Pathogenesis Of Nodular Regenerative Hyperplasia Research Articles

Nodular Regenerative Hyperplasia Induced by Trastuzumab Emtansine: Role of Emtansine?

Trastuzumab is a monoclonal antibody targeted against the Human Epidermal Growth Factor Receptor 2 (HER2) overexpressed in some breast cancer. This targeted therapy significantly improves the prognosis of these cancers. Recently an anti-HER2 antibodydrug conjugate was shaped in order to facilitate the targeted delivery of potent cytotoxic drug to cancer cells and to reduce resistance. This formulation, called trastuzumab emtansine (T-DM1), consists of the monoclonal antibody trastuzumab linked to a cytotoxic drug (a derivative of maytansine) via a chemical linker. Little is known about adverse reactions due to this new formulation. Herein we described the case of a woman suffering from a HER2-positive breast cancer, treated with trastuzumab for 30 months followed by T-DM1 monotherapy. After 12 months of T-DM1 treatment, a nodular regenerative hyperplasia confirmed by liver biopsy occurred. T-DM1 was stopped and medical imagery showed a resolution of the nodular regenerative hyperplasia. Unfortunately, hepatic metastasis progressed. Few cases of nodular regenerative hyperplasia induced by T-DM1 have been described so far. Further studies are needed to explore pathogenesis of nodular regenerative hyperplasia with this new antibody-drug conjugate treatment.

Nodular regenerative hyperplasia in a patient with generalized essential telangiectasia: Endotheliopathy as a causal factor

A 60-year-old Caucasian man was referred to the outpatient clinic for evaluation of splenomegaly. The patient's history revealed only a noninsulin-dependent diabetes mellitus and a generalized essential telangiectasia (GET), which developed over the past 20 years with extensive telangiectasias primarily on the arms, legs, and trunk (Fig. 1A). Face and oral/nasal mucosa were spared, epistaxis was denied, and family history of telangiectasias was absent, which clearly distinguishes GET from hereditary hemorrhagic telangiectasia (HHT). The patient stated occasional wine consumption; viral hepatitis and autoimmune serologies were negative. Abdominal ultrasound revealed splenomegaly and a recanalized umbilical vein. Upper gastrointestinal endoscopy showed portal-hypertensive gastropathy (Fig. 1B) and grade II esophageal varices (Fig. 1C), as further evidence of portal hypertension. Prominent mucosal vasculature and angiectatic vessels were found throughout the small and large intestine (Fig. 1D). Transjugular measurement of the hepatic venous pressure gradient (HVPG) was surprisingly normal with a gradient of 4 mmHg, suggesting a prehepatic or presinusoidal form of portal hypertension. Correspondingly, liver biopsy revealed nodular regenerative hyperplasia (NRH) with grade 3 nodularity and megasinusoids (arrowheads, Fig. 1F) in the absence of fibrosis. Hepatic plates were compressed by dilated sinusoids and regenerating hepatocytes, resulting in the typical nodular appearance characteristic for NRH. The patient showed progression to grade III esophageal varices despite treatment with propranolol and developed refractory ascites. Therefore, it was decided to place a transjugular intrahepatic portosystemic shunt (TIPS). During TIPS placement, invasively measured portal pressure was severely increased to 30 mmHg, which was reduced to a portal pressure of 10 mmHg after TIPS placement. Follow-up showed reduction of varices and resolution of ascites. Although the pathogenesis of NRH is not fully understood, a growing body of evidence based on autopsy studies and multiple case series indicates that NRH is the response to impaired hepatic blood supply.1 These hemodynamic changes can be due to thrombotic events or endothelial injury of the microvasculature. NRH has been described in association with vascular disorders, i.e., polyarteritis nodosa, rheumatoid vaculitis, or HHT,2, 3 providing further evidence that an endotheliopathy is a causative factor inducing secondary changes of the liver architecture leading to NRH. Systemic vascular diseases can directly lead to impaired hepatic blood flow through vascular stenosis after endothelial changes/injury or indirectly by causing obliteration due to thrombi generation. GET is another endotheliopathy characterized by widespread telangiectasias with primarily cutaneous involvement, whereas internal organs are usually not affected. Here we describe for the first time a patient with NRH in association with the vascular disorder GET. The availability of a liver biopsy for molecular analysis from our patient allowed measuring messenger RNA (mRNA) expression levels of genes that are known to regulate endothelial differentiation. In comparison to controls,4 we observed a down-regulation of Notch1, Dll4, EphrinB2, and Tek in our patient (Fig. 1F). These genes have recently been shown to be implicated in the process of vascular remodeling in a murine model displaying features of NRH after deletion of Notch1.5 NRH occurred as a secondary event following activation of the sinusoidal endothelium, with ensuing vascular dedifferentiation and intussusceptive angiogenesis. Furthermore, down-regulation of the same set of genes was confirmed in NRH patients.4 Thus, also on the genetic level, endothelial involvement in the pathogenesis of NRH was proven in the presented case. In conclusion, we describe the first case of NRH in a patient with general essential telangiectasia. Our findings suggest that NRH is the hepatic manifestation of this systemic endotheliopathy. Molecular analysis showing dysregulated Notch, Ephrin, and Tek signaling is in line with the recent description in a murine NRH model, further strengthening the hypothesis that NRH is driven by a vascular disorder.

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

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. To summarise the data on the association between NRH and thiopurine therapy in patients with IBD. 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. 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. 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.

Portal Hypertension, Nodular Regenerative Hyperplasia of the Liver, and Obstructive Portal Venopathy due to Metastatic Breast Cancer

Nodular regenerative hyperplasia (NRH) of the liver is associated with noncirrhotic portal hypertension, rheumatologic and hematologic disorders, administration of certain drugs, and other underlying conditions. This report describes a 64-year-old man with clinically presumed cirrhosis who presented to our institution with coffee-ground emesis, esophageal varices, ascites, and encephalopathy. Eleven years earlier he had been treated for breast cancer with mastectomy and chemo-radiotherapy. He died suddenly, and the autopsy showed no evidence of cirrhosis but instead demonstrated NRH with extensive emboli of recurrent breast carcinoma within the portal vein and its intrahepatic branches. Neoplastic occlusion of the portal vein as a cause of presinusoidal noncirrhotic portal hypertension has not previously been reported for metastatic breast carcinoma. This case highlights the importance of obstructive portal venopathy in the pathogenesis of NRH as well as the diagnostic difficulties that may be encountered in determining the cause of portal hypertension.

Disruption of Notch1 Induces Vascular Remodeling, Intussusceptive Angiogenesis, and Angiosarcomas in Livers of Mice

Notch signaling mediates embryonic vascular development and normal vascular remodeling; Notch1 knockout mice develop nodular regenerative hyperplasia (NRH). The pathogenesis of NRH is unclear, but has been associated with vascular injury in the liver sinusoids in clinical studies. We investigated the role of Notch1 signaling in liver sinusoidal endothelial cells (LSECs). We studied MxCre Notch1(lox/lox) mice (conditional knockout mice without tissue-specific disruption of Notch1); mice with hepatocyte-specific knockout were created by crossing Notch1(lox/lox) with AlbCre(+/-) mice. Portal vein pressure was measured; morphology of the hepatic vasculature was assessed by histologic and scanning electron microscopy analyses. We performed functional and expression analyses of isolated liver cells. MxCre-induced knockout of Notch1 led to NRH, in the absence of fibrosis, with a persistent increase in proliferation of LSECs. Notch1 deletion led to de-differentiation, vascular remodeling of the hepatic sinusoidal microvasculature, intussusceptive angiogenesis, and dysregulation of ephrinB2/EphB4 and endothelial tyrosine kinase. Time-course experiments revealed that vascular changes preceded node transformation. MxCre Notch1(lox/lox) mice had reduced endothelial fenestrae and developed portal hypertension and hepatic angiosarcoma over time. In contrast, mice with hepatocyte-specific disruption of Notch1 had a normal phenotype. Notch1 signaling is required for vascular homeostasis of hepatic sinusoids; it maintains quiescence and differentiation of LSECs in adult mice. Disruption of Notch1 signaling in LSECs leads to spontaneous formation of angiosarcoma, indicating its role as a tumor suppressor in the liver endothelium.

Noncirrhotic portal hypertension and nodular regenerative hyperplasia of the liver in dogs with mucopolysaccharidosis type I.

Nodular regenerative hyperplasia (NRH) is an uncommon hepatic lesion often associated with noncirrhotic portal hypertension (PHT). We have noted that NRH and PHT are frequent occurrences in a colony of dogs with the genetic storage disease, mucopolysaccharidosis I (MPS-I). This observation provides the opportunity to study the histology and pathogenesis of NRH and noncirrhotic PHT in a new animal model. Thirteen of 32 dogs (41%) with MPS-I developed multiple portocaval shunts between 4 and 48 months of age that were grossly visible at necropsy. Seven of the 13 developed marked ascites, whereas all those without shunts and littermates (n = 24) heterozygous for the mutated alpha-L-iduronidase allele (carriers unaffected by the storage disease) did not. The large and medium-sized portal veins were widely patent without thrombosis or vascular malformations. Hepatic parenchymal fibrosis was absent or mild and did not correlate with shunt formation. All 32 livers had varying degrees of diffuse periportal hepatocellular hyperplasia with multifocal atrophy and compression of centrolobular cords (NRH) most prominent in dogs with shunts. Many small portal veins were reduced in diameter or absent, especially in animals with shunts. Noncirrhotic PHT and NRH appear to be related to the obliteration of small portal veins in these dogs, but the pathogenesis of this vascular change remains unknown.

Nodular Regenerative Hyperplasia of the Liver in Systemic Lupus Erythematosus

Recent reports have indicated that nodular regenerative hyperplasia (NRH) associated with systemic lupus erythematosus (SLE) is related to anticardiolipin antibodies (aCL) and/or lupus anticoagulant (LA). We describe a patient with SLE complicated by NRH, who did not show neither aCL nor LA activity. This case suggests that the pathogenesis of NRH in patients with autoimmune diseases is heterogeneous and not confined to aCL and LA.

Nodular Regenerative Hyperplasia of the Liver

The frequency and pathogenesis of nodular regenerative hyperplasia of the liver (NRHL) were examined in general autopsy series. We found NRHL in 12 cases (2.1%) of 577 consecutive autopsy livers without hepatic necrosis, fibrosis, cirrhosis, or tumors. All of these cases were middle-aged to elderly adults, and there was a slight female predominance of 2:1. Symptoms related to the liver were absent in all but two cases. NRHL was an incidental finding in these 12 cases at autopsy. The main other diseases in these cases were classified into four groups: (a) organic cardiac diseases (four cases), (b) pulmonary diseases with right-sided cardiac hypertrophy (four cases), (c) small arterial diseases involving the liver (two cases), and (d) systemic amyloidosis involving intrahepatic small arterial branches (two cases). The frequency of NRHL in these four groups at autopsy was 3.8, 7.1, 33.3, and 22.2%, respectively, suggesting that while NRHL is rare, clinicians should be aware of its association or development of NRHL in several conditions. Disturbances of outlet venous blood flow and inlet arterial blood flow may contribute to the development of NRHL in the former two and latter two groups, respectively.

Nodular regenerative hyperplasia of the liver associated with macroglobulinemia: A clue to the pathogenesis

Nodular regenerative hyperplasia of the liver is an infrequent condition characterized by transformation of the hepatic parenchyma into nodules with only mild fibrosis. Little is known about the etiology except that there is usually an underlying chronic disease, such as Felly's syndrome, which antedates the development of clinical liver disease. It is poorly understood how the associated diseases contribute to the pathogenesis of nodular regenerative hyperplasia. Presented are four cases of nodular regenerative hyperplasia in which macroglobulinemia was also present. This new association suggests to us a hypothesis for the pathogenesis of nodular regenerative hyperplasia. Histologic examination of the livers in these and other cases of nodular regenerative hyperplasia reveals widespread obliteration of the small portal veins. Postmortem angiography of one liver in the present series demonstrated that the nodules were well perfused and that the atrophic areas were poorly perfused with portal blood. This supports the view that atrophy of lobules results from a lack of portal blood supply and that nodules develop from lobules well supplied with portal blood. In each of the clinical conditions associated with nodular regenerative hyperplasia, including macroglobulinemia, inflammatory or thrombotic vascular lesions are found in many organs. Therefore, nodular regenerative hyperplasia may be the hepatic expression of a more widespread vascular disease.

Nodular regenerative hyperplasia of the liver

Abstract The authors report the cases of 6 adult patients suffering from nodular regenerative hyperplasia of the liver, an uncommon lesion characterized by small-sized hepatocytic nodules scattered throughout the liver, with no or slight fibrosis. The histological recognition of nodular regenerative hyperplasia of the liver was easy on large specimens taken intraoperatively, but was difficult or impossible on small specimens such as those provided by needle biopsy. In all of the patients of this series, the main consequence of nodular regenerative hyperplasia of the liver was portal hypertension. In this series, nodular regenerative hyperplasia of the liver was not associated with rheumatoid arthritis, whereas such an association has been noted in most of the cases previously reported. The etiology and pathogenesis of nodular regenerative hyperplasia of the liver is unknown.

Nodular regenerative hyperplasia of the liver: Report of six cases and review of the literature

The authors report the cases of 6 adult patients suffering from nodular regenerative hyperplasia of the liver, an uncommon lesion characterized by small-sized hepatocytic nodules scattered throughout the liver, with no or slight fibrosis. The histological recognition of nodular regenerative hyperplasia of the liver was easy on large specimens taken intraoperatively, but was difficult or impossible on small specimens such as those provided by needle biopsy. In all of the patients of this series, the main consequence of nodular regenerative hyperplasia of the liver was portal hypertension. In this series, nodular regenerative hyperplasia of the liver was not associated with rheumatoid arthritis, whereas such an association has been noted in most of the cases previously reported. The etiology and pathogenesis of nodular regenerative hyperplasia of the liver is unknown.