Hepatic focal nodular hyperplasia after pediatric hematopoietic stem cell transplantation: The impact of hormonal replacement therapy and iron overload.

BACKGROUND: The advent of techniques for the assessment of iron overload (liver T2*-MRI) has led to the awareness that focal nodular hyperplasia (FNH) represents a possible incidental finding after hematopoietic stem cell transplantation (HSCT), though its pathogenesis is still unclear. METHODS: We performed a retrospective analysis of the liver T2*-MRI scans performed between 2013 and 2018 in a single pediatric HSCT Unit and recorded the number of patients with FNH (group A). Patients incidentally diagnosed with FNH at imaging performed for different clinical indications were included in group B. RESULTS: Nine of 105 (8.6%) patients from group A were diagnosed with FNH. Group B included three patients. Overall, 12 patients were diagnosed 4.4 ± 3.1 years after HSCT. At univariate analysis, female gender (odds ratio [OR] 3.77, P = .03), moderate-to-severe iron overload (OR 6.97, P = .01), and hormone replacement therapy (HRT) administered for at least 6 months (OR 18.20, P = .0002) exposed patients to a higher risk of developing FNH. The detrimental effect of HRT was significant also at multivariate analysis (OR 7.93, P = .024). MRI-T2* values in affected patients were statistically lower than healthy controls (P < .001). CONCLUSIONS: We confirm the high incidence of FNH among transplanted pediatric patients and demonstrate the potential pathogenic role of HRT and iron overload.

Focal Nodulary Hyperplasia of the Liver Due to Congenital Portosystemic Shunt: A Rare Condition Mimicking Hepatocellulary Carcinoma.

Congenital portosystemic shunts are rare vascular malformations that lead to several complications including liver tumors, pulmonary hypertension, and metabolic encephalopathy. We describe a rare case of a 17-year-old girl with an extrahepatic portosystemic shunt presenting recurrent syncope episodes and a liver mass mimicking hepatocellulary carcinoma.

Molecular patterns of diffuse and nodular parathyroid hyperplasia in long-term hemodialysis.

Secondary hyperparathyroidism is a well-known complication of end-stage renal disease (ESRD). Both nodular and diffuse parathyroid hyperplasia occur in ESRD patients. However, their distinct molecular mechanisms remain poorly understood. Parathyroid tissue obtained from ESRD patients who had undergone parathyroidectomy was used for Illumina transcriptome screening and subsequently for discriminatory gene analysis, pathway mapping, and gene annotation enrichment analysis. Results were further validated using quantitative RT-PCR on the independent larger cohort. Microarray screening proved homogeneity of gene transcripts in hemodialysis patients compared with the transplant cohort and primary hyperparathyroidism; therefore, further experiments were performed in hemodialysis patients only. Enrichment analysis conducted on 485 differentially expressed genes between nodular and diffuse parathyroid hyperplasia revealed highly significant differences in Gene Ontology terms and the Kyoto Encyclopedia of Genes and Genomes database in ribosome structure (P = 3.70 × 10-18). Next, quantitative RT-PCR validation of the top differently expressed genes from microarray analysis proved higher expression of RAN guanine nucleotide release factor (RANGRF; P < 0.001), calcyclin-binding protein (CACYBP; P < 0.05), and exocyst complex component 8 (EXOC8; P < 0.05) and lower expression of peptidylprolyl cis/trans-isomerase and NIMA-interacting 1 (PIN1; P < 0.01) mRNA in nodular hyperplasia. Multivariate analysis revealed higher RANGRF and lower PIN1 expression along with parathyroid weight to be associated with nodular hyperplasia. In conclusion, our study suggests the RANGRF transcript, which controls RNA metabolism, to be likely involved in pathways associated with the switch to nodular parathyroid growth. This transcript, along with PIN1 transcript, which influences parathyroid hormone secretion, may represent new therapeutical targets to cure secondary hyperparathyroidism.

Nodular Regenerative Hyperplasia after Liver Transplantation Complicated with Inferior Vena Cava Stenosis: a Clue for Etiopathogenesis?

Nodular regenerative hyperplasia is a histopathological diagnosis characterized by the diffuse transformation of the liver parenchyma into regenerative nodules associated with rheumatologic and hematologic disorders, azathioprine immunosuppression or vascular injuries. The authors report the case of a 60-year-old female patient with a diagnosis of familial systemic paramyloidosis submitted to liver transplantation complicated by a hepatic artery thrombosis. A second liver transplant was performed and after 6 months she developed ascites and peripheral edema. The abdominal computed tomography (CT) showed an inferior vena cava stenosis. She underwent balloon angioplasty and an endovascular prosthesis was placed. The patient remained asymptomatic under immunosuppression with tacrolymus for 4 years, when she complained of peripheral edema and ascites. Laboratory work-up showed anemia and hypoalbuminemia with liver chemistry within the normal range. The ascites fluid analysis revealed a serum ascites albumin gradient superior to 1.1 g/L. Abdominal Doppler ultrasound and abdominopelvic CT angiogram confirmed endovascular prosthesis permeability. A percutaneous hepatic biopsy specimen was taken and histologic analysis showed, with reticulin stain, focal regenerative nodules of hyperplastic hepatocytes and internodular hepatocyte atrophy, compatible with the diagnosis of nodular regenerative hyperplasia. The case described is of particular interest as the nodular regenerative hyperplasia occurred after liver transplantation complicated with inferior vena cava stenosis, which might have contributed in a crucial way to liver parenchyma transformation.

Hepatocellular nodules resulting from congenital extrahepatic portosystemic shunts can differentiate into potentially malignant hepatocellular adenomas.

BACKGROUND: Hepatocellular nodules caused by congenital extrahepatic portosystemic shunts (CEPS) occur as a result of abnormal portal blood flow, and are mostly cases of benign focal nodular hyperplasia (FNH). However, hepatocellular adenomas (HCA) and hepatocellular carcinomas have been documented in the CEPS patients. HCA can now be immunohistochemically diagnosed; therefore, the concept of hepatocellular nodules resulting from CEPS should be revisited. In this study, we performed a retrospective immunohistochemical investigation of hepatocellular nodules from livers isolated from the CEPS patients undergoing living donor liver transplantation (LDLT). METHODS: Hepatocellular nodules from livers of five patients with CEPS who underwent LDLT between June 2004 and October 2012 at our institution were immunohistochemically investigated. HCA were classified into four subtypes (HNF1α-inactivated HCA (H-HCA); inflammatory HCA; ß-catenin-activated HCA (b-HCA); unclassified HCA). RESULTS: Sixteen hepatocellular nodules were collected from livers of five patients with CEPS who underwent LDLT. Ten hepatocellular nodules were categorized as FNH (62.5%), five were categorized as b-HCA (31.3%), and one was categorized as H-HCA (6.2%). CONCLUSIONS: Some of the hepatocellular nodules resulting from CEPS were indicative of HCAs, especially the b-HCA subtype which has the potential for malignant transformation. Surgical or interventional treatments might have to be performed when hepatocellular nodules appear in the CEPS patients.

Multiple hyperplastic nodular lesions of the liver in the Budd-Chari syndrome: a case report and review of published reports.

The Budd-Chari syndrome (BCS) is a group of disorders of hepatic vein outflow at various levels from the hepatic veins to inferior vena cave. We describe a 49-year-old man with multiple intrahepatic lesions who had been diagnosed with the BCS. The inferior vena cavography showed hepatic vein occlusion and long-range obstruction of inferior vena cava. The biopsy proved to be hyperplastic nodules, also called large regenerative nodules (LRNs). Both benign regenerative nodules and hepatocellular carcinoma (HCC) appear in patients with BCC; however, published reports about the diagnosis and differential diagnosis are limited. The incidence of HCC in patients with BCS varies greatly depending on geography. This case illustrates that benign nodules can arise in BCS patients. We reviewed published reports and speculated that medical procedures leading to portal perfusion decrease may be associated with the development of these hyperplastic nodules.

Multiple liver lesions in a patient with Budd-Chiari syndrome secondary to polycythemia vera.

Focal nodular hyperplasia and nodular regenerative hyperplasia are occasionally seen in patients with hepatic venous outflow obstruction as a consequence of circulatory stress in the liver. In addition, neoplastic processes such as hepatic adenoma, hepatocellular carcinoma, and metastatic disease may arise in these patients. Histologic evaluation is necessary when imaging modalities are unable to distinguish these lesions. We present a case of multiple hepatic lesions, suspicious for metastases, in a patient with Budd-Chiari syndrome secondary to polycythemia vera. However, the biopsy findings were consistent with focal nodular hyperplasia. Budd-Chiari syndrome may be associated with multiple nodules of focal nodular hyperplasia, which may be difficult to diagnose radiologically.

Nodular Regenerative Hyperplasia in Patients Undergoing Liver Resection for Colorectal Metastases After Chemotherapy: Risk Factors, Preoperative Assessment and Clinical Impact.

BACKGROUND: Nodular regenerative hyperplasia (NRH) is a severe form of chemotherapy-related liver injury (CALI) that may worsen the short-term outcome of liver resection (LR) for colorectal metastases (CRLM). The present study aimed to clarify the incidence, risk factors, preoperative assessment, and clinical impact of NRH. METHODS: Overall, 406 patients undergoing 478 LRs for CRLM after chemotherapy between 2000 and 2012 were studied. All resection specimens were reviewed. After Gomori staining, NRH was graded according to the Wanless score. RESULTS: NRH was diagnosed in 87 (18.2 %) patients, grades 2-3 in 14 (2.9 %) patients. At multivariate analysis, the prevalence of NRH was increased after oxaliplatin administration (21.4 vs. 8.4 %; p = 0.003), and reduced by the addition of bevacizumab (11.7 vs. 19.8 %; p = 0.020). Two parameters predicted the presence of NRH: the APRI score (AST to platelet ratio index: 25.5 % if >0.36 vs. 9.8 % if ≤0.36; p = 0.004), and the platelet count (63.6 % if <100 × 10(3)/mm(3) vs. 25.3 % if 100-200 × 10(3)/mm(3) vs. 11.9 % if >200 × 10(3)/mm(3); p = 0.032). Ninety-day mortality and liver failure rates were 0.6 and 3.6 %. NRH was an independent predictor of postoperative liver failure (9.2 % if present vs. 2.3 % if not present; p = 0.021). In patients with grades 2-3 NRH, the rate of liver failure was 14.3 %, 25.0 % after major hepatectomy. No other forms of CALI impacted short-term outcomes. CONCLUSIONS: NRH was the most relevant form of CALI, increasing the risk of postoperative liver failure. Oxaliplatin increased the incidence of NRH, while bevacizumab decreased it. The APRI score and platelet count were useful tools for predicting NRH.

Focal nodular hyperplasia of the liver: an emerging complication of hematopoietic SCT in children.

Hepatic focal nodular hyperplasia (FNH) is a nonmalignant condition rarely affecting children previously treated for cancer, especially those who received hematopoietic SCT (HSCT). Some aspects of its pathogenesis still remain unclear and a strong association with specific risk factors has not yet been identified. We report here a single institution's case series of 17 patients who underwent HSCT and were diagnosed with FNH, analyzing retrospectively their clinical features and the radiological appearance of their hepatic lesions. We aimed to compare the diagnostic accuracy of ultrasound (US) and magnetic resonance imaging (MRI) and to explore the role of transient elastography (FibroScan) to evaluate the degree of hepatic fibrosis in FNH patients. Our analysis showed an association of FNH with age at transplant ⩽12 years (hazard ratio (HR) 9.10); chronic GVHD (HR 2.99); hormone-replacement therapy (HR 4.02) and abdominal radiotherapy (HR 4.37). MRI proved to be a more accurate diagnostic tool compared with US. Nine out of 12 patients who underwent FibroScan showed hepatic fibrosis. Our study points out that FNH is an emerging complication of HSCT, which requires a lifelong surveillance to follow its course in cancer patients.

Differentiation of focal nodular hyperplasia from hepatocellular adenomas with low-mechanical-index contrast-enhanced sonography (CEUS): effect of size on diagnostic confidence.

PURPOSE: The purpose of this study was to assess the diagnostic performance of contrast-enhanced sonography (CEUS) for the differentiation of focal nodular hyperplasia (FNH) from hepatocellular adenoma (HCA) according to lesion size. MATERIALS AND METHODS: Forty patients with a definite diagnosis of FNH or HCA who underwent CEUS were included in this institutional review board (IRB)-approved study. A total of 43 FNHs and 20 HCAs, including 15 inflammatory HCAs and five unclassified HCAs, were analysed. Two radiologists reviewed the diagnostic CEUS parameters separately and in consensus, including the presence or absence of centrifugal filling and central vessels. The sensitivity (Se), specificity (Sp), and inter-observer confidence (Kappa) of CEUS diagnostic parameters were assessed. RESULTS: Inter-observer agreement of CEUS for FNH diagnosis was high (kappa = 0.81) with an overall Se of 67.4% [29/43 (CI 95%: 51.4-80.1 %)] and an Sp of 100% [20/20 (CI 95%: 81-100%)]. Significantly higher Se figures were found for lesions ≤ 35 mm than for lesions > 35 mm [respectively, 93 % (28/30) (CI 95%: 77.6-99.2) vs. 7.7% (1/13) (CI 95%: 0.2-36%), p = 0.002] with unchanged specificity. CONCLUSION: CEUS is highly specific for the diagnosis of FNH, with very good inter-observer agreement, whatever the size, but its sensitivity is significantly reduced in diagnosing lesions larger than 35 mm. KEY POINTS: • CEUS is highly specific for the diagnosis of FNH, regardless of lesion size • CEUS shows reduced sensitivity in diagnosing FNH lesions larger than 35 mm • The filling patterns of hepatocellular adenomas are not affected by lesion size.

Hepatic focal nodular hyperplasia with congenital portosystemic shunt.

Hepatic focal nodular hyperplasia (FNH) is a rare benign tumor in children. Vascular anomalies have been identified as pathological features of FNH, but the etiology remains unclear. We describe a rare case including the time course of formation of hepatic FNH in response to congenital portosystemic shunt (PSS). A 4-month-old girl was identified on newborn mass screening to have hypergalactosemia, but no inherited deficiencies in galactose-metabolizing enzymes were found. Ultrasonography and per-rectal portal scintigraphy showed intrahepatic PSS of the right lobe as a cause of the hypergalactosemia. At age 12 months, the patient had elevated hepatic enzymes and small hypoechoic hepatic lesions around the shunt. On abdominal contrast-enhanced ultrasonography spoke-wheel sign and central stellate scar were seen, which are typical features of hepatic FNH without biopsy. Congenital intrahepatic PSS should be evaluated on abdominal contrast-enhanced ultrasonography and observed over time because of its potential to develop into hepatic FNH.

Hiperplasia nodular regenerativa hepática como complicación tardía de la artritis idiopática juvenil de inicio sistémico / Nodular regenerative hyperplasia of the liver as a complication of long-standing systemic-onset juvenile idiopathic arthritis

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Development of multiple focal nodular hyperplasia lesions after portocaval shunting. A case report.

It has been postulated that altered hepatic blood flow, particularly reduced portal flow, is responsible for the induction of hyperplasia of liver cells and nodule formation. This report describes the case of a 31-year old female patient developing multiple focal nodular hyperplasia (FNH) lesions two years after portocaval shunting and extended right hemihepatectomy due to the suspicion of a malignant liver tumor. Portocaval shunting became necessary due to iatrogenic thrombosis of the entire portal vein after preoperative embolization of the right portal vein. This observation provides for the first time direct evidence for the pathogenesis of FNH in humans.

Review article: the association between nodular regenerative hyperplasia, inflammatory bowel disease and thiopurine therapy.

BACKGROUND: Nodular regenerative hyperplasia (NRH) is increasingly being recognised in patients with inflammatory bowel disease (IBD). However, the pathogenesis and incidence of NRH in IBD, and the putative roles played by azathioprine (AZA), mercaptopurine (MP), or tioguanine (TG) remain unclear. AIMS: To summarise the data on the association between NRH and thiopurine therapy in patients with IBD. METHODS: A literature search was performed in PubMed and MEDLINE databases using the keywords 'nodular regenerative hyperplasia AND (inflammatory bowel disease OR Crohn's disease OR ulcerative colitis) AND (azathioprine OR mercaptopurine OR tioguanine OR thioguanine).' No time limit was placed on studies included. RESULTS: Inflammatory bowel disease patients treated with AZA have a cumulative incidence of NRH of approximately 0.6% and 1.28% at 5 and 10 years, respectively, whereas those treated with high-dose TG (>40 mg/day) have a frequency of NRH of up to 62%, which is higher in patients with elevated liver enzymes and/or thrombocytopaenia than those without these abnormalities (frequency 76% vs. 33%). Conversely, low-dose TG therapy (<20 mg/day) is relatively safe, with no cases of NRH observed. NRH has also been found in 6% of operated thiopurine-naïve IBD patients. Male gender, older age, and stricturing disease/small bowel resection have been consistently identified as high-risk factors for NRH. CONCLUSIONS: The pathogenesis of nodular regenerative hyperplasia in patients with IBD is complex and multifactorial involving disease-specific, genetic and iatrogenic risk factors. Clinicians should maintain a high index of suspicion for diagnosing nodular regenerative hyperplasia, especially in IBD patients with high-risk factors on thiopurine therapy, regardless of the presence of laboratory abnormalities.

Hepatotoxicidad inducida por azatioprina en paciente con enfermedad de Crohn / Azathioprine-induced hepatotoxicity in a patient with Crohn’s disease

Los inmunosupresores se encuentran entre los grupos farmacológicos con mayor potencial teórico de inducir reacciones adversas, entre ellas las hepáticas. Presentamos el caso de un paciente de 35 años con enfermedad de Crohn en tratamiento con azatioprina por corticodependencia al que se le diagnosticó tras realización de una biopsia hepática de hiperplasia nodular regenerativa secundaria a este tratamiento (AU)

Immunosuppressive drugs are among the pharmacological groups with the most theoretical potential to induce adverse reactions, including hepatic reactions. We report the case of a 35-year-old patient with Crohn’s disease treated with azathioprine for steroid dependence which, after a hepatic biopsy, was diagnosed with nodular regenerative hyperplasia secondary to this treatment (AU)