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□ CASE REPORT □

Development of Nodular Regenerative Hyperplasia (NRH)with Portal Hypertension Following the Administration

of Oxaliplatin for the Recurrence of Colon Cancer

Hiroaki Takaya, Hideto Kawaratani, Keisuke Nakanishi, Shinya Takeyama, Chie Morioka,

Masayoshi Sawai, Masahisa Toyohara, Masao Fujimoto, Hitoshi Yoshiji,

Junichi Yamao and Hiroshi Fukui

Abstract

Nodular regenerative hyperplasia (NRH) is associated with autoimmune and hematologic diseases and may

lead to portal hypertension. We herein report a case of NRH diagnosed based on a liver biopsy. A 63-year-

old woman developed esophageal varices and splenomegaly. She had undergone surgery for transverse colon

cancer 24 years earlier and received systemic chemotherapy (FOLFOX4 including oxaliplatin) to treat lymph

node metastasis 21 years after the operation. The present liver biopsy confirmed NRH, and, after two years,

she received endoscopic injection sclerotherapy. Oxaliplatin was suspected to be the causative agent of NRH

in this case. Therefore, physicians must consider the possibility of NRH in patients who receive chemother-

apy.

Key words: nodular regenerative hyperplasia (NRH), esophageal varices, oxaliplatin, colon cancer

(Intern Med 54: 383-387, 2015)(DOI: 10.2169/internalmedicine.54.2461)

Introduction

Nodular regenerative hyperplasia (NRH) was first de-

scribed by Steiner in 1959 (1). NRH of the liver is charac-

terized by innumerable small areas of focal regeneration

more or less distinctively demarcated by adjacent compres-

sive, atrophic or other degenerative and circulatory effects.

Lacking a true increase in fibrotic tissue, the lesion does not

conform to the definition of cirrhosis, which it sometimes

resembles. NRH is associated with rheumatic and hemato-

logical diseases, leading to the development of portal hyper-

tension in 4.6% of patients (2). We herein report a rare case

of NRH diagnosed based on a liver biopsy after systemic

chemotherapy for colon cancer. The patient subsequently un-

derwent endoscopic injection sclerotherapy for esophageal

varices.

Case Report

A 63-year-old woman was referred to our hospital due to

worsening of esophageal varices and enlargement of the

spleen. She had a maternal family history of diabetes melli-

tus (DM) and had smoked 20 cigarettes per day, although

she did not drink alcohol. She had undergone surgery for

transverse colon cancer approximately 24 years previously

and had been treated for DM and rheumatoid arthritis (RA)

for approximately 15 years. She received insulin, voglibose,

bucillamine and methotrexate. As she was found to have in-

guinal lymph node metastasis of colon cancer three years

earlier, she had a history of treatment with FOLFOX4 (con-

taining 5-fluorouracil, oxaliplatin and leucovorin), having re-

ceived 37 courses of FOLFOX4 for approximately two

years. After the treatment, the inguinal lymph node metasta-

sis had healed, and she stopped the medications. Thereafter,

she experienced no recurrence of transverse colon cancer or

Third Department of Internal Medicine, Nara Medical University, Japan

Received for publication January 14, 2014; Accepted for publication June 23, 2014

Correspondence to Dr. Hideto Kawaratani, kawara@naramed-u.ac.jp

Intern Med 54: 383-387, 2015 DOI: 10.2169/internalmedicine.54.2461

384

Table.　Laboratory Data on Admission

Peripheral Blood Blood urea nitrogen 13 mg/dLWhite blood cell 3,600 / L Serum creatinine 0.7 mg/dLRed blood cell 471× 104/ L Serum sodium concentration 141 mEq/LHemoglobin 12.2 g/dL Serum potassium concentration 4.2 mEq/LHematocrit 32.80% Serum calcium concentration 7.4 mg/dLPlatelet 12.7 x104/ L Fasting blood glucose 83 mg/dL

Hemoglobin A1c 4.8%Blood Coagulation Immunoreactive insulin 126 U/mLProthrombin time 12.6 secActivated partial thromboplastin time 33.7 sec Hepatitis Virus

HBs antigen negativeBlood Chemistry HBc antigen negativeC-reactive protein 1.5 mg/dL HBs antibody negativeTotal protein 6.8 g/dL HCV antibody negativeSerum albumin 4.5 g/dLAspartate aminotransferase 18 IU/L Immunological InvestigationAlanine aminotransferase 14 IU/L Anti-nuclear antibody 4 foldAlkaline phosphatase 471 IU/L Anti-liver/kidney microsome type 1 37.3 INDEX-glutamyl transpeptidase 24 IU/L Immunoglobulin A 273 mg/dL

Lactate dehydrogenase 228 IU/L Immunoglobulin M 220 mg/dLSerum total bilirubin 0.7 mg/dL Immunoglobulin G 1,118 mg/dL

Figure　1.　Abdominal CT imaging of the liver performed on admission revealed a rough inner structure, central swelling and peripheral atrophy resembling liver cirrhosis.

inguinal lymph node metastasis for one year. At that time,

she had no symptoms, and her Eastern Cooperative Oncol-

ogy Group (EGOG) performance status was 0. However, the

platelet level had declined from 35.5×104/μL to 12.7×104/μL

within three years. Meanwhile, the hepatic and biliary enzy-

matic activities were almost normal [aspartate aminotrans-

ferase (AST): 18 IU/L, alanine aminotransferase (ALT): 14

IU/L, alkaline phosphatase (ALP): 471 IU/L, lactate dehy-

drogenase (LDH): 228 IU/L and γ-GTP: 24 IU/L], and HBs

antigens and HCV antibodies were negative. The titer of

anti-nuclear antibodies (ANA) was increased 4-fold, and

anti-liver/kidney microsome type 1 (LKM-1) antibodies

were positive (37.3 INDEX). In contrast, the immunoglobu-

lin levels were normal (IgA: 273 mg/dL, IgG: 1,118 mg/dL

and IgM: 220 mg/dL), and the DM and RA were well con-

trolled. The glucose level was 83 mg/dL, the HbA1c level

was 4.8% and the C-reactive protein (CRP) level was 1.5

mg/dL (Table).

Computed tomography (CT) of the liver revealed a rough

inner structure, central swelling and peripheral atrophy

(Fig. 1). The spleen had also become enlarged within two

years (Fig. 2), although the portal vein exhibited no throm-

bosis or stenosis. Esophagogastroduodenoscopy (EGD)

showed grade 2 esophageal varices (3). Since the patient

had no history of viral hepatitis, and anti-LKM-1 antibodies

were positive, a diagnosis of type 2 autoimmune hepatitis

(AIH) with liver cirrhosis was initially suspected. However,

a liver biopsy specimen demonstrated a disturbed architec-

ture with a nodular appearance in the liver parenchyma in

addition to areas of sinusoidal congestion. A regenerative

nodule was bordered by irregular small-sized hepatic trabe-

culae, with hardly any fibrous septa (Fig. 3). We therefore

diagnosed the patient as NRH with portal hypertension of

the liver. Two years after the liver biopsy, the esophageal

varices worsened (Fig. 4A, B), and the patient underwent

endoscopic injection sclerotherapy. Since then, she has expe-

rienced no further recurrence of esophageal varices

(Fig. 4C).

Discussion

It is widely known that chemotherapy-induced hepatic

toxicity (CIHT) is subclassified into non-alcoholic fatty liver

disease (NAFLD) and sinusoidal obstruction syndrome

(SOS) (4, 5). Sometimes NRH is classified as a severe form

of SOS. NRH is a rare liver disease with an etiology that is

not well understood. The pathogenesis of NRH is thought to

involve endothelial damage, which subsequently induces the

widespread obliteration of small portal veins throughout the

liver parenchyma. Initially, the present patient was suspected

of having type 2 AIH because anti-LKM-1 antibody was

positive. However, the liver biopsy specimen exhibited no

Intern Med 54: 383-387, 2015 DOI: 10.2169/internalmedicine.54.2461

385

Figure　2.　Comparison of abdominal CT imaging findings. The size of the spleen increased over two years. (A) Two years earlier. (B) On admission.

(A) (B)

Figure　3.　Histology of the liver biopsy specimen. The liver had a disturbed architecture with a nodular appearance in the liver parenchyma (arrow), characteristic of nodular regenerative hyper-plasia. Areas with sinusoidal congestion were also present. A regenerative nodule was bordered by irregular small-sized hepatic trabeculae (arrowhead). However, the liver specimen showed hardly any areas of fibrous. (A) Hematoxylin and Eosin (H&E) staining, ×40. (B) H&E staining, ×100. (C) Azan staining, ×40.

(A) (B)

(C)

piecemeal necrosis, plasma cell infiltration or rosette forma-

tion. Therefore, the possibility of AIH was excluded. Anti-

LKM-1 antibody is associated with thyroid disease, polyar-

thritis, collagen disease, colon cancer, vitiligo, insulin-

dependent DM, pernicious anemia and autoimmune hemo-

lytic anemia (6, 7). Some patients do not display evidence

of liver disease, although they are positive for anti-LKM-1

antibody (8). NRH is associated with autoimmune and he-

matologic diseases. For example, Wanless reported finding a

spectrum of NRH disorders among 64 cases at 2,500 autop-

sies, with an increased frequency of NRH in patients with

systemic arteritis, polymyalgia rheumatica, massive tumor

infiltration and mineral oil deposition (2). On the other

hand, Thung et al. reported a case of NRH associated with

maturity-onset DM accompanied by an elevated serum insu-

lin level and proposed that hepatotrophic hormones, such as

Intern Med 54: 383-387, 2015 DOI: 10.2169/internalmedicine.54.2461

386

Figure　4.　Images of esophagogastroduodenoscopy. (A) EGD showed grade 2 (moderate-sized clubbed varices) esophageal varices with (B) the red color sign. (C) The varices were completely eradicated 14 months after endoscopic injection sclerotherapy.

(A) (B)

(C)

insulin and glucagon may play a role in the development of

NRH (9). Moreover, a case of NRH that developed after the

administration of neoadjuvant oxaliplatin-containing chemo-

therapy for colon cancer was reported in 2006 (10). Re-

cently, the incidence of NRH following treatment with

oxaliplatin-based chemotherapy has increased (11). Among

the administered drugs during FOLFOX4 treatment, leuco-

vorin and 5-fluorouracil are sometimes associated with the

onset of fatty liver. Furthermore, Ortiz Morales reported a

case of colon cancer in a patient who received oxaliplatin-

based systemic chemotherapy and developed bleeding

varices (12). In the present case, the patient had used oral

hypoglycemic and anti-rheumatic agents over a period of 15

years, although no changes in the liver function or spleen

size were detected. Since the spleen only became enlarged

after FOLFOX4 treatment, we suspected that the administra-

tion of oxaliplatin may induce the development of NRH.

Wanless reported that NRH includes both arterial and ar-

teriolar sclerosis and is characterized by nonspecific tissue

adaptations to a heterogeneous distribution of the blood

flow (2). In addition, a change in the sinusoid in patients

with microvascular injuries is a primary event that may re-

sult in the onset of hepatocyte hypoxia with liver dysfunc-

tion and disruption of the portal circulation (13). Oxaliplatin

potentially causes injury to endothelial cells as it stimulates

the overproduction of reactive oxygen species and depletion

of glutathione in endothelial cells followed by the unregu-

lated expression of matrix metalloproteinase (MMP)-2 and

MMP-9 (14) and the rupture of the sinusoidal barrier, with

the possible extravasation of erythrocytes in the space of

Disse and formation of perisinusoidal fibrosis. Moreover,

NRH is attributed to the development of chronic ischemia in

centrilobular zones (10); this process is thought to be due to

the effects of ischemic atrophy associated with secondary

nodular hyperplasia in regions with a favorable blood flow.

In the present case, treatment with oxaliplatin may have in-

duced a circulatory disturbance, thus leading to the develop-

ment of NRH.

It is often difficult to distinguish NRH from focal nodular

hyperplasia (FNH), alcoholic regenerative nodules and idi-

opathic portal hypertension (IPH). FNH lesions display cen-

tral scarring and thick vessels. Alcoholic regenerative nod-

ules exhibit similar characteristics, but without central scar-

ring, while IPH involves peripheral portal vein stenosis and

aberrant vessels. Meanwhile, NRH includes many regenera-

tive nodules, with areas of sinusoidal enlargement, but no fi-

brotic lesions (15). Recently, the concept of SOS was pro-

posed. SOS lesions are characterized by hepatic sinusoidal

dilatation, hepatocyte atrophy, perisinusoidal fibrosis and

nodular regenerative hyperplasia (4); NRH is part of the

SOS spectrum. In the current case, the liver histology re-

vealed many regenerative nodules with sinusoidal enlarge-

ment, although no fibrotic lesions, central scarring, periph-

eral portal vein stenosis or aberrant vessels were detected,

supporting the diagnosis of NRH. Treatment for NRH pri-

marily involves eliminating the underlying causative factors;

no other standard therapies have been established. The prog-

nosis of NRH is influenced by the development of portal

hypertension and its complications (16). Therefore, control-

ling portal hypertension provides the basis for delivering

therapeutic treatment for NRH and improving the prognosis.

However, once esophageal varices develop, they should be

treated.

The present report describes a rare case of NRH with por-

Intern Med 54: 383-387, 2015 DOI: 10.2169/internalmedicine.54.2461

387

tal hypertension that developed after oxaliplatin administra-

tion in which the patient was later treated for esophageal

varices. When portal hypertension, such as that due to

splenomegaly or the formation of esophageal varices, with-

out liver dysfunction is noted after systemic chemotherapy

with oxaliplatin, physicians should consider the possibility

of NRH with portal hypertension. Because the standard

treatment for NRH has not yet been established, new thera-

peutic strategies must be developed in the near future.

The authors state that they have no Conflict of Interest (COI).

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