Prognostic significance of hyperammonemia in neuroendocrine neoplasm patients with liver metastases

Julie Refardt*, Caroline M. den Hoed, Janneke Langendonk, Wouter T. Zandee, Ayoub Charehbili, Richard A. Feelders, Wouter W. de Herder, Tessa Brabander, Johannes Hofland

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Scopus)


Neuroendocrine neoplasms (NENs) are rare, usually slow-growing tumors, often presenting with extensive liver metastases. Hyperammonemia due to insufficient hepatic clearance has been described in NEN cases; however, no systematic evaluation of risk factors and outcomes of NEN-associated hyperammonemia exists so far. This case report and retrospective review of NEN patients developing hyperammonemia from the years 2000 to 2020 at the Erasmus Medical Center in Rotterdam, the Netherlands, aimed to describe these patients and determine prognostic factors to improve evaluation and treatment. Forty-four NEN patients with documented hyperammonemia were identified. All patients had liver metastases with 30% (n = 13) showing signs of portal hypertension. Patients who developed encephalopathy had higher median ammonia levels, but there was no association between the severity of hyperammonemia and liver tumor burden or presence of liver insufficiency. Eighty-four percent (n = 37) of patients died during follow-up. The median (IQR) time from diagnosis of hyperammonemia to death was 1.7 months (0.1–22.7). Hyperbilirubinemia, hypoalbuminemia, elevated international normalized ratio, presence of liver insufficiency, encephalopathy and ascites were associated with worse outcomes. Their role as independent risk factors for mortality was confirmed using the Child–Pugh score as a summary factor (P < 0.001). No difference was seen concerning overall survival between our hyperammonemia patients and a propensity score-matched control stage IV NEN cohort. In conclusion, hyperammonemia comprises a relevant and potentially underdiagnosed complication of NEN liver metastases and is associated with worse outcomes. Assessment of signs of encephalopathy, risk factors and the Child–Pugh score could be helpful in selecting patients in whom ammonia levels should be measured.

Original languageEnglish
Pages (from-to)241-250
Number of pages10
JournalEndocrine-Related Cancer
Issue number5
Early online date24 Mar 2022
Publication statusPublished - May 2022

Bibliographical note

Funding Information:
J R: supported by a grant from the Swiss National Science Foundation (P2BSP3-181720).

Publisher Copyright: © 2022 Society for Endocrinology Published by Bioscientifica Ltd.


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