What is nodular regenerative hyperplasia?

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Nodular Regenerative Hyperplasia: Definition and Clinical Significance

Nodular regenerative hyperplasia (NRH) is a rare, non-cirrhotic liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules without fibrous septa, which can lead to portal hypertension while preserving liver synthetic function. 1

Pathological Definition

NRH is defined histologically by diffuse micronodular transformation of the entire hepatic parenchyma without intervening fibrous septae between nodules. 2 This distinguishes it fundamentally from cirrhosis, where regenerative nodules are surrounded by complete fibrous septa. 1

Key Histological Features

  • The absence of perinodular collagen tissue is the critical distinguishing feature that separates NRH from typical regenerative nodules seen in cirrhotic liver. 1
  • Nodules consist of normal hepatocytes showing regenerative activity, either diffuse or partial throughout the liver parenchyma. 2
  • Additional findings include phlebosclerosis (obliterative portal venopathy), sinusoidal dilatation, para-portal shunt vessels, and perisinusoidal fibrosis. 2
  • Phlebosclerosis is regarded as the primary lesion that triggers the intrahepatic hemodynamic changes leading to parenchymal remodeling. 2

Clinical Presentation and Pathophysiology

NRH typically presents with manifestations of non-cirrhotic portal hypertension rather than liver failure. 1, 3

Portal Hypertension Mechanism

  • Portal hypertension in NRH develops from obliteration of portal venules, which causes disturbed intrahepatic circulation and subsequent compensatory parenchymal remodeling. 2
  • The condition leads to "pseudocirrhosis"—a combination of fibrosis around abnormal vessels, nodular regeneration, and portal hypertension that mimics cirrhosis but is not associated with liver insufficiency. 2

Common Clinical Features

  • Splenomegaly is observed more commonly and prominently in NRH than in other causes of portal hypertension (including cirrhosis and portal vein thrombosis). 2
  • Esophageal varices develop in approximately 26-31% of patients, with variceal bleeding occurring in about 12% of cases. 3, 4
  • Liver synthetic function remains well preserved at initial diagnosis, with normal serum albumin, bilirubin, and prothrombin time in most patients. 2, 3
  • Cholestatic pattern of liver enzyme elevation is typical, with elevated alkaline phosphatase and gamma-glutamyl transpeptidase. 3
  • Ascites may develop but is less common than in cirrhotic portal hypertension and when present may be associated with poorer survival. 2

Associated Conditions and Etiology

NRH develops through multiple pathogenic mechanisms including autoimmune, hematological, infectious, neoplastic, or drug-related causes. 1

Major Associated Conditions

  • Thrombophilic disorders are present in 40% of Western patients with NRH, particularly in the context of idiopathic non-cirrhotic portal hypertension (INCPH). 2
  • Rheumatological conditions, especially systemic lupus erythematosus with antiphospholipid syndrome, are strongly associated with NRH development. 5, 6
  • Malignancy is associated in approximately 29% of cases. 4
  • Immunosuppressive medications, particularly azathioprine, have been implicated in NRH development. 6

Diagnostic Approach

Liver histology remains essential for definitive diagnosis of NRH to exclude severe fibrosis or cirrhosis. 2

Critical Diagnostic Pitfall

  • Patients with NRH are frequently misclassified radiologically as cirrhotic because abdominal ultrasonography demonstrates liver surface nodularity and thickening of portal vein walls combined with signs of portal hypertension. 2
  • A key diagnostic clue is low liver stiffness measurement by transient elastography (<12 kPa) despite imaging findings suggesting cirrhosis. 2

Biopsy Requirements

  • Large liver specimens containing sufficient portal tracts are required to demonstrate the characteristic lesions; transjugular specimens are often too small. 2
  • Macroscopic examination may reveal liver surface nodularity, liver dysmorphism, and organized thrombi in large portal vein branches. 2

Prognosis and Natural History

Mortality from variceal hemorrhage in NRH is significantly lower than in cirrhotic patients due to preserved liver function. 2

Survival Characteristics

  • Mean survival after diagnosis is approximately 8.1 years, though highly variable. 4
  • Survival is related to age and the underlying disease process, but not to the presence of portal hypertension or varices per se. 4
  • Liver synthetic function generally remains well preserved throughout the disease course. 2, 3, 4
  • Overall survival may be lower than expected due to high mortality related to NRH-associated disorders (malignancy, thrombophilia, autoimmune conditions) rather than liver-related mortality. 2

Risk of Progression

  • A minority of patients develop liver failure over time, which may necessitate liver transplantation. 2
  • Portal vein thrombosis occurs at higher incidence in NRH compared to cirrhosis. 2
  • Liver function impairment when it occurs is likely explained by reduction in portal flow and subsequent atrophy of peripheral hepatic parenchyma. 2

Relationship to Other Conditions

NRH has been historically classified alongside other entities but is now recognized as part of a spectrum of idiopathic non-cirrhotic portal hypertension (INCPH). 2

  • INCPH was previously subdivided into four morphological categories: idiopathic portal hypertension, nodular regenerative hyperplasia, partial nodular transformation, and incomplete septal cirrhosis. 2
  • These entities share histopathological characteristics (obliterative vascular lesions) and are now viewed as a single entity with various pathological aspects rather than distinct clinicopathological entities. 2
  • In specific contexts like hereditary hemorrhagic telangiectasia (HHT), hepatocellular regenerative activity can lead to either diffuse NRH or focal nodular hyperplasia (FNH). 2
  • In Fontan-associated liver disease, benign nodules may show overlapping features between large regenerative nodules and FNH, termed "FNH-like nodules." 2

References

2
Guideline

Guideline Directed Topic Overview

Dr.Oracle Medical Advisory Board & Editors, 2025

5
Guideline

Portal Hypertension in Systemic Lupus Erythematosus

Praxis Medical Insights: Practical Summaries of Clinical Guidelines, 2026

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Professional Medical Disclaimer

This information is intended for healthcare professionals. Any medical decision-making should rely on clinical judgment and independently verified information. The content provided herein does not replace professional discretion and should be considered supplementary to established clinical guidelines. Healthcare providers should verify all information against primary literature and current practice standards before application in patient care. Dr.Oracle assumes no liability for clinical decisions based on this content.

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