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

Authors

  • Sonja Rothweiler,

    1. Department of Biomedicine, University Hospital Basel, University Basel, Basel, Switzerland
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  • Markus H. Heim,

    1. Department of Biomedicine, University Hospital Basel, University Basel, Basel, Switzerland
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  • David Semela

    Corresponding author
    1. Department of Biomedicine, University Hospital Basel, University Basel, Basel, Switzerland
    2. Division of Gastroenterology and Hepatology, St. Gallen, Switzerland
    • Address reprint requests to: David Semela, M.D., Ph.D., Liver Biology, Department of Biomedicine, University Hospital Basel and University of Basel, Hebelstrasse 20, CH-4031 Basel, Switzerland. E-mail: david.semela@unibas.ch; fax: +41 61 265 5352.

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  • Potential conflict of interest: Nothing to report.

  • Supported by SNF Score Grant 32323B_123815 to D.S.

Abbreviations
GET

generalized essential telangiectasia

HHT

hereditary hemorrhagic telangiectasia

HVPG

hepatic venous pressure gradient

NRH

nodular regenerative hyperplasia

TEK

tyrosine kinase, endothelial

TIPS

transjugular intrahepatic portosystemic shunt

Case Report

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.

Figure 1.

(A) Lower limb showing generalized telangiectasias. (B) Endoscopic picture showing portal hypertensive gastropathy with the characteristic snakeskin appearance of the gastric mucosa. (C) Upper gastrointestinal endoscopy revealed grade II esophageal varices. (D) Prominent vasculature and mucosal telangiectasia in the colon. (E) Histology demonstrating nodular appearance of the liver and dilated sinusoids (arrowheads). Hypertrophic hepatocytes form regenerating nodules alternated with atrophic regions of compressed hepatocytes in the absence of fibrosis (Novotny reticulin stain, original magnification ×5). (F) mRNA levels of endothelial genes measured in liver biopsy from our patient in comparison to controls (HCV-infected patients with minimal inflammation and fibrosis resembling normal liver). *P < 0.05, **P < 0.005.

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.

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