Development of Nodular Regenerative Hyperplasia (NRH) with Portal Hypertension Following the Administration of Oxaliplatin for the Recurrence of Colon Cancer

Takaya, Hiroaki; Kawaratani, Hideto; Nakanishi, Keisuke; Takeyama, Shinya; Morioka, Chie; Sawai, Masayoshi; Toyohara, Masahisa; Fujimoto, Masao; Yoshiji, Hitoshi; Yamao, Junichi; Fukui, Hiroshi

doi:10.2169/internalmedicine.54.2461

Cited by 7 publications

(4 citation statements)

References 14 publications

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“…The onset of NRH has been associated with a large variety of autoimmune, inflammatory, hematological, and lymphoproliferative disorders, and with the use of various drugs (e.g. highly active antiretroviral therapy (HAART), platinum-based chemotherapy, and thiopurines) [87][88][89]. The indisputable role of TG and the other thiopurine-derivatives, especially AZA, in this (drug-induced) vasculopathy has not been elucidated yet.…”

Section: Hepatotoxicitymentioning

confidence: 99%

The continuous rediscovery and the benefit–risk ratio of thioguanine, a comprehensive review

Bayoumy

Simsek

Seinen

et al. 2020

Expert Opinion on Drug Metabolism & Toxicology

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Introduction: In the 1950s, thioguanine (TG), a thiopurine-derivative together with azathioprine (AZA) and mercaptopurine (MP), were developed for the treatment of childhood leukemia. Over the years, the use of TG was also explored for other, mainly immune-mediated and inflammatory, diseases such as in the field of dermatology and rheumatology (e.g. psoriasis, systemic lupus erythematosus (SLE)) and gastroenterology and hepatology (e.g. inflammatory bowel diseases (IBD), autoimmune hepatitis).Areas covered: This review provides a comprehensive overview of all the clinical uses of TG and describes its mechanism of action, pharmacokinetic/pharmacodynamic features, and toxicity. Expert opinion: Thioguanine has shown beneficial clinical effects in hematological (particularly leukemia) and several immune-inflammatory diseases including psoriasis, SLE, polycythemia vera, Churg-Strauss syndrome, IBD, collagenous sprue, refractory celiac disease, and autoimmune hepatitis. Thioguanine is not effective in treating solid-cancers. At relatively low dosages, i.e. 0.2-0.3mg/kg/day or 20 mg/day, TG has a favorable risk-benefit ratio and is a safe and effective drug in the long-term treatment of amongst other IBD patients. Thioguanine toxicity, especially myelotoxicity, and hepatotoxicity, including nodular regenerative hyperplasia (NRH) of the liver, is limited when dosed adequately. The occurrence of NRH appears dose-dependent and has been especially described during high dose TG above 40 mg/day.

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Section: Hepatotoxicitymentioning

confidence: 99%

The continuous rediscovery and the benefit–risk ratio of thioguanine, a comprehensive review

Bayoumy

Simsek

Seinen

et al. 2020

Expert Opinion on Drug Metabolism & Toxicology

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“…5 The development of NRH has been associated with a variety of systemic disorders including myelo-and lymphoproliferative diseases, autoimmune diseases, inflammatory and immunodeficiency disorders as well as certain medications. 6 Drugs associated with NRH are highly active anti-retroviral therapy, 7 platin-based chemotherapy 8 and thiopurines, in particular azathioprine (AZA) and thioguanine (TG). [9][10][11] The diagnosis of NRH is challenging since the clinical presentation is variable and the majority of patients present without symptoms or abnormalities in laboratory parameters.…”

Section: Introductionmentioning

confidence: 99%

Nodular regenerative hyperplasia rarely leads to liver transplantation: A 20‐year cohort study in all Dutch liver transplant units

et al. 2017

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Background: Nodular regenerative hyperplasia is an uncommon liver condition associated with several autoimmune disorders and drugs. The clinical symptoms of nodular regenerative hyperplasia vary from asymptomatic to severe complications of portal hypertension (nodular regenerative hyperplasia-syndrome). Objective: The purpose of this study was to identify the prognosis and optimal management, as well as the role of liver transplantation, in nodular regenerative hyperplasia. Methods: The pathology databases of all three Dutch liver transplant units were retrospectively scrutinised for explanted livers diagnosed with nodular regenerative hyperplasia or without clear diagnosis. Pre-and post-transplantation clinical, biochemical, radiological and histological information was obtained from electronic and paper records. Results: In total, 1886 patients received a liver transplant. In 255 patients, nodular regenerative hyperplasia could not be excluded. After detailed chart review, the native livers of 11 patients (0.6%) (82% male, median age: 44 years) displayed nodular regenerative hyperplasia. Seven patients (64%) had underlying disorders or drug exposure which possibly caused nodular regenerative hyperplasia. Laboratory and imaging abnormalities were present in all patients but did not contribute to the diagnosis of nodular regenerative hyperplasia. Five-year survival was 73% (median follow-up: four years, range: 2-248 months). Conclusion: Nodular regenerative hyperplasia is a rare finding in patients, predominantly young males, transplanted for end-stage liver disease with unknown aetiology. Nonetheless, liver transplantation may have an important role in end-stage nodular regenerative hyperplasia-syndrome.

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“…In this cohort of patients, an increase of 50% or more of the spleen at the end of chemotherapy is associated with moderate to severe sinusoidal damage in 55% of patients undergoing hepatic metastasectomy [25]. In addition, although thrombocytopenia during treatment is very common, and secondary to medullar suppression and immune mechanisms, it typically reverts at the end of the treatment, while the persistence of a low platelet count should raise the suspicion of damage sinusoidal [26]. Between potencial risk factors associated to PSVD associated to oxaliplatin, are age, female sex, neurotoxicity, non resecable metastasis, preIQ elevated liver tests and metacronic or sincronic tumor [23].…”

Section: Oxaliplatin and Liver Damagementioning

confidence: 86%

Porto-Sinusoidal Vascular Disease Associated to Oxaliplatin: An Entity to Think about It

Puente

Fortea

Pozo

et al. 2019

Cells

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Portal sinusoidal vascular disease is a presinusoidal cause of portal hypertension (PHT) of unknown etiology, characterized by typical manifestations of PHT (esophageal varices, ascites, portosystemic collaterals), plaquetopenia and splenomegaly with a gradient of portal pressure slightly increased, according to the presinusoidal nature of the PHT. A few cases in the literature have shown a relationship between oxaliplatin and the development of presinusoidal portal hypertension, years after the chemotherapy for colorectal cancer (therefore, different to sinusoidal obstruction syndrome). There are three mechanisms through which oxaliplatin can cause sinusoidal damage: (1) damage at the level of endothelial cells and stimulates the release of free radicals and depletion of glutathione transferase, with altering the integrity of the sinusoidal cells. The damage in the endothelial sinusoidal cells allows to erythrocytes to across into the Dissé space and formation of perisinusoidal fibrosis, (2) the appearance of nodular regenerative hyperplasia is favored by the chronic hypoxia of the centrilobular areas and, finally, (3) oxaliplatin can generate an obliteration of the blood capillaries and zones of parenchymal extinction. These three facts can develop, in a minority of cases, the appearance of a presinusoidal increase of portal pressure, which typically appears years after the completion of chemotherapy and sometimes is underdiagnosed until variceal bleeding, ascites or encephalopathy appear. The knowledge of this pathology is essential to be able to perform an early diagnostic and consult to the hepatologist.

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Development of Nodular Regenerative Hyperplasia (NRH) with Portal Hypertension Following the Administration of Oxaliplatin for the Recurrence of Colon Cancer

Cited by 7 publications

References 14 publications

The continuous rediscovery and the benefit–risk ratio of thioguanine, a comprehensive review

The continuous rediscovery and the benefit–risk ratio of thioguanine, a comprehensive review

Nodular regenerative hyperplasia rarely leads to liver transplantation: A 20‐year cohort study in all Dutch liver transplant units

Porto-Sinusoidal Vascular Disease Associated to Oxaliplatin: An Entity to Think about It

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