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. Author manuscript; available in PMC: 2015 Apr 1.
Published in final edited form as: J Pediatr. 2014 Jan 30;164(4):720–725.e6. doi: 10.1016/j.jpeds.2013.12.024

Significant Hepatic Involvement in patients with Ornithine Transcarbamylase Deficiency

Renata C Gallagher 1,#, Christina Lam 2,*,#, Derek Wong 2, Stephen Cederbaum 2,3, Ronald J Sokol 4
PMCID: PMC4070427  NIHMSID: NIHMS562600  PMID: 24485820

Abstract

Objective

To determine the frequency of significant liver injury and acute liver failure (ALF) in patients with ornithine transcarbamylase deficiency (OTCD), the most common urea cycle defect (UCD).

Study design

A historical cohort study was performed. Charts were reviewed at two centers to assess the proportion of 71 individuals with OTCD who had evidence of ALF (INR ≥ 2.0), liver dysfunction (INR 1.5–1.99), or hepatocellular injury (AST/ALT≥ 250 IU/L).

Results

57% of the 49 patients with symptomatic OTCD had liver involvement: 29% met the criteria for ALF, 20% had liver dysfunction, and 8% had isolated hepatocellular injury. The proportion with ALF was greatest in those with more severe OTCD, including neonates with markedly elevated ammonia levels (> 1,000 μmol/L). Some patients with severe liver involvement (INR ≥ 2.0 and AST/ALT > 1,000 IU/L) had only moderate hyperammonemia (100 – 400 μmol/L). ALF was the initial presenting symptom of OTCD in at least 3 of 49 symptomatic OTCD patients.

Conclusions

Episodes of hepatocellular injury, liver dysfunction, and ALF were identified in a high proportion of individuals with symptomatic OTCD. The more severely affected OTCD patients had a higher likelihood of ALF. The diagnosis of a UCD should be considered in unexplained ALF, liver dysfunction or hepatocellular injury.

Keywords: Urea cycle defects, hyperammonemia, acute liver failure, elevated AST/ALT, Reye syndrome, orotic acid

Accurate diagnosis of an underlying etiology is crucial to outcome in acute liver failure (ALF)1. Up to 50% of children with ALF2, and ~15% of adults with ALF1, are of “indeterminate” cause. Genetic metabolic disorders are an important cause of ALF in children, comprising 9.7% of final diagnoses in a large international multi-site observational study2, and 42.5% of final diagnoses in patients presenting at less than one year to a single center3. Metabolic disorders presenting with ALF include galactosemia, tyrosinemia type 1, fatty acid oxidation defects, Wilson disease, mitochondrial hepatopathies, and others4,5. Narkewicz et al2 emphasized that a systematic evaluation for treatable causes in children with ALF, including metabolic diseases, does not occur routinely in many centers.

Urea cycle defects (UCDs) occur in approximately 1/30,000 live births6. These disorders are not considered prominent among metabolic diseases that cause severe hepatic dysfunction and ALF4,5, despite past reports of hepatocellular injury and ALF in individuals with ornithine transcarbamylase deficiency (OTCD)7–11. OTCD is the most common UCD, and is an X-linked genetic disorder that affects both males and females. Severely affected males present with marked hyperammonemia in the newborn period. There is variable clinical expression in heterozygote females and in males with residual OTC enzyme activity; individuals of either sex may remain asymptomatic throughout their lifetime with no episodes of hyperammonemia, and symptomatic individuals, with at least one episode of hyperammonemia, can present at any age12. Hepatic histology in OTCD may show microvesicular steatosis, focal cell necrosis, aggregates of clear hepatocytes, portal to portal bridging fibrosis, abnormal mitochondria, abnormal peroxisomes, or may appear normal13–19. Other UCDs have been associated with hepatocellular injury and liver failure as well20–28. Sundaram et al29 reported that 2 of 148 infants less than 3 months of age (1.4%) with ALF were diagnosed with a UCD, one with OTCD. Despite these reports, OTCD and other UCDs are rarely considered in children and adults presenting with severe liver injury or ALF unless profound hyperammonemia is present; this has resulted in delayed or post-mortem diagnosis11. The goal of this study was to determine the frequency of significant liver injury and ALF in patients with OTCD.

An illustrative case is a 19-month-old female who was transferred to UCLA Medical Center for evaluation for liver transplant because of ALF of unknown origin. She had presented to an outside hospital with fever, vomiting, and lethargy, and was found to have an ALT of 906 IU/L, an INR of 3.9, a PTT of 46, and ammonia of 161 μmol/L. Evaluation for infectious hepatitis, autoimmune hepatitis, Wilson disease, and acetaminophen toxicity was negative. Liver biopsy showed acute hepatocellular injury with mild lobular necrosis. Upon further testing it was noted that orotic acid and uracil were elevated in the patient's urine. Pharmacologic treatment of OTCD was initiated on day 10 of hospitalization. Laboratory abnormalities normalized after treatment (Figure 1). The diagnosis of OTCD was confirmed by genotyping which identified a heterozygous c.67C>T (p.R23X) mutation. Liver tissue was not available for enzyme analysis (part 2, case 8, Table III; available at www.jpeds.com).

Figure 1.

Figure 1

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Time course of plasma ammonia, ALT, and INR in a severe OTCD female during her initial hospitalization at 19 months of life. Dietary treatment was instituted on day 7, and full medical therapy on day 10. The vertical black arrow indicates the time point collected for the chart review in this hyperammonemic episode (part 2, case 8; Table III).

Table 3.

Part 1 OTCD Cases at Children's Hospital Colorado

Case No.
Current
status/Rx
Liver
Injury		 Gender Age Presentation AST
IU/L		 ALT
IU/L		 PT
sec		 INR PTT
sec		 Bili NH3
umol/L		 V VII VIII Liver histology Fibrinogen D-
dimers
Neonatal Males
1
Deceased
ALF 		M 4 d 3 day h/o increased RR, progressive encephalopathy 104 81 37.6 3.83 65 6.0 2634 ND ND ND ND 71 5.73
2
Deceased
ALF 		M 2 d Increased RR, jitteriness, progressive encephalopathy 91 22 35.6 3.3 >250 Dialysis 10.0 2125 ND ND ND ND 119 1.62
3
Deceased
ALF 		M 2 d Respiratory distress, lethargy ND ND 24.3 ND 39.3 5.1 1398 ND ND ND Normal 140 ND
4
Deceased
ALF 		M 2 d Increased RR, twitching, apnea 45 32 24.0 2.1 45 8.4 1308 ND ND ND OTC enzyme activity 2%. Microvesicular steatosis, mild cholestasis 112 3.64
5
Deceased
LD 		M 2 d Poor feeding, lethargy 37 130 17.0 1.57 109 3.1 24 (peak 1939) ND ND ND ND 108 1017
6
Tx
LD
HCI 		M 2 d Emesis 467 256 17.8 1.43 39 5.4 1152 ND ND ND Unremarkable 214 1.79
Severe OTCD
7
Tx
ALF
HCI 		F 1 year Liver failure, h/o emesis, “reflux”
(Had multiple later HA events without LF)		 4139 2089 63.7 5.7 49.9 0.4 207 ND ND ND Microvesicular steatosis, mild inflammation, mild portal fibrosis ND ND
8
Tx
ALF
HCI 		F Prenatal Known family history, liver failure at 2 years 2232 2127 23.8 2.52 45 0.8 49 (was > 100) 55 (low) 9.2 (low) 230 OTC enzyme activity 4% Increased glycogen, no fibrosis, diffuse microvesicular steatosis 263 333
ALF
HCI 		Same pt as above Same pt as above Same pt as above 1538 1165 21.5 1.8 45.4 1.2/0.5 40 (was 178) ND ND ND Same pt as above ND ND
ALF
HCI 		Same pt as above Same pt as above Same pt as above 2401 1692 23.6 1.97 43.6 0.5 216 39.9 (low) 17.7 (low) 130.2 Same pt as above ND < 200
ALF
HCI 		Same pt as above Same pt as above Same pt as above 74 (went up to 869) 178 (went up to 997) 52.3 3.76 58.5 0.4 171 60.4 (low) <4.0 (low) 192 Same pt as above 227 < 230
9
Tx
ALF
HCI 		F 5 years Emesis, lethargy with UTIs 377 1083 19 2.4 ND ND ND ND ND ND OTC enzyme activity 7.8% Diffuse glycogenation of hepatocytes with minimal portal fibrosis ND ND
ALF
HCI 		Same pt as above Same pt as above Same pt as above 57 446 18.8 2.66 ND ND ND ND ND ND Same pt as above ND ND
ALF
HCI 		Same pt as above Same pt as above Same pt as above 1212 1749 28.4 ND ND 1.1/0.4 41 (was 167) 49 (low) 19 (low) ND Same pt as above ND ND
LD Same pt as above Same pt as above Same pt as above ND ND 15.7 1.52 ND ND 88 (was 118) ND ND ND Same pt as above ND ND
10
Diet/Bu/Cit
LD
HCI 		F 3 years 2 year h/o emesis, AMS, recurrent vision loss 2039 1605 17.5 1.39 40 0.8 111 (was 410) ND ND ND ND 227 1.09
11
Tx
No liver injury		 F 4 years Mother died of OTCD 20 41 14.9 1.29 37.3 0.4 106 ND ND ND Path at tx – mild peripoprtal fibrosis, patchy centrilobular architectural collapse ND ND
12
Tx
No liver injury		 F 3 d Lethargy and poor feeding, progressive encephalopathy 80 169 ND ND ND 0.4 192 ND ND ND OTC activity very low Ballooning hepatocytes, multinucleation granular cytoplasm, minimal periportal fibrosis ND ND
Moderate OTCD
13
Diet/Bu/Arg
ALF
HCI 		M 3 years Recurrent emesis 615 1938 22.8 1.84 38 0.2/0.0 46 (was 160) ND ND ND OTC activity 10% Patchy ballooning hepatocytes, glycogneated nuclei ND ND
ALF
HCI 		Same pt as above Same pt as above See above ND 1088 ND 2.1 ND ND ND ND ND ND Same pt as above ND ND
HCI Same pt as above Same pt as above See above ND 1530 ND ND ND ND ND ND ND ND Same pt as above ND ND
14
Diet/Bu/Arg
ALF
HCI 		M 3 years Illness, affected sib 785 1223 34.9 3.1 48 0.3 108 ND ND ND ND ND ND
Mild OTCD
15
Diet/Be/Cit
LD 		F 2 years Altered mental status 41 67 17.6 1.4 55 0.4 198 ND ND ND ND ND ND
16
LD
Arg		 M 11 y Valproate induced hyperammonema h/o autism, delay, recurrent emesis 14 14 15.6 1.21 29 0.1 144 ND ND ND ND ND ND
LD Same pt as above Same pt as above Same pt as above 23 10 16 1.28 33 0.4 <9 ND ND ND Same pt as above 232 ND
17
Cit
LD 		F NA Family history, brother with neonatal OTC 18 27 15.4 1.16 30 0.6 91 ND ND ND ND ND ND
LD Same pt as above Same pt as above Same pt as above 17 27 15.8 1.28 32 0.7 99 ND ND ND Same pt as above 236 ND
LD Same pt as above Same pt as above Same pt as above 21 28 15.3 1.18 31 0.9 35 ND ND ND Same pt as above ND ND
LD Same pt as above Same pt as above Same pt as above 26 43 15.6 1.22 30 1.2 ND ND ND ND Same pt as above 281 ND
18
Bu/Cit
LD 		F 2 y Intermittent ataxia, abnormal eye movements, family history, brother with neonatal OTC 43 31 15.1 1.16 39 0.3 48 ND ND ND ND ND ND
LD Same pt as above Same pt as above Same pt as above 25 18 15.2 1.14 33 0.5 56 ND ND ND Same pt as above ND ND
LD Same pt as above Same pt as above Same pt as above 26 14 15.4 1.19 37 0.4 36 ND ND ND Same pt as above 175 ND
19
Arg
HCI 		M 1st year Recurrent emesis, increased AST/ALT 519 689 ND ND ND 0.2/0.8 ND ND ND ND Scattered individual hepatocytes with nonspecific degeneration ND ND
20
No Rx
HCI 		M Neonatal presentation, suspected mosaic due to current status 150 317 13.6 1.26 35 0.5 33 ND ND ND ND ND ND
21
Bu/Arg
No liver injury		 F 27 y Son with neonatal OTCD 30 14 14.0 1.04 28 0.6 23 ND ND ND ND 208 ND
22
No current Rx, was on Bu/Arg
No liver injury		 F 37 y Family history, possible seizures 23 39 13 0.95 29 0.2 29 ND ND ND ND 271 ND
No Symptoms/Treatment
23
No Rx
LD 		F NA Family history 12 14 16.2 1.27 32 0.4 57 ND ND ND ND 195 ND
24
No Rx
LD 		F NA Family history 51 44 15.6 1.21 33 0.4 40 ND ND ND ND 201 ND
25
No Rx
No liver injury		 M 10 y Brother with hyperammonemia 37 19 14.2 1.09 32 0.7 22 ND ND ND ND 252 ND
26
No Rx
No liver injury		 F NA Family history 34 49 13.3 0.98 30 0.3 <9 ND ND ND ND 304 ND
27
No Rx
No liver injury		 F NA Family history 19 11 12.7 0.92 29 0.3 13 ND ND ND ND 369 ND
28
Cit since birth, Asx
No liver injury		 F NA Affected brother 62 21 13.4 0.98 30 1.2 20 ND ND ND ND 249 ND
29
No Rx
No liver injury		 F NA Three affected children 20 12 13.1 0.96 32 0.5 57 ND ND ND ND 351 ND
30
No Rx
No liver injury		 F 37 Affected son 34 19 13.6 1.01 29 0.5 39 ND ND ND ND 285 ND
31
No Rx
No liver injury		 F 21 Affected son 15 12 12.8 0.94 29 0.4 < 9 ND ND ND ND 342 ND
Table 3 Part 2. OTCD Cases at UCLA.
Case No.
Current
status/Rx
Liver
Injury		 Gender Age Presentation AST
IU/L		 ALT
IU/L		 PT
sec		 INR PTT
sec		 Bili NH3
umol/L		 V VII VIII Liver
histology		 Fibrinogen D-
dimers
Neonatal Males
1
Deceased
ALF 		M 2 d Poor feeding, lethargy, then seizure, then apnea, and then NH3 = 1734. 202 188 32.9 3.2 151.2 14.1/1.9 1293 ND ND ND ND 67 ND
2
Deceased
ALF 		M 9 d Pulmonary hemorrhage on DOL 3, hyperammonemia on DOL 9. 138 94 22.8 2.3 38.7 25.2/14.6 1744 19.9% act. 19.6% act. ND Hepatomegaly, splenomegaly; green, homogeneous liver parenchyma, geographic fibrosis with bile stasis noted. 158 ND
3
Tx
ALF
HCI		 M 1 d Brother had passed away of OTC, lethargy on DOL 1, needed hemodialysis. 406 242 32.6 6.4 >180 8.2/5.8 256 ND ND ND Diffuse macro and micro vesicular steatosis, moderate cholestasis, no evidence of hepatitis. 66 ND
4
Tx
No Liver Injury		 M 2 d Poor feeding, irritable, hyperammonemia, coma by 36 hours of life 93 93 14.3 1.1 41 4.3 143 ND ND ND ND ND ND
5
Diet/Bu/Be
No Liver Injury		 M prenatal Diagnosed in utero (mother is OTC carrier), neonatal seizures. 49 39 10.8 1.1 31.3 0.6 41 ND ND ND ND 159 ND
6
Tx
No Liver Injury		 M 1 d Poor feeding and lethargy at 24–30 hours of life. 25 22 8.6 0.9 26 2.2/1.0 754 ND ND ND 233 ND
Severe OTCD
7
Diet/cit/arg/Be/Ac
ALF
HCI 		F 5 y Increased irritability with ketosis. 419 900 37.7 3.5 62 0.6 133 ND ND ND ND ND ND
ALF
HCI 		Same pt as above Same pt as above See above 3204 4407 26.3 2.4 43 1.4 492 ND ND ND ND 176 2
8
Diet/Bu/Cit
ALF
HCI 		F 1 yo 7 m Presented with h/o chronic n/v, with acute fever, vomiting, seizures found to be in acute liver failure. 1932 2042 39.5 4.1 39.9 0.4/0.1 220 70% 11% act. 211% act Acute hepatocellular injury with mild lobular necrosis, paucity of inflammatory infiltrate. 245 ND
ALF
HCI 		Same pt as above Same pt as above Same pt as above 6299 5519 21.4 2.1 35.1 0.3 443 39% 13% ND ND 228 ND
9
Diet/Bu/Arg Carnitine
No Liver Injury		 F 6 y Reccurent abd pain/n/v/ataxia. 16 16 10.6 1 27.8 0.4 174 ND ND ND ND 242 ND
Moderate OTCD
10
Diet/Bu/Cit
HCI 		F 3 yo 7 m AGE with persistently elevated AST/ALT 59 216 11.9 1.2 31.3 0.5 253 ND ND ND ND 236 ND
HCI Same pt as above Same pt as above Same pt as above 309 65 ND ND ND 0.6 ND ND ND ND ND ND ND
11
Diet/Be
LD) 		F 12 m Lethargy, hyperammonemia, left sided weakness, multiple, bilateral foci of stroke R>L. 123 167 17.5 1.8 30.2 0.5 97 ND ND ND ND 181 ND
12
Diet/Bu
LD 		M 20 m Chronic emesis, elevated ammonia. 21 25 15.2 1.5 26 0.5 235 ND ND ND ND 206 ND
13
Diet/Be/Cit
LD
HCI 		F 13 m Fever, emesis × 5 mo, lethargy, irritability, elevated liver enzymes, coagulopathy. 337 959 16.6 1.7 53 0.2 159 ND ND ND ND 305 ND
14
Diet/Bu
No Liver Injury		 F 4 y N/v + FH of OTC. in brother 11 13 11.6 1.1 26.3 0.4 213 ND ND ND ND 192 ND
15
Diet/Bu
No Liver Injury		 M 9 y Occasional lethargy and inability to function, hyperammonemia. 14 25 10.6 1 27.2 0.6 132 ND ND ND ND 222 ND
16
Diet
No Liver Injury		 M 13 m URI + lethargy, hyperammonemia. 102 191 11.4 1.1 28 0.5 214 (later 332) ND ND ND ND 198 ND
17
Diet/Cit
No Liver Injury		 M 12 y Hyperammonemia with coma. 18 28 11.4 1.1 30 0.8 55 ND ND ND ND 165 ND
18
Diet/BuCit
No Liver Injury		 F ND ND 20 13 10.4 1 26 0.4 38 ND ND ND ND 226 ND
19
Diet/Cit/Arg Carnitine
No Liver Injury		 F 16–20 m Hyperammonemia and coma. 14 21 10.8 1.1 29.6 ND 86 ND ND ND ND 285 ND
Mild OTCD
20
Diet/Bu
HCI 		F 7 yo 2 m Frank confusion and hyperammonemia with h/o intermittent abdominal pain and nausea. 97 252 11.3 1.1 ND 0.3 27 (was 297) ND ND ND ND ND ND
21
Diet/Be/Cit
No Liver Injury		 F 1 y Nausea/vomiting + FH with sister with OTC. 41 14 ND ND ND 0.4 35 ND ND ND ND 226 ND
22
Diet/BuArg
No Liver Injury		 F 2 m FH of brother with OTC 25 20 11.3 1.2 ND ND 55 ND ND ND ND ND ND
23
Diet/Be/Cit/Carnitine
No Liver Injury		 M 3 y 2 m Lethargy, hyperammonemia, nausea, vomiting, and history of headache head hitting and decreased attention. 24 11 10.7 1 29.6 0.7 42 ND ND ND ND 253 ND
24
Deceased
No Liver Injury		 M 13 y 11 m H/o learning disabilities, and schizoaffective disorder, lethargy, coma, hyperammonemia, brain herniation 78 63 13.4 1.4 43 0.4/0.1 2372 ND ND ND Hepatomegaly (3030g), diffuse micro and macrovesicular steatosis. ND ND
25
Diet/Bu
No Liver Injury		 F 9 m Stroke and hyperammonemia 14 10 ND ND ND 0.3 63 ND ND ND ND ND ND
26
No Rx
No Liver Injury		 M 30 y Coma with Meclizine + FH (brother with OTC) 14 22 10.4 1 30.5 ND 32 ND ND ND ND 335 ND
27
Diet/Cit
No Liver Injury		 F ND Infrequent irritability, + FH (3 sisters with OTC) 23 18 11.8 1.1 30.5 2.1 60 ND ND ND ND ND ND
No Symptoms/Treatment
28
No Rx
No Liver Injury		 F N/A Family History 12 11 10.8 1.1 27 0.4 65 ND ND ND ND 282 ND
29
No Rx
No Liver Injury		 F N/A Family History 15 15 10.4 1 27.9 0.4 39 ND ND ND ND 245 ND
30
No Rx
No Liver Injury		 F N/A Family History 12 13 10.4 1 25.9 0.4 43 ND ND ND ND 319 ND
31
No Rx
No Liver Injury		 F N/A ADHD and Family History 17 26 10.6 1 28 0.7 49 ND ND ND ND 249 ND
32
No Rx
No Liver Injury		 F N/A Family History 10 11 11 1.1 29.1 0.5 40 ND ND ND ND 230 ND
33
No Rx
No Liver Injury		 F N/A Family History 21 18 10.1 1 28.3 0.5 37 ND ND ND ND 298 ND
34
No Rx
No Liver Injury		 F N/A Family History 10 11 10.7 1 28.9 0.3 23 ND ND ND ND 341 ND
35
No Rx
No Liver Injury		 F N/A Family History (son) 14 17 11 1.1 27.5 0.5 26 ND ND ND ND 310 ND
36
No Rx
No Liver Injury		 F N/A Family History (son) 24 22 10.5 1 25.9 0.5 34 ND ND ND ND 217 ND
37
No Rx
No Liver Injury		 F N/A Family History 20 16 11.2 1.1 24.5 0.6 25 ND ND ND ND 142 ND
38
No Rx
No Liver Injury		 F N/A Family History 14 12 10.8 1 26.7 0.5 105 ND ND ND ND 250 ND
39
No Rx
No Liver Injury		 F N/A Family History 20 20 10.6 1 28.7 1.1 32 ND ND ND ND 256 ND
40
No Rx
No Liver Injury		 M N/A Family History (daughters) 24 25 11.7 1.2 29.4 1 78 ND ND ND ND 212 ND
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Legend: LF: Acute liver failure. LD: Liver dysfunction. HCI: Hepatocellular injury. RR: Respiratory rate. Rx: Treatment. Tx: Liver transplant. ND: Not done. AMS: Altered mental status. Diet: Dietary therapy, restriction of natural protein +/− use of essential amino acids. Arg: Arginine therapy. Cit: Citrulline therapy. Bu: Sodium phenylbutyrate. Be: Sodium benzoate. Asx: Asymptomatic. NH3: Ammonia. HA: Hyperammonemic.

Legend: ALF: Acute liver failure. LD: Liver dysfunction. HCI: Hepatocellular injury. RR: Respiratory rate. Rx: Treatment. Tx: Liver transplant. ND: Not done. AMS: Altered mental status. Diet: Dietary therapy, restriction of natural protein +/− use of essential amino acids. Arg: Arginine therapy. Cit: Citrulline therapy. Bu: Sodium phenylbutyrate. Be: Sodium benzoate. Asx: Asymptomatic. NH3: Ammonia. HA: Hyperammonemic. N/v: Nausea and vomiting. DOL: day of life. FH: Family History. URI: Upper respiratory tract infection. ADHD: Attention deficit hyperactivity disorder.

METHODS

A historical cohort study was conducted at two large metabolic disease centers (Children's Hospital Colorado and UCLA Medical Center). The study was approved by the Institutional Review Board at each center. Records were reviewed of all individuals with OTCD who were followed at these centers between the years 2000 and 2011. They were identified by site records and ongoing clinical care, and through enrollment in the NIH funded, multi-site Longitudinal Study of Urea Cycle Disorders at these two centers, which is an IRB approved, natural history study30, for which written informed consent was obtained. Many individuals followed clinically for OTCD were also subjects in the NIH study, some asymptomatic individuals were not seen clinically, but were subjects in the NIH study. These two groups constituted all known individuals followed for OTCD at the two centers. OTCD was established in each subject by biochemical test results, molecular diagnosis, or by enzymology. For each subject the following historical information was recorded: age at presentation, sex, OTC mutation if known, clinical presentation, OTC enzyme activity in liver, and liver histology. To assess liver injury the following tests were recorded at least once for every subject: AST, ALT, prothombin time (PT), PTT, and INR. Values were obtained from clinic visits, Longitudinal Study research visits, or hospitalizations. If available, concurrent total and direct bilirubin, Factor V, Factor VII, Factor VIII, D-dimers and fibrinogen were also recorded, as was plasma ammonia. For each subject the time point at which the available liver injury related laboratory results were collected was at the time of the highest recorded PT or INR (or AST/ALT if PT/INR was not performed). Some of the recorded tests may have been obtained at an earlier or later time point that same day. Liver injury related tests were also recorded on every identified occasion that the AST/ALT or PT/INR values met the criteria defined in this study for ALF, liver dysfunction or hepatocellular injury, see below. When possible, outside medical records, including evaluations prior to the identification of a UCD, were reviewed.

For the purposes of this study, acute liver failure (ALF) was defined as acute liver injury with an INR ≥ 2.0, or PT ≥ 20 seconds in the absence of disseminated intravascular coagulation2,29; liver dysfunction as INR ≥ 1.5 and < 2.0 or PT ≥ 15 seconds and < 20 seconds; and hepatocellular injury as AST or ALT ≥ 250 IU/L. Lack of response of elevated INR or PT to vitamin K was not included as a criterion for ALF, as this is a retrospective study and vitamin K was not given uniformly.

For the purposes of this study individuals were placed in one of five groups of clinical severity with respect to their urea cycle defect. Individuals were considered to be Asymptomatic with respect to OTCD if they had not had episodes of hyperammonemia requiring medical intervention. Individuals with symptomatic OTCD were classified into four groups: Neonatal Males who lack residual enzyme activity are the most severe and developed symptoms of hyperammonemia in the first two days of life; Severe males and females developed symptoms of hyperammonemia after two days of life, required maximal medical and dietary therapy, and had frequent hospitalizations; Moderate males and females required medical and/or dietary therapy, and had less frequent hospitalizations; Mild males and females did not have recurrent hyperammonemia after establishment of the diagnosis of OTCD.

Statistical Analyses

A two sample test of proportions was performed comparing the proportion of symptomatic versus asymptomatic OTCD subjects who had ALF, liver dysfunction, or hepatocellular injury. Descriptive statistics (mean, standard deviation, and range for AST, ALT, ammonia, PT and INR) were performed using the STATA program.

RESULTS

Charts of 89 subjects were reviewed from the two centers, and 71 subjects were included in the analysis; 18 subjects were excluded due to lack of sufficient laboratory data, 12 of thom were asymptomatic (Table III; online). For each of the 71 subjects, available liver injury related laboratory tests were recorded at least once. Additional events of ALF, liver dysfunction or hepatocellular injury were observed in several cases and these data were recorded on separate rows. For each individual the most severe liver injury identified (ALF> liver dysfunction>hepatocellular injury) was used for Tables I and II); each individual is included only once in the summary tables.

Table 1.

Liver Laboratory Values in 71 Individuals with OTCD

Clinical Classification (N) Ammonia μmol/L ALT IU/L AST IU/L PT seconds INR
Mean SD Range Mean SD Range Mean SD Range Mean SD Range Mean SD Range
Neonatal Male (12) 1232 817.6 41.1, 2634 109 85.6 22, 256 151 151 25, 467 23 9.8 8.6, 37.6 2.48 1.64 0.9, 6.41
Severe (9) 202 92.1 106, 410 923 827.6 16, 2089 1063 1405 16, 4139 32 19.4 10.6, 63.7 2.92 1.64 1.0, 5.7
Moderate (12) 155 92.4 37.6, 332 331 467.1 13, 1223 137 236 11, 785 14.8 7.4 10.4, 34.9 1.48 0.62 1.0, 3.1
Mild (15)* 72.2 79.7 9, 297 102 187.6 10, 689 71.1 129 14, 519 13 2.4 10.4, 17.6 1.15 0.14 0.95, 1.4
Asymptomatic (22) 39 22.97 9, 104.5 19 10.04 11, 49 23 13.5 10, 62 12 1.8 10.1, 16.2 1.04 0.09 0.92, 1.27
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*

One individual was classified as mild but did not survive the initial presentation, his values are not included here.

Normal values: Ammonia: < 50 μmol/L (< 80 μmol/L in Neonates ); ALT: 10 – 35 IU/L; AST: 15 – 40 IU/L; PT: 12.0 – 15.0 seconds; INR: < 1.5

Table 2.

Acute Liver Failure, Liver Dysfunction, and Hepatocellular Injury in 71 Individuals with OTCD

Clinical Classification (N) Acute Liver Failure Liver Dysfunction Hepatocellular Injury Only No Known Liver Lab Abnormality Percent with either ALF/LD/HCI
Neonatal Male (12) 58% 17% 0% 25% 75% (9/12)
Severe (9) 56% 11% 0% 33% 67% (6/9)
Moderate (12) 17% 25% 8% 50% 50% (6/12)
Mild (16) 0% 25% 19% 56% 44% (7/16)
Asymptomatic (22) 0% 9% 0% 91% 9% (2/22)
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ALF: Acute Liver Failure: INR ≥ 2.0, or PT ≥ 20 LD: Liver Dysfunction: INR ≥ 1.5 and < 2.0, or PT ≥ 15 and < 20 HCI: Hepatocellular Injury: AST or ALT ≥ 250 IU/L

In this historical cohort of 71 individuals with OTCD, the severity of hepatic synthetic dysfunction, reflected by the PT and INR, correlated with the severity of the OTCD (Table I). The mean PT and INR were higher in Neonatal Males and Severe Females than in those classified as Moderate and Mild. Markedly elevated AST (1,063 ± 1,405 IU/L) and ALT (923 ± 828 IU/L) were identified in individuals classified as Severe, all of whom were female. Elevations of AST and ALT were moderate in Neonatal Males (AST 151 ± 151, ALT 109 ± 86). Mild elevations of ammonia, minimal elevations of AST and ALT, and mild elevations of PT and INR were identified in Asymptomatic individuals. Symptomatic individuals classified as Moderate or Mild had intermediate elevations of ammonia, ALT, AST, PT and INR.

The risk of ALF, liver dysfunction and isolated hepatocellular injury varied with OTCD clinical severity (Table II); 75% of Neonatal Males and 67% of Severe females showed evidence of liver involvement. Those with less severe OTCD had lower frequencies of liver involvement. ALF was identified most often in individuals classified as Neonatal Male (7/12, 58%), or Severe (5/9, 56%). Almost half of individuals classified as Mild OTCD showed evidence of liver dysfunction or isolated hepatocellular injury at least once in their clinical course. In some cases ALF or liver dysfunction was associated with hepatocellular injury as defined for this study. All six Severe females with ALF or liver dysfunction had concurrent elevated AST or ALT ≥ 250 IU/L and met criteria for hepatocellular injury. Two of nine Neonatal Males, with ALF or liver dysfunction had concurrent elevated AST or ALT ≥ 250 IU/L. The two Moderate individuals with ALF met had concurrent elevated AST or ALT ≥ 250 IU/L, as did one of three with liver dysfunction. Mild individuals with liver dysfunction did not have concurrent AST or ALT ≥ 250 IU/L.

Type of liver injury in symptomatic versus asymptomatic individuals with OTCD is shown in Figure 2. In those individuals with liver injury, serum bilirubin was normal for age, or only mildly elevated (Table III). The proportion of OTCD subjects who had ALF, liver dysfunction or hepatocellular injury was significantly higher in the symptomatic (28 of 49) compared with the asymptomatic (2 of 22) group (p=0.0002).

Figure 2.

Figure 2

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Summary of types of liver injury present in cases of OTCD followed at the two metabolic disease centers.

ALF was the initial clinical presentation of at least three individuals (part 1, cases 7 and 8; part 2, case 8; Table III). ALF was documented to be recurrent in five individuals (part 1, cases 8, 9 and 13; part 2, cases 7 and 8; Table III). Liver dysfunction and hepatocellular injury were also recurrent in some cases. Liver laboratory abnormalities were not always recurrent in subsequent episodes of hyperammonemia, though this was not formally assessed in this study. Two females with severe OTCD had recurrent hyperammonemia, but never had documented liver test abnormalities using the criteria established for this study. Notably, liver histology was abnormal in these two subjects (part 1, cases 11 and 12; Table III).

DISCUSSION

We report the results of a historical cohort study conducted at two large genetic metabolic disease centers, which has identified the presence of significant liver injury and dysfunction in over 50% of individuals with symptomatic OTCD at some time in their clinical history. This report represents a systematic investigation of this association and suggests that a clinical liver presentation, including ALF, is not uncommon among patients with OTCD.

The most severe clinical presentations of UCDs occur in the newborn period, and later-onset presentations may be precipitated by infection, the post-partum period, valproate therapy, or corticosteroid use12,24,31,32. As these are treatable conditions in which delay of treatment can result in irreversible neurologic injury or death, testing for UCDs is critical when indicated. Although the urea cycle enzymes are active in the liver, standard liver function has generally been considered to be largely unaffected in UCDs4,5,33. However, elevated AST and ALT and coagulopathy were identified in the first reported cases of OTCD in the 1960s and 1970s34–38, and a Reye syndrome presentation of OTCD was recognized in the 1970s and 1980s39–42 (Table IV; available at www.jpeds.com). In the late 1980s and early 1990s, neurologic presentations of OTCD were emphasized, with little focus on hepatic injury43–47. Since the 1990s there have been rare reports of significant clinical liver disease in patients with OTCD8,10,48.

Table 4.

Twenty-Four Literature Cases of OTCD with Acute Liver Failure, Liver Dysfunction or Hepatocellular Injury

Sex
Liver Injury		 Age Presentation AST IU/L ALT IU/L PT INR PTT Bili NH3 μmol/L V Author Year
F
HCI 		4 y Recurrent emesis, lethargy, hemiparesis stupor (Case 10 in literature) 2,232 2,610 NR NR NR NR 658 NR Sunshine38 1972
M
HCI 		10 m Emesis, hypotonia, brother died at 7 months 1,590 740 NR NR NR NR NR NR Van der Heiden53 1978
F
HCI 		14 m Episodic emesis, loss of milestones 600 NR NR NR NR NR Unknown (later 315 and 407) NR La Brecque13 1979
M
HCI 		15 m Recurrent “Reye syndrome” 542 481 NR NR NR NR 29 NR Yokoi41 1981
M
ALF
HCI 		9m Emesis, seizures, encephalopathy NR 1,200 28% NR NR NR 406 NR Landrieu15 1982
M
HCI 		21 y Emesis, nausea, progressive encephalopathy, death, brother died at 10 years 720 561 NR NR NR Nl 1,012 NR Tallan16 1983
F
HCI 		2 y Emesis, lethargy, “Reye syndrome” 679 976 NR NR NR NR 113 NR Hayasaka54 1987
M
HCI 		6 m Emesis, episodic lethargy, Coagulation “severely disturbed” 900 600 NR NR NR NR NR NR Wendel55 1989
M
LD 		12.5 years Emesis, lethargy, altered mental status – combative 90 86 17.2 NR NR 6.4 282 NR Capistrano-Estrada56 1994
F
HCI 		23 m Recurrent emesis, lethargy, 777 1,213 NR NR NR NR 1026 NR Pridmore46 1994
extensor plantar reflexes
F
HCI 		22 m Recurrent emesis, lethargy, delay, acute cerebellar ataxia with increased AST/ALT, “atypical Reye syndrome” 1,052 275 NR NR NR NR 218 NR Pridmore46 1994
M
HCI
LD 		13 y Emesis, ataxia, altered mental status, clonus 68 347 16.5 NR NR 2.4 (0.1) 408 NR Myers47 1995
F
HCI 		3 y Emesis 1,206 1,663 42% NR 43 NR 294 NR Zammarchi48 1996
F
ALF
HCI 		5 m Emesis 1,692 2,328 18% NR 48 NR 150 NR Zammarchi48 1996
F
LD 		3 y Coma in illness 187 114 17.6 NR NR NR 343 NR Inui57 1996
F
ALF 		3 d Hypoglycemia, lactic acidemia, seizures, hypotonia NR NR NR NR NR NR 2301 10% Klowsowski58 1998
F
HCI 		3 y Aggression, confusion, abnormal movements NR 299 NR NR NR NR NR NR Schultz59 2000
F
HCI 		28 y GI bleed 196 466 15 1.3 NR 1.1 247 NR Trivedi7 2001
M
HCI 		15 m Recurrent emesis, elevated AST/ALT, FTT, normal ammonia, Gln, orotic, possible HFI 300 1,727 NR NR NR NR 40 NR Burlina60 2006
F
ALF
HCI 		14 m Emesis 2,212 3,609 NR 5.1 67 s Nl 74 NR Mustafa8 2006
M
HCI 		36 y Lethargy post steroid treatment 295 317 NR 1.1 NR 3.1/0.9 494 NR Atiq9 2008
F
ALF
HCI 		3 y Emesis, lethargy, aggression 7,900 5,000 NR 3.1 NR NR 161 25% Teufel10 2009
M
ALF 		24 y Emesis, hallucinations, h/o ADHD, growth retardation 114 NR NR 2.7 NR Nl 348 Low Thurlow11 2010
F
ALF 		1.5 y Cyclic vomiting, lethargy NR 3,500 55 NR NR NR 207 NR Mira61 2011
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Legend: ALF: Acute liver failure. LD: Liver dysfunction. HCI: Hepatocellular injury. V: Factor V. RR: Respiratory rate. Rx: Treatment. Tx: Liver transplant. ND: Not done. AMS: Altered mental status. HFI: Hereditary fructose intolerance. ADHD: Attention deficit hyperactivity disorder. FTT: Failure to thrive. NR: Not recorded. Gln: Glutamine F: Female. M: Male, m: Months old. y: Years old. Nl: Normal

As in the case presented here, liver injury in OTCD is often seen in association with elevated ammonia levels (Figure 1). Our study, therefore, required review of the highest recorded liver laboratory tests (AST, ALT, PT, PTT and INR) during hyperammonemic episodes. These data were not collected through the Longitudinal Study, and required local chart review. A limitation of this study is that liver tests were collected for some subjects during hospitalizations, and for others, largely those asymptomatic with respect to OTCD, at study visits in the outpatient setting. This is due to the fact that asymptomatic individuals were not hospitalized frequently, therefore, in some cases the only available liver test results were obtained during study visits. However, in symptomatic individuals, many of whom who were hospitalized, the highest mean PT and INR were in those more severely affected, and the frequency of liver test abnormalities correlated with the severity of OTCD (Tables I and II). This suggests the underlying OTCD as the cause of, or a predisposing factor to, the liver injury. The pathogenesis of liver injury in OTCD is unknown and this study suggests that further work is indicated. It is possible that the liver injury is caused by direct toxicity of ammonia; toxicity of carbamoyl phosphate has been proposed, but this is speculative49,50.

The observation that liver blood tests may be elevated in individuals with OTCD raises the question of whether regular assessment of liver tests, especially during episodes of hyperammonemia, should be performed. These abnormal tests may resolve with treatment (Figure 1)25 and may not change initial care, however, in at least one reported case urgent liver transplantation for acute liver failure in OTCD was performed10. In addition, the finding of histological abnormalities on liver biopsy13–19 and reports of hepatocellular carcinoma (HCC) in OTCD patients49 suggest that recurrent liver injury and chronic inflammation could predispose to the development of HCC, as in other genetic metabolic liver diseases51. An increased risk of HCC has implications for long-term treatment and monitoring of patients with OTCD49. There are currently no recommendations for HCC screening in OTCD.

The finding of an ALF presentation in OTCD raises the question as to whether undiagnosed OTCD may be responsible for a significant number of indeterminate pediatric ALF patients. In the past decade, a renewed interest in pediatric ALF revealed that an appropriate evaluation to define treatable underlying genetic and metabolic etiologies is not completed for most patients2. As a result, patients with metabolic disorders, such as UCDs, may have gone undiagnosed and labeled indeterminate ALF. Indeed, in the Pediatric ALF Study Group registry, only 1 of 148 infants less than 3 months of age had the diagnosis of OTCD (another had an unspecified urea cycle defect) and 56 (38%) were labeled indeterminate29. However, OTCD was not investigated in the majority of the indeterminate cases. OTCD can also be a cause of liver failure in adults11. Therefore, the current study suggests that OTCD should be considered in all patients with indeterminate ALF, especially those with normal, or mildly elevated, serum bilirubin concentration.

In conclusion, this study demonstrates that clinical hepatic presentations of OTCD may include ALF, liver dysfunction and hepatocellular injury as defined in this report, which may be associated with only moderate elevations of blood ammonia levels that may not call attention to a UCD. To investigate a UCD in a patient with ALF, laboratory evaluation should be expedited6. Initial testing should include quantitative plasma amino acids, urine organic acids and a quantitative urine orotic acid. Specific metabolic treatment can be life-saving, and may reverse ALF, obviating consideration of emergency liver transplantation23. The failure to correctly diagnose and treat OTCD may result in irreversible neurologic disability or death, and is a lost opportunity to evaluate family members and to provide genetic counseling52.

ACKNOWLEDGMENTS

We thank the members of the Urea Cycle Disorders Consortium, particularly the local site study coordinators: Curtis Coughlin II, MS, MBe (Colorado), Shannon Scrivner, MS (Colorado), and Nagmeh Dorrani, MS (UCLA). We thank Robert McCarter, DSc, for critical reading of the manuscript. All of the acknowledged individuals are funded by NIH (U54HD061221).

Appendix

Funded by the National Institute of Child Health and Human Development (U54HD061221 to R.G.) and the National Institutes of Health (NIH) Office of Rare Diseases Research. The Longitudinal Study of Urea Cycle Disorders is conducted by the Urea Cycle Disorders Consortium, which is a part of the NIH Rare Diseases Clinical Research Network. The Urea Cycle Disorders Consortium is supported by the O'Malley Foundation, the Rotenberg Family Fund, the Dietmar-Hopp Foundation, and the Kettering Fund; Children's Hospital Colorado received funding from the O'Malley Foundation, and the Kettering Family Fund. R.G. and D.W. served as local site principal investigators for a clinical trial of a novel medication for urea cycle disorders, sponsored by Hyperion Therapeutics (registered with ClinicalTrials.gov: <<>>) The views expressed in written materials or publications do not necessarily reflect the official policies of the Department of Health and Human Services; nor does mention by trade names, commercial practices, or organizations imply endorsement by the US Government. The authors declare no conflicts of interest.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Funding and conflict of interest information available at www.jpeds.com (Appendix).

Portions of the study have been presented at the annual Meeting of the Urea Cycle Disorder Consortium <<>>, as well as a poster at the meet of the Society for Inherited Metabolic Disease, March 2012.

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