated with serious complications that can by themselves be life-threatening, including swelling of the abdomen as a result of fluid build-up (called “ascites”) and variceal bleeding (“varices” are veins that have become abnormally widened) in the digestive tract. This results in a person vomiting blood or their poo being black or bloody. Ascites and variceal bleeding are mainly caused by the development of portal hypertension.

What Is Portal Hypertension?

The term “portal hypertension” describes an increase in the blood pressure in the portal vein. It can be caused by resistance in the liver increasing as a result of cirrhosis or because there is a blockage, such as a blood clot. As the drainage of the blood from the abdomen becomes impeded, it starts to try to leave the abdomen via other veins that become more fragile as they are stretched wider.

In addition to ascites and varices, portal hypertension can cause a number of other serious complications. Because prompt treatment of portal hypertension with medication that reduces blood pressure is known to be able to slow the progression of chronic liver disease, it is important that any increases in blood pressure in the portal vein are detected as early as possible. A variety of different techniques are used or are in development to assess whether a patient has pulmonary hypertension.

Detecting Portal Hypertension

Hepatic vein catheterization.

Hepatic vein catheterization is currently considered to be the most effective way to measure the difference in blood pressure between the portal and hepatic veins.

• First, a flexible tube called a “catheter” with a tiny balloon on the end is inserted into the jugular vein in the neck.
• X-ray imaging is then used to guide the catheter into the hepatic vein so that the blood pressure inside it can be measured.
• The balloon on the end of the catheter is then inflated and a second measurement of blood pressure is taken.
• The two values can then be used to calculate whether portal hypertension is present (classed as a portal venous pressure gradient greater than 5 mm Hg, and regarded as clinically significant if greater than 10 mm Hg).

Although hepatic vein catheterization is effective and it is rare for there to be problems while it is carried out, it is invasive and needs to be done under local or general anesthetic. In addition, it can only be done at highly specialized medical centers and cannot be used to take a series of measurements as the chronic liver disease progresses over time. As a result, researchers are investigating whether non-invasive methods are as effective at assessing pulmonary hypertension.

Serum Biomarkers

These have included serum biomarkers that can be detected by analyzing blood samples that are taken from patients (sometimes called “liquid biopsies”). Serum is the liquid that you have left if all the cells and clotting factors are removed from the blood. The term “biomarker” describes a measurable characteristic, such as a molecule in your blood or a change in your genes, that indicates what is going on in the body.

Endoscopic Ultrasound

Among the other methods available are endoscopic ultrasound, which uses a camera device (endoscope) with a small ultrasound device (which emits high-frequency sound waves) on the end to look at the digestive tract and the surrounding organs. Although this approach is invasive, with the endoscope inserted into the mouth or anus, it can be repeated over time and has been shown to have good accuracy.

Scoring Systems

Scoring systems have also been developed that include measurements of stiffness of the liver and/or spleen being taken using a non-invasive technique called transient elastography. This method works by a vibrating probe and transducer being applied to the skin over the liver or spleen that produces something called a “shear wave”. The speed at which the shear wave travels through the organ is linked to its level of stiffness and indicates how much fibrosis there is.

Although these approaches are not currently as effective as hepatic vein catheterization by themselves, there is some evidence that the combination of different techniques may improve accuracy. Future research in this area aims to improve the non-invasive early detection of pulmonary hypertension.

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Pregnancy in Patients with Non-cirrhotic Portal Hypertension: A Literature Review

Affiliations.

• 1 Department of Gastroenterology, Seth GS Medical College and KEM Hospital, Mumbai, Maharashtra, India.
• 2 Department of Maternal and Fetal Medicine, Fernandez Hospital, Hyderabad, Telangana, India.
• PMID: 35760363
• PMCID: PMC9948258
• DOI: 10.1055/s-0042-1748973

Abstract in English, Portuguese

Pregnancy in non-cirrhotic portal hypertension (NCPH) is an uncommon condition. Its management is challenging both to the obstetricians as well as to the gastroenterologists due to the lack of more extensive studies and standard clinical practice guidelines. These patients are at increased risk of portal hypertension (PTH) complications, especially variceal bleeding, and with an increased incidence of adverse maternal and fetal outcomes. Hence, a multidisciplinary approach is required for management of pregnancy in NCPH. This short review describes the different aspects of pregnancy with NCPH, emphasizing specific strategies for preventing and managing PTH from the preconceptional period to postpartum.

A gravidez na hipertensão portal não cirrótica (HPNC) é uma condição incomum. Seu manejo é desafiador tanto para os obstetras quanto para os gastroenterologistas devido à falta de estudos mais extensos e diretrizes de prática clínica padrão. Esses pacientes apresentam risco aumentado de complicações da hipertensão portal (PTH) especialmente sangramento por varizes e têm maior incidência de desfechos maternos e fetais adversos. Portanto uma abordagem multidisciplinar é necessária para o manejo da gravidez na NCPH. Esta breve revisão descreve os diferentes aspectos da gravidez com HPNC enfatizando estratégias específicas para prevenção e manejo do PTH desde o período pré-concepcional até o pós-parto.

Federação Brasileira de Ginecologia e Obstetrícia. This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/).

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Conflict of interest statement

The authors have no conflict of interests to declare.

Effect of pregnancy hemodynamics on…

Effect of pregnancy hemodynamics on portal hypertension. Source: López-Méndez and Avila-Escobedo (2006).

( A ) Management of…

( A ) Management of portal hypertension in the preconceptional period and pregnancy,…

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• Maternal and perinatal outcome in pregnancies complicated with portal hypertension: a systematic review and meta-analysis. Pal K, Sadanandan DM, Gupta A, Nayak D, Pyakurel M, Keepanasseril A, Maurya DK, Nair NS, Keepanasseril A. Pal K, et al. Hepatol Int. 2023 Feb;17(1):170-179. doi: 10.1007/s12072-022-10385-w. Epub 2022 Jul 8. Hepatol Int. 2023. PMID: 35802227
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• Review Article
• Special issue: Topics from The 45 the Annual Scientific meeting of the Japanese Society of Hypertension (JSH 2024)
• Open access
• Published: 29 August 2024

Obstructive sleep apnea -related hypertension: a review of the literature and clinical management strategy

• Kazuki Shiina 1  

Hypertension Research ( 2024 ) Cite this article

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Obstructive Sleep Apnea (OSA) and hypertension have a high rate of co-occurrence, with OSA being a causative factor for hypertension. Sympathetic activity due to intermittent hypoxia and/or fragmented sleep is the most important mechanisms triggering the elevation in blood pressure in OSA. OSA-related hypertension is characterized by resistant hypertension, nocturnal hypertension, abnormal blood pressure variability, and vascular remodeling. In particular, the prevalence of OSA is high in patients with resistant hypertension, and the mechanism proposed includes vascular remodeling due to the exacerbation of arterial stiffness by OSA. Continuous positive airway pressure therapy is effective at lowering blood pressure, however, the magnitude of the decrease in blood pressure is relatively modest, therefore, patients often need to also take antihypertensive medications to achieve optimal blood pressure control. Antihypertensive medications targeting sympathetic pathways or the renin-angiotensin-aldosterone system have theoretical potential in OSA-related hypertension, Therefore, beta-blockers and renin-angiotensin system inhibitors may be effective in the management of OSA-related hypertension, but current evidence is limited. The characteristics of OSA-related hypertension, such as nocturnal hypertension and obesity-related hypertension, suggests potential for angiotensin receptor-neprilysin inhibitor (ARNI), sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucose-dependent insulinotropic polypeptide receptor/ glucagon-like peptide-1 receptor agonist (GIP/GLP-1 RA). Recently, OSA has been considered to be caused not only by upper airway anatomy but also by several non-anatomic mechanisms, such as responsiveness of the upper airway response, ventilatory control instability, and reduced sleep arousal threshold. Elucidating the phenotypic mechanisms of OSA may potentially advance more personalized hypertension treatment strategies in the future.

Clinical characteristics and management strategy of OSA-related hypertension. OSA obstructive sleep apnea, BP blood pressure, ABPM ambulatory blood pressure monitoring, CPAP continuous positive airway pressure, LVH left ventricular hypertrophy, ARB: angiotensin II receptor blocker, SGLT2i Sodium-glucose cotransporter 2 inhibitors, ARNI angiotensin receptor-neprilysin inhibitor, CCB calcium channel blocker, GIP/GLP-1 RA glucose-dependent insulinotropic polypeptide receptor and glucagon-like peptide-1 receptor agonist.

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Recent advances in the management of secondary hypertension—obstructive sleep apnea

Obstructive sleep apnea and ambulatory blood pressure monitoring: current evidence and research gaps

Obstructive sleep apnoea heterogeneity and cardiovascular disease

Introduction.

Obstructive sleep apnea (OSA) is characterized by recurrent episodes of complete or partial collapse of the upper airway during sleep, resulting in apnea or hypopnea, and is recognized as an independent risk factor for cardiovascular disease such as hypertension, heart failure, arrhythmia, and coronary heart disease [ 1 , 2 ]. OSA increases blood pressure (BP) by enhancing various risk factors including the sympathetic nervous system, renin-angiotensin-aldosterone system (RAAS), and inflammation through mechanisms such as obesity, decreased intrathoracic pressure, pulmonary stretch receptor stimulation, chemoreceptor stimulation, hypoxemia, and hypercapnia [ 3 , 4 ]. The 2023 European Society of Hypertension (ESH) Guidelines for the diagnosis and treatment of hypertension emphasize the importance of the obese state and of the metabolic syndrome, one of the causes of hypertension, as the main partially reversible risk factors for OSA [ 5 ].

The presence of OSA has been related to an increase in the prevalence and incidence of hypertension, regardless of other factors (OR: 1.5–2.9) [ 6 , 7 ]. In fact, approximately 30–50% of hypertensive patients have OSA, whereas 50% of patients with OSA present hypertension [ 6 ], especially about 80% of patients with resistant hypertension have OSA. Therefore, screening for OSA is recommended in patients with resistant hypertension [ 8 , 9 ].

This review aims to summarize the latest findings on the clinical features of OSA-related hypertension to its treatment strategies.

Symptoms and clinical findings in OSA

In patients with OSA, extremely loud snoring and sleep apnea are typical symptoms, often prompting visits based on the partner’s observations (Table  1 ). However, the rational clinical examination systematic review by Myers, et al. [ 10 ] reported that the most useful observation for identifying patients with OSA was nocturnal choking or gasping (summary likelihood ratio [LR], 3.3; 95% CI, 2.1–4.6) when the diagnosis was established by apnea-hypopnea index: AHI ≥ 10/h). Snoring is common in OSA patients but is not useful for establishing the diagnosis (summary LR, 1.1; 95% CI, 1.0–1.1). Daytime excessive sleepiness is a common subjective clinical symptom, although it has been reported that awareness of symptoms is often lacking [ 11 ], particularly among patients with cardiovascular diseases [ 12 , 13 ]. As there is controversy regarding the association of morning headache and obstructive sleep apnea syndrome (OSAS), Goksan, et al. demonstrated that prevalence of morning headache increases with increasing OSAS severity [ 14 ]. Atrial stretch due to the large negative pressure swings by OSA results in secretion of atrial natriuretic peptide, causing nocturia. The prevalence of OSA increases with factors such as obesity and aging, but in Asia, there are many non-obese OSA patients related to craniofacial bony restriction [ 15 ].

Therefore, when examining hypertensive patients, it is important to pay attention to typical symptoms such as sleepiness and abnormalities in facial and pharyngeal morphology, even in non-obese patients, and to actively perform OSA screening tests when these abnormalities are suspected. Additionally, it is necessary to actively suspect OSA in patients with left ventricular hypertrophy (LVH), aortic disease, atrial fibrillation (AF), and those undergoing dialysis [ 9 ].

New concept of mechanisms in OSA

Recently, OSA has been considered to be caused not only by upper airway anatomy but also by several non-anatomic mechanisms [ 16 ]. These factors include the responsiveness of the upper airway responce, ventilatory control instability [ 17 ], and reduced sleep arousal threshold [ 18 ]. The relative contributions of these processes may vary from one patient to another and have therapeutic implications [ 19 ]. For example, upper-airway stimulation device is a new treatment for OSA that targets the responsiveness of the upper airway response [ 20 ]. Future treatments for OSA-related hypertension may need to consider these phenotypes.

Hypertension Risk and OSA

OSA and hypertension are not merely comorbidities; OSA itself can potentially be a causative factor for hypertension. The Wisconsin Sleep Cohort study, a prospective, community-based study, it has been demonstrated that an increase in AHI independently of age and body mass index (BMI) is associated with the new-onset hypertension [ 6 ]. In contrast, the 5-year follow-up study of the Sleep Heart Health Study, conducted with 2470 participants without hypertension at admission, found that after adjusting for BMI, AHI was no longer a significant predictor of hypertension [ 21 ]. The findings that do not support the relationship between OSA and hypertension were attributed to the lower rate of participants with moderate to severe OSA. Indeed, the vast majority of the participants included in the 5-year follow-up of the Sleep Heart Health Study had mild OSA [ 21 ]. On the other hand, Marin, et al. demonstrated that the presence of OSA was associated with increased adjusted risk of incident hypertension in a large prospective cohort study (median follow-up periods 12.2 years) without hypertension [ 22 ]. The incidence of hypertension increased with severity of OSA. These findings suggest that untreated “severe” OSA is independently of BMI associated with an increased risk for developing new-onset hypertension, and there is a “dose–response” relation between OSA and the risk of developing hypertension.

Pathogenesis of Hypertension in OSA

The mechanisms promoting hypertension in OSA are multifactorial and complex. Sympathetic activity due to intermittent hypoxia and/or fragmented sleep is the most important mechanisms triggering the elevation in BP in OSA. The pathophysiology begins with obstructed airfow into the lungs, which causes transient hypoxia and hypercapnia. The sympathetic nervous system is activated simultaneously by these repetitive blood gas derangements, which stimulate both central and peripheral chemoreceptors, apnea-induced cessation of pulmonary stretch receptor-mediated inhibition of central sympathetic outflow, and silencing of sympathoinhibitory input from carotid sinus baroreceptors by reductions in stroke volume and BP during obstructive apneas. When the apnea is interrupted by arousal from sleep, the latter process simultaneously augments sympathetic nervous activity and reduces cardiac vagal activity [ 3 , 4 , 23 ]. The result is a postapneic surge in BP [ 24 ].

These acute adverse effects of OSA on the autonomic nervous system are not confined to sleep. Patients with OSA and cardiac dysfunction also have elevated sympathetic nervous activity and depressed cardiac vagal activity when awake [ 23 ]. The mechanisms for such daytime carryover effects remain unclear but may relate to the adaptation of chemoreceptor reflexes or central processes governing autonomic outflow.

Consequently, RAAS is activated, the endothelin-1 level is increased, and the nitric oxide level is decreased, all of which contribute to the increase in vascular resistance and the development of hypertension [ 25 , 26 ]. Sympathetic hyperactivity leads to a proinflammatory state, resulting in endothelial dysfunction and increased arterial stiffness [ 27 , 28 , 29 ].

Characteristics of OSA-related HT

Resistant hypertension.

Resistant hypertension is defined as BP that is uncontrolled despite using ≥3 medications of different classes (Table  2 ), commonly a long-acting calcium channel blocker (CCB), angiotensin converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) and a diuretic (Fig.  1 ). Multiple studies have demonstrated a high prevalence of OSA in patients with resistant hypertension. The prevalence is reported to be 70–80% [ 30 , 31 , 32 , 33 , 34 ]. Several mechanisms may exlain the potential role of OSA in promoting resistant hypertension [ 35 ]. These include sympathetic nervous system activation, endothelial dysfunction, increased arterial stiffness, and fluid retention due to OSA. Among these mechanisms, increased arterial stiffness due to OSA is a major cause of resistant hypertension. Roderjan et al. reported that among resistant hypertensives, the more severe the apnea was associated with the greater the arterial stiffness, and that patients with increased pulse wave velocity (PWV) have an adverse clinical and polysomnographic profile pointing to a higher cardiovascular risk, especially women, patients with true resistant hypertension [ 36 ]. We have demonstrated that OSA and metabolic syndrome were independently associated with elevated PWV in large Sleep Cohort [ 29 ]. Although it is not clear what the roles of arterial stiffness in contributing to resistant hypertension are, it is reasonable to speculate that the vascular remodeling promoted by OSA may exacerbate BP in patients with hypertension [ 37 ].

Proposed pathways through which OSA may contribute to the development of resistant hypertension. OSA obstructive sleep apnea, RAAS RAAS: renin–angiotensin– aldosterone system, T2DM type 2 diabetes mellitus, CKD chronic kidney disease, ASCVD atherosclerotic cardiovascular disease

Non-dipper phenomenon

OSA-related hypertension is predominantly nocturnal and characterized by a non-dipping pattern [ 38 , 39 , 40 ]. Systolic BP (SBP) and diastolic BP (DBP) reduce by ~10 mmHg (about 10–20%) during sleep, but this dipping phenomenon is reversed in those with OSA. The prevalence of non-dipping was 84% in a population of untreated patients with mild to severe OSA [ 41 ]. OSA increases sympathetic nerve activity due to arousals in sleep, which counteracts the normal nocturnal BP dip and results in increased intravascular pressure. This chronic hypertension leads to vascular remodeling, decreased endothelial production of vasodilatory nitric oxide, and insensitive baroreceptors, further inhibiting the reflex of nocturnal BP dip [ 28 , 42 , 43 ]. In patients with severe OSA, positive airway pressure (CPAP) turns a non-dipping into a dipping BP profile [ 44 ].

BP variability (BPV)

In OSA, BP variability (BPV) has been studied mainly as very short-term (beat-to-beat) and short-term (24-hour BP profile) variability [ 45 , 46 ].

BP measured on consecutive heartbeats has been demonstrated to be highly variable, due to repeated peaks during sleep, so that an accurate assessment of nocturnal BP levels in OSA may require peculiar methodologies [ 47 , 48 , 49 , 50 ].

Consistent evidence indicates that the presence of OSA may be associated with increased short-term BPV, but the information on its relationship with long-term BPV, assessed on a visit-to-visit variability (VVV) is limited [ 51 ]. We observed that patients with severe OSA had significantly higher systolic VVV than controls matched for age, BMI and SBP [ 52 ]. Moreover, in this study, the plasma noradrenaline level and the AHI were independently and positively correlated with VVV and VVV was significantly reduced by CPAP. In a different study, Kansui et al. demonstrated the impact of OSA on long-term (yearly) BPV in Japanese work-site population [ 53 ].

Inter-arm BP difference

Inter-arm SBP difference (IAD) is a non-invasively and easily measurable parameter. Recent evidence suggests the existence of correlations between IAD and the risk of cardiovascular events and mortality in patients with hypertension, diabetes mellitus, and coronary artery disease, as also in the general population [ 54 ]. IAD of BP is important but the measurement methodology has a major influence on IAD results. According to a meta-analysis, the number of subjects with a systolic and diastolic IAD ≥ 10 mmHg was significantly lower when BP measurements were performed simultaneously instead of sequentially [ 55 ]. This could have overestimated the prevalence of IAD ≥ 10 mmHg. The results from Tokyo Sleep Heart Study, moderate to severe OSA was independently associated with the IAD accessed by simultaneously BP measurements [ 56 ]. The plausible explanation is that the negative intrathoracic pressure caused by OSA may exert an adverse impact on the structural properties of the thoracic aorta.

Cardiovascular damage by OSA-related HT

Cardiac morphology and function, left ventricular hypertrophy (lvh).

Several studies have observed an association between OSA and LVH [ 57 , 58 , 59 ], but it has been difficult to demonstrate an association between OSA and higher LVH independent of obesity and hypertension. Indeed, Usui, et al. demonstrated that no significant differences in left ventricular mass index by OSA severity in 74 healthy non-obese men [ 60 ]. However, recent meta-analysis showed that OSA was significantly associated with an increased risk of LVH (OR = 1.70, 95% CI 1.44–2.00, P < 0.001) [ 61 ]. Although significant variability in prevalence estimates exists between studies, recent meta-analysis suggests that in the OSA setting concentric LVH is more frequent than eccentric LVH [ 62 ].

Left ventricular systolic function

Literature reports concerning left ventricular systolic function in OSA patients are controversial. The meta-analysis by Yu, et al. demonstrated that significant decreases in left ventricular ejection fraction (LVEF) were observed in OSAS patients [ 63 ], however, the alterations in LVEF seemed not to be remarkable enough to induce obvious clinical symptoms of LV dysfunction. Recent study demonstrated that global longitudinal strain (GLS), a more sensitive measurement of LV systolic function, is impaired in patients with OSA, thus allowing to identify subclinical alterations of the systolic function not captured by LVEF [ 64 ].

Left ventricular diastolic function

Several studies demonstrated the association between OSA and　echocardiographic parameters of left ventricular diastolic dysfunction. Wachter, et al. reported that moderate-to-severe OSA is independently associated with diastolic dysfunction in a primary care cohort of 352 patients with cardiovascular risk factors [ 65 ]. OSA may be independently associated with left ventricular diastolic dysfunction perhaps due to higher LV mass [ 66 ]. Usui, et al. reported that coexistence of OSA and metabolic syndrome is independently associated with LVH and diastolic dysfunction in Japanese sleep cohort [ 67 ]. Clinicians should pay attention to the significance of the coexistence of these disorders so as to prevent the development of heart failure with preserved LVEF.

Based on these results, although comorbidities such as hypertension play a role in OSA, it is particularly associated with LVH and decreased left ventricular diastolic function. Therefore, it is important to consider the presence of OSA in patients with hypertension that exhibits these characteristics.

Atrial fibrillation (AF)

The prevalence of OSA in patients with atrial fibrillation (AF) is extremely high [ 68 , 69 ], making screening for OSA essential in these patients. The high-frequency intermittent hypoxia, negative intrathoracic pressure, atrial stretching, neurohumoral activation, and chronic concomitant conditions, such as hypertension, metabolic syndrome, and obesity, associated with OSA create progressive structural remodeling of the atrium [ 69 ]. This progressive atrial structural remodeling, along with the electrophysiological changes contributes to the reentry mechanism for AF and establishes an arrhythmogenic substrate in the atrium.

Recently, we reported that nutritional status and sleep quality are associated with AF in patients with OSA [ 70 ]. Undernutrition, as assessed by the CONtrolling NUTritional status (CONUT) score [ 71 ], and reduced slow-wave sleep were factors significantly related to the presence of AF. The CONUT scores were calculated from total peripheral lymphocyte counts, the serum albumin levels, and total cholesterol levels. On the other hand, several meta-analyses have demonstrated that CPAP therapy [ 72 , 73 ] suppresses the recurrence of pulmonary vein isolation for AF. Therefore, CPAP therapy should also be actively considered in managing BP and preventing AF recurrence in OSA-related hypertension with AF.

Vascular remodeling

A potential pathophysiological role linking OSA to vascular remodeling (i.e., progressive aortic dilatation, increased risk for aneurysms, and aortic dissection) has been reported by several clinical studies [ 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 ]. Pathophysiological conditions associated with the development of these vascular remodeling in OSA include negative intrathoracic pressure, increased BP via sympathetic hyperactivity, and oxidative stress via cyclical hypoxemia-reoxygenation due to OSA (Fig.  2 ). Recent meta-analysis actually showed that aortic size was higher in patients with OSA than in their counterparts without OSA [ 75 ]. However, the results of this meta-analysis should be considered in the context of some limitations, such as the paucity of available data, and the methodological differences of the various studies.

Vascular Damage by OSA. OSA: obstructive sleep apnea, FMD Flow mediated dilation, PWV pulse wave velocity

Regarding the relationship between aortic dissection (AD) and OSA severity, a greater relation was found between moderate-to-severe OSA and AD (OR 4.43; 95% CI 2.59–7.59) [ 79 ]. Gaisl, et al. demonstrated the strong evidence for a positive association of thoracic aortic aneurysms (TAA) expansion with AHI [ 80 ]. On the other hand, in abdominal aortic aneurysms (AAA) patients, the rate of aortic diameter enlargement was significantly higher by 2.2 mm/year in the population with an AHI ≥ 30/h compared with an AHI 0–5/h [ 81 ]. We also demonstrated that patients with TAA, AAA, and AD showed high incidences of moderate to severe OSA [ 82 ]. Negative intrathoracic pressure could theoretically dilate the thoracic aorta via increased stress in the aortic wall, but would have little effect on the abdominal aorta. However, it is inconclusive which of the thoracic and abdominal vasculatures OSA more strongly impacts.

Treatment of OSA-related hypertension

Among the treatment modalities that come to the fore in OSA-related hypertension are CPAP, antihypertensive medications (beta-blocker, diuretics, ARB and CCB), and renal denervation (RDN). There are currently no specific clinical recommendations on whether to prioritize CPAP or antihypertensive medications in OSA-related hypertension. However, in hypertensive patients with moderate to severe OSA accompanied by sleepiness, it is common to prioritize CPAP therapy to improve sleep quality. Weight loss, physical exercise, reducing alcohol consumption, and smoking cessation are among the primary lifestyle changes recommended for OSA-related hypertension [ 83 ].

CPAP therapy

A number of studies have demonstrated that CPAP has modest but significant BP-lowering effects of 2–7 mmHg in SBP and of 2–5 mmHg in DBP in OSA-related hypertension [ 84 , 85 , 86 , 87 , 88 , 89 , 90 , 91 ] (Fig.  3 ). The effect of CPAP on BP varies among patients (Fig.  3 ). Higher BMI, severe OSA (AHI ≥ 30), hypersomnolence, higher BP values, untreated hypertension, nocturnal hypertension, treatment-resistant hypertension and adherence to CPAP are variables that have been associated with a greater improvement in BP in several studies [ 92 , 93 , 94 , 95 , 96 , 97 ]. HIPARCO RCT found a significant correlation between CPAP usage and reductions in 24-h mean BP, SBP, and DBP [ 98 ]. Best results for quality of life improvements and optimal reductions in BP occur when CPAP usage exceeds 4 hour/night [ 87 , 99 ]. Furthermore, recent meta-analyses suggest an even higher degree of daily CPAP adherence (at least 4.0–5.5 hour/night) to improve BP in patients with resistant hypertension and sleepiness [ 100 ].

Recent meta-analyses regarding the effect of CPAP treatment on blood pressure. CPAP Continuous positive airway pressure, SBP Systolic blood pressure, DBP Diastolic blood pressure

In the patients with non-sleepy OSA, CPAP therapy have no overall beneficial effects on subjective sleepiness, SBP, or cardiovascular risk compared with no active therapy. OSA patients who were less sleepy had lower BMI and lower CPAP adherence. This probably might be due to a lower respiratory arousal threshold. Comprehensive management including an active lifestyle and regular support of CPAP use is key to managing this kind of OSA [ 101 ]. Furthermore, CPAP withdrawal results in a clinically relevant increase in BP (office SBP): +5.4 mm Hg, home SBP : +9.0 mm Hg), which is considerably higher than in conventional CPAP trials [ 102 ].

In patients with nocturnal hypertension (non-dipper/riser types), CPAP often selectively lowers BP during sleep, leading to a normal dipper pattern [ 103 ]. In the aforementioned studies, HIPARCO RCT, among patients with OSA and resistant hypertension, CPAP treatment for 12 weeks compared with control resulted in a decrease in 24 h mean (−3.1 mmHg) and DBP (−3.2 mmHg) and an improvement in the nocturnal BP pattern [ 98 ].

As mentioned above, the antihypertensive effects of CPAP are modest. However, CPAP therapy exert beneficial effects on sympathovagal balance and arterial stiffness, independent of BP lowering [ 104 ]. Therefore, patients with moderate-to- severe OSA-related hypertension should undergo CPAP therapy as a first-line treatment.

Antihypertensive medications

CPAP therapy is effective at lowering BP, however, the magnitude of the decrease in BP is relatively modest, therefore, patients often need to also take antihypertensive medications to achieve optimal BP control (Table  3 ). However, current guidelines do not specify what type of antihypertensive therapy should be offered to patients with OSA and concomitant hypertension [ 5 , 8 ]. An earlier study conducted by Kraiczi et al. compared the effects of atenolol, hydrochlorothiazide, amlodipine, enalapril, and losartan on office and ambulatory BP in 40 OSA-related hypertension patients [ 105 ]. Compared with the other four medications, atenolol lowered the office DBP as well as mean night-time ambulatory SBP and DBP. These findings support the hypothesis that overactivity of the sympathetic nervous system is the most important mechanism involved in the development of hypertension in patients with OSA. Kario, et al. reported the BP-lowering effects of CCBs and beta-blockers using a trigger sleep BP monitor with an oxygen-triggered function in OSA-related hypertension [ 106 ]. The BP-lowering effects of nifedipine on the mean and minimum sleep SBP were stronger than those of carvedilol, but sleep SBP surge was only significantly reduced by carvedilol.

On the other hand, in terms of suppressing organ damage, RAAS inhibitors, such as ARB, may be useful in patients with OSA-related hypertension, especially in obese patients, because the RAAS is hyperactive and LVH is a common complication [ 107 , 108 ].

Fluid retension from the lower extremities to the upper body during sleep is strongly associated with OSA in hypertensive patients. Therefore, in OSA patients with obesity and a fluid retention, diuretics may be beneficial. Spironolactone reduced the severity of OSA and reduced BP in resistant hypertension patients with moderate-to-severe OSA [ 109 , 110 ]. A propensity score-matched cohort analysis of data from the French national sleep apnea registry demonstrated that diuretics appear to have a positive impact on OSA severity in overweight or moderately obese patients with hypertension [ 111 ].

Recently, Svedmyr, et al. investigated 5970 hypertensive patients with OSA on current antihypertensive treatment from the European Sleep Apnea Database (ESADA) cohort [ 112 ]. Monotherapy with beta-blocker was associated with lower SBP, particularly in non-obese middle-aged males with hypertension. Conversely, the combination of a beta-blocker and a diuretic was associated with lower SBP and DBP in hypertensive patients with moderate–severe OSA. Furthermore, another report in ESADA cohort suggests that ACEI or ARB, alone or in combination with other drug classes, provides a particularly strong reduction of BP and better BP control when combined with CPAP in OSA [ 113 ]. Considering that CPAP will remove repetitive hypoxia, most arousals, and the chronic sympathetic activation, it is likely that other mechanisms, such as RAAS activation, may play a dominant role following OSA treatment. This is speculated to be the reason why ACEI or ARB were effective in the CPAP treated OSA.

Sodium-glucose cotransporter 2 inhibitors (SGLT2i)

A recent series of mega-scale clinical trials for sodium-glucose cotransporter 2 inhibitor (SGLT2i) indicated cardio-renal protective effects of SGLT2i [ 114 , 115 , 116 , 117 , 118 ], and some SGLT2is have now become the first-line treatment for T2DM with comorbid atherosclerotic cardiovascular disease (ASCVD) and heart failure. Furthermore, several studies have reported a lowering effect of SGLT2i on BP [ 119 , 120 ]. Although mechanisms underlying the BP-lowering effects of SGLT2i are unclear, SGLT2i presumably acts primarily by decreasing circulating plasma volume through osmotic and natriuretic diuresis in the early stages of administration and later by suppressing sympathetic nerve activity in the long term [ 121 , 122 ]. Wojeck, et al. reported that Ertugliflozin reduced incident OSA [ 123 ]. In the meta-analysis, Lin, et al. demonstrated that SGLT2i was shown to reduce AHI [ 124 ]. These results suggest that SGLT2i may not only have beneficial effects on OSA-related hypertension but also on OSA itself [ 125 ].

Angiotensin receptor-neprilysin inhibitor (ARNI)

The angiotensin receptor neprilysin inhibitor (ARNI) has recently been approved in Japan to treat hypertension [ 126 ]. Reductions in 24-hour, daytime, and nighttime BP have been documented during treatment with ARNI in patients with hypertension [ 127 , 128 , 129 ]. This potent 24-hour BP-lowering effects of ARNI may be effective for OSA-related hypertension characterized by resistant, nocturnal, and non-dipper hypertension [ 130 ]. Additionally, as previously mentioned, since OSA-related hypertension is associated with LVH [ 57 , 58 , 59 , 61 , 62 ] and left ventricular diastolic dysfunction [ 65 , 66 , 67 ], ARNI, which is characterized by so-called “reverse remodeling”, may be useful for OSA-related hypertension. Furthermore, in chronic heart failure patients with sleep apnea, ARNI treatment for 3 months in patients with OSA decreased the severity of OSA itself (the ENTRESTO-SAS study) [ 131 ].

However, both ARNI and SGLT2i are used in the United States to treat heart failure. In addition, there may be considerably less research on antihypertensive in OSA. Future research is needed to investigate the effect of ARNI and SGLT2i on BP in patients with OSA-related hypertension.

Glucose-dependent insulinotropic polypeptide receptor/ glucagon-like peptide-1 receptor agonist (GIP/GLP-1 RA)

Recently, a study evaluating the safety and efficacy of tirzepatide for the treatment of OSA and obesity was published (The SURMOUNT-OSA trials) [ 132 ]. Tirzepatide is a long-acting glucose-dependent insulinotropic polypeptide (GIP) receptor and glucagon-like peptide-1 (GLP-1) receptor agonist that selectively binds to and activates both the GIP and GLP-1 receptors. The SURMOUNT-OSA trials were two 52-week, phase 3, multicenter, parallel-group, double-blind, randomized, controlled trials that were conducted at 60 sites across nine countries to evaluate the efficacy and safety of the maximum tolerated dose of weekly tirzepatide (10 mg or 15 mg) in adults with moderate-to-severe OSA and obesity. In this trial, tirzepatide reduced the AHI, body weight, hypoxic burden, high-sensitivity C-reactive protein concentration, and SBP [Estimated treatment differences :−7.6 mmHg (95% CI, −10.5 to −4.8), P  < 0.001, not receiving CPAP group]. The effect of tirzepatide on OSA-related hypertension is expected in the future.

Renal denervation

Increased sympathetic activity, consistently evident in patients with OSA, plays a key role in the development of resistant hypertension [ 35 ]. Therefore, OSA-related hypertension may represent a promising indication for RDN. In an RCT conducted with moderate-to-severe OSA patients with resistant hypertension, Warchol-Celinska, et al. demonstrated that RDN safely provided significant BP reduction compared with the control group [ 133 ]. However, the effect of RDN for OSA-related hypertension remains unclear due to differences in research design and other factors, such as sham procedure, ablations catheter, treatment adherence, sample size, observational periods, etc. Further large scale studies are warranted to assess the impact of RDN on OSA and its relation to BP decline and cardiovascular risk.

Future directions

As previously mentioned, it has become clear that OSA is caused not only by upper airway anatomic factors but also by several non-anatomic mechanisms [ 16 , 17 , 18 , 19 ]. Therefore, it is hypothesized that the pathophysiology of OSA-related hypertension is also not a single condition but is divided into several phenotypes. Elucidating the phenotypic mechanisms of OSA may potentially advance more personalized hypertension treatment strategies in the future.

Conclusions

OSA occurs at a high prevalence in hypertensive patients, particularly those with resistant hypertension. Additionally, it is highly prevalent among AF patients, warranting OSA screening. OSA-related hypertension is characterized by morning hypertension, nocturnal hypertension, non-dipper pattern, increased BPV, and pronounced arterial remodeling. CPAP therapy is the gold standard therapy for OSA but its effects on BP are relatively modest, often requiring combination therapy with antihypertensive medications. While there is insufficient evidence regarding the choice of antihypertensive medications, beta-blockers, diuretics, and ARBs may be used as monotherapy or in combination therapy depending on individual cases. Further evaluation of the efficacy of novel agents such as SGLT2i and ARNI, and GIP/GLP-1 RA is necessary. Elucidating the phenotypic mechanisms of OSA may potentially advance more personalized hypertension treatment strategies in the future.

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Shiina, K. Obstructive sleep apnea -related hypertension: a review of the literature and clinical management strategy. Hypertens Res (2024). https://doi.org/10.1038/s41440-024-01852-y

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New Trends in the Diagnosis and Management of Hypertension

Mohammad tinawi.

1 Medicine, Indiana University School of Medicine Northwest-Gary, Gary, USA

2 Nephrology, Nephrology Specialists, Munster, USA

Hypertension is the leading risk factor for disability and death globally. This is attributed to two major complications of hypertension, cerebrovascular accidents (CVA) and ischemic heart disease. This update provides a concise overview of several timely hypertension topics. These topics were chosen based on recent significant advances in the field. Examples include the use of renin-angiotensin-aldosterone inhibitors in coronavirus disease 2019 (COVID-19) patients, the landmark Systolic Blood Pressure Intervention Trial (SPRINT), management of resistant hypertension, and primary aldosteronism. The articles reviewed also include other recent landmark clinical trials, prior clinical trials of great significance, and medical societies guidelines. Ten topics were chosen based on their relevance to the practicing clinician. Each topic is discussed in a condensed manner highlighting recent advances in the field of hypertension.

Introduction and background

The focus of this review is on recent advances in the diagnosis and management of hypertension which is the leading cause of death and disability worldwide [ 1 ]. An update on ten timely topics in the vast field of hypertension is presented. Included is Renin-Angiotensin-Aldosterone (RAAS) Inhibitors in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the significance of this topic is clear in light of the current coronavirus disease 2019 (COVID-19) pandemic. New definitions of normal blood pressure (BP), elevated BP, stage 1, and stage 2 hypertension are presented. The main findings of the Systolic Blood Pressure Intervention Trial (SPRINT) and SPRINT MIND (MIND is an acronym derived from Memory and cognition IN Decreased hypertension) are summarized. The importance of ambulatory BP monitoring is emphasized. Strategies to manage resistant hypertension are discussed. An update on screening of primary aldosteronism is provided. Other relevant topics include obstructive sleep apnea, obesity, and isolated diastolic hypertension. Finally, the initial treatment of hypertension is discussed.

A PubMed search was conducted using “Hypertension” as a medical subject heading (MeSh) Major Topic. The following filters were applied: Clinical Trial, Phase III, Randomized Controlled Trial, Publication Date 5 years or less, English Language, and Adults participants. The search yielded 1,230 results. The results were then restricted to the following journals: Hypertension, Journal of Hypertension, The New England Journal of Medicine (NEJM), Kidney360, Nephrology Self-Assessment Program (NephSAP), JAMA Network Open, Circulation, Kidney International, Journal of the American Medical Association (JAMA), Lancet, Journal of the American Society of Nephrology (JASN), Annals of Internal Medicine, Journal of Clinical Endocrinology and Metabolism, American Journal of Hypertension, Journal of the American College of Cardiology (JACC), American Journal of Kidney Disease (AJKD), and Clinical Journal of The American Society of Nephrology (CJASN). The journals were chosen because of their prominence in publishing major trials and guidelines in the field of hypertension. No duplicate results were found. The articles included were mainly randomized clinical trials and recent guidelines. The studies were included based on originality, importance to the practicing clinician, impact on clinical practice, and applicability to broad categories of patients. Guidelines from major professional societies were included based on their clinical impact as well as acceptance and endorsement by other specialty societies and practicing clinicians. Additional references related to prior major studies in hypertension were included such as the Modification of Diet in Renal Disease (MDRD study), and African American Study of Kidney Disease and Hypertension (AASK trial). Examples of studies excluded are small clinical trials, studies related to pulmonary hypertension, studies of hypertension in pregnancy, and studies related to specialized topics such as hypertension and potassium binders. Major clinical trials such as SPRINT have numerous posthoc analyses and sub-studies, only SPRINT in chronic kidney disease (CKD) and the SPRINT MIND were included. There may be other topics in hypertension that are worthy of this discussion, however, the purpose of the author is to keep this update focused and clinically relevant. The methods employed yielded high impact clinical trials (such as SPRINT, SPRINT MIND, STEP Study {Trial of Intensive Blood-Pressure Control in Older Patients with Hypertension}, and Chlorthalidone in Chronic Kidney Disease {CLICK} Study), and major society guidelines such as American College of Cardiology (ACC)/American Heart Association (AHA) guidelines. The data collected were then arranged to provide a timely update in ten areas of hypertension. 

Selected basic science topics were searched in the following journals: Journal of Molecular Endocrinology, Cell, Journal of Clinical Investigation, Natures Reviews Nephrology, and Journal of Epidemiology. Examples include sympathetic neural mechanisms in sleep apnea, obesity, and the SARS-CoV-2 cell entry mechanism. A summary of the methods used in this article is provided in Table ​ Table1 1 and Figure ​ Figure1 1 .

1. Renin-angiotensin-aldosterone (RAAS) inhibitors in patients with SARS-CoV-2

Angiotensin-converting enzyme 2 (ACE2) inactivates angiotensin II. ACE2 functions as an enzyme and also as the functional receptor for SARS-CoV-2 [ 2 ]. The virus spike proteins bind to ACE2 on the surface of the alveolar epithelial cells in the lung. This increases angiotensin II due to down-regulation of ACE2, and subsequently causes oxidative injury in the lungs. Treatment with converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARBs) can increase ACE2 activity [ 3 ]. The effect of these medications on ACE2 expression in the lung is unknown, and there is a potential benefit of treatment with RAAS inhibitors rather than harm [ 4 ]. There is no evidence that continuation of treatment with ACEI/ARBs alters the course of COVID-19 infection, nor is there evidence that patients on ACEI/ARBs have increased susceptibility to COVID-19 infection. In a case-control study in Italy involving 6272 patients with confirmed SARS-CoV-2, the use of ACEI and ARBs was more frequent in COVID-19 patients than matched controls, but this usage did not affect the risk of COVID-19 infection including severe infection [ 5 ]. Chaudhri et al. reported on 80 patients with a history of ACEI or ARBs use prior to hospitalization at Stony Brook University Medical Center in New York with COVID-19 infection [ 6 ]. Approximately 60% were continued on these medications during their hospitalization. Prior use of ACEI or ARBs was not associated with worse outcomes, moreover, continued use of these medications predicted fewer intensive care unit (ICU) admissions (odds ratio {OR}=0.25, 0.08-0.81). Professional societies from across the globe uniformly recommend the continuation of treatment with RAAS inhibitors [ 7 ]. A recent systematic review and meta-analysis confirmed this recommendation [ 8 ]. Factors that should be included in the decisions making include the duration of treatment on RAAS and chronicity of underlying diseases rather than the relationship between pretreated patients with RAAS inhibitors and COVID-19. The decision for use of RAAS inhibitors should be made on a case-by-case basis for patients who develop complications such as sepsis or organ failure and are severely ill from COVID-19.

2. Blood pressure targets

There are numerous national and international guidelines on the diagnosis and treatment of hypertension. There is no agreement among the guidelines on the definition of hypertension or on blood pressure (BP) treatment goals. The guidelines issued in 2018 by the ACC/AHA are gaining significant acceptance and endorsement by professional societies [ 1 ]. They are principally based on the SPRINT. These guidelines define normal BP as systolic BP (SBP) < 120 mm Hg and diastolic BP (DBP) < 80 mm Hg. Elevated BP is SBP = 120-129 mm Hg and DBP < 80 mm Hg. Hypertension is divided into two categories, stage 1: SBP = 130-139 mm Hg or DBP 80-89 mm Hg; and stage 2: SBP ≥ 140 mm Hg or DBP ≥ 90 mm Hg. Hypertension diagnosis is based on ≥ 2 BP readings at ≥ 2 visits. The same guidelines recommend a BP goal of less than 130/80 mm Hg. This goal is the same in patients with co-morbidities such as stable ischemic heart disease, diabetes mellitus, and CKD. This goal does not apply to patients with acute intracerebral hemorrhage or acute ischemic stroke. The prevalence of hypertension has increased worldwide after the application of the new ACC/AHA definition of hypertension. In the US the prevalence of hypertension has increased by 13.7% (about 31 million adults) from 32% to 45.6% [ 9 ]. The greatest impact was in the age group of 20 to 44 years, where the prevalence has increased from about 11% to 24%.

The 2020 International Society of Hypertension guidelines define normal BP as <130/85 mm Hg, high-normal BP as 130-139/85-89 mm Hg, grade 1 hypertension as 140-159/90-99 mm Hg, and grade 2 hypertension as ≥ 160/100 mm Hg. Elevated SBP, DBP, or both is sufficient to establish the diagnosis [ 10 ].

The 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines on the management of blood pressure in CKD patients recommend a target systolic blood pressure SBP of <120 mm Hg using standardized office BP measurement (2B recommendation: supporting evidence is moderate) [ 11 ]. The KDIGO guidelines emphasize that the advantage of intensive BP lowering (SBP <120 mm Hg) is less certain in those with A3 albuminuria (>300 mg/g, or >30 mg/mmol), stage 5 CKD, or diabetics with CKD [ 12 ]. This statement is based on the results of several landmark clinical trials (Table ​ (Table2 2 ) [ 13 - 16 ].

MDRD: The Modification of Diet in Renal Disease Study [ 13 ]; AASK: The African American Study of Kidney Disease and Hypertension [ 14 ]; REIN-2: Ramipril in non-diabetic renal failure Study-2 [ 15 ]; ACCORD: Action to Control Cardiovascular Risk in Diabetes Study [ 16 ]; BP: blood pressure; SBP: systolic blood pressure; MAP: mean arterial pressure; CKD: chronic kidney disease; GFR: Glomerular filtration rate; ESRD: end-stage renal disease.

3. The systolic blood pressure intervention trial (SPRINT)

SPRINT was published in 2015 [ 17 ]. It is one of the most important trials in hypertension. This multicenter randomized controlled trial enrolled 9361 subjects with a median follow-up of 3.26 years. The subjects were 50 years or older with SBP > 130 mm Hg and one of the following: history of cardiovascular disease (CVD), CKD (estimated glomerular filtration rate {eGFR} 20-59 ml/min/1.73 m 2 ), intermediate to high risk for CVD other than CVA, or age over 75 years. The intensive treatment target was SBP < 120 mm Hg, and the standard treatment target was < 140 mm Hg. SPRINT used a fully automated oscillometric BP monitor to document BP measurements. The measurements were attended by staff at some study centers and unattended at other centers. This automated approach reduces errors in obtaining BP measurements and may lessen the white coat effect. SPRINT showed a 25% decrease in the primary combined cardiovascular endpoints (first occurrence of CVA, myocardial infarction, acute coronary syndrome, heart failure, or death), and a 27% reduction in death from any cause in the group randomized to the lower SBP goal of (< 120 mm Hg). Heart failure decreased by 38% in the intensive treatment group. 

Of note, 28% of SPRINT participants had CKD (eGFR 20-59 ml/min/1.73 m 2 ) but none had polycystic kidney disease or proteinuria ≥ 1 g/day per SPRINT inclusion and exclusion criteria. In this CKD cohort, there was no difference in the incidence of end-stage renal disease (ESRD) or primary combined cardiovascular endpoints between the standard and intensive treatment groups [ 18 ]. In participants with CKD, mortality was significantly lower in the intensive treatment group (hazard ratio {HR}, 0.72, 95% CI, 0.53-0.99). There was a higher risk of ≥ 30% decline in eGFR in the intensive treatment group. The decline was attributed to the hemodynamic effect of intensive BP lowering and improved after the first six months of intensive BP therapy. This eGFR decline did not attenuate the benefit of intensive BP lowering on all-cause mortality or cardiovascular events [ 19 ]. As mentioned above, the value of intensive BP lowering (SBP <120 mm Hg) is less certain in individuals with diabetes, proteinuria >1 g/day, and CKD 4 and 5. These patient populations were not included in SPRINT. the clinicians should be cautious about generalizing the SPRINT findings to these populations.

The SPRINT MIND substudy showed that the combined endpoints of probable dementia and mild cognitive impairment were significantly lower in the intensive treatment group (HR, 0.85, 95% CI, 0.74-0.97) [ 20 ]. This result alleviated the concern that intensive BP lowering increases the risk of dementia.

The final report of SPRINT was published in 2021 [ 21 ]. It combined the trial and post-trial data extending the follow-up to 3.88 years. The report showed no change in the benefits and the risks of intensive treatment. During the observation period, 32 participants in the intensive arm had heart failure compared to only 13 in the standard treatment. The etiology of increased heart failure events in the intensive group remains unclear, and it is not related to the difference in diuretics use between the two groups.

The STEP study applied the lessons learned from SPRINT to an older cohort. It enrolled 8511 hypertensive Chinese patients 60 to 80 years of age [ 22 ]. They were randomized either to intensive BP-lowering treatment (SBP 110-129 mm Hg) or to standard treatment (SBP 130-149 mm Hg) for a median follow-up of 3.34 years. The intensive treatment group had a lower incidence of cardiovascular events including stroke, acute coronary syndrome, and acute decompensated heart failure by 33%, 33%, and 73% respectively. The authors did not elaborate on the possible causes of the remarkable reduction in acute decompensated heart failure; the 0.27 hazard ratio had a wide 95% confidence interval (CI, 0.08-98), reflecting the small number of events for this outcome (3 patients in the intensive treatment, and 11 in the standard treatment). Therefore, based on STEP study the benefits of intensive lowering of SBP outweighed the adverse effects in middle-aged and older adults with less than 80 years of age. However, the benefit appeared to be mainly reductions in stroke and acute coronary syndrome.

4. Ambulatory BP monitoring (ABPM)

A systematic review by the U.S. Preventive Services Task Force concluded that ABPM predicated long-term cardiovascular outcomes independently of office BP [ 23 ]. ABPM is done by wearing an automated monitor for 24-48 h. ABPM should be used to confirm elevated office BP when feasible [ 1 ]. ABPM is useful is diagnosing masked hypertension (normal office BP and elevated BP out of the office), and white coat hypertension (normal BP out of the office and elevated in office BP). Self BP monitoring is more convenient and less costly. Self BP monitoring should be done using a validated device. A list of such devices in the United States was published online by the American Medical Association after an independent review process. It can be found at:  https://www.validatebp.org .

5. Management of resistant hypertension

In 2018, the AHA published a scientific statement on resistant hypertension [ 24 ]. Hypertension is considered resistant if BP remains above target despite treatment with ≥ 3 optimally dosed antihypertensives including a diuretic, or treatment with four antihypertensives. Secondary causes of hypertension should be excluded, and lifestyle interventions should be maximized in all patients. It was previously taught that thiazide-type diuretics such as chlorthalidone, hydrochlorothiazide or indapamide maintain their efficacy down to eGFR of 30 ml/min/1.73 m 2. The CLICK study enrolled 160 patients with stage 4 CKD and poorly controlled hypertension. It concluded that chlorthalidone, at a dose 12.5-50 mg daily, improved blood pressure control compared to placebo at 12 weeks [ 25 ]. Chlorthalidone has a long half-life (40-60 hours) and is associated with a higher risk of hyponatremia and hypokalemia compared with hydrochlorothiazide. A loop diuretic such as torsemide is commonly utilized in CKD patients with eGFR < 30 ml/min/1.73 m 2 , especially in presence of hypervolemia. 

If BP is still not at target, adding a mineralocorticoid receptor antagonist (MRA) such as spironolactone or eplerenone should be considered. Caution is required if eGFR is < 30 ml/min/1.73 m 2  due to the risk of hyperkalemia. If BP is still not at target, the following steps can be taken based on expert opinion [ 24 ]

· The addition of a beta-blocker (heart rate should be ≥ 70) or a combined alpha-beta blocker such as labetalol or carvedilol.

· If a beta-blocker is contraindicated, consider a central alpha-agonist such as clonidine.

· If an alpha-agonist is poorly tolerated, consider once-daily diltiazem.

· If BP remains elevated, add hydralazine starting at 25 mg orally three times daily and titrate upward to achieve BP target.

· If hydralazine fails to bring BP to desired target, substitute minoxidil for hydralazine starting at 2.5 mg 2-3 times daily and titrate upward to achieve BP target. Also consider referral to a hypertension specialist.

6. Primary aldosteronism

Hypertensive patients should be screened for primary aldosteronism if they have resistant hypertension, hypertension with hypokalemia (serum potassium <3.5 mEq/L, even if they are on a diuretic), incidental adrenal mass, or family history of hypertension or CVA under age 40 [ 1 ]. The recommended screening test for primary aldosteronism based on current guidelines is measuring plasma aldosterone-renin ratio (ARR) [ 26 ]. Positive screening is followed by further confirmatory tests. In a recent thought-provoking cross-sectional study by Brown et al., ARR was found to have poor sensitivity and poor negative predictive value for detection of primary aldosteronism [ 27 ]. The study enrolled 289 participants with normotension (BP<140/90), 115 participants with stage 1 hypertension, 203 participants with stage 2 hypertension and 408 participants with resistant hypertension. All participants had sodium loading per protocol. In patients with high urine sodium and suppressed plasma renin activity, urine aldosterone was measured. The authors defined biochemically overt primary aldosteronism as urine aldosterone > 12 mcg/24 h. Estimated prevalence of biochemically overt primary aldosteronism was 3-5 times higher than expected with ARR: 11% in normotensives, 16% in stage 1 hypertension, and 22% in stage 2 and resistant hypertension. The authors concluded that primary aldosteronism exists as a continuum that parallels the severity of hypertension. Moreover, current guidelines that rely on ARR as the preferred screening for primary aldosteronism may need to be reevaluated.

7. Obstructive sleep apnea (OSA)

OSA is associated with hypertension. Patients with OSA have elevated sympathetic activity while awake. In OSA intermittent hypoxia during sleep increases sympathetic activity and BP. Treatment with continuous positive airway pressure (CPAP) ameliorates these increases [ 28 ].

Warchol-Celinska et al. studied 60 patients with OSA and resistant hypertension at the Institute of Cardiology in Warsaw, Poland [ 29 ]. In this phase II randomized trial, 30 patients who had catheter-based renal denervation (RDN) were compared to 30 controls. At three months, patients randomized to the RDN group had a significant decrease in OSA severity and a significant reduction in ambulatory and office BP. At three months, the mean difference between the two groups in office SBP was -17 (-27 to -6) (95% CI), and in-office DBP was -6 (-15 to 3) (95% CI). At three months, the mean difference for 24 h ambulatory SBP was -9 (-17 to -3) (95% CI), and for 24 h ambulatory DBP was -5 (-10 to 0) (95% CI). These BP reductions were sustained at six months.

8. Obesity and hypertension

Increased adiposity is responsible for 65-75% of primary hypertension [ 30 ]. Sodium reabsorption in the kidney and renal sympathetic nerve activity (RSNA) are both increased in obesity. Adipokines such as leptin are increased. Leptin increases RSNA via stimulation of the proopiomelanocortin-melanocortin 4 receptor pathway in the central nervous system. Leptin may also increase aldosterone secretion from the adrenal glands [ 31 ]. Aldosterone antagonists such as spironolactone may have a role in the management of resistant hypertension in obese patients [ 32 ]. A recent study in approximately 20,000 obese children and adolescents from China (aged 6-18 years) concluded that abnormal adipokine levels are associated with increased risk of hypertension [ 33 ]. A randomized clinical trial in 100 obese patients found the Roux-en-Y gastric bypass (RYGB) was more effective in maintaining BP below 140/90 compared to medical therapy (MT) alone, 73% in RYGB group vs. 11% in MT group at three years (relative risk, 6.52 {95% CI, 2.50 to 17.03}; P < 0.001) [ 34 ]. Patients who were randomized to RYBG achieved the above BP target with lower number of medications at three years. Median number of antihypertensive in the RYGB and MT groups at three years was 1 (0 to 2) and 3 (2.8 to 4), respectively (P <0.001). Clearly, surgical treatment of obesity may not be appealing or appropriate for many patients.

9. Isolated diastolic hypertension 

Isolated systolic hypertension (ISH) and combined systolic-diastolic hypertension are both associated with increased cardiovascular risk. Less is known about isolated diastolic hypertension (IDH). The new ACC/AHA guidelines define IDH as SBP <130 mm Hg and DBP ≥ 80 mm Hg. McEvoy et al. studied patients from two large prospective cohorts: 9590 adults from the National Health and Nutrition Examination Survey (NHANES) 2013-2016, and 8703 adults from the Atherosclerosis Risk in Communities (ARIC) study [ 35 ]. Using the ACC/AHA definition, the prevalence of IDH in NHANES was 6.5% and in ARIC was 10.7%. The authors concluded that IDH was not significantly associated with increased cardiovascular risk. Flint et al. conducted a retrospective cohort study in outpatients belonging to Kaiser Permanente Northern California [ 36 ]. They reviewed data from 1.3 million adults and arrived at a different conclusion. Both systolic and diastolic hypertension were independently associated with increased cardiovascular risk (composite outcome of ischemic stroke, hemorrhagic stroke, or myocardial infarction). Systolic hypertension had a larger effect. For example, a patient with a weighted average systolic BP of 160 mm Hg (z score, +3) had a predicted risk of a composite outcome event at eight years of 4.8%, while a patient with a weighted average diastolic BP of 96 mm Hg (z score, +3) had a predicted risk of 3.6% over the same interval. Using the ACC/AHA guidelines 56.4% of the study patients had normal BP, 21.9% had ISH, 6.1% had IDH and 15.5% had combined systolic-diastolic hypertension. The difference in population size between the two studies and their retrospective design, may explain the contrasting conclusions.

10. Initial drug treatment of hypertension

Lifestyle modifications should be recommended to all patients including sodium restriction, exercise, alcohol moderation, weight loss in overweight patients, and increased intake of potassium-rich foods (unless the patient has a tendency for hyperkalemia) [ 1 ]. When a pharmacological agent is needed, it should be chosen from one of the following four classes: thiazide-type diuretics, calcium-channel blockers (CCBs), ACEI or ARBs. The choice of a specific agent depends on age, race, and co-morbidities. Most patients with hypertension are started on monotherapy but a low-dose combination pill is more effective to lower the BP [ 37 ]. Patients with a tendency for hyponatremia and those over 65 years of age should be started on a thiazide-type diuretic with caution [ 38 ]. Sodium should be rechecked in 1-2 weeks to rule out hyponatremia. ACEI and ARBs are appropriate choices for patients with systolic heart failure, as well as patients with diabetes mellitus and CKD, especially if proteinuria if present. In black patients, CCBs or thiazide-type diuretics are more effective than ACEI [ 39 ].

Beta-blockers are no longer first-line agents. They should be reserved for specific indications. For example, patients with hypertension and left ventricular systolic dysfunction will benefit from certain beta-blockers such as carvedilol, sustained-release metoprolol (metoprolol succinate), and bisoprolol.

Neal et al. enrolled approximately 21,000 subjects from rural china [ 40 ]. Participants had a history of CVA or were 60 years of age and were on hypertensives. Participants were randomly assigned to use regular salt (the control group), or a salt substitute (75% sodium chloride and 25% potassium chloride, the intervention group). After a follow up of 4.74 years, participants in the intervention group had a lower rate of stroke (HR, 0.86, 95% CI, 0.77-0.96), major CV events (HR, 0.87, 95% CI, 0.80-0.94), and death (HR, 0.88, 95% CI, 0.82-0.95). Hyperkalemia was not significantly higher in the intervention group. Systolic blood pressure was lower by 3.34 mm Hg (95% CI 2.18-4.51) in the intervention group. Serial potassium levels were not checked; therefore, the results of this trial should not be generalized to patients at risk of hyperkalemia such as those with CKD. Potassium could potentially have a role in the management of hypertension. Table ​ Table3 3 summarizes the major advances in hypertension discussed in this review.

RAAS: Renin-Angiotensin-Aldosterone Inhibitors; SPRINT: The Systolic Blood Pressure Intervention Trial; STEP: Trial of Intensive Blood-Pressure Control in Older Patients with Hypertension

Conclusions

Treatment with ACEI or ARBs does not confer increased risk in patients with COVID-19 and should not be interrupted. The pivotal SPRINT trial was the first study to show a significant decrease in morbidity and mortality in patients randomized to a lower SBP goal of (< 120 mm Hg). The prevalence of primary aldosteronism may be significantly larger than previously reported. Current guidelines that recommend plasma ARR as the preferred screening for primary aldosteronism may need to be reconsidered. Obesity is responsible for approximately two-thirds of the cases of primary hypertension. Aldosterone antagonists may play a role in the management of resistant hypertension in obese patients. Initial pharmacological treatment of hypertension should start with one or more drugs from the following four classes: thiazide-type diuretics, CCBs, ACEI, or ARBs. A recent trial expands the utilization of chlorthalidone for blood pressure control in patients with CKD-4. Isolated diastolic hypertension is potentially associated with a small increase in cardiovascular events. It is important to note that the findings of the trials presented are not generalizable to all patients population and the attending physicians should ultimately decide management based on individual cases.

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