Liver transplantation in acute liver failure: Dilemmas and challenges

Table 1 Prognostic scoring systems for patients with acute liver failure

Prognostic model/marker	Parameters included	Predictive values	Remarks/drawbacks
KCC[25,26]	Age, INR, serum bilirubin, icterus-encephalopathy interval, drug toxicity	For NAALF, Pooled Sn and Sp are 68% and 82%, respectively. For AALF, Pooled Sn and are 58.2% and 94.6%, respectively	Major limitation is poor sensitivity, only 58% in recent studies (after 2005). Perform better with advanced HE which is a late event. Combining lactate with the KCC improves sensitivity but reduces specificity
MELD score[34,37]	Serum bilirubin, serum creatinine and INR	For NAALF, DOR, Sn, and Sp of MELD scores > 30 are 8.42, 76%, and 73%, respectively. For AALF, DOR, Sn, and Sp of MELD scores > 30 are 6.6, 80%, and 53%, respectively	The discriminatory cut-offs and predictive values vary across the studies. Laboratory variations in the determination of serum bilirubin, creatinine and INR
Clichy criteria[38]	Advanced HE with factor V levels < 20% in patients < 30 years and < 30% in patients ≥ 30 yr	For NAALF, Sn 69%, Sp 50%, PPV 64%, and NPV 55%. For AALF, Sn 75%, Sp 56%, PPV 50%, and NPV 79%	Inferior to KCC and MELD in validation studies. Poor Sp and PPV. Factor V level assay is not a routine parameter
Arterial ammonia[51,52]	Baseline arterial ammonia > 124 mol/L	Sn 78.6%, Sp 76.3%, and DA 77.5%	Ammonia levels can be influenced by renal impairment, sepsis, bleeding, haemolysis, drugs etc. Not validated at LT centres. Persistent hyperammonemia is better predictor, but decision is delayed[52]
Blood lactate[28]	Post-resuscitation arterial lactate cut-off 3.0 mmol/L in AALF	Sn 76%, Sp 97%, PLR 30, and NLR 0.24	Variability in the timing of lactate measurements. Contradictory results with regard to its performance in NAALF
Serum phosphate[43,54]	Level of 1.2 mmol/L at 48 to 96 h after acetamenophen overdose	Sn 89%, Sp 100%, PPV 100%, and NPV 98%	Such results could not be replicated in subsequent studies[43]
Serum Gc globulin[53]	A cut-off level of 80 mg/L in the NAALF	Sn 49%, Sp 90%, PPV 85%, and NPV 43%	Poor sensitivity and NPV. Lacks validation studies
Cytokeratin 18-based modification of the MELD[55]	CK18 M65, INR, MELD. A baseline cut-off of 53.5 modified MELD	Sn 81%, Sp 82%, PPV 65%, and NPV 91%	Reported to be better than MELD and KCC, but lack validation studies
APACHE II[46]	Multiple parameters. APACHE II >15	Sn 82% and Sp 98% for AALF	Not specific to liver disease. Lacks validation studies. Cumbersome for routine clinical use
SOFA[45]	SOFA score of > 6 by 72 h post-acetamenophen overdose	Sn 90%, Sp 69%, PPV 42%, and NPV 96% for AALF	Not specific to liver disease. Relatively lower specificity and PPV. Difficulties in calculating the neurological component in intubated patients
Monocyte HLA-DR expression[50]	Monocyte HLA-DR expression 15% or less in AALF	Sn 96%, Sp 100%, DA 98%	Lacks validation studies. Reduction in monocyte HLA-DR expression was not associated with outcome in NAALF
BiLE score[49]	Bilirubin, lactate, and etiology	Sn 79% and Sp 84%	Scores derived from retrospective analysis. No validation study
ALFED model[27]	Over 3 d values of arterial ammonia, serum bilirubin, INR, and advanced HE	AUROC for ALFED: 0.92. ALFED score of ≥ 4 had a PPV 85% and NPV 87%	Needs further validation. Decision will be delayed. Patients died before 3 d were excluded from analysis. Advanced HE is a late feature
ALFSG index[47]	Coma grade, INR, serum bilirubin and phosphorus levels, and log(10) M30	Sn 85.6% and Sp 64.7%	Requires additional laboratory testing and costs for M30. Found better than MELD and KCC, but requires validation studies

AALF: Acetaminophen-associated acute liver failure; ALFED: Acute liver failure early dynamic; ALFSG: Acute liver failure study group; APACHE: Acute physiology and chronic health evaluation; AUROC: Area under receiver operating characteristic; DA: Diagnostic accuracy; DOR: Diagnostic odds ratio; INR: International normalized ratio; KCC: King’s college criteria; MELD: Model of end stage liver disease; NAALF: Non-acetaminophen-associated acute liver failure; NPV: Negative predictive value; PPV: Positive predictive value; Sn: Sensitivity; Sp: Specificity; SOFA: Sequential organ assessment score; HE: Hepatic encephalopathy.

Table 2 Problems with prognostic scoring systems in acute liver failure

Sr No	Issues	Remarks
1	All available prognostic scoring systems have limited accuracy	Error of both commission and omission can happen
2	Heterogeneity in the studies evaluating prognosis in ALF: Variations in the definitions of ALF, etiologies, & management protocol	The heterogeneity makes it difficult to compare the results between studies and draw a uniform conclusion
3	Survival rates of ALF patients on medical treatment have improved but models used are still the old ones	Reduced performance of old models (e.g., KCC) have been noted in the newer studies compared to the old ones
4	Many studies have considered and analyzed transplanted patients as ‘non-survivors’	This may falsely elevate the positive predictive value of a prognostic, increasing the risk of unnecessary LT in some patients
5	Lack of reproducibility and validation studies for many prognostic scores	A model cannot be implemented in the clinical practise without adequate validation studies
6	Dynamic models are better than models based on baseline parameters, but critical time at which decision should be made is not clear	A very late decision may results in loss of opportunity to transplant, and very early decision may lead to unnecessary LT
7	Many models have included non-ideal parameters, such as factor V, apoptotic markers, monocyte HLA, etc	These markers are not routinely available and their measurement involve additional investigations and cost
8	Some prognostic markers, such as serum bilirubin and INR, are subject to laboratory variations	This may cause error in selection of LT candidates
9	Inclusion of advanced HE in some prognostic models	HE is subjective markers, and advanced HE is usually a late feature of ALF
10	Inclusion of CE in prognostic models	CE is difficult to diagnosed clinically, and a clinically overt CE is usually a late feature

ALF: Acute liver failure; CE: Cerebral edema; HE: Hepatic encephalopathy; KCC: Kings college criteria; LT: Liver transplantation; INR: International normalized ratio; HLA: Human leukocyte antigen.

Table 3 Factors associated with poor outcomes of liver transplantation in acute liver failure patients

Ref.	Country	Patients	Determinant of poor outcomes
Barshes et al[67], 2006	United States	n = 1457	Body mass index > or = 30 kg/m2. Serum creatinine > 2.0 mg/Dl. Recipient age > 50 years old. History of life support.
Bernal et al[56], 2009	United Kingdom	n = 310	Age > 45 years old. Vasopressor requirement. Transplantation before 2000. Use of high-risk grafts.
Park et al[88], 2010	South Korea	n = 44	Older age. Higher MELD.
Germani et al[6], 2012	Europe	n = 4903	Recipient > 50 yr. Incompatible ABO matching. Donors > 60 yr. Reduced size graft.
Yuan et al[58], 2012	China	n = 20	Pre-transplant waiting time > 5 d.
Yamashiki et al[77], 2012	Japan	n = 209	Older age of recipient and donor. Incompatible ABO.
Hoyer et al[89], 2014	Germany	n = 57	Lowest pH of the recipient before LT. PH ≤ 7.26 have the worst outcome.
Pamecha et al[90], 2019	India	n = 61	Postoperative worsening of cerebral edema. Systemic inflammatory response syndrome. Preoperative culture positivity. Longer duration of anhepatic phase.

LT: Liver transplantation; MELD: Model for end stage liver disease; ABO: Arquivos brasileiros de oftalmologia.