Of the 841 patients enrolled in the PALF registry, 148 were ≤ 90 days old at enrollment (57.4 % male and 73.0 % Caucasian). The median age at enrollment was 18 days (1st quartile (Q1)=11 days, 3rd quartile (Q3)= 37 days). The median weight at enrollment was 3.5 (Q1=2.8, Q3= 4.2) kilograms and the median weight for age z score was -1.3 (Q1= -2, Q3= -0.2). The smallest infant weighed 1.7 kilograms (weight for age z score: -3.10) and the largest infant weighed 6.4 kilograms (weight for age z score: 3.32). The most common presenting symptoms were lethargy (49%), fever (20%), and nausea/vomiting (20%). Common physical signs included hepatomegaly (71%), splenomegaly (41%), ascites (39%) and peripheral edema (38%).
A standard diagnostic evaluation revealed elevated aminotransferases, cholestasis and synthetic dysfunction consistent with the diagnosis of ALF. The median ALT of 156 IU/L (Q1= 47, Q3=526) and AST of 215 IU/L (Q1= 84, Q3=1186)were lower in young infants compared with older children with non-APAP induced ALF (median ALT 1616, Q1=615, Q3=3078 and median AST 1778, Q1=629, Q3=3476), p < 0.0001. Sub-group analysis of infants with neonatal hemochromatosis (NH) showed a median ALT of 35 (Q1= 29, Q3=44) and AST of 84 IU/L (Q1= 57, Q3=143), compared with infants with other causes of liver failure, in whom the median ALT was 211 (Q1= 71, Q3=2858) and median AST 289 IU/L (Q1= 94, Q3=1842), p <0.0001. Direct hyperbilirubinemia in young infants with non-NH induced liver failure was less pronounced (median 5.1 mg/dL, Q1= 2.3, Q3= 9.8) than in older children with non-APAP induced liver failure (median 7.6 mg/dL, Q1=2.2, Q3=13.7), p= 0.02. White blood cell count, hemoglobin, arterial and venous ammonia level, and plasma lactate and pyruvate concentration were similar between groups.
Based on the available clinical data, the etiology of ALF was assigned by the local investigator(). Fifty six (38%) patients were classified as having an indeterminate etiology, lower than the indeterminate rate (47%) in patients > 90 days at enrollment, p=0.05.
Etiology of ALF in infants 0-90 days of age.
Significant differences in ALT, AST, total and direct bilirubin, GGT, INR, BUN and creatinine were found between different groups, based on ALF etiology(metabolic, viral, NH, indeterminate and other), p<0.05 (). Therefore, the relationship between the aggregate of four biochemical parameters (ALT, AST, direct bilirubin and INR) and ALF etiology was assessed using multivariate analysis ona subset of 69 patients with complete data, using neonatal hemochromatosisas the reference group. There was a strong relationship between the cumulative biochemical profile and the presence of viral induced ALF, with extremely high aminotransferase levels, severe cholestasis and coagulopathy, as compared withNH, (effect size 1.66, 95% CI: 1.05-2.28; p <0.0001). There was a moderate relationship between the cumulative biochemical profile and the presence of metabolic induced ALF, with moderately elevated aminotransferase levels, moderate cholestasis and minimal coagulopathy compared withNH, (effect size 0.24, 95% CI: 0.02-0.46; p= 0.03). There was a moderate relationship between the cumulative biochemical profile and an indeterminate etiology of ALF, with moderately elevated aminotransferase levels, moderate cholestasis and moderate coagulopathy as compared withNH, (effect size 0.29, 95% CI: 0.07-0.52; p= 0.01). White blood cell count, hemoglobin, platelet, arterial and venous ammonia level, plasma lactate and pyruvate concentrationsand albumin were similar between groups.
Laboratory values of infants 0-90 days of age at enrollment in the PALF Study by etiology of acute liver failure.
The outcomes of infants with encephalopathy at entry into the PALF Study were analyzed. Encephalopathy was assessed in 129 patients at enrollment(9
). At entry, no encephalopathy was present in 83 (64%) subjects, of whom 67% spontaneously survived, 17% survived with transplant and 16% died without transplant. Mild encephalopathy (grades 1 and 2) was present in 34 subjects, of whom 53% spontaneously survived, 21% survived with transplant and 26% died without transplant. Moderate to severe encephalopathy (grades 3 and 4) was present in 12 subjects, of whom33% spontaneously survived, 9% survived with transplant and 58% died without transplant. Spontaneous survival was highest in those with no or mild encephalopathy, p=0.03. Poor outcomes (death or transplant), however, occurred frequently, even in subjects with no or mild encephalopathy.
The outcomes of infants with ALF based on etiology of liver failure were assessed. Of 148 subjects, 88 (60%) survived without transplant. Of these, 18 (20.5%) had a metabolic disease, 13 (19.8%) had NH, 9 (10.2%) had a viral infection, 34 (38.6%) were indeterminate and 14(15.9%) had other diagnoses. An additional 24 patients underwent liver transplant: 4 with metabolic diseases, 4 with NH, 15 with indeterminate disease and 1 with other disease. Only 41% of young infants with ALF were listed for transplant, compared with 58% of the older non-APAP cohort, p=0.008. Similar to the older cohort, 20 (71%) of 28 infants with metabolic diseases were not listed for transplant. Of 20 infants with NH, only 6 (30%) were not listed for transplant. Of the 24 infants with viral induced ALF, 20 (83.3%) were not listed for transplant. In contrast, in the older ALF cohort, only 41.2% of those with viral induced ALF were not listed for transplant, p=0.001. Similar to the older ALF cohort, 24 (43%) of the 56 infants with an indeterminate etiology of ALF were not listed for transplant. Only 40% of infants in liver failure listed for transplant received an organ by 21 days post-enrollment into the study, as compared with 66% of older patients, p <0.0001. Young infants experienced a mortality rate of 24% (n=36), higher than that of patients > 90 days(10.5%), p=0.001. The etiology of death in these young infants included multi-organ failure (64%), sepsis (8%), pulmonary hemorrhage or edema (8%) and intracranial edema(3%). A competing risk analysis demonstrated age as an important factor in the likelihood of subjects undergoing liver transplantation or dying without liver transplantation.
At up to 21 days post-enrollment, subjects with an indeterminate etiology were most likely to have been transplanted (32%), followed by NH induced ALF(20%), p=0.0002 (). provides an analysis of the cumulative incidence of death without transplant at up to 21 days post-enrollment, taking into account the competing risk of transplant. The percentage of patients who died was higher for infants diagnosed with a viral etiology (64%) comparedwiththose with metabolic disease (29%), NH (16%) or indeterminate etiology (14%), p=0.0007. Data on the use of specific therapeutic regimens such as anti-viral medications or anti-oxidant cocktails were unavailable.
The cumulative incidence of transplantation by etiology in infants 0-90 days of age in the PALF Study.
The cumulative incidence of death without transplantation by etiology in infants 0-90 days of age in the PALF Study.