Oxaliplatin related multiple focal nodular hyperplasia mimicking metastasis from a gastric cancer.

INTRODUCTION: The FOLFOX6 scheme is a combination drug chemotherapy that contains calcium leucovorin (folinic acid), fluorouracil, and oxaliplatin, the chronic use of chemotherapy with oxaliplatin can progress to focal nodular hyperplasia (FNH), which is a benign hepatic lesion. CASE REPORT: We present a case of a 26- year-old female diagnosed with an ovarian mixed germ cell tumor with extension to the peritoneum, treated with 12 cycles in 9 months with neoadjuvant chemotherapy FOLFOX 6 scheme and oophorectomy. A three-year follow-up CT showed three nodular and hypervascular hepatic lesions suspicious of metastatic disease; an MRI with liver-specific contrast confirmed the diagnosis of FNH. MANAGEMENT AND OUTCOME: The patient continued her follow-up without other treatment and metastatic disease. DISCUSSION: While most multiple liver lesions in a patient with cancer will be suspicious of metastasis, a careful drug history should be obtained, as an oxaliplatin-related side effect to develop FNH has been reported. MRI with liver-specific contrast has a positive predictive value of 95% because of the biliary excretion through OATP1B3 transporter, expressed in functional hepatocytes and overexpressed in some liver tumors such as FNH, so it should be performed when FNH is suspected.

Fluctuation of Hepatic Focal Nodular Hyperplasia Size with Oral Contraceptives Use.

BACKGROUND Focal nodular hyperplasia (FNH) of the liver is a rare benign nodular lesion that arises in women of reproductive age. Although a role of female hormones has been suggested, their influence on the course of FNH has remained controversial. CASE REPORT A 44-year-old woman with a 12-year history of oral contraceptive use was referred to our hospital for examination of an asymptomatic liver mass (3 cm in diameter) identified by computed tomography. We diagnosed FNH using imaging methods and fine-needle biopsy. Oral contraceptives were discontinued because the mass increased over a period of 21 months. Four months later, the mass had decreased in size, indicating that FNH can spontaneously regress when oral contraceptives are discontinued. CONCLUSIONS Discontinuation of oral contraceptives use can reduce the size of FNH, as in this case.

Limited relevance and progression of histological alterations in the liver during thioguanine therapy in inflammatory bowel disease patients.

Background: Thioguanine is associated with liver toxicity, especially nodular regenerative hyperplasia (NRH). We assessed if liver histology alters during long-term maintenance treatment with thioguanine in patients with inflammatory bowel disease (IBD). Methods: Liver specimens of thioguanine treated IBD patients with at least two liver biopsies were revised by two independent liver pathologists, blinded to clinical characteristics. Alterations in histopathological findings between first and sequential liver specimen were evaluated and associated clinical data, including laboratory parameters and abdominal imaging reports, were collected. Results: Twenty-five IBD patients underwent sequential liver biopsies prior to, at time of, or after cessation of thioguanine treatment. The median time between the first and second biopsy was 25 months (range: 14-54). Except for one normal liver specimen, any degree of irregularities including inflammation, steatosis, fibrosis and some vascular disturbances were observed in the biopsies. The rates of perisinusoidal fibrosis (91%), sinusoidal dilatation (68%) and nodularity (18%) were the same in the first and second liver biopsies. A trend towards statistical significance was observed for phlebosclerosis (36% of the first vs. 68% of the second biopsies, p = .092). Presence of histopathological liver abnormalities was not associated with clinical outcomes. Furthermore, two patients in this cohort had portal hypertension in presence of phlebosclerosis. In another two patients, nodularity of the liver resolved upon thioguanine withdrawal. Conclusion: Vascular abnormalities of the liver were commonly observed in thioguanine treated IBD patients, although these were not progressive and remained of limited clinical relevance over time.

Focal Nodular Hyperplasia After Treatment With Oxaliplatin: A Multiinstitutional Series of Cases Diagnosed at MRI.

OBJECTIVE: Benign hepatic lesions may occur after chemotherapy treatment and may mimic metastases at imaging. We describe focal nodular hyperplasia (FNH) lesions diagnosed at MRI that occurred de novo after treatment with oxaliplatin. MATERIALS AND METHODS: This is a multiinstitutional case series. We report 14 adult patients with cancer (eight men and six women) with a history of treatment with oxaliplatin and development of new hepatic lesions diagnosed as FNH at pathologic analysis or MRI or both. Imaging and pathology features of the included lesions, the interval since chemotherapy, and the temporal evolution were reviewed. RESULTS: The mean interval between the completion of oxaliplatin treatment and the identification of new hepatic FNH at imaging was 47.6 months. In seven of 14 (50%) patients, the index lesion was diagnosed at pathologic analysis (biopsy or resection) as FNH. In the remaining seven cases, the diagnosis was based on highly accurate MRI features (e.g., hyper- or isointensity of the lesion on hepatobiliary phase images). Lesion growth or occurrence of new lesions was present in 75% of patients at imaging follow-up. CONCLUSION: FNH lesions can occur de novo after treatment with oxaliplatin. Recognizing the typical MRI appearance of these lesions may avoid unnecessary biopsy or surgery and reduce patients' anxiety.

Is there a role for thioguanine therapy in IBD in 2017 and beyond?

INTRODUCTION: Conventional thiopurines are effective for the maintenance of remission of Crohn's disease and ulcerative colitis, however, up to half of patients are intolerant or unresponsive to these medications. Thioguanine is an alternative thiopurine that has shown efficacy in inflammatory bowel disease, and is particularly useful to circumvent certain side effects associated with conventional thiopurines, for example, pancreatitis. Its association with nodular regenerative hyperplasia of the liver has hindered its widespread use. Areas covered: We aim to outline the rational use of thioguanine, including safety monitoring, with particular regard to hepatotoxicity. A literature search was performed: PubMed was searched for full papers and abstracts published in English since January 2000 using the following terms, alone and in combination: 'azathioprine', 'thiopurine', 'Crohn's disease', 'inflammatory bowel disease', 'nodular regenerative hyperplasia', 'mercaptopurine', 'thioguanine', 'ulcerative colitis'. Further relevant papers were identified from the reference lists of selected papers. Expert commentary: Despite optimisation strategies such as metabolite measurements and the use of allopurinol, a significant proportion of patients will remain intolerant to thiopurines, especially those with allergic reactions, including pancreatitis. For this subgroup of patients we suggest that low dose thioguanine is an alternative to other therapies that are either parenteral or expensive.

Nodular Regenerative Hyperplasia of the Liver in Patients with IBD Treated with Allopurinol-Thiopurine Combination Therapy.

BACKGROUND: Thiopurine therapy, particularly thioguanine, has been associated with nodular regenerative hyperplasia (NRH) of the liver. Combination therapy of allopurinol and an adapted low-dose thiopurine leads to a pharmacokinetic profile that has similarities to that of thioguanine. Therefore, allopurinol-thiopurine combination therapy may also be associated with NRH of the liver. We assessed the prevalence of NRH in patients with inflammatory bowel disease (IBD) treated with allopurinol-thiopurine combination therapy by liver biopsy specimen examination. METHODS: An observational, cross-sectional study was conducted in a Dutch IBD-referral center. Adult patients with IBD, treated for at least 1 year with allopurinol-thiopurine combination therapy were eligible. All patients underwent a liver biopsy, after standard laboratory and thiopurine metabolite concentration assessments. Histopathology was assessed by an experienced liver pathologist. RESULTS: Twenty-two patients with IBD were included. The mean duration of combination therapy at the time of the liver biopsy was 24.7 months (SD 5.7). NRH was observed in one of the biopsies (4.8%), any grade of nodularity was observed in 3 biopsy specimens (14%). Other findings included phlebosclerosis (24%), perisinusoidal fibrosis (81%), sinusoidal dilatation (43%), perivenular fibrosis (14%), and periportal fibrosis (29%). Around the time of biopsy, the median 6-thioguanine nucleotide and 6-methylmercaptopurine ribonucleotide concentrations were 705 pmol × 10 red blood cells (RBC) (interquartile range 498-915) and 355 pmol × 10 RBC (interquartile range 225-670). CONCLUSIONS: The prevalence of histologically assessed NRH in patients with IBD, who were treated with allopurinol-thiopurine combination therapy, was 5%. This percentage is in line with thiopurine-naive and thioguanine-using patients with IBD. None of the included patients had clinical symptoms or signs suggestive of (noncirrhotic) portal hypertension.

The Prevalence of Nodular Regenerative Hyperplasia in Inflammatory Bowel Disease Patients Treated with Thioguanine Is Not Associated with Clinically Significant Liver Disease.

BACKGROUND: Nodular regenerative hyperplasia (NRH) of the liver is associated with inflammatory-mediated diseases and certain drugs. There is conflicting data on the prevalence of NRH and its clinical implications in inflammatory bowel disease (IBD) patients treated with thioguanine. METHODS: A retrospective cohort study involving 7 Dutch centers comprised all IBD patients who were being treated with thioguanine and underwent a liver biopsy as part of the standard toxicity screening. Liver biopsy specimens were reviewed by 2 experienced liver pathologists. Clinical data as well as liver chemistry, blood counts, and abdominal imaging were collected. RESULTS: One hundred eleven IBD patients who submitted to liver biopsy were treated with thioguanine in a daily dose of 0.3 mg/kg for a median duration of 20 (4-64) months. NRH was detected in 6% of patients (7; 95% confidence interval, 3-14 patients). Older age (P = 0.02), elevated gamma-glutamyl transferase (P = 0.01) and alkaline phosphatase (P = 0.01) levels, a higher mean corpuscular volume (P = 0.02), and a lower platelet or leukocyte count (P < 0.01 and P = 0.02, respectively) were associated with NRH. Three of the 7 patients with NRH did not have any associated clinical symptoms or signs. The other 4 had minor biochemical abnormalities only. Ultrasonography revealed splenomegaly in 3 of the 78 patients (4%; 95% confidence interval, 0%-9%), only one of whom had NRH. There was no clinically overt portal hypertension. CONCLUSIONS: The prevalence of NRH was 6% in liver biopsies obtained from IBD patients treated with thioguanine. Histopathological irregularities including NRH were not associated with clinically significant findings over the period of observation.

Hiperplasia nodular regenerativa hepática múltiple asociada a oxaliplatino / Regenerative multiple hepatic nodular hyperplasia associated with oxalyplati

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Drug-induced nodular regenerative hyperplasia.

Drug-induced nodular regenerative hyperplasia is an uncommon injury with unique pathophysiology, clinical, and diagnostic considerations. This injury is characteristically asymptomatic in its early phases with only mild elevations in transaminases (< 3× upper limit of normal [ULN]). The latency period is typically more than 6 months. Once clinically apparent, it is marked by complications of portal hypertension, including hypersplenism, ascites, and variceal bleeding, with little or no hepatic dysfunction. Hence, it is an important cause of noncirrhotic portal hypertension. The most commonly associated drugs include thiopurines, chemotherapeutic agents, and antiretroviral agents. Diagnosis is aided by the recognition of noncirrhotic portal hypertension, a detailed history of prior drug exposure, and exclusion of the other causes of nodular regenerative hyperplasia. Clinical history, abdominal imaging, and hepatic hemodynamic studies provide important diagnostic clues, but histologic examination remains the diagnostic gold standard. Therapeutic intervention is aimed at earliest discontinuation of the offending agent and of portal hypertension complications. The natural history varies widely, and portal hypertension can progresses despite drug discontinuation.

Nodular regenerative hyperplasia (NRH) complicating oxaliplatin chemotherapy in patients undergoing resection of colorectal liver metastases.

INTRODUCTION: Sinusoidal obstructive syndrome (SOS) is well associated with the use oxaliplatin-based chemotherapy, and represents a spectrum of hepatotoxicity, with nodular regenerative hyperplasia (NRH) representing the most significant degree of injury. The aim of this study was to determine the prevalence of NRH in patients undergoing resection of colorectal liver metastases (CRLM) and to determine its impact on outcome. METHODS: From January 2000 to December 2010, some 978 first primary liver resections were performed for CRLM. A prospectively maintained database was analysed to identify all patients with evidence of NRH in the non-tumour portion of their histopathology specimens. Clinical data of these patients was reviewed and outcomes assessed. RESULTS: Five patients exhibited NRH (four males, one female) with a median age of 69 years (range: 35-74). Three patients presented with synchronous hepatic metastases, and two with metachronous lesions. All received at least 6 cycles of oxaliplatin as either adjuvant or neo-adjuvant chemotherapy. Only one patient developed a post-operative complication namely transient hepatic failure that required a 4-day stay in the intensive care unit. The median hospital stay was 6 days (range: 6-14 days). There were no 90-day mortalities. One patient is alive and disease free at 55 months, the remaining 4 died of recurrent disease between 37 and 70 months following diagnosis of their primary tumours. CONCLUSIONS: NRH is not an uncommon finding amongst patients with SOS with all patients having received oxaliplatin-based chemotherapy. Data on outcome would suggest no increased morbidity and mortality associated with the presence of NRH.

Trombosis venosa portal e hiperplasia nodular regenerativa hepática; posible efecto adverso asociado a bevacizumab y oxaliplatino / Portal vein thrombosis and nodular regenerative hyperplasia associated with the use of bevacizumab and oxaliplatin. Report of one case

Nodular regenerative hyperplasia (NRH) consists in diffuse transformation of the hepatic parenchyma into small regenerative nodules without fibrosis, secondary to vascular occlusion and flow alterations. This gives a nodular appearance to theliver, as there is atrophy and compensatory hypertrophy of hepatocytes. We reporta 69-year-old male who suffered of colon cancer and was treated with Oxaliplatin (OX) and Bevacizumab (B). During treatment with B the patient presented a partial thrombosis of the portal vein, that one year later became permeable. Esophageal varices were found in an upper digestive endoscopy. Hepatic tests were normal. Aliver biopsy was performed and informed nodular regenerative hyperplasia. Thus, the different factors that could explain this pathology are analyzed. B, a monoclonal antibody against vascular endothelial growth factor, reduces the anti-apoptotic, anti-inflammatory and survival effects produced by this factor, affecting the vascular protection of the endothelial cell. On the other hand, OX activates metalloproteinasesand depletes sinusoidal glutathione producing sinusoidal lesions. Thus, (OX) would be associated with sinusoidal obstruction and NRH sporadically. It is important to discuss the possible etiologic factors that can cause NRH reviewing the hepatotoxic effects caused by both drugs.

Treatment with adalimumab in a patient with regenerative nodular hyperplasia secondary to azathioprine.

INTRODUCTION: regenerative nodular hyperplasia (RNH) is a rare liver disease with an etiology that is not well understood. Among the etiological factors are purine-analogue drugs such asazathioprine. CASE REPORT: we present a case of a 47-year-old patient diagnosed with Crohn´s disease in treatment with azathioprine due to corticosteroid dependency who developed RNH with clinical and laboratory signs of portal hypertension one year after starting treatment. After discontinuation of azathioprine, the patient started treatment and, given the poor disease progression, started treatment with adalimumab. This was continued with an excellent response and without deleterious effects on the liver. DISCUSSION: the relevance of this case is twofold: First, this is a rare and early side effect of azathioprine treatment and this is an irreversible disease with potentially serious complications. Second, because treatment was carried out with biological drugs (adalimumab) despite the patient having advance liver disease with portal hypertension without any evidence of it worsening, nor signs of deleterious effects or complications, given that there is scarce or no experience with adalimumab treatment in this type of situation.

Focal nodular hyperplasia and hepatic regenerating nodules in pediatric oncology patients: how much invasive approach is necessary?

INTRODUCTION: Hepatic regenerating nodules (HRN) and focal nodular hyperplasia (FNH) are benign regenerating lesions of the liver that rarely occur in children. An increased incidence of these lesions is reported in children treated for cancer. MATERIAL AND METHODS: Eight children who developed FNH and HRN after treatment for malignancies in the Oncology unit at the "Bambino Gesù" Pediatric Hospital in Rome, were retrospectively analyzed. RESULTS: The lesions, considered in the differential diagnosis with metastatic relapse of the primitive disease, have been monitored with US or other available imaging techniques. Evolution of the lesions was observed in only 1 patient three years after the initial diagnosis of FNH. CONCLUSION: In conclusion serial monitoring with imaging techniques is sufficient to rule out liver metastasis and to monitor the evolution of the lesions. Surgery is suggested only in the case of complications.

[Portal vein thrombosis and nodular regenerative hyperplasia associated with the use of bevacizumab and oxaliplatin. Report of one case]. / Trombosis venosa portal e hiperplasia nodular regenerativa hepática; posible efecto adverso asociado a bevacizumab y oxaliplatino.

Nodular regenerative hyperplasia (NRH) consists in diffuse transformation of the hepatic parenchyma into small regenerative nodules without fibrosis, secondary to vascular occlusion and flow alterations. This gives a nodular appearance to theliver, as there is atrophy and compensatory hypertrophy of hepatocytes. We reporta 69-year-old male who suffered of colon cancer and was treated with Oxaliplatin (OX) and Bevacizumab (B). During treatment with B the patient presented a partial thrombosis of the portal vein, that one year later became permeable. Esophageal varices were found in an upper digestive endoscopy. Hepatic tests were normal. Aliver biopsy was performed and informed nodular regenerative hyperplasia. Thus, the different factors that could explain this pathology are analyzed. B, a monoclonal antibody against vascular endothelial growth factor, reduces the anti-apoptotic, anti-inflammatory and survival effects produced by this factor, affecting the vascular protection of the endothelial cell. On the other hand, OX activates metalloproteinasesand depletes sinusoidal glutathione producing sinusoidal lesions. Thus, (OX) would be associated with sinusoidal obstruction and NRH sporadically. It is important to discuss the possible etiologic factors that can cause NRH reviewing the hepatotoxic effects caused by both drugs.

Hiperplasia nodular regenerativa del hígado secundaria a uso de azatioprina por trasplante renal previo, tratado con trasplante combinado hepático y renal / Combined hepatic and renal transplant after nodular regenerative hyperplasia of the liver secondary to azathioprine in renal transplant patient

Nodular regenerative hyperplasia is an uncommon condition, characterized by the presence of regenerative nodules with minimal or absence of fibrosis, which can lead to non-cirrhotic portal hypertension. There are numerous diseases, conditions and drugs that can cause it. Thiopurines, a group of immunosuppressors used in transplanted patients, has been linked to this entity. We report a case of a renal transplant woman, who has been on chronic therapy with azathioprine and that develops portal hypertension and end-stage renal disease, undergoing combined hepatic and renal transplant. Histological examination of the explanted liver was compatible with nodular regenerative hyperplasia. How azathioprine causes this entity is unknown, but endothelial vascular damage in a dose-dependent manner is postulated as the main mechanism. To our knowledge, this is the first case report of a renal transplant patient who develops nodular regenerative hyperplasia of the liver in association with azathioprine, and undergoes combined hepatic and renal transplant, with a favorable outcome 5 years post procedure.

La hiperplasia nodular regenerativa es una entidad infrecuente, que se caracteriza por la presencia de nódulos hepáticos con ausencia o mínima fibrosis y que puede llevar a hipertensión portal de origen no cirrótico. Existen diversas enfermedades, condiciones y medicamentos que la causan, destacando entre estos últimos las tiopurinas, inmunosupresores utilizados habitualmente en trasplantados. Se presenta el caso de una paciente trasplantada renal usuaria crónica de azatioprina, que desarrolla hipertensión portal además de deterioro de la función renal, requiriendo de un doble trasplante hepático y renal, destacando en la biopsia del explante hallazgos histológicos compatibles con hiperplasia nodular regenerativa. Los mecanismos de daño por azatioprina en esta entidad son desconocidos, pero se postula al daño endotelial dosis-dependiente como principal causa. La revisión de la literatura demuestra que este caso corresponde al primero de hiperplasia nodular regenerativa secundaria a azatioprina en trasplantado renal, que requiere de doble trasplante hepático y renal con evolución favorable hasta 5 años post trasplante.

Synchronous occurrence of multiple focal nodular hyperplasia and huge hepatic perivascular epithelioid cells tumor (PEComa) in young woman after oral contraceptive use--is there a common pathogenesis?

The association of focal nodular hyperplasia (FNH) and various neoplasms was described, but coincidence of multiple FNH and hepatic perivascular epithelioid cells tumor (PEComa) has not been reported. The clinical debate of oral contraceptive (OC) influence on FNH growth is ongoing, but no evidence exists about association of hepatic PEComa with OC use. Herein, we report a case of two FNH lesions and huge (150x100x80 mm) left hepatic lobe PEComa that occurred simultaneously in 18-year-old female with previous two year history of OC use, who underwent left hemihepatectomy and right hepatic FNH enucleation. Up to date, the patient has been followed-up for 65 months and remained disease-free. FNH and PEComa have a common vascular cytogenetic denominator. Our case raising a question of a causal relationship of FNH and PEComa with OC use that might be attributed to vascular changes. Future researches of larger sample sizes should further address this issue.

[Steatohepatitis after chemotherapy for colorectal liver metastases (CASH)]. / Steatohepatitis bei der Chemotherapie kolorektaler Lebermetastasen (CASH).

Neoadjuvant chemotherapy provides an important treatment option for patients who, as a consequence of colorectal cancer, have developed liver metastases. Regression of metastases prior to surgery may substantially improve prognosis. However, chemotherapeutics may harm non-tumorous liver tissue, particularly if this is already impaired prior to chemotherapy. The present article discusses the risks of chemotherapeutics for liver tissue-including sinusoidal obstruction syndrome, nodular regenerative hyperplasia, and chemotherapy-associated steatohepatitis, amongst others-which should be borne in mind when selecting therapy.