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-yearold 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 chemotherapy. Key words: nodular regenerative hyperplasia (NRH), esophageal varices, oxaliplatin, colon cancer (Intern Med 54: 383-387, 2015) (DOI: 10.2169/internalmedicine.54.2461)


Case Report

Nodular regenerative hyperplasia (NRH) was first described by Steiner in 1959 (1). NRH of the liver is characterized by innumerable small areas of focal regeneration more or less distinctively demarcated by adjacent compressive, 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 hematological diseases, leading to the development of portal hypertension 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 underwent endoscopic injection sclerotherapy for esophageal varices.

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 mellitus (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 inguinal lymph node metastasis of colon cancer three years earlier, she had a history of treatment with FOLFOX4 (containing 5-fluorouracil, oxaliplatin and leucovorin), having received 37 courses of FOLFOX4 for approximately two years. After the treatment, the inguinal lymph node metastasis 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, [email protected]


Intern Med 54: 383-387, 2015

DOI: 10.2169/internalmedicine.54.2461

Table. Laboratory Data on Admission Peripheral Blood White blood cell Red blood cell Hemoglobin Hematocrit Platelet Blood Coagulation Prothrombin time Activated partial thromboplastin time Blood Chemistry C-reactive protein Total protein Serum albumin Aspartate aminotransferase Alanine aminotransferase Alkaline phosphatase Ȗ-glutamyl transpeptidase Lactate dehydrogenase Serum total bilirubin

Blood urea nitrogen Serum creatinine Serum sodium concentration Serum potassium concentration Serum calcium concentration Fasting blood glucose Hemoglobin A1c Immunoreactive insulin

3,600 /ȝL 471× 104/ȝL 12.2 g/dL 32.80% 4 12.7 x10 / ȝL

12.6 sec 33.7 sec

Hepatitis Virus HBs antigen HBc antigen HBs antibody HCV antibody

1.5 mg/dL 6.8 g/dL 4.5 g/dL 18 IU/L 14 IU/L 471 IU/L 24 IU/L 228 IU/L 0.7 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 Oncology 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 enzymatic activities were almost normal [aspartate aminotransferase (AST): 18 IU/L, alanine aminotransferase (ALT): 14 IU/L, alkaline phosphatase (ALP): 471 IU/L, lactate dehydrogenase (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 immunoglobulin levels were normal (IgA: 273 mg/dL, IgG: 1,118 mg/dL and IgM: 220 mg/dL), and the DM and RA were well controlled. The glucose level was 83 mg/dL, the HbA1c level was 4.8% and the C-reactive protein (CRP) level was 1.5

13 mg/dL 0.7 mg/dL 141 mEq/L 4.2 mEq/L 7.4 mg/dL 83 mg/dL 4.8% 126 ȝU/mL

negative negative negative negative

Immunological Investigation Anti-nuclear antibody 4 fold Anti-liver/kidney microsome type 1 37.3 INDEX Immunoglobulin A 273 mg/dL Immunoglobulin M 220 mg/dL Immunoglobulin G 1,118 mg/dL

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 thrombosis 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 architecture 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 trabeculae, 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 experienced 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



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




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 hyperplasia. 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.

piecemeal necrosis, plasma cell infiltration or rosette formation. Therefore, the possibility of AIH was excluded. AntiLKM-1 antibody is associated with thyroid disease, polyarthritis, collagen disease, colon cancer, vitiligo, insulindependent DM, pernicious anemia and autoimmune hemolytic 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 autopsies, 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 insulin level and proposed that hepatotrophic hormones, such as


Intern Med 54: 383-387, 2015

DOI: 10.2169/internalmedicine.54.2461




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.

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 chemotherapy for colon cancer was reported in 2006 (10). Recently, the incidence of NRH following treatment with oxaliplatin-based chemotherapy has increased (11). Among the administered drugs during FOLFOX4 treatment, leucovorin 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 oxaliplatinbased 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 administration of oxaliplatin may induce the development of NRH. Wanless reported that NRH includes both arterial and arteriolar 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 result in the onset of hepatocyte hypoxia with liver dysfunction 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 unregulated 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 induced a circulatory disturbance, thus leading to the development of NRH. It is often difficult to distinguish NRH from focal nodular hyperplasia (FNH), alcoholic regenerative nodules and idiopathic portal hypertension (IPH). FNH lesions display central scarring and thick vessels. Alcoholic regenerative nodules exhibit similar characteristics, but without central scarring, while IPH involves peripheral portal vein stenosis and aberrant vessels. Meanwhile, NRH includes many regenerative nodules, with areas of sinusoidal enlargement, but no fibrotic lesions (15). Recently, the concept of SOS was proposed. 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 revealed many regenerative nodules with sinusoidal enlargement, although no fibrotic lesions, central scarring, peripheral portal vein stenosis or aberrant vessels were detected, supporting the diagnosis of NRH. Treatment for NRH primarily involves eliminating the underlying causative factors; no other standard therapies have been established. The prognosis of NRH is influenced by the development of portal hypertension and its complications (16). Therefore, controlling 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

tal hypertension that developed after oxaliplatin administration 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, without 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 therapeutic strategies must be developed in the near future. The authors state that they have no Conflict of Interest (COI).





References 11. 1. Steiner PE. Nodular regenerative hyperplasia of the liver. Am J Pathol 35: 943-953, 1959. 2. 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 11: 787-797, 1990. 3. Thakeb F, Zakaria MS, Hunter M, et al. A study of the oesophagus by endoscopy and radiology after sclerotherapy. In: Gastrointestinal Endoscopy: An Egyptian view. El-Sona El-Mohamadia, Egypt, 1988: 51. 4. Rubbia-Brandt L, Audard V, Sartoretti P, et al. Severe hepatic sinusoidal obstruction associated with oxaliplatin-based chemotherapy in patients with metastatic colorectal cancer. Ann Oncol 15: 460-466, 2004. 5. Fernandez FG, Ritter J, Goodwin JW, et al. Effect of steatohepatitis associated with irinotecan or oxaliplatin pretreatment on resectability of hepatic colorectal metastases. J Am Coll Surg 200: 845853, 2005. 6. Smith MG, Williams R, Walker G, et al. Hepatic disorders associ-


13. 14.



ated with liver-kidney microsomal antibodies. Br Med J 2: 80-84, 1974. Hornberg JC, Abuaf N, Bernard O, et al. Chronic active hepatitis associated with antiliver/kidney microsome antibody type 1: a second type of “autoimmune” hepatitis. Hepatology 7: 1333-1339, 1987. Manns MP, Johnson EF, Griffin KJ, et al. Major antigen of liver kidney microsomal autoantibodies in idiopathic autoimmune hepatitis is cytochrome P450db1. J Clin Invest 83: 1066-1072, 1989. Thung SN, Gerber MA, Bodenheimer HC Jr. Nodular regenerative hyperplasia of the liver in a patient with diabetes mellitus. Cancer 49: 543-546, 1982. Arotçarena R, Cales V, Berthelemy P, et al. Severe sinusoidal lesions: a serious and overlooked complication of oxaliplatincontaining chemotherapy? Gastroenterol Clin Biol 30: 1313-1316, 2006. Wicherts DA, de Haas RJ, Sebagh M, et al. Regenerative nodular hyperplasia of the liver related to chemotherapy: impact on outcome of liver surgery for colorectal metastases. Ann Surg Oncol 18: 659-669, 2011. Ortiz Morales CM, Arraiza Sarasa M, BenitoB oillos A, et al. Direct embolization of stomal varices in portal hypertension after the treatment of liver metastases. Radiologia 52: 556-559, 2010. DeLeve LD. Hepatic microvasculature in liver injury. Semin Liver Dis 27: 390-400, 2007. Ribero D, Wang H, Donadon M, et al. Bevacizumab improves pathologic response and protects against hepatic injury in patients treated with oxaliplatin-based chemotherapy for colorectal liver metastases. Cancer 15: 2761-2767, 2007. Kondo F, Nagao T, Sato T, et al. Etiological analysis of focal nodular hyperplasia of the liver, with emphasis on similar abnormal vasculatures to nodular regenerative hyperplasia and idiopathic portal hypertension. Pathol Res Pract 194: 487-495, 1998. Hartleb M, Gutkowski K, Milkiewicz P. Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension. World J Gastroenterol 17: 1400-1409, 2011.

Ⓒ 2015 The Japanese Society of Internal Medicine


Development of nodular regenerative hyperplasia (NRH) with portal hypertension following the administration of oxaliplatin for the recurrence of colon cancer.

Nodular regenerative hyperplasia (NRH) is associated with autoimmune and hematologic diseases and may lead to portal hypertension. We herein report a ...
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