Pathophysiology and Management of Liver Cirrhosis PDF

TYPE Review PUBLISHED 15 June 2023 DOI 10.338...

TYPE Review PUBLISHED 15 June 2023 DOI 10.3389/fmed.2023.1060073 Pathophysiology and OPEN ACCESS management of liver cirrhosis: from portal hypertension to EDITED BY Golo Ahlenstiel, Western Sydney University, Australia REVIEWED BY Sith Siramolpiwat, acute-on-chronic liver failure Thammasat University, Thailand Ashwani K. Singal, University of South Dakota, United States Rakesh Kumar Jagdish1† , Akash Roy2† , Karan Kumar3 , *CORRESPONDENCE Madhumita Premkumar4 , Mithun Sharma5 , Padaki Nagaraja Rao5 , Anand V. Kulkarni [email protected] Duvvur Nageshwar Reddy5 and Anand V. Kulkarni5* 1 † These authors share first authorship Department of Hepatology, Gastroenterology and Liver Transplant Medicine, Metro Hospital, Noida, India, 2 Department of Gastroenterology, Institute of Gastrosciences and Liver Transplantation, Apollo RECEIVED 02 October 2022 Hospitals, Kolkata, India, 3 Department of Hepatology, Mahatma Gandhi Medical College and Hospital, ACCEPTED 19 May 2023 Jaipur, India, 4 Department of Hepatology, Post Graduate Institute of Medical Education and Research PUBLISHED 15 June 2023 (PGIMER), Chandigarh, India, 5 Department of Hepatology, Asian Institute of Gastroenterology (AIG) CITATION Hospitals, Hyderabad, India Jagdish RK, Roy A, Kumar K, Premkumar M, Sharma M, Rao PN, Reddy DN and Kulkarni AV (2023) Pathophysiology and management of Cirrhosis transcends various progressive stages from compensation liver cirrhosis: from portal hypertension to acute-on-chronic liver failure. to decompensation driven by the severity of portal hypertension. The Front. Med. 10:1060073. downstream effect of increasing portal hypertension severity leads to various doi: 10.3389/fmed.2023.1060073 pathophysiological pathways, which result in the cardinal complications of COPYRIGHT cirrhosis, including ascites, variceal hemorrhage, and hepatic encephalopathy. © 2023 Jagdish, Roy, Kumar, Premkumar, Sharma, Rao, Reddy and Kulkarni. This is an Additionally, the severity of portal hypertension is the central driver for further open-access article distributed under the terms advanced complications of hyperdynamic circulation, hepatorenal syndrome, and of the Creative Commons Attribution License cirrhotic cardiomyopathy. The management of these individual complications has (CC BY). The use, distribution or reproduction in other forums is permitted, provided the specific nuances which have undergone significant developments. In contrast to original author(s) and the copyright owner(s) the classical natural history of cirrhosis and its complications which follows an are credited and that the original publication in insidious trajectory, acute-on-chronic failure (ACLF) leads to a rapidly downhill this journal is cited, in accordance with accepted academic practice. No use, course with high short-term mortality unless intervened at the early stages. The distribution or reproduction is permitted which management of ACLF involves specific interventions, which have quickly evolved does not comply with these terms. in recent years. In this review, we focus on complications of portal hypertension and delve into an approach toward ACLF. KEYWORDS portal hypertension, liver cirrhosis, HVPG, acute-on-chronic liver failure, chronic liver disease 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. Frontiers in Medicine 01 frontiersin.org Jagdish et al. 10.3389/fmed.2023.1060073 2. Basic pathophysiological measurement, although access to the procedure at all centers is mechanisms of development of PH limited (11, 12). Patients with VH who have an HVPG > 20 mmHg should be evaluated for an early transjugular portosystemic shunt Central to the development of PH is the occurrence of (TIPSS) (13). 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 3.2. Risk factors for VH and risks associated from a combination of structural (fibrosis, nodule formation) and with re-bleeding functional alterations (6). The static or architectural changes behind the development of PH are driven by alterations VH from esophageal varices or gastric varices can result in in the interplay between hepatic stellate cells (HSCs) and high mortality (10–20% at 6 weeks) (3, 14). Other rare ectopic liver sinusoidal endothelial cells (LSECs). In response to any sites for VH (5 mm), higher HVPG, higher grade a phenotypic remodeling leading to capillarization of the of the child class, presence of red color signs (RCS) markings, sinusoids, thereby increasing intrahepatic resistance. Coupled active alcohol consumption, and presence of sepsis. There are with this, a dynamic component arising from myofibroblast also certain high-risk factors for re-bleeding, including a pressure contraction and decreased vasodilators like nitric oxide gradient measured within 24 h of bleeding more than 20 mmHg, further accentuate the resistance pathway (6, 7). These two presence of large varices, age ≥ 60 years, renal failure, and fundamental mechanisms lead to the progressive development severe initial bleeding (on admission, hemoglobin < 8 g/dL) of PH, leading to splanchnic vasodilation, neurohormonal (11, 15). disturbances, systemic vasodilatation, decreased mean arterial pressures (MAP), and an overall hyperdynamic state (8) (Figure 1). In combination with these, gut microbial alterations, increased 3.3. Management of acute variceal bleeding intestinal permeability, and systemic inflammation act as both precipitants and perpetrators of worsening PH and further The management consists of controlling acute bleeding to downstream complications (8) (Figure 2). In the following prevent death and prevention of re-bleeding. Hemodynamic sections, we elaborate on the individual consequences of PH and resuscitation is the initial treatment considering patient age, co- their management. 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 3. Variceal hemorrhage resuscitation can worsen PH and bleeding (16). INR-based corrections with fresh frozen plasma, factor VII transfusion, 3.1. Development of varices and platelet, cryoprecipitate, or other blood products are not warranted importance of hepatic venous pressure (17, 18). Moreover, overzealous use of these products can be gradient harmful due to the increase in PH due to volume overload or transfusion-related lung injury (14, 19). After gastrointestinal Resistance to portal blood flow and increased portal venous (GI) bleeding, blood acts as a culture media to grow infections; blood inflow result in the reversal of flow and formation of therefore, adequate purging should be done to prevent post-bleed alternate blood flow channels between the portal and systemic sepsis, HE, ascites, or other complications of PH. Post-bleed sepsis circulation, which result in varices. The development of varices can increase mortality; thus mandating the use of antibiotics acts as a surrogate marker of PH and signifies clinically significant during bleeding events as per local antibiograms. Currently, third- portal hypertension (CSPH). HVPG is the closest surrogate marker generation cephalosporins are recommended (ceftriaxone 1 gm IV of actual portal pressure and PH, with the presence of PH every 24 h for 7 days) (20, 21). Vasoconstrictors should be started being defined as an HVPG > 5 mm Hg, while a value of >10 as early as possible in VH, along with proton-pump inhibitors. mmHg signifies CSPH (9) (Table 1). In patients with VH, an Vasoconstrictors should be continued for at least 2–5 days (15). HVPG > 20 mmHg (measured within 24 h after admission) Somatostatin, octreotide, and terlipressin are the recommended is the best predictor of a poor outcome. A reduction in the agents with comparable efficacy and safety (22). HVPG < 12 mm Hg or a reduction of more than 20% from Endoscopy-based endotherapy is definitive in managing VH the baseline value has been associated with a decreased risk and should be done within 12 h after hemodynamic resuscitation of VH and improved survival (10). HVPG > 20 mm Hg has (23). Prokinetics (intravenous erythromycin) and anti-emetics been associated with a 5.21-fold likelihood of rebleeding, and should be given before the endoscopy for better visualization (24). reducing HVPG below this threshold using a vasoactive drug Patients with altered mentation, severe sepsis, shock, and acidosis improves outcomes. Patients with HVPG > 20 mmHg or 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 3.5. Primary prophylaxis of VH with or without NSBB or prophylactic cyanoacrylate injection is suggested in addition to NSBB. For patients with low-risk Non-selective beta-blockers (NSBBs) or EBL are the GOV2/IGV1 (10 carvedilol was introduced, which has a better profile than Bleeding from varices >12 propranolol. The addition of carvedilol to EBL than propranolol Relatively no chances of re-bleed 20 patients with refractory ascites (RA) and/or VH, but controversies Early TIPS >20 in advanced decompensated patients with ascites remain (41). CSPH, clinically significant portal hypertension. TIPSS is traditionally performed for patients with refractory FIGURE 3 Treatment of variceal hemorrhage. HE, hepatic encephalopathy; IV, intravenous. Frontiers in Medicine 04 frontiersin.org Jagdish et al. 10.3389/fmed.2023.1060073 bleeding who fail EBL + NSBB. A recent study on early TIPSS (stent followed by loop diuretics) (54). Use of albumin replacement and placement within 5 days of variceal bleed) has shown significant increased oral protein intake helps ascites mobilization. A recent mortality benefits with a substantial reduction in the recurrence pilot study has shown that early use of midodrine for a short of variceal bleeding without increasing the risk of HE (42). In course can control ascites better than diuretics alone, with a lesser gastric variceal bleeding, TIPSS has been shown to prevent gastric occurrence of diuretic complications (55). variceal re-bleeding in patients with high HVPG (43, 44). BRTO, RA: A weight loss of 5 L) with results in intrahepatic vasoconstriction and peripheral vasodilation, albumin infusion (8 gm/L of ascites removed) is the recommended including splanchnic vasodilation, which results in hypoperfusion therapy to relieve the symptoms. However, LVP is associated with of the renal system, even when the patient is euvolemic or the risk of paracentesis-induced circulatory dysfunction (PICD), hypervolemic (52). This state of relative hypovolemia due to which is mitigated with concomitant albumin usage. In a network vasodilation results in the activation of the renin-angiotensin- meta-analysis, midodrine was reported as superior to albumin aldosterone system (RAAS) and sympathetic nervous system in preventing PICD (55, 58, 59). NSBBs are contraindicated in (SNS), leading to salt and fluid retention (50). This leads to the patients with RA requiring LVP due to compromised cardiac retention of blood and a significant rise in blood volume leading performance (60). Midodrine, an alpha-1 agonist, is beneficial in to filtration from the liver surface and the mesenteric vessels. High RA as it increases urine sodium loss and urinary volume (61, 62). hydrostatic pressure, low oncotic pressure (hypoalbuminemia), By reducing endotoxemia, rifaximin may offer an additional benefit and increased vascular permeability contribute to increasing in RA (63). Tolvaptan is beneficial in ascites control with survival filtration through mesenteric vessels. The resorptive capacity of the benefit (64). However, tolvaptan has a black box warning as it peritoneum and lymphatics cannot counteract these mechanisms can cause or precipitate bleeding episodes by platelet aggregation (53). Any inflammation or infection of the peritoneum can affect inhibition and depleting vitamin-K-dependent clotting factors and peritoneal resorption. Dysregulation of these can lead to an increase has a risk of liver injury (65). Therefore, its use should be cautious in ascitic fluid formation. 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 4.1. Management of ascites (HRS) and RA, helps in ascites control by mobilizing ascites and increasing renal perfusion, glomerular filtration rate (GFR), and The foremost important part of the treatment of ascites is urinary sodium excretion (66). Long-term albumin administration sodium restriction (salt intake of 6 h in patients with cirrhosis and ascites in the absence of other with cirrhosis are termed type C. HE is graded as per West- evident cause for acute renal injuries such as proteinuria, shock, or Haven criteria. HE can be covert [minimal HE (MHE) and Grade nephrotoxins is termed HRS-AKI (76). I HE], which needs to be identified with the help of specialized Recently, there has been a suggestion for a change in neuropsychological tests. Covert HE is reported among 80% of terminology, with previous terms like HRS-1 and HRS-2 being patients with advanced liver disease, while overt HE is reported replaced by more physiologic HRS-AKI, HRS-acute kidney disease among 40% (86). Overt HE can be new onset, episodic, with (AKD), and HRS-chronic kidney disease (CKD). The estimated an interval between episodes of >6 months, or recurrent, where incidence of HRS is around 18% at 1 year and 39% at 5 years and is further episode occurs within 6 months. Persistent HE refers associated with an inferior median survival of ≤3 months without to an uncommon entity with no resolution of HE. Refractory a transplant (51, 56). HE (lack of response after treatment of precipitants and on Although several medical management options remain in treatment with lactulose and rifaximin for 48 h) is an uncommon HRS, LT is the definitive therapy. Vasoconstrictors (terlipressin, but serious condition and requires active investigation into octreotide in combination with midodrine and noradrenaline) hidden precipitating events (i.e., portosystemic shunt) and requires and albumin infusion are the cornerstones of the treatment of alternative diagnosis to be ruled out (87). Important alternative HRS. The crux of HRS therapy still revolves around an attempt causes include septic encephalopathy (23%), alcohol withdrawal, to rule out other causes (infections, glomerular disease, shock, seizure, dyselectrolytemia, metabolic disorders, drugs/toxins (7%), and acute tubular necrosis) concomitant with volume expansion intracranial structural lesions (5%), psychiatric disorders (1%), and with albumin for 48 h followed by initiation of vasoconstrictors. multiple causes together (8%) (88). Frontiers in Medicine 06 frontiersin.org Jagdish et al. 10.3389/fmed.2023.1060073 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. 6.1. Pathophysiology of HE and effect of valve,” a compensatory mechanism to reduce the portal pressure ammonia and bypass normal liver flow. More than 90% of patients with large SPSS have enlarged spleen, hepatic atrophy, and thrombocytopenia Alterations in neurotransmission and brain–blood barrier (93). Identification of these shunts is essential as these need to be coupled with persistent neuroinflammation and oxidative stress, ligated at the time of liver transplant, or else the patient can have apart from GABA-ergic or benzodiazepine pathway abnormalities, persistent HE, even after liver transplant. 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 6.2. Management strategies in HE which exerts its systemic effects and neurotoxicity through multiple pathways, including astrocyte swelling, inflammation, oxidative Correct identification of the precipitant is the key to stress, mitochondrial permeability alterations, alteration in energy the management of HE. Non-absorbable disaccharidases kinetics, and membrane potential alterations (89). Despite this (lactulose/lactitol) are the first-line therapy. Adding polyethylene implicating pathophysiological basis, no direct correlation has glycol to non-absorbable disaccharidases leads to earlier, been established between the severity of HE and ammonia sustainable improvement in HE with survival benefits (94). concentrations. However, it is imperative to state that in the Studies have shown a positive role of rifaximin and intravenous presence of a normal ammonia level, the diagnosis of HE is almost L-ornithine L-aspartate (LOLA) in overt HE management (95, 96). always an exclusion. Diet and calorie requirements must be met, especially for A venous ammonia level of >55 µmol/L is 47% sensitive and patients with altered mentation who cannot take orally. Adequate 78.3% specific to diagnose HE (90). Other studies have identified a calories (35–45 kcal/kg/day) and protein (1–1.5 gm/kg/day) are blood ammonia level cutoff of >133 µg/dl as a diagnostic of HE. essential to improve overall nutritional status. BCAA may be Arterial ammonia is an excellent surrogate marker for the severity beneficial as they are metabolized in muscle and brain and of HE in ACLF in advanced stages, and an ammonia level above promote protein synthesis, suppress protein catabolism, and 140 µg/dl at baseline or at any time point in first week with grades act as gluconeogenesis substrates (97). Rifaximin is an oral III–IV HE serves as a poor prognostic marker for 28- and 90- antibiotic with minimal absorption (