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Urea(lly) Got Me: An Uncommon Etiology of Peripartum Liver Failure

Spiller, Robert E. DO, MS1; Colombo, Christopher J. MD, FCCM1; Lindholm, Phillip C. MD, FACG1; Kwon, James MD1

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doi: 10.14309/crj.0000000000000780
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Urea cycle disorders (UCDs) are relatively rare (1 in 35,000 births), and presentations can be categorized into 2 types: early onset (first 28 days of life) and late onset (>28 days after birth).1 Late-onset disease may present at any time and typically occur during periods of high catabolic stress (eg, sepsis, surgery, and pregnancy).2 Although most cases of UCDs are diagnosed in the neonatal period, it is important to include UCDs in the differential for peripartum acute liver failure (ALF) because early diagnosis may significantly improve patient prognosis.


A 23-year-old woman presented to the emergency room (ER) 4 days postpartum with agitation and confusion. Earlier in the day, the patient's mother noticed that she was having word-finding difficulties, although did not seek care. This progressed to inappropriate laughter, repetitive speech, and dilated pupils. On ER arrival, her condition quickly deteriorated, and she became unresponsive (Glasgow Coma Scale of 4), prompting intubation. Initial laboratory evaluation noted multiple abnormalities: aspartate aminotransferase (AST) 86 U/L, alanine transaminase (ALT) 96 U/L, albumin 2.6 g/dL, international normalized ratio (INR) 2.2, and ammonia 149 μmol/L. Based on clinical presentation and laboratory findings, the patient seemed to be in ALF. The patient's family reported daily prescription prenatal vitamin use but denied herbal or dietary supplements or over-the-counter medications. Urine drug screen, alcohol, acetaminophen, and salicylates were negative. The viral hepatitis A-C panel was nonreactive, and antinuclear antibodies, Epstein-Barr virus, and cytomegalovirus testing were all negative. Smooth muscle antibodies and immunoglobulin G levels were within the normal range. There was no evidence of hemolysis, thrombocytopenia, proteinuria, or hypertension. Head computed tomography/magnetic resonance imaging was normal and right upper quadrant ultrasound with Doppler showed hepatic steatosis without evidence of obstruction.

After lactulose administration, the patient became responsive the following morning and was subsequently extubated. Her ammonia levels fluctuated and seemed unaffected by lactulose administration (72–400 μmol/L). She remained asymptomatic during her hospitalization. She met >6 Swansea criteria, suggestive of acute fatty liver of pregnancy (AFLP). However, AST and alanine transaminase continued to rise, reaching peak levels of 1,745 U/L and 1,868 U/L, respectively, prompting additional workup.

An amino acid panel sent to evaluate for UCDs showed high citrulline (1,512.5 mcmol/L) and low argininosuccinate (<0.1 mcmol/L), suggestive of citrullinemia type 1 (CTLN1) (Figure 1). A liver biopsy noted histology consistent with ALF, including apoptotic bodies and lymphohistiocytic inflammation, without evidence of microvesicular steatosis (Figure 2). The patient was started on arginine supplementation and transferred to a tertiary center for glycerol phenylbutyrate, a nitrogen scavenger, and liver transplant evaluation. After starting the medication and diet modification, her AST/ALT downtrended and albumin returned to premorbid levels. Genetic testing using a blood sample revealed her to be a compound heterozygote for the argininosuccinate synthetase gene, confirming the diagnosis. At the 1-year follow-up, the patient had not had any further episodes of hepatic decompensation or liver dysfunction.

Figure 1.:
The dysfunctional pathway of CTLN1 is displayed within the urea cycle (abnormal enzyme outlined in red). The mechanism of action for the nitrogen scavenger medication, glycerol phenylbutyrate, can be seen in red. Key results from the amino acid panel are seen, diagnosing CTLN1. CTLN1, citrullinemia type 1.
Figure 2.:
Apoptotic bodies (open arrows) and lymphohistiocytic inflammation (blue solid arrows) in the lobules (H&E stain, 3400).


Our previously healthy 23-year old woman had acute onset liver failure with severe encephalopathy 4 days postpartum, responding to dietary modifications and nitrogen scavenger medications used for the treatment of CTLN1. On presentation, she met the Swansea criteria for AFLP, making this the presumed diagnosis. However, these criteria risked early closure of her clinical care because AFLP most often presents during the third trimester and resolves with supportive care. Her diagnosis of CTLN1 was confirmed by an amino acid panel and serum genetic testing.

ALF is defined as a rise in liver-associated enzymes, coagulopathy (INR >1.5), and hepatic encephalopathy in a patient without pre-existing liver disease and illness duration less than 26 weeks.3 Peripartum ALF presents a unique differential diagnosis ranging from the common to the esoteric. Many diagnoses are specific to pregnancy, including pre-eclampsia/eclampsia, HELLP syndrome, acute hepatic rupture, and AFLP. Budd-Chiari syndrome, viral hepatitis, gallstone disease, or genetic diseases, such as UCDs, may be unmasked or exacerbated during pregnancy. The final category of peripartum ALF is unrelated to the pregnant state and often occurs because of drug-induced liver disease, shock, or trauma. Maternal and fetal outcomes often depend on early diagnosis and prompt management of the inciting etiology.

Despite ALF being associated with primary presentations of UCDs, the liver is biopsied infrequently. To the best of our knowledge, this is the first case to present hepatic histopathologic findings in CTLN1. The histologic changes are nonspecific to any specific etiology of ALF but may be consistent with citrullinemia-associated liver injury, warranting further research in this area.

AFLP is pregnancy-specific and only occurs in the third trimester or early postpartum period. Its incidence is 5/100,000 with an 18% maternal and 20% fetal mortality.4,5 The hallmark pathologic finding, microvesicular steatosis and infiltration, is believed to be the primary pathophysiologic mechanism and can distinguish this disorder from many other causes of ALF.6 However, liver biopsy is rarely performed because of coexisting coagulopathies. The Swansea criteria allow the diagnosis of AFLP without liver biopsy in coagulopathic patients.7 A minimum of 6 criteria are needed to make the diagnosis, and it is generally used when patients do not have evidence of hemolysis, thrombocytopenia, or hypertension (Figure 3). If AFLP is appropriately diagnosed, maternal mortality rates drastically decrease with prompt delivery and supportive care.8

Figure 3.:
Swansea criteria used to diagnose acute fatty liver of pregnancy.

UCDs should be suspected when patients present with hyperammonemia, a normal anion gap, and euglycemia. Initial testing should include a serum amino acid panel and confirmatory genetic testing, allowing for further delineation among the various disorders. On diagnosis, patients should be educated on protein restriction, based on their specific disorder. Furthermore, families should be counseled on emergency plans during metabolic crises. Nitrogen scavenger medications can be used to circumvent the aberrant pathways, and studies have suggested that a majority of adult-onset cases can be managed with only medical therapy. Liver transplant should be considered in patients presenting with hyperammonemic crises within the first year of life or in patients with recurrent hyperammonemic crises despite optimal medical therapy.9–11

Distinguishing between UCDs and AFLP may be particularly difficult in the peripartum setting because there are multiple clinical similarities. The Swansea criteria were originally proposed after a 15-month study in Swansea, UK which examined obstetric patients (6 weeks gestation to 6 days postpartum) with abnormal liver tests. However, there is a relative paucity of studies further validating these criteria. Only 1 such study has performed histologic confirmation of this disease, with the results suggesting that the criteria had 100% sensitivity but only 57% specificity.12

Our patient met Swansea criteria, yet further testing suggested an alternative diagnosis, radically changing the patient's treatment and prognosis. Therefore, we strongly recommend that UCDs be considered with amino acid testing in patients meeting criteria for AFLP, particularly those who do not respond quickly to supportive care. Distinguishing between these diseases, among other common causes of postpartum liver failure (eg, viral hepatitis, preeclampsia, and HELLP syndrome), can be a potentially lifesaving diagnosis.


Author contributions: RE Spiller, primary contributor to drafting and revising the manuscript, data acquisition and interpretation, creator of imaging, and is the article guarantor; CJ Colombo, coprimary editor of draft and revisions, and data acquisition and interpretation; PC Lindholm, coprimary editor of draft and revisions, and data acquisition and interpretation; J. Kwon, secondary editor of draft and revisions, obtained and interpreted images within manuscript.

Previous presentation: Presented at Tri-Service ACP Conference; September 2020; Virtual Conference.

Financial disclosure: None to report.

Informed consent was obtained for this case report.


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