Liver Transplantation for Yellow Phosphorus Poisoning: Do We Fully Understand?

Yellow phosphorus (YP) is a commonly used component of rodenticides in the southern states of the Indian subcontinent and some regions of South America.1-3 It is also used in the fireworks industry in parts of Asia. Accidental or intentional consumption of this highly toxic substance (fatal dose is as low as 1 mg/kg) has been increasingly implicated as a cause of acute liver failure (ALF) in these parts and is the most common cause of death after YP poisoning (YPP).1,2,4 Although the actual clinical course depends on many factors including the dose of YP and other additives, it usually follows 3 stages with an initial course consisting of gastrointestinal symptoms followed by a quiescent second stage—providing a false sense of reassurance, which then leads to liver damage and ALF beyond 4 d of ingestion.1,2,4 Liver transplantation (LT) is the standard of care for YPP-ALF, unresponsive to conservative measures. The King's College Criteria, a commonly used metric to identify those who benefit from an urgent LT, may not be applicable for YPP. The presence of coumadin-like compounds in these commercially available products may confound the true value of international normalized ratio (INR). Also, INR and bilirubin may not be accurately depicted in patients who undergo therapeutic plasma exchange (TPE). Moreover, the time interval between the onset of encephalopathy and rapid deterioration beyond which LT has no survival benefit is much narrower in YPP.1,2,5,6 Although the exact indication remains undefined, several criteria, including those proposed by the Liver Transplantation Society of India (LTSI) consensus guidelines, include an INR of >6 and a model for end-stage liver disease score of ≥36 with encephalopathy as predictors of mortality without LT.2 Additionally, based on small reports and personal experience, the LTSI consensus suggested that encephalopathy (West Haven grading ≥2) can be used as a sole criterion for LT listing.2 It is known that patients with YPP-ALF can recover without LT. There is a threshold beyond which these patients will not recover without LT; this "point of no return" is the true indication for LT. So far, this metric has not been clearly defined, and encephalopathy alone has been used as the point of no return for the liver to regenerate. Auxiliary partial orthotopic LT (APOLT) potentially provides the important advantage of allowing for native liver regeneration and immunosuppression withdrawal. Given that the liver is the major visceral depository of YP, there have been concerns about performing an APOLT with the fear that the allograft could get damaged from the residual YP leaching out of the native liver.1,2 Using encephalopathy as a single criterion, Kumar et al7 bucked this trend and showed uniformly good outcomes of APOLT for YPP-ALF. Serendipitously, one of the important points the authors make is that even when the patient has reached the above-mentioned "point of no return," the liver is capable of regeneration—an experiment only possible with APOLT.7 Thus, it still cannot be said that encephalopathy is indeed this point of no return. Over the past 5 y, we have managed 29 patients with YPP. Of those, 23 patients were managed conservatively with TPE and 16 (69.5%) recovered without requiring LT. Of these 16 patients, 8 (50%) had encephalopathy (grade >2) and yet recovered. According to Kumar et al,7 these patients should have undergone APOLT because they fulfilled the LTSI criterion for LT; the native liver in these patients recovered without APOLT.2 Furthermore, within the algorithm of conservative management is the key role of TPE, which has been shown to achieve a 65%–70% LT-free survival in YPP across several series including ours.1,5,8 Satish et al8 showed an impressive 68.7% LT-free survival with TPE among patients who met the above-mentioned LT criteria. Hence, in this TPE era, there again remains the concern that these patients may get transplanted too early, which may not allow time for spontaneous liver recovery. Having just a chance of immunosuppression-free survival through APOLT should not encourage clinicians to choose APOLT as an early option for any form of ALF, especially YPP-ALF. SOLUTIONS AND THE WAY FORWARD The long-term solution to YPP is not a consideration of the type of LT but one of social transformation via public health initiatives. There are antecedents to such measures, such as the ones used in the United Kingdom, which helped to drastically reduce the number of LT for acetaminophen-induced ALF.9 In the state of Tamil Nadu (TN), India, which has one of the highest incidences of YPP, several government reforms, including legislation passed in December 2022 to permanently ban the sale and distribution of YP-based pesticides, have been a reassuring trend in this direction.10 Other public health measures, as reflected by those instituted in the firecracker industry, such as modifying manufacturing practices, have also helped reduce the incidence of YPP.1,8 Although these legislative measures take time to percolate through the system, there continue to be cases of YPP in the state. The TN Government has taken steps to provide TPE facilities in the secondary-level district, and taluk (subdistrict) hospitals to provide timely access to TPE. Online sensitization and training are periodically imparted to doctors, nurses, and technicians at the primary healthcare level.8 A hub-and-spoke model of care escalation has been set up, wherein the need for an urgent transfer to any one of the (currently 32 of the 38 districts) TPE hospitals in the state after immediate resuscitation at a primary health center is a mandatory provision.8 These positive actions are evidenced by the data that, of 1237 patients with acute liver toxicity caused by YPP in TN who were treated with TPE, 825 (63.9%) survived and were discharged. A similarly heartening statistic of 80.2% (65/81) LT-free survival with early initiation of TPE was demonstrated in a tertiary care hospital in the state. In this cohort, of the 32 patients who met the LT criteria, an LT-free survival of 68.75% (22/32) was demonstrated.8 Thus, it is envisaged that like acetaminophen, YPP as an indication for LT—APOLT or OLT—may be relegated to the history books.