Acute on Chronic Liver Failure (ACLF) denotes an acute deterioration of liver function in patients with Chronic Liver Disease (CLD). In individuals with pre-existing chronic liver disease, acute-on-chronic liver failure (ACLF) is a clinical syndrome of abrupt hepatic decompensation linked to one or more extra-hepatic organ failures and a higher risk of death [1-2]. The hallmark of ACLF is a rapidly worsening course of a chronic liver disease that may be reversible and has either been previously recognized or is unknown [3]. With a range of 50 to 90%, ACLF has a significant short-term mortality rate [4]. There are now two primary working definitions of ACLF that are agreed upon. "Acute hepatic insult manifesting as jaundice (defined as serum bilirubin level >5 mg/dl) and Coagulopathies (defined as international normalized ratio >1.5), complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease," is how the Asia Pacific Association for the Study of Liver (APASL) defined ACLF [5]. "Acute deterioration of pre-existing chronic liver disease usually related to a precipitating event and associated with increased mortality at 3 months due to multi-system organ failure [6]" is the alternative definition of ACLF provided by the European Association for Study of Liver (EASL)-American Association for Study of Liver Disease (AASLD) in 2013. Since ACLF is a dynamic illness, it may get better, get worse, or have a mild, protracted course that enables us to assess the possibility of a liver transplant. The prognosis is unaffected by the aetiology of the precipitating trigger that causes ACLF [7]. One of the hallmarks of ACLF is systemic inflammation. For this reason, individuals with ACLF have greater white cell counts, plasma levels of C-reactive protein (CRP), and pro-inflammatory molecules such interleukin (IL)-6, IL-1β, and IL-8 than patients without [8, 9]. Both viral and non-infectious precipitating factors can occur in ACLF. Reactivation of hepatitis B virus (HBV) infection, particularly in the Asian region, is a common infectious aetiology. Hepatitis E virus infection, particularly in the Indian subcontinent, is also widespread [10]. Although bacterial infection has been identified as a major contributing factor to the development of ACLF in the West, it is not included in the APASL definition as a precipitating event. Hepatotoxic medications, herbal indigenous remedies, acute variceal hemorrhage, and major surgical procedures are among the non-infectious aetiologies that contribute to ACLF [11].

Aims & objectives: The present study asses the various precipitating events, underlying chronic liver disease, the clinical and biochemical spectrum and also the factors predicting mortality in ACLF patients

This was a prospective cross-sectional study conducted in the collaboration of Department of medicine and biochemistry in a tertiary care Indian hospital. Based on the Asia-Pacific Association for the Study of the Liver (APASL) criteria [12], 200 patients with ACLF were included in the study.

Inclusion criteria:

• Patients age>118 years and both gender
• Patients diagnosed as ACLF according to APASL criteria
• Patients who provided written informed consent for the study

Exclusion criteria:

• Patients were under the age of 18 year
• Pregnant women, portal vein thrombosis and hepatocellular cancer patients
• Patients who unwilling to take part in the study

All subjects meeting the eligibility criteria were included in the study Data were recorded patients demographic characteristics, Body Mass Index (BMI), clinical presentation, aetiology, precipitating factors, laboratory results, and endoscopic features. Nutritional assessment score were used to assess nutritional status.  The presence of precipitating factors such as alcoholic hepatitis, infection, drug toxicity, acute hepatitis A and E virus infection, and acute flare-up of chronic hepatitis B was further assessed in patients with ACLF.

These patients underwent estimation of haemogram, liver function tests, renal function tests, serum electrolytes (Na/K), viral serology (HIV/HBsAg/Anti-HCV/IgM HAV/IgM HEV), and urine routine / microscopic examination, chest X-ray and ultrasonography abdomen.

All laboratory parameters were compared between the ACLF and non ACLF groups.

Statistical analysis: All the data were entered on a excel sheet. Statistical analysis was done by SPSS 22 software. Mean and median were calculated for appropriate variables. Variables significant by univariate analysis were again compared by multivariate analysis. P value <0.05 was taken as significant.

A total of 200 patients diagnosed as ACLF were enrolled and analysed in this study. Majority of the patients (46%) were more than 50 years age group with mean age was 42.6±5.3 years. Majority were males (87%), most of them (61.5%) were resided at rural areas and 45% belong to lower socio-economic class. 44% patients had education up to primary school and 41.5% had overweight.

Table 1: Socio-Demographic features, among ACLF patients at admission

The common clinical presentations are summarized in graph 1. Jaundice was present in all (100%) cases, acute onset ascites was seen in 94.3% patients. esophageal varices (>grade 2) were seen in 66%, Splenomegaly was seen in 60%, Hepatic encephalopathy was seen 46%, severe malnutrition in 32% cases, hepatomegaly 30% and fever in 20% patients.

Graph 1: Clinical presentation and prognostic variables among ACLF patients

Aetiology of underlying CLD

Major aetiology of the underlying cirrhosis was chronic alcohol use (85.7%), followed by HBV infection in (8.2%) and cryptogenic (3.5%) patients (Table 2).

Table 2: Aetiology of the underlying chronic liver disease in all patients

HBV: Hepatitis B Virus related, HCV: Hepatitis C virus related, AIH: Autoimmune Hepatitis related

Precipitating insults

In the ACLF patients, cause of acute insult among Chronic Hepatitis B related cirrhosis was acute flare of Hepatitis B in 60% patients, alcohol hepatitis in 46.6% among alcohol related cirrhosis. Sepsis was diagnosed as precipitating factor in 28.9%. Recent use of drugs was attributed to 44.8%. Hepatitis A was seen in 2% and Acute Hepatitis E in 1.2%. In ninety eight (40%) patients, multiple acute predisposing insults were identified of which 32.2%, 2 simultaneous insults and 19 (7.7%) patients had had 3 or more insults. Ninety eight patients (40%) had single acute insult. In forty nine patients (20%) no precipitating factor could be identified. Mortality in patients with multiple insults was significantly higher than patients with single insult.

Graph 2: Precipitating factors in ACLF patients

SBP: Spontaneous Bacterial Peritonitis, UTI: Urinary Tract Infection, HRS: Hepatorenal Syndrome, UGIB: Upper Gastrointestinal Bleed.

Biochemical parameters

Among the laboratory parameters, significantly high mean bilirubin level was seen among ACLF 11.4±6.8 mg/dl. Seventy one patients (28.9%) had leukocytosis (>12 x 103/uL), blood, mean leukocyte count 10.4 6.6 (103/uL) blood, but infection was documented in only 17/71patients (23.9%), 8/71 patients (11.2%) had positive ascites culture, 3/71 (4.2%) had positive sputum culture, 6/71 patients (8.4%) had positive urine culture and no patients had positive blood culture.

Table 3: Biochemistry in patients with ACLF and Non ACLF

AST: Aspartate Transaminase, ALT: Alanine Transaminase, ALK phos: Alkaline phosphatase, INR: International Normalized Ratio, TLC: Total Leukocyte count

Majority of patients with compensated cirrhosis progress to decompensated disease, which is characterized by jaundice, coagulopathy. Four stages of cirrhosis are: First is cirrhosis without either varices or ascites, second is compensated cirrhosis with varices that have not bled, third is ascites without bleed, fourth is variceal bleed. Cirrhosis with sepsis has been proposed as the fifth stage of cirrhosis. ACLF occurs as a natural history of chronic liver disease. There is a risk for multiple organ failure and an increased mortality [13].

In this prospective study, majority of the ACLF patients were elderly males, similar findings were reported by Makhija S [14] and Duseja A, et al [15].

All of the cases in our study had underlying cirrhosis, and the most common cause of this condition was alcohol consumption, followed by persistent Hepatitis B Virus infection, in agreement with the Nishant Saxena et al [16] and Khatun UF, et al [17], observed that Alcohol is the most common cause of underlying liver cirrhosis in their research.

In our analysis, the most frequent precipitating factors were hepatitis B flare-ups, which occurred mainly with hepatitis B infection followed by alcoholic hepatitis, drug-induced hepatitis, and sepsis. According to a study by Garg et al [18], 85% of the cases were caused by a Hepatitis B flare. However, the majority of literature lists sepsis, upper gastrointestinal bleeding, and alcoholic hepatitis as the typical precipitating factors [19-20].

In the present study the common clinical presentation are Jaundice (present in all cases), followed by acute onset ascites. Esophageal varices (>grade 2), Splenomegaly, hepatomegaly, Hepatic encephalopathy, severe malnutrition, and fever, our results were comparable with the Bhattacharyya M, et al [21] and Kumar R, et al [22].

Acute insult was caused by alcoholic hepatitis in 46% of our ACLF patients, which is consistent with research by Dhiman RK, et al [23].

The current clinical definition of sepsis and SIRS may not be totally appropriate due to hyperdynamic circulation and portal hypertension; consequently, a high index of suspicion and cautious consideration were employed to diagnose sepsis in our patients. Fever, SIRS, and a high total leukocyte count were considered, our report was concordance with the Das AK, et al [24].

Duseja et al from Chandigarh found alcohol as the most common insult followed by viral hepatitis and autoimmune hepatitis [25]

In our study biochemical parameters like serum bilirubin, AST, ALT and alkaline phosphatase were significantly higher among ACLF patients as compared to non ACLF patients, our results were correlates with the a study done by T K Anand, et al [26].

Patients with alcoholic liver disease are more prone for infection and its complications. It has been observed by Mookerjee et al [27] that these patients have defective neutrophil function and phagocytosis. These neutrophils show increased oxidative burst means there is a functional failure.

In addition to producing multi-organ failure, acute triggering insults further injure the liver, which has underlying chronic liver disease, making ACLF a devastating condition that frequently results in high mortality. Finding the modifiable triggering factors and organ failure as soon as possible is crucial to improving patient outcomes because multiorgan failure has been linked to a death rate of about 90%. Since current therapy approaches are symptomatic, a more accurate description of the illness will help future researchers create novel management plans.

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