Acute Liver Failure: Indian Perspective.

Abstract

Content available: Author Interview and Audio Recording Acute liver failure (ALF) is an infrequent, unpredictable clinical sequela of acute liver injury (ALI) in an individual without any previous history of liver disease and is associated with a mortality rate of 50% to 75%.1 Encephalopathy subsequent to ALI (icterus) is the usual presentation in ALF, and coagulopathy (international normalized ratio [INR] >1.5) is frequent.1 The etiology of ALF is geographically distinct with varying icterus-encephalopathy interval (IEI), from 4 weeks in India to 26 weeks in the United States.2 In the United Kingdom, United States, and Europe, ALF etiology is heterogenous (paracetamol, nonsteroidal anti-inflammatory drugs [NSAIDs], autoimmune hepatitis [AIH], and metabolic diseases).2 In India, ALF has a homogeneous etiology (hepatitis virus in 90%).1, 2 Etiology influences phenotypic presentation. In the United Kingdom, Japan, and France, ALF with IEI of 1 week or 10 days had significantly higher survival than with IEI of longer than 1 week or 10 days, leading to subclassification in ALF as hyperacute (IEI ≤ 7 days), acute (IEI > 7 days to ≤4 weeks), and subacute (IEI of 5 to ≤12 weeks).3 In India, as a result of homogenous etiology, rapidity of encephalopathy does not influence survival, and all ALF cases have IEI of ≤4 weeks. Therefore, the Indian National Association for the Study of Liver (INASL) consensus in ALF defines it “as a clinical syndrome characterized by encephalopathy, jaundice, and prolonged prothrombin time (international normalized ratio >1.5) developing in a patient without pre-existing liver disease within 4 weeks of the onset of symptoms. A few patients presenting with severe acute liver injury, mostly due to drug induced liver injury (DILI), may develop encephalopathy after 4 to 8 weeks.”1 Hepatitis viruses are frequent causes (60%-90%) of ALI and ALF in India. The drugs implicated in ALF are predominantly antituberculosis drugs (ATDs; 5%-15%). Complementary and alternative medicines (CAMs) and rat poison containing yellow phosphorous have been recently documented to cause ALI and ALF in South Indian states. However, cryptogenic causes presenting with similar phenotype (non-A/non-E viral infection) account for a substantial proportion of ALF (Table 1).1 India is endemic for feco-orally transmitted hepatitis A virus (HAV) and hepatitis E virus (HEV). They are the most frequent causes of ALI and ALF. In epidemics of HEV outbreaks, ALF was documented in 1% to 2% of affected people with predominant predilection in pregnant females (10%-17%), of whom about 22% develop ALF.4 In sporadic setup, the HEV among ALF is frequent (15%-45%), but in those with pregnancy, HEV frequency was reported in about 60%.1 HAV is not an uncommon cause in India. The proportion of HAV-ALF has regional variation. There has been an increase in the incidence of ALF caused by HAV infection over the last two decades (Table 1) because of improved hygiene resulting in a decrease in childhood exposure to HAV leading to regionally varied increases in nonimmune adolescents and adults. Hepatitis B virus (HBV) is an infrequent cause of ALF in India. Hepatitis C virus and hepatitis D virus have not been reported as a cause of ALF. About 15% to 47% of patients with ALF in India do not have identifiable serological markers of known acute hepatitis virus infection despite similar clinical phenotype to HEV or HAV ALF and have been named as non-A/non-E ALF and summarized in the INASL consensus on ALF.1 In India, ATDs, CAMs, antiepileptics, sulphonamides, and antiretrovirals are associated with drug-induced ALF.1, 5 ATD-induced ALF constituted three-fourths of all DILI in a large single-center series and 63% in the Indian Network for Drug-Induced Liver Injury (INDILI).5, 6 ALF caused by paracetamol drug–induced hepatotoxicity is rare in India.5, 6 The INDILI was started in 2013 under the aegis of INASL. Data were collected from various tertiary care centers all over India in a predesigned case record form and sent to St. John's Medical College Hospital, Bangalore, which was the nodal center for the INDILI. Recently, the INDILI has reported the prospectively collected information from 2013 to 2018, which provides the details on their methods of diagnosis (based on criteria adopted by international DIII expert group and causality assessment by Roussel Uclaf Causality Assessment Method model), etiology, clinical presentation, outcome, and prognostic markers in Indian patients with DILI (n = 1288).5 In this study, the most frequent causes of DILI in chronological sequence were combination ATDs (46.4%), CAMs (13.9%), antiepileptic drugs (AEDs; 8.1%), non-ATD antimicrobials (6.5%), antimetabolites (3.8%), antiretroviral drugs (ARTs; 3.5%), NSAIDs (2.6%), hormones (2.5%), and statins (1.4%). About 10% of the patients with DILI had or progressed to ALF, and among these patients with ALF (n = 124), the most frequent etiology was ATDs (63%), CAMs (12.1%), AEDs (8.1%), other drugs used for central nervous system disorders (3.2%), Dapsone (2.4%), ARTs (3.2%), and infrequently other drugs (chemotherapeutic agents, hormones, methotrexate, NSAIDs, and statins: 5%). Although overall mortality rate among the total cohort of DILI was 12.3%, the same for DILI-ALF was 64.8%. Even though the demography and clinical and laboratory parameters were similar among the causes of DILI, the severity of liver injury and mortality varied as per etiology of DILI (ATD, 15%; AED, 15.5%; CAM, 13.6%; antibiotics, 5.8%; and NSAIDs, 0%). Further, CAM also has been implicated as a leading cause of ACLF in India.7 ATD and CAM were DILIs unique to India, causing most frequently DILI and DILI-ALF. Age and sex, unlike reported from Western countries, were not identified as risk factors in the above study; rather, it reported DILI in predominantly in young males. However, those with ALF had a female predominance. Even though the exact CAM responsible for DILI could not be specified in the earlier study, the possibility of types of CAM in India is discussed in the following section.5 Alternative systems of medicine (ASM)–induced ALF is more frequently being recognized in India. The INDILI also found CAMs and ASMs to be the second most common cause of DILI and drug-induced ALF.5 The combination of various herbs as ayurvedic medicines is the commonest form of CAM in India, but other indigenous medicines, such as Unani, are also frequently consumed. CAMs also have been reported to be one of the not infrequent causes of DILI from countries such as Spain (3.4%), the United States (16.1%), and Iceland (16%).8 In the latter countries, CAM is consumed as a weight-reducing agent available as food supplements, whereas in India, often it has been used for various ailments such as dermatological problems, arthritis of various etiologies, and many chronic nonspecific disorders as well, as in advanced cancers (particularly in rural India, as well as because of unaffordability of expensive modern western medicine/surgery and failure of later form of treatment) and for simple well-being. However, recently from the United States and Iceland, ayurvedic drug–induced DILI has been reported, which had a mixed pattern (hepatitic and cholestatic) of liver injury and recovered within 1 to 5 months, but ALF as a result of ayurvedic medicines from these countries has yet to be reported.9, 10 A recent case series and review on ayurvedic drug–induced DILI from the United States mentions that, from 2002 to 2021, consumption of ayurvedic medicine in the United States has increased by 57%.9 The later report implicated Giloy Kwath (Tinospora cordifolia), combination of Manjishthadi Kwatham and Aragwadhadi Kwatham (containing 52 and 10 individual plant extracts, respectively), and Kanchnar Guggul (containing 10 individual plant extracts) as the ayurvedic medicine causing DILI in the reported case series.9 Ashwagandha (root of Withania somnifera) is another ayurvedic therapy used for mood elevation and alleviation and chronic fatigue that has been reported to cause DILI in Japan and Iceland.10 Other causes, such as Wilson’s disease, acute fatty liver of pregnancy, AIH, amanita poisoning, and Budd-Chiari syndrome, are rarely found to cause ALF.1, 2 Rat poisons that contain yellow phosphorous (3% phosphorous, 15 g) have been implicated in causing ALF in South India. Rat poison is accessible as a rodenticide in rural south India, and subsequent to its accidental consumption or suicidal intent causes ALF.1 Among 450 patients with rat poison ingestion, 57% had ALF, with mortality in one-third.11 This study also suggested a promising role of standard volume plasma exchange in these cases. In a report of 1462 consecutive cases of ALF over 30 years,12 the survival in HEV-ALF (55.1%) was significantly higher (P < 0.001) than other ALFs (ATD: 30.0%; non-A/non-E: 38.1%; HBV: 35.9%). There were no significant differences in survival in the later groups. There was a trend toward improved survival in HEV-ALF over the past three decades (1986-1995: 50%; 1996-2005: 54.9%; 2006-2015: 61.5%). In India, among the general population, about 933 females for every 1000 males exist, and approximately 3% of females are pregnant at any time.1, 2, 4 In contrast with such sex distribution, reports on ALF documented a female preponderance (50%-60%), and about half of them were pregnant, with 60% of ALF cases caused by HEV alone. Pregnant women in India with ALI are at high risk for ALF. HEV infection is more frequent among the pregnant population and is a common cause of ALF in pregnancy in India, particularly in the third trimester. The prognosis of ALF in pregnancy is similar to that in the nonpregnant/male ALF population and is independent of the etiology of ALF or the trimester of pregnancy. ALF in India affects young people.1, 2, 12 In the study mentioned earlier (n = 1462), the median age was 25 years (females: 56%).12 All of the patients had an IEI of 2 to 10 days, with advanced encephalopathy (West Haven classification grade >II) in 70% and overt cerebral enema in 50%. Median hospital stay was 5 days (3-10 days), within which half survived and half died. During hospitalization, infection documented by microbiological/radiological/clinical method was present in 40% with predominant gram-negative bacteria, and the commonest site was the respiratory tract. Gastrointestinal bleed and renal failure were infrequently documented in 10% and 15% patients, respectively. In most reports from India, irrespective of the etiology, similar observations have been reported except in drug-induced ALF where encephalopathy infrequently has been documented to occur at up to 8 weeks of onset of icterus. In India, infections such as Plasmodium falciparum, dengue, scrub typhus, and leptospirosis, are common and not infrequently present with liver involvement (biochemical and clinical) with altered sensorium mimicking ALF; they need to be differentiated by specific clinical characteristics and laboratory investigations (Table 2).1 Liver transplant is an established treatment in ALF with a long-term survival rate of 80%.1 Prognostic models identify those to be transplanted or to be treated medically. Popular prognostic models used frequently are King’s College Hospital criteria, Clichy criteria, and Model for End-Stage Liver Disease (MELD) score, which are scores determined at baseline. However, in India, ALF usually occurs as a result of ALI over naive liver, and liver regeneration is critical for the outcome; therefore, depending on the later process, the course of ALF is dynamic, and various parameters are documented at baseline, that is, changes over subsequent days resulting in lower sensitivity and specificity of the western prognostic models mentioned earlier. Indian studies described various prognostic models,1 and the recently described the Acute Liver Failure–Early Dynamic (ALFED) model,13 which assesses dynamicity of various parameters associated with mortality or survival, seemed to be more appropriate (Table 3 and Fig. 1 explain the components of the ALFED model).12, 13 In Indian patients with ALF, the ALFED model was documented to be better than the models described from the West (Fig. 2).13, 14 Management of ALF in India has been recently provided in the form of INASL consensus guidelines15 and is being invariably followed in all regions in India. The essential components of management remain similar as in other parts of the world, including high-volume plasma exchange (HVP), which has been shown in recent trials to improve survival in Indian patients.16 The ALFED prognostic model also has been recommended by the INASL to be the criteria to select patients for transplant in ALF. As mentioned earlier, rat poisoning is an important cause of ALF in south India, and HVP in these patients has shown to be promising. Currently, about 1000 liver transplants are being performed in the country; 85% of them are living donor liver transplant, and 5% to 7.5% of them were ALF with a survival rate of 80% at 1 year.17, 18 ALF in India is predominantly due to hepatitis virus(es). ATD and CAM are important causes of DILI-ALF. These patients are young with a female preponderance. Pregnant females with viral hepatitis are at high risk for development of ALF. Survival frequency with expectant management as per INASL guideline is about 50% to 60%, with lower mortality in HEV and HAV ALF than other causes. A recently described dynamic prognostic model, ALFED, has been recommended to be suitable in Indian patients. Liver transplant is offered to patients with ALF in India, and deceased donor liver transplantation is the predominant modality with a reported 1-year survival rate of 80%.