Risk factors for the mortality of hepatitis B virus-associated acute-on-chronic liver failure: a systematic review and meta-analysis

Despite the availability of effective vaccinations against Hepatitis B virus (HBV) infection, this infection continues to be a serious public health problem worldwide [1]. 257 million people worldwide are subjected to chronic HBV infection, and 60,000 people worldwide die from chronic hepatitis B each year, as estimated by The World Health Organization (WHO). China has been reported as one of the areas with a high incidence of HBV, since nearly 30 million people in China are suffering from chronic HBV infection [2]. Approximately 20% of HBV chronic infection patients will progress to acute-on-chronic liver failure (ACLF), [3, 4] which is a devastating entity [5]. The core of ACLF suggests that a patient subjected to chronic liver disease will abruptly lose their present level of liver function in the event of an acute insult [6]. It is noteworthy that ACLF may occur at any point during chronic hepatitis B development [7].

To be more specific, hepatitis B virus-associated acute-on-chronic liver failure (HBV-ACLF) has been confirmed as a prevalent pattern of end-stage liver disease in patients subjected to chronic HBV infection, which is manifested as a fast worsening of preexisting chronic liver problems with multisystem organ failure [4, 8]. HBV-ACLF exhibits substantial short-term mortality, ranging from 40 to 80%, in accordance with the diagnostic criteria [9‐11]. It has been widely recognized that scores of variables can facilitate the advancement of HBV-ACLF. Numerous variables (e.g., infection [12, 13], COSSH-ACLF grade [14], and gastrointestinal bleeding [15]) have been reported as the risk factors for the mortality of HBV-ACLF in individual retrospective research. On that basis, discovering HBV-ACLF and encouraging the early diagnosis and treatment of this failure take on critical significance to lowering the mortality of HBV-ACLF.

Nevertheless, the effect and compelling evidence of possible risk variables have not been validated thus far. Moreover, the collection and analysis of the risk variables for HBV-ACLF mortality have never been the subject of a meta-analysis. Inspired by the above-described analysis, we conducted a systematic review and meta-analysis to determine and evaluate the risk factors for the mortality of HBV-ACLF.

Begg’s Test and Egger’s Test were performed to assess the publication bias of the included studies. Table 4 presents the results. In line with the findings of this meta-analysis, none of the risk variables had any publication bias (P > 0.05).

A substantial short-term mortality rate is present in the acute phase of HBV-ACLF. In this systematic review and meta-analysis, 22 case–control or cohort studies published from 2014 to 2022 were included and analyzed, with a sample size of 11,559 cases. As indicated by the results, INR, Monocytes, cirrhosis, HE, HE grade, SBP, hyponatremia, and HRS may serve as risk factors for the mortality of HBV-ACLF patients, such that evidence can be provided for reducing mortality.

This study has suggested that INR is the most relevant risk factor for the mortality of HBV-ACLF among the laboratory indicators. HBV-ACLF refers to a type of severe liver dysfunction. When liver functions are significantly compromised, plasminogen, a protein unique to the liver, would dramatically decline along with other coagulation factors. In theory, a drop in the plasminogen levels in individuals with HBV-ACLF should be accompanied by an elevation of the INR value due to the liver's decreased ability to synthesize proteins. HBV-ACLF patients will have greater mortality since the danger of excessive bleeding increases with the INR values [42]. Thus, it may be necessary that proper measures should be adopted to get the INR value back to normal, so as to lessen the effect of INR on the mortality of HBV-ACLF.

Moreover, systemic inflammatory response syndrome (SIRS) was reported as the main contributor by speculating on the potential mechanism of Monocytes as a risk factor for HBV-ACLF mortality. ACLF is considered a syndrome of innate immune dysfunction. As revealed by the pathophysiological basis of ACLF, significant tissue and organ damage primarily arises from a systemic hyperinflammatory condition. Tissue damage is made worse by the significant production of inflammatory mediators that causes immune-mediated tissue damage [43]. Dysfunction of monocytes and macrophages significantly affects the development of ACLF illness. Innate effector cells are drawn to the wounded liver since Kupffer cells are activated by pathogen and damage-associated molecular patterns. Early monocyte infiltration may facilitate local tissue degradation during the propagation phase and produce pro-inflammatory cytokines that trigger SIRS. After local reprogramming is completed, monocytes recruited in the hepatic milieu develop into macrophages to support resolution reactions and preserve tissue integrity [44, 45]. On that basis, Monocytes serves as a vital risk factor for the mortality of HBV-ACLF.

As indicated by the analysis of the mechanism for complication risk factors, cirrhosis arising from by HBV and renal impairment can account for the three complication risk factors listed. HBV has been reported as the main cause of liver cirrhosis among the Chinese [46]. In general, functional renal impairment occurs in severe cirrhosis patients [47]. Existing research has suggested that HBV-ACLF patients with cirrhosis are subjected to more extrahepatic organ failures and a less favorable outcome, i.e., more mortality [48]. Renal failure, the most frequent extrahepatic organ failure, is associated with systemic circulatory insufficiency and reduced renal perfusion in liver cirrhosis patients. Nephritis is likely to jeopardize renal microcirculation and cell function. Thus, it may also directly affect the development of the condition [49]. Cirrhosis patients often develop ascites. For patients with ascites attributed to cirrhosis, SBP has been reported as one of the most prominent infections, and it leads to dangerous consequences. SBP refers to an infection that develops in the abdominal cavity without a direct bacterial cause in nearby abdominal organs [50, 51]. The mortality may be increased under a higher frequency of detection of irreversible renal impairment, HRS, and gram-positive bacteria in ACLF patients with SBP [52, 53]. Previous research has suggested that ACLF patients with SBP have a 50% chance of dying within 28 days [54, 55]. Hyponatremia increased renal sodium retention and solute-free water retention can cause ascites and hyponatremia, and they are considered the characteristics of renal failure in ACLF patients. As revealed by an early investigation, the existence or lack of concurrent hyponatremia deeply affects the prognosis of ACLF patients. ACLF and hyponatremia patients exhibited a lower three-month death expectancy than those patients subjected to ACLF and hyponatremia [47, 56]. Hyponatremia in cirrhotic patients has long been considered a distinct risk factor for death. Hyponatremia has long been recognized as a separate risk factor for the mortality of cirrhotic patients. A secondary hyperaldosteronism condition has been reported in cirrhosis patients. Aldosterone, a mineralocorticoid hormone, can increase the number of open sodium channels to facilitate sodium reabsorption and potassium secretion. Furthermore, patients with advanced cirrhosis have a gradual vasodilatory condition that reduces the effective arterial blood volume and activation of the renin–angiotensin–aldosterone system (RAAS). Antidiuretic hormone and aldosterone result in ascites and hyponatremia through the retaining process of water and sodium [57].

Under the effect of renal failure, HRS, as an underlying mechanism, becomes a risk factor more pertinent to the mortality of HBV-ACLF compared with cirrhosis and renal impairment. The kidney is the organ in which extrahepatic organ failure most often occurs [58, 59]. HRS refers to a type of functional renal failure characterized by inadequate central filling, which arises from inadequate cardiac output, dilated visceral arteries, and systemic peripheral blood vessels. Arterial dilatation has been confirmed as the main pathogenic event in HRS, reducing effective blood volume, steadily activating the RAAS, and resulting in renal vasoconstriction by activating the sympathetic nervous system [60‐62]. HRS refers to a severe HBV-ACLF complication and serves as a strong predictor of high short-term and long-term death. Existing research has suggested that the 30-day mortality rate of HBV-ACLF patients without HRS just reaches 13.95%; besides, for HBV-ACLF patients with HRS, 57.14% pass away during the hospital's 30-day observation period [62]. Accordingly, it serves as a reminder that effective surveillance plans and prompt therapies for aberrant renal behavior are crucial.

HE serves as the second critical risk factor for the mortality of HBV-ACLF, and it is non-negligible. The presence of hepatic encephalopathy (HE) and the progression of its grade can lead to the increased death rate for ACLF patients [63]. In ACLF, HE has a significant mortality rate that is not reliant on other organ failures. Existing studies have suggested that ACLF patients have obviously increased intracranial pressure and mortality from cerebral edema [64]. Since glutamine synthetase is active in ACLF, hyperammonemia can increase intracellular glutamine content and osmotic pressure concentration, resulting in astrocyte swelling and increased oxidative stress. Hyponatremia is likely to cause a second osmotic assault on astrocytes, exacerbating intracellular edema [47]. A tiny percentage of ACLF patients develop symptoms (e.g., brain swelling). Younger cirrhotic, accompanied by severe liver dysfunction, a widespread inflammatory response, bacterial infections, excessive drinking, and dilutional hyponatremia are more susceptible to HE linked with ACLF [65]. Even though the exact mechanism of HE in ACLF remains unclear, ammonia and the body's inflammatory response may serve as key players [66].

This study still had several limitations. First, four databases were only searched, such that we could have omitted some relevant studies and data. Second, some included studies had a small size of sample that tended to generate bias and affected the reliability of the conclusion. Third, the results may deviate due to the intricate relationships between different risk variables and other factors.

In brief, HRS, HE, and HE grade are the most relevant risk factors for the mortality of HBV-ACLF, followed by INR and hyponatremia. Other important risk factors for the mortality of HBV-ACLF comprise Monocytes, cirrhosis, and SBP. Attention should be placed on all risk factors, and a wide variety of preventative or treatment methods should be implemented for distinct risk variables to lower the mortality of HBV-ACLF.