Long-term liver disease in methylmalonic and propionic acidemias

Imbard, Apolline; Segarra, Nuria Garcia; Tardieu, M.; Broué, Pierre; Bouchereau, Juliette; Pichard, Samia; Baulny, Hélène Ogier de; Slama, Abdelhamid; Mussini, Charlotte; Touati, Guy; Danjoux, Marie; Gaignard, Pauline; Vogel, Hannes; Labarthe, François; Schiff, Manuel; Benoist, Jean‐François

doi:10.1016/j.ymgme.2018.01.009

Cited by 25 publications

(30 citation statements)

References 42 publications

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“…Hepatoblastoma and hepatocellular carcinoma develop by malignant transformation of fetal and well‐differentiated hepatocytes, respectively. Cases 1 to 3 showed evidence of cirrhosis/fibrosis, as previously reported in MMA and might per se increase the risk of developing liver neoplasms. Cirrhosis is a recognized complication in other inborn errors of metabolisms, such as Wilson disease, tyrosinemia type I, argininosuccinic aciduria or glycogen storage disorders; the latter three diseases identified with significant risk of developing hepatocellular carcinoma …”

Section: Discussionmentioning

confidence: 99%

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Liver neoplasms in methylmalonic aciduria: An emerging complication

Forny

Hochuli

Rahman

et al. 2019

J of Inher Metab Disea

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Methylmalonic aciduria (MMA) is an inherited metabolic disease caused by methylmalonyl‐CoA mutase deficiency. Early‐onset disease usually presents with a neonatal acute metabolic acidosis, rapidly causing lethargy, coma, and death if untreated. Late‐onset patients have a better prognosis but develop common long‐term complications, including neurological deterioration, chronic kidney disease, pancreatitis, optic neuropathy, and chronic liver disease. Of note, oncogenesis has been reported anecdotally in organic acidurias. Here, we present three novel and two previously published cases of MMA patients who developed malignant liver neoplasms. All five patients were affected by a severe, early‐onset form of isolated MMA (4 mut0, 1 cblB subtype). Different types of liver neoplasms, that is, hepatoblastoma and hepatocellular carcinoma, were diagnosed at ages ranging from infancy to adulthood. We discuss pathophysiological hypotheses involved in MMA‐related oncogenesis such as mitochondrial dysfunction, impairment of tricarboxylic acid cycle, oxidative stress, and effects of oncometabolites. Based on the intriguing occurrence of liver abnormalities, including neoplasms, we recommend close biochemical and imaging monitoring of liver disease in routine follow‐up of MMA patients.

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Section: Discussionmentioning

confidence: 99%

“…Despite the significant role of the liver in MMA metabolism, hepatic complications have been scarcely described. A recent study reported on longitudinal elevations of alpha‐fetoprotein, the occurrence of hyperechoic liver tissue on ultrasound, and marked pathological changes on liver biopsy, ranging from fibrosis to cirrhosis …”

Section: Introductionmentioning

confidence: 99%

Liver neoplasms in methylmalonic aciduria: An emerging complication

Forny

Hochuli

Rahman

et al. 2019

J of Inher Metab Disea

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“…In addition, Kölker et al describe that the mean concentration of alanine aminotransferase is 12% above the reference range in MMA and 16% in PA patients. For aspartate aminotransferase this is 20% in MMA and 19% in PA patients and for gamma‐glutamyl transferase the reported value is 9% and 33% in MMA and 10% and 25% in PA patients . Fibrosis/cirrhosis diagnosed by liver biopsy is described in three patients, with decreased respiratory chain activities .…”

Section: Complicationsmentioning

confidence: 86%

“…For aspartate aminotransferase this is 20% in MMA and 19% in PA patients and for gamma-glutamyl transferase the reported value is 9% and 33% in MMA and 10% and 25% in PA patients. 74,75 Fibrosis/cirrhosis diagnosed by liver biopsy is described in three patients, with decreased respiratory chain activities. 74 Chandler et al 72 described megamitochondria with dysmorphic and shortened cristae, and a less electron-dense mitochondrial matrix in hepatocytes of Mut −/− mice with MMA, already early in life.…”

Section: Livermentioning

confidence: 99%

“…74,75 Fibrosis/cirrhosis diagnosed by liver biopsy is described in three patients, with decreased respiratory chain activities. 74 Chandler et al 72 described megamitochondria with dysmorphic and shortened cristae, and a less electron-dense mitochondrial matrix in hepatocytes of Mut −/− mice with MMA, already early in life. They found similar morphological changes in the hepatocytes of a MMA patient (MUT type).…”

Section: Livermentioning

confidence: 99%

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Pathophysiology of propionic and methylmalonic acidemias. Part 1: Complications

Haijes

Jans

Tas

et al. 2019

J of Inher Metab Disea

127

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Over the last decades, advances in clinical care for patients suffering from propionic acidemia (PA) and isolated methylmalonic acidemia (MMA) have resulted in improved survival. These advances were possible thanks to new pathophysiological insights. However, patients may still suffer from devastating complications which largely determine the unsatisfying overall outcome. To optimize our treatment strategies, better insight in the pathophysiology of complications is needed. Here, we perform a systematic data‐analysis of cohort studies and case‐reports on PA and MMA. For each of the prevalent and rare complications, we summarize the current hypotheses and evidence for the underlying pathophysiology of that complication. A common hypothesis on pathophysiology of many of these complications is that mitochondrial impairment plays a major role. Assuming that complications in which mitochondrial impairment may play a role are overrepresented in monogenic mitochondrial diseases and, conversely, that complications in which mitochondrial impairment does not play a role are underrepresented in mitochondrial disease, we studied the occurrence of the complications in PA and MMA in mitochondrial and other monogenic diseases, using data provided by the Human Phenotype Ontology. Lastly, we combined this with evidence from literature to draw conclusions on the possible role of mitochondrial impairment in each complication. Altogether, this review provides a comprehensive overview on what we, to date, do and do not understand about pathophysiology of complications occurring in PA and MMA and about the role of mitochondrial impairment herein.

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Aminotransferase trends in propionic acidemia

Silva,

Raski,

Charrow

et al. 2024

American J of Med Genetics Pt A

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Propionic acidemia is a metabolic condition with multiple serious acute and chronic presentations that require strict monitoring. Literature on liver function abnormalities in propionic acidemia is scarce, and the mechanism of liver impairment in this condition remains unclear. Currently, there is no indication for liver‐function tests during follow‐up and their clinical or prognostic utility is unknown. This study aimed to determine aminotransferase trends in individuals with propionic acidemia at a single institution. We retrospectively evaluated and classified the aminotransferases of 12 patients with propionic acidemia during hospital admissions and routine office visits. The present findings suggest that aminotransferase elevations are very common in this population and can persist beyond acute illness. During hospitalization events, aminotransferases were not a predictor of severity, duration of stay, and readmission within 1 month. Understanding aminotransferase trends in these patients will help clinicians make decisions in the acute setting and potentially in the follow‐up of new therapies.

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Long-term liver disease in methylmalonic and propionic acidemias

Cited by 25 publications

References 42 publications

Liver neoplasms in methylmalonic aciduria: An emerging complication

Liver neoplasms in methylmalonic aciduria: An emerging complication

Pathophysiology of propionic and methylmalonic acidemias. Part 1: Complications

Aminotransferase trends in propionic acidemia

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