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ORIGINAL ARTICLE Arch Dis Child: first published as 10.1136/adc.87.1.54 on 1 July 2002. Downloaded from Natural history and risk factors in hepatic failure U Poddar, B R Thapa, A Prasad, A K Sharma, K Singh ......

Arch Dis Child 2002;87:54–56

Background: The natural history of fulminant hepatic failure (FHF) without transplantation is not well known. Aims: To study the natural history and prognostic factors, especially the presence of ascites and spon- taneous bacterial (SBP), in children with FHF. Methods: FHF was defined by the onset of within 12 weeks of onset of . From August 1997 to December 2000, 67 children (<12 years) were diagnosed with FHF. Their clinical features, investigations and outcome were noted. Viral markers A to E (IgM, anti-HAV; IgM, anti-HEV, HBsAg, and anti-HCV) were determined by ELISA. SBP was defined by the presence of >250 neutrophils with or without a positive culture in ascitic fluid. Results: Mean age of the children was 5.8 years with an almost equal sex distribution. Viral markers See end of article for were positive in 63 (94%) cases: A in 34 (54%), E in 17 (27%), A+E in seven (11%), and B authors’ affiliations ...... in five (8%). Thirty one children presented with grade I or II encephalopathy and all recovered, whereas 17 of 36 children who had grade III or IV encephalopathy died. Ascites was detected (both clinically Correspondence to: and ultrasonically) in 34 (51%) cases, nine (26%) of which had SBP. Overall mortality was 25%. Mor- Dr U Poddar, H.No. tality was higher in those who had ascites than in those who did not (32% v 18%); among those with 1156A, Sector 32-B, Chandigarh–160030, ascites it was maximum in those who had SBP (78% v 16%). Total serum and grade of India; encephalopathy were significantly higher, serum was significantly lower, and prothrombin [email protected] time was significantly prolonged in those who died than in those who recovered. Accepted Conclusion: The natural history of FHF in Indian children depends on age, grade of encephalopathy, 7 February 2002 ascites, and SBP. SBP depicts worse outcome. In all cases of FHF with ascites, the presence of SBP ...... should be investigated. http://adc.bmj.com/ ulminant hepatic failure (FHF) is a rare but potentially markers, in the absence of history of exposure to drugs or tox- fatal of acute hepatitis. With the availability ins. Underlying chronic liver was excluded by clinical, Fof , the natural history of FHF has biochemical, and abdominal ultrasound examination. changed. However, in developing countries like India, where From August 1997 to December 2000 consecutive cases liver transplantation is not widely available, it is possible to admitted to our unit with a diagnosis of FHF as a result of viral study the natural history of the condition and risk factors in hepatitis were studied. A structured proforma comprising relation to outcome. Recently it has been shown that ascites clinical features, results of investigation, and outcome was

and spontaneous bacterial peritonitis (SBP) are poor prognos- maintained. The peak grade of encephalopathy during hospi- on September 23, 2021 by guest. Protected copyright. tic factors in FHF in adults.1 Although ascites is an important talisation was noted. Encephalopathy was graded from grade feature of decompensated chronic , it has been I to IV according to the criteria of Teasdale and Jennett.11 reported infrequently in patients with fulminant hepatic Baseline liver function, kidney function tests, full blood count, failure.12 SBP, which occurs in 15–25% of patients with (PT) and partial thromboplastin time were ,34has occasionally been reported in FHF in adults.5–7 checked and repeated twice a week. For comparison a Though studies in children with FHF have shown a prevalence prothrombin time index (PTI) was calculated (PTI = standard of ascites in 32–55%, SBP has not been reported.89 We PT/observed PT × 100). prospectively studied the natural history and prognostic Viral markers for to E (IgM, anti-HAV; IgM, factors, and especially the occurrence of ascites and SBP in anti-HEV, HBsAg, anti-HCV) were determined by ELISA with children with FHF. commercial kits. Acute was diagnosed if there was HBsAg positivity together with IgM-anti HBc positivity. When all viral markers were negative, the case was labelled as non-A METHODS to E hepatitis. The diagnosis of ascites was made clinically and The study was carried out in a tertiary care hospital in North ultrasonically. An ascitic tap was performed in all cases with India where liver transplantation is not available. FHF was ascites and fluid was analysed for total leucocyte count, defined according to the criteria laid down by O’Grady and 10 differential count, and serum ascites albumin gradient colleagues : onset of occurring within (SAAG). Ascitic fluid was cultured in bottles. 12 weeks of onset of jaundice in the absence of pre-existing symptomatic liver disease. This was further subclassified depending on the interval between the onset of jaundice and ...... the onset of encephalopathy into hyperacute (HALF; interval 0–7 days), acute liver failure (ALF; interval Abbreviations: ALF, acute liver failure; CNNA, culture negative neutrocytic ascites; FHF, fulminant hepatic failure; GI, gastrointestinal; 8–28 days), and subacute hepatic failure (SAHF; interval 29 HALF, hyperacute liver failure; PT, prothrombin time; PTI, prothrombin days to 12 weeks). A viral aetiology was presumed if there was time index; SAAG, serum ascites albumin gradient; SAHF, subacute a classical prodromal illness, with or without positive viral hepatic failure; SBP, spontaneous bacterial peritonitis

www.archdischild.com Natural history and risk factors in fulminant hepatic failure 55

Table 1 Aetiology and outcome of FHF (n=67) Table 4 Outcome of children in various clinical Arch Dis Child: first published as 10.1136/adc.87.1.54 on 1 July 2002. Downloaded from subsets Aetiology No. of children (%) Death (%) Subsets No. of children Death (%) HAV 34 (51) 10 (29) HEV 17 (25) 6 (35) 1. FHF 67 17 (25) HAV + HEV 7 (10) 0 2. FHF + ascites 36 11 (30) HBV 5 (7.5) 1 (20) 3. FHF, no ascites 31 6 (19) Non-A to E 4 (6) 0 4. FHF + ascites + SBP 9 7 (78) 5. FHF + ascites, no SBP 27 4 (15)

NS between 2 and 3; p<0.001 between 4 and 5.

Table 2 Mortality in various types of FHF aetiology. Viral markers were positive in 63 (94%) cases; the Type of FHF* No. of children (%) Death (%) remaining four (6%) had non-A to E hepatitis. The overall mortality in the study population was 25% (17 1. Hyperacute 43 (64) 5 (11) 2. Acute 21 (31) 10 (47) deaths). All children with grade I or II and 19 (53%) with 3. Subacute 3 (5) 2 (67) grade III or IV encephalopathy recovered within an average period of 3 days (range 2–5 days). Table 2 shows outcome *p<0.001 between 1 and 2; p<0.01 between 1 and 3; NS between according to the various subtypes of FHF. Two thirds of cases 2 and 3. were in hyperacute liver failure; mortality was lowest in them. Table 3 compares those who survived and those who did not. The non-survivors had more severe disease indicated by SBP was defined as the combination of a positive culture, an significantly higher serum bilirubin, higher grade of encepha- 3 ascitic fluid neutrophil count of >250 cells/mm , and no lopathy, lower serum albumin, and more prolonged pro- 12 evidence of a source of infection. Culture negative neutro- thrombin time (low PTI). Interestingly, non-survivors were cytic ascites (CNNA) was defined as ascitic fluid infection in significantly younger than survivors. Five children had gastro- 3 which the neutrophil count was >250 cells/mm with no intestinal (GI) haemorrhage; despite fresh frozen plasma 13 growth of ascitic fluid culture. All cases of SBP and culture infusion, continued and all five died. negative neutrocytic ascites were treated with parenteral cefo- Ascites was detected clinically in 34 (51%) cases and ultra- taxime (100 mg/kg/day). Clinically significant ascites was sonically in 36 (54%). Ascites was high gradient (serum treated with salt restriction and diuretics (spironolactone 2–8 ascites albumin gradient >1.1) in all (mean (SD) SAAG = 1.8 mg/kg/day and furosemide 1–2 mg/kg/day) for as long as there (0.5)). Thirteen children (40%) with ascites required diuretic was ascites. therapy for a brief period (3–14 days); in the remaining 23 All cases received supportive treatment without cortico- (60%) cases, ascites improved spontaneously. Nine children steroids or specific antiviral agents. Hepatic encephalopathy with ascites (25%) had SBP,three had culture positive SBP (E was managed with a standard protocol including a protein coli in two and Acinetobacter in one), and six had culture nega- free diet, oral (ampicillin 50 mg/kg/day), and lactu- tive neutrocytic ascites. Table 4 shows the outcome of the vari- http://adc.bmj.com/ lose, either orally or by retention enema. All cases with grade ous clinical subsets of cases. Mortality was higher in children III and grade IV encephalopathy received parenteral mannitol with ascites compared to those without. (20%) and when appropriate, hyperventilation. Fresh frozen plasma was infused if bleeding occurred. DISCUSSION Subclassification of FHF into hyperacute, acute, and subacute Statistics liver failure carries a prognostic significance. In a study of 376 Results were expressed in terms of mean (SD). Comparisons cases of FHF in adults, O’Grady and colleagues10 found that χ2 were made using Student’s t test and the test. 60% of cases were hyperacute, 24% acute, and 16% subacute. on September 23, 2021 by guest. Protected copyright. The best chance of survival was in the hyperacute group (36%) RESULTS compared to acute (7%) or subacute (14%). This classification During the study period 67 children (<12 years of age) had has not previously been validated in children. We found that in FHF. The mean (SD) age of the study population was 5.8 (3) children, 64% of cases were in the hyperacute group and 31% years (range 3 months to 12 years). There was just one child in the acute liver failure group, with significantly higher mor- aged 3 months; the others were more than 1 year old. The male tality in acute and subacute groups. to female ratio was 39:28. Prodromal symptoms (fever, Although it has been shown that HEV alone or in combina- anorexia, vomiting) were present in 64 (95.5%) cases. Thirty tion with other hepatotropic viruses can produce more severe one children had grade I or II, and 36 had grade III or IV hepatitis in children,8 we found only 10% of children with encephalopathy. Table 1 presents the outcome according to mixed infection with HAV and HEV, and none died. The same

Table 3 Comparison between survivors and non-survivors

Survivors (n=50) Non-survivors (n=17) p value

Mean (SD) age (y) 6.2 (3) 4.4 (2.9) <0.05 Male:female 2.4:1 1.2:1 0.50 Encephalopathy (grade III or IV) 38% 100% <0.005 GI haemorrhage 0 29% <0.001 Total serum bilirubin (µmol/l) 219 (195) 434 (217) <0.001 Serum albumin (g/l) 33 (5) 27 (5) <0.001 PTI (%) 43 (17) 24.6 (19) <0.001 ALT (U/l) 120 (60) 106 (29) 0.50

PTI, prothrombin time index; ALT, alanine aminotransferase (normal up to 15 U/l).

www.archdischild.com 56 Poddar, Thapa, Prasad, et al kind of aetiological spectrum has been documented in a study ...... of 261 Egyptian children with sporadic acute hepatitis where Authors’ affiliations Arch Dis Child: first published as 10.1136/adc.87.1.54 on 1 July 2002. Downloaded from mixed infection was documented in <1% of cases.14 U Poddar, B R Thapa, A Prasad, A K Sharma, K Singh, Division of The outcome in FHF is altered by the availability of liver Pediatric , Department of Gastroenterology, transplantation. In the absence of liver transplantation, Postgraduate Institute of Medical Education and Research, Chandigarh, outcome depends on various clinical and biochemical factors. India Psacharopoulos and colleagues,15 in a study of 31 cases of FHF in children, showed that poor outcome was related to the grade of encephalopathy, prolonged prothrombin time (>90 second), GI haemorrhage, and renal failure. Arora and REFERENCES colleagues8 found infection to be a marker for poor prognosis. 9 1 Chu CM, Chiu KW, Liaw YF. The prevalence and prognostic significance Another study by Srivastava and colleagues in 41 children of spontaneous bacterial peritonitis in severe acute hepatitis with ascites. with FHF, showed the presence of GI bleeding, the degree of 1992;15:799–803. , and serum bilirubin to be independent predictors of 2 Valla D, Flejou JF, Lebrec D, et al. and ascites in mortality. In this study we found that those who died were acute hepatitis: clinical, hemodynamic and histological correlations. younger, suffered GI bleeding, had higher bilirubin, a higher Hepatology 1989;10:482–7. 3 Pinzello G, Simonetti RG, Craxi A, et al. Spontaneous bacterial grade of encephalopathy, and a lower prothrombin time index peritonitis: a prospective investigation in predominantly nonalcoholic than survivors. cirrhosis patients. Hepatology 1993;3:545–9. 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