Work-up for the acute insult and underlying chronic liver disease:
The likely acute insult and the chronic liver disease were thoroughly investigated (supplementary text). The acute insult was evaluated for viruses [HAV, HEV, HBV, HSV, and EBV (when clinically suspected)], flare of autoimmune hepatitis (ANA, IgG), and drug induced liver injury (history and temporal association), flare of Wilson’s disease, malaria, leptospira or dengue (if strong clinical suspicion existed) or sepsis. Active alcohol consumption within the last 4 weeks prior to presentation was considered as an acute insult, i.e. severe alcoholic hepatitis (SAH) if they had DF Score >32 and satisfied the AARC criteria. The work-up for chronic liver disease included etiology [viral, autoimmune, NASH, Wilson’s, cholestatic (PSC, PBC, Overlap, etc] and presence of underlying cirrhosis and portal hypertension. The diagnosis of cirrhosis was based on a composite of clinical signs, laboratory tests, endoscopy, and radiologic imaging with/without liver biopsy, if available. In a proportion of patients, transjugular liver biopsy (TJLB) was done for the diagnosis, particularly when the etiology of acute and chronic insult was uncertain.
Patient management and organ support:
All patients received nutritional support with a target of 1.5 grams of protein/kg and 30-35 Kcal/kg/day as oral, enteral tube feeding (in case of poor oral intake) in addition to nutritional supplement. The patients were closely observed for events, i.e. variceal bleed, HE, sepsis, extra-hepatic organ failure(s), such as renal, respiratory and cardiac failure. Acute variceal bleed was managed by endoscopic band ligation and vasoactive drugs. Coagulopathy was corrected only in the presence of active bleeding, recent bleeding with deranged coagulation tests. Prophylactic correction of coagulation parameters was not undertaken. AKI was managed with intravenous albumin administration with or without terlipressin infusion. Renal replacement therapy by Slow Low Efficient Dialysis (SLED) was considered in cases unresponsive to above therapy or with progressive azotemia, anuria, overload or metabolic acidosis. HE was managed by ammonia lowering therapy, bowel lavage and elective endotracheal intubation in grade III-IV HE. Patients were supported for acute lung injury (ALI) or ARDS initially with noninvasive ventilation (NIV) followed by mechanical ventilation upon failure to achieve effective ventilation or with worsening respiratory distress. Sepsis screening was done by peripheral blood culture, urine routine, microscopic examination and culture, sputum or tracheal aspirate/ bronchoalveolar lavage (BAL) sample (if on mechanical ventilation) for gram stain, KOH stain for fungal and culture, chest x-ray, ascitic fluid analysis and serum procalcitonin. The screening was done at baseline, day 4, 7 and 15, in addition to on-demand screening based on clinical suspicion. All the patients received prophylactic antibiotic at admission and, it was upgraded if sepsis was suspected or confirmed as per the institute’s antibiotic policy or based upon the microbial sensitivity pattern. Septic shock was managed with fluid resuscitation, escalation of antibiotic(s), and administration of noradrenaline as a vasopressor and addition of terlipressin as second agent as and when required. The patients were followed-up for 28 days, death or till liver transplantation, which ever was earlier. Etiology specific treatment was given to patients like HBV reactivation or HBV related CLD with nucleoside analogue (entecavir or tenofovir, as per center protocol), autoimmune hepatitis flare (prednisolone 40mg once daily for 4 weeks, tapering in another 4 weeks to 10mg as maintenance, add on azathioprine 1-2mg/kg in two divided doses with bilirubin below <3mg/dl), Wilson’s flare preferentially considered for transplant with therapeutic plasma exchange as a bridging to transplant, Severe alcoholic hepatitis i.e. DF >32 considered fro steroid therapy i.e. prednisolone 40mg once daily for 7 days followed by Lille’s score to define responders, nonresponders considered for standard of care therapy). The treatment is agreed upon by all the centers and the respective ethical committee had approved the same.
Study Definitions- (please see the supplementary text)
Acute on Chronic Liver Failure (ACLF) was defined as acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy, in a patient with previously diagnosed or undiagnosed chronic liver disease associated with high 4week mortality [2].
Organ failure: The organ failure was defined by CLIF- SOFA score [3] which had been developed much after the present study was initiated. We applied this score during the analysis of the ACLF data.