Indian Journal of Pathology and Microbiology
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Year : 2008  |  Volume : 51  |  Issue : 1  |  Page : 78-80
Nodular regenerative hyperplasia of liver

1 Department of Pathology, Armed Forces Medical College, Pune, Maharashtra, India
2 Department of Pathology, Command Hospital (SC), Pune, Maharashtra, India
3 Department of Surgery, Armed Forces Medical College, Pune, Maharashtra, India

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Nodular regenerative hyperplasia of the liver (NRHL) is a very rare cause of portal hypertension and liver failure. The condition is characterized by diffuse micronodular transformation of hepatic parenchyma without fibrous septa between the nodules. We present our experience with a 32-year-old woman who presented with recurrent episodes of upper gastrointestinal bleeding associated with massive splenomegaly who was subsequently found to have NRHL. This article considers the salient aspects of this rare condition, how it affects the patients and the options available in its management. A plea is made for the need for liver biopsy for all patients with portal hypertension especially those being considered for surgery.

Keywords: Liver, nodules, regeneration, hyperplasia

How to cite this article:
Shelly D, Tevatia M S, Praharaj A K, Mehta A, Harish S, Baskaran V. Nodular regenerative hyperplasia of liver. Indian J Pathol Microbiol 2008;51:78-80

How to cite this URL:
Shelly D, Tevatia M S, Praharaj A K, Mehta A, Harish S, Baskaran V. Nodular regenerative hyperplasia of liver. Indian J Pathol Microbiol [serial online] 2008 [cited 2023 May 28];51:78-80. Available from:

   Introduction Top

Nodular regenerative hyperplasia of the liver (NRHL) is a very rare cause of portal hypertension and liver failure. This is characterized by hepatocellular nodules distributed throughout the liver in the absence of fibrous septa between the nodules. [1] The clinical expression of this histological lesion is variable. The prognosis depends on the existence and severity of portal hypertension, which occurs in up to 69% of cases. [1],[2] Correct diagnosis is important to prognostigate as patients with NRH and portal hypertension fare better than patients with cirrhosis, [2] with whom they may be confused. Apart from a reported prevalence of 3.1/100,000 from Spain, [1] the prevalence and clinical load of the disease is not known elsewhere. To the best of our knowledge there has been but a single report from India and that too where the diagnosis was made on autopsy. [3] We report a rare case of NRHL presenting with portal hypertension and hypersplenism which we managed successfully.

   Case History Top

A 32-year-old woman presented to our tertiary care teaching hospital with a history of recurrent episodes of upper gastrointestinal bleeding. The last episode of GI bleeding was a day prior to admission. Clinically she had severe pallor, facial puffiness, bilateral pitting pedal edema, hepatomegaly 4 cm below subcostal margin, massive splenomegaly 15 cm below subcostal margin, and minimal ascites. Laboratory investigations revealed severe reduction of all three blood cell lines with Hb - 2.7 g% total leukocyte count - 2700/mm 3 , Platelets - 40.000/mm 3 with normal liver and renal functions. Ultrasonography abdomen and color dopler studies of splenoportal axis showed coarse echotexture of the liver with no nodularity, portal vein measuring 23 mm at porta, splenic vein measuring 14 mm with perihilar collaterals, and minimal ascites. Grade III esophageal varices were detected on gastroduodenoscopy.

A diagnosis of portal hypertension secondary to noncirrhotic portal fibrosis (NCPF) being the best fit, was made. Cirrhosis was considered unlikely in the absence of history suggestive of viral hepatitis or alcoholism or evidence of hepatic decompensation. Endoscopic variceal banding was done as secondary prophylaxis and she was transfused six units of packed cells over a period of 5 days. She was also started on aldactone, propranolol, and hematinics.

In view of the features of hypersplenism with recurrent variceal bleeding and noncirrhotic liver, splenectomy possibly with proximal leinorenal shunt was planned as one-time treatment option and the patient was taken up for surgery accordingly. The operative findings were diffusely nodular beefy liver, significant periesophageal and leinorenal collaterals, and minimal ascites. On a clinical suspicion of cirrhosis or nodular NCPF, the procedure was changed to splenectomy with devascularization after taking a wedge biopsy of liver. Postoperative course was uneventful and the patient is well and asymptomatic after 4 months.

Pathological findings

Section examined showed nodules which were formed by hyperplastic hepatocytes, distorting but not effacing the normal architecture. Hepatocytes were arranged in two or more cell plates. The intervening liver parenchyma was atrophic, but no fibrous septa are seen. The sinusoids were congested. Central vein was compressed and showed fibrosis. Portal inflammation in form of lymphocytic infiltration was present. No portal tract fibrosis noted. Reticulin stain showed thickening of hepatocyte plates within the nodules and atrophy of hepatocytes at the periphery of nodules [Figure - 1],[Figure - 2].

   Discussion Top

Nodular regenerative hyperplasia of the liver is defined by hepatocellular nodules distributed throughout the liver in the absence of fibrous septa between the nodules. [1],[4] The condition has also been recognized under a variety of synonyms, including "nodular transformation," "noncirrhotic nodulation," "hepatocellular adenomatosis," and "adenomatous hyperplasia" in the past.

The existing literature on this pathological entity is predominantly composed of case reports, [2],[3],[4],[5] and hence the prevalence and clinical significance of NRHL is uncertain. The main reason for this is that the diagnosis is mostly made postmortem [3],[6] or after explant of the diseased liver during liver transplantation in the developed countries. [7] Like many conditions, its actual prevalence in autopsy studies is much higher than what is seen in clinical practice. A review of hepatic histology of 2500 consecutive autopsies revealed that 2.6% of these livers exhibited a spectrum of NRHL with higher expression in livers with cirrhosis and with incomplete cirrhosis. [6]

The etiology of NRHL is not fully understood and there are many theories explaining its pathogenesis. The critical lesion is the obliterative portal venopathy, presenting with obstruction to terminal radicals of hepatic arterioles, and portal venules. [1],[4] The resultant hepatic ischemia may be responsible for induction of nodular regenerative change. [6] It is believed that nodular regenerative hyperplasia is a secondary and nonspecific tissue adaptation to heterogeneous distribution of blood flow and does not represent a specific entity. The vascular hypothesis postulates that the basic pathologic lesion leading to NRHL is obliteration or thrombus in the portal venous system leading to ischemic atrophy in the most vulnerable central areas. [4],[6] A support for the mechanism of hepatic obliterative angiopathy in NRHL stems from the fact that many of its associated conditions described later are known to cause vasculitis or nonvasculitic thrombosis. [2],[4] The central atrophy is compensated by proliferation of the hepatocytes from the portal region which form regenerative nodules. The histologic findings in NRHL support this sequence of events as most of the hepatocyte regeneration is seen in the portal region, and the central area is atrophied and compressed by the regenerating nodules.

An alternate mechanism for its pathogenesis is that NRHL may be a proliferative disorder of the liver. A possible pathogenicity as a premalignant condition which may progress to hepatocyte dysplasia and hepatocellular carcinoma has also been attributed to NRHL based on high association between NRHL and dysplasia. [2],[8] A report showed that 23 of 342 noncirrhotics who had hepatocellular carcinoma also had NRHL and that majority of these had liver cell dysplasia. [8] This suggests that hepato cellular carcinoma (HCC) may develop within the dysplastic foci that occur in NRHL. [8] However, these findings do not exclude the converse possibility that NRH may also develop in a noncirrhotic liver with HCC, the mechanism being portal venous occlusion by HCC with ischemic cascade of NRHL development. [8]

In addition, based on the study of CD8+ T-lymphocyte concentration in liver biopsies, it has been proposed that some NRH cases might result from chronic, cytotoxic CD8+ T-lymphocyte targeting of sinusoidal endothelial cells. [9] It is probable that the spectrum of NRHL is caused by multiple agents and through multiple pathways.

Nodular regenerative hyperplasia of the liver occurs more often in adults than in children [2],[5] and often has an association with a variety of conditions, such as collagen disorders, Felty's syndrome, congestive heart failure, hematologic abnormalities (especially myeloproliferative disorders), metabolic diseases, neoplasms, and drugs. [1],[2],[5] In our patient further investigations did not reveal any collagen vascular diseases, myeloproliferative disorders or underlying malignancy. Patients with NRHL may be asymptomatic or may present with features of portal hypertension or other nonspecific abdominal symptoms. Some of these nonspecific symptoms are attributable to the coexisting diseases. [2],[6],[7] The origin of portal hypertension in this condition is primarily sinusoidal, similar to that seen with cirrhosis [10] which may be due to the compression of the intrahepatic portal radicles by the regenerating nodules or due to the thrombosis of portal veins and venules.

The therapy of NRHL is aimed at portal hypertension and liver cell failure when they exist. Opinion is divided as to the appropriate management of patients with NRHL who have variceal bleeding. While porto systemic shunt procedures are recommended by some authors, [1],[2],[5] others believe that the incidence of encephalopathy following shunts is unacceptably high. Liver transplantation may be the choice of treatment for end stage NRHL when it may not be distinguishable from cirrhosis, [1],[2] though it has also been done in early stages on the mistaken belief of cirrhosis. [7]

In our patient, we performed a devascularization procedure on the suspicion of either cirrhosis or nodular NCPF, or both of which have high incidence of encephalopathy following shunt procedure. It is likely that cases of NRHL in India may be mistaken to be NCPF or even cirrhosis on the appearance of the liver alone and when no biopsy is done the actual diagnosis may go unnoticed. We believe that a liver biopsy should be performed in all cases of portal hypertension, especially those considered for surgery for PHT. Here emphasis is more on wedge biopsies because needle biopsies may not reveal focal changes leading to wrong interpretation. This would help in prognostication as well as choosing appropriate operative procedure.

   References Top

1.Naber AH, Van Haelst U, Yap SH. Nodular regenerative hyperplasia of the liver: an important cause of portal hypertension in non-cirrhotic patients. J Hepatol 1991;12:94-9.  Back to cited text no. 1  [PUBMED]  [FULLTEXT]
2.Colina F, Alberti N, Solis JA, Martinez-Tello FJ. Diffuse nodular regenerative hyperplasia of the liver (DNRH). A clinicopathologic study of 24 cases. Liver 1989;9:253-65.  Back to cited text no. 2    
3.Vora IM, Deodhare SS. Nodular transformation (multifocal regenerative hyperplasia) of the liver (a case report). J Postgrad Med 1984;30:129-32.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Dogan E, Ozgar R, Erkan V, Tekin A, Senkal O, Cevikbas U, Nodular regenerative hyperplasia of the liver: a case report; Turkish J Gastroenterol 2003;14; 64-7.  Back to cited text no. 4    
5.Moran CA, Mullick FG, Ishak KG. Nodular regenerative hyperplasia of the liver in children. Am J Surg Pathol 1991;15:449-54  Back to cited text no. 5  [PUBMED]  
6.Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 1990;11:787-97.  Back to cited text no. 6  [PUBMED]  
7.Elariny HA, Mizrahi SS, Hayes DH, Boudreaux JP, Hussey JL, Farr GH Jr. Nodular regenerative hyperplasia: a controversial indication for orthotopic liver transplantation. Transplant Int 1994;7;309-13.  Back to cited text no. 7    
8.Nzeako UC, Goodman ZD, Ishak KG. Hepatocellular carcinoma and nodular regenerative hyperplasia; possible pathogenetic relationship. Am J Gastroenterol 1996;91:879-84.  Back to cited text no. 8  [PUBMED]  
9.Ziol M, Poirel H, Kountchou GN, Boyer O, Mohand D, Mouthon L, Tepper M, Guillet JG, Guettier C, Raphael M, Beaugrand M. Intrasinusoidal cytotoxic CD8+ T cells in nodular regenerative hyperplasia of the liver. Hum Pathol 2004;35:1241-51.  Back to cited text no. 9    
10.Ueno S, Tanabe G, Sueyoshi K, Yoshinaka H, Yamamoto S, Kurita K, Yoshidome S, Nuruki K, Aikou T. Hepatic hemodynamics in a patient with nodular regenerative hyperplasia. Am J Gastroenterol 1996;91:1012-5.  Back to cited text no. 10  [PUBMED]  

Correspondence Address:
M S Tevatia
Department of Pathology, Command Hospital (SC), Pune, Maharashtra
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0377-4929.40408

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