Nodular Regenerative Hyperplasia Associated with Idiopathic Thrombocytopenic Purpura in a Young Girl: A Case Report and Review of the Literature

INTRODUCTION Nodular regenerative hyperplasia (NRH) of the liver is a rare benign entity, which has been known by many names in the literature including nodular transformation, noncirrhotic nodulation, and partial nodular transformation (1). It is a benign proliferative process in which the normal hepatic architecture is entirely replaced by diffuse regenerative nodules of hepatocytes (2). Nodular regenerative hyperplasia occurs predominantly in older patients (2) however there are some reports of NRH in children (3-11). A number of systemic diseases and drugs have been reported in association with NRH: myeloproliferative syndromes, lymphoproliferative syndromes, chronic vascular disorders, Felty's syndrome, polyarteritis nodosa, scleroderma, calcinosis cutis, Raynaud's phenomenon, sclerodactyly and telangiectasia, lupus erythematosus, and use of steroids or antineoplastic medication (1). Familial cases have also been described (1). Antiphospholipid syndrome has also been associated with NRH (12). Portal hypertension is an associated finding in up to 50% of cases. NRH is the major cause of noncirrhotic portal hypertension in the Western world and is often associated with esophageal varices and ascites. The most common cause for an acute onset of thrombocytopenia in an otherwise well child is idiopathic (immune) thrombocytopenic purpura (ITP) (13). Circulating antibody-coated platelets are recognized by the Fc receptors of the splenic macrophages, ingested, and destroyed. A preceding history of a viral illness is described in 50-65% of cases of childhood ITP. Virtually every common infectious virus has been described in association with ITP. Ten to 20% of children who present with acute ITP go on to develop chronic ITP. In these cases, a diagnostic evaluation for associated disorders should be performed. The commonest entities are autoimmune diseases such as SLE and chronic infectious disorders such as human immunodeficiency virus. Nonimmune causes of chronic thrombocytopenia such as type 2B von Willebrand disease, X-linked thrombocytopenia, and Wiskott-Aldrich syndrome are infrequently found. We report a case of a young girl who presented with abdominal pain and abnormal liver enzymes, thrombocytopenia, and mild leucopenia without evidence of portal hypertension who was subsequently diagnosed with NRH and ITP. This association has not been previously reported. CASE REPORT A previously healthy eight-year-old girl presented to her pediatrician with abdominal pain of several days duration without fever, vomiting, or diarrhea. Her parents were unrelated healthy Arab Muslims. She has two healthy sisters. There was a negative history of liver disease in the family. She had no history of medication or drug use. On physical examination she looked well, she had a body temperature of 37°C. Abdominal examination revealed no hepatosplenomegaly and no purpura was noted on the skin. Ophthalmologic examination was normal. The rest of the physical examination was normal. Laboratory results over the follow-up period are presented in Table 1. Urine microscopy and cultures as well as stool for cultures and parasites were normal. Hepatitis B surface antigen was negative, antibodies against hepatitis A virus, hepatitis C virus, human immunodeficiency virus, Epstein-Barr virus, Cytomegalovirus, Brucella, endomesial, tissue transglutaminase, gliadin, liver kidney microsomal, smooth muscle, anti nuclear, were all negative.TABLE 1: Laboratory resultsLevels of thyroid hormones, copper (blood and urine), ceruloplasmin, iron, ferritin, alpha-1 antitrypsin, alpha-feto protein, lactate dehydrogenase, creatine phosphokinase, and C-reactive protein were normal. Antinuclear antibody, C3, C4, antiphospholipid, cardiolipin were negative. Lupus anticoagulant was slightly elevated (dilute Russell Viper Venom Time assay), 1.49 (normal values up to 1.3), and normal using Activated Partial Thromboplastin Time assay. Antiplatelet antibodies (platelet specific, flow cytometry) were positive for IgM and IgG and negative for IgA. Coombs test was negative. Abdominal-ultrasound with Doppler was normal showing a normal liver with a normally aged spleen. Portal vein dilatation and ascites were not demonstrated. Liver scintigraphy was normal. Gastroscopy showed no evidence for esophageal or gastric varices. Due to a continuing thrombocytopenia, the bone marrow was examined and was consistent with idiopathic thrombocytopenic purpura. No evidence for myeloproliferative disease was found (Fig. 1).FIG. 1: Bone marrow with active hematopoiesis. All three series represented. Some micromegakaryocytes are seen. (hematoxylin and eosin; magnification 400).She received intravenous immune globulins treatment which resulted only in slight elevation of the platelets number. Therefore, an open liver biopsy was performed, and was consistent with NRH (Fig. 2). Blood counts and liver enzymes were found to be normal for the other family members. Our patient has been followed up for two years. She has developed no signs of hepatosplenomegaly or a purpuric rash. She performs as an active healthy child and grows well. Her relevant laboratory studies are shown in Table 1.FIG. 2: A surgical liver biopsy showing exaggerated nodular pattern of the liver. Note the portal tracts with their relation to the patent central veins. Neither bridging nor collagen fibrosis was found. 2a: hematoxylin and eosin; magnification 25. 2b: Reticulin stain; magnification 25.DISCUSSION The etiology of NRH is not fully understood, there are two theories regarding its pathogenesis. The vascular hypothesis postulates that the basic pathologic lesion leading to NRH is obliteration or thrombus in the portal venous system (2,14). The reduced blood flow results in atrophy in the central areas (zone III), which are most vulnerable to ischemia. The central atrophy is compensated by proliferation of the hepatocytes from the portal region which form regenerative nodules. The histologic findings in NRH support this sequence of events. Most of the hepatocyte regeneration is in the portal region, and the central area is atrophied and compressed by the regenerating nodules (2). The portal venous system also reveals abnormalities in NRH patients. Findings of phlebosclerosis of the portal radicles and portal venule obliteration have been reported in patients with NRH (14,15). Not all investigators, however, have confirmed these findings (16). A possible explanation for these abnormalities in the hepatic vessels in NRH is that many of the conditions associated with NRH are known to cause vasculitis or nonvasculitic thrombosis. The second theory is that NRH is a primary generalized proliferative disorder of the liver. Some investigators claim that NRH is a premalignant condition which may progress to hepatocyte dysplasia and hepatocellular carcinoma. Liver cell dysplasia is a common finding in NRH and has been noted in between 20% to 42% of cases (16,17). Nzeako et al. (17) demonstrated that 23 of 342 patients without cirrhosis who had hepatocellular carcinoma also had NRH. They found that 73.9% of their patients with NRH and hepatocellular carcinoma had liver cell dysplasia. This rate was significantly higher than that in controls. The origin of portal hypertension in this condition may be related to the compression of the intrahepatic portal radicles by the regenerating nodules or due to the thrombosis of portal veins and venules (2). The clinical presentation of patients with NRH can vary. In many patients, the associated rheumatologic or lymphoproliferative condition dominates the clinical picture, and NRH is an incidental finding. The clinical findings and laboratory tests are variable and must be interpreted leaving in mind the possibility of primary systemic illness. Liver function tests are usually normal or slightly elevated (2). Stromeyer and Ishak reported a less than two-fold elevation of serum aspartate aminotransferase in 11 of 14 patients, an elevation of alkaline phosphatase of less than 2.5 the normal levels in 10 of 15 patients, and a serum bilirubin elevation of less than 2 mg/dL in 6 of 14 cases (2,16). These results are similar to our patient's values. The physical findings also vary in patients with NRH. The most common findings are splenomegaly and hepatomegaly. The radiologic features of NRH are relatively nonspecific and are not always demonstrated as in our case (18,19). On ultrasound evaluation the nodules are isoechoic. The computed tomography scan shows nodules which are nonenhancing and hypodense. The nodules of NRH may be confused with the regenerative nodules of cirrhosis on either computed tomography scan or ultrasound imaging (18,19). There are only a few reports on the magnetic resonance imaging findings of NRH. Lesions are described as isointense to normal liver on T2-weighted images and contain foci of high signal intensity compatible with hemorrhage on T1-weighted scans (20). Low-power microscopic examination of NRH reveals nodules of regenerating hepatocytes separated by atrophic parenchyma. Regeneration is more pronounced in the portal areas with centrilobular atrophy. Curvilinear compression of the central veins by the regenerating nodules may be seen with a reticulin stain. Unlike cirrhosis, there is no increase in fibrous tissue or bands of fibrous scar between the nodules. The histologic findings of NRH may not be detected by a needle biopsy of the liver (2). NRH is uncommon in children. It has been demonstrated in 4.5% of a large series of 716 pediatric liver tumors and was only 2.1% of liver tumors from birth to two years of age (8). From the age 5 to 20 years, it is the 4th most common liver tumor in children after hepatocellular carcinoma, focal nodular hyperplasia, and undifferentiated embryonal sarcoma. Table 2 presents the clinical features of pediatric cases with NRH. The largest series in children was reported by Moran et al. (6). They described 16 pediatric patients with this disorder. The patients, 10 girls and six boys, were between the ages of seven months and 13 years, with a median age of six years. Nine presented with hepatomegaly or splenomegaly with and without signs of portal hypertension. A history of anticonvulsant drug therapy was obtained in four patients. Associated conditions in the remaining three cases were Donohue's syndrome, disseminated intravascular coagulation, and angiomyolipoma of the kidney. Five patients had an intra-abdominal tumor. Two of these patients had thrombocytopenia, one associated with retroperitoneal mass, and the other was associated with abdominal tumor and disseminated intravascular coagulation. Another patient had pancytopenia. Follow up was available for eight patients, six patients died of causes unrelated to the nodular hyperplasia. Two patients were asymptomatic when last seen five and 18 years after the initial diagnosis of nodular hyperplasia.TABLE 2: Clinical features of children with NRH of the liverOther pediatric reports have been associated with congenital heart disease (9,10), Krabbe disease (5), Still's disease (21), chronic inflammation (7), sacrococcygeal teratoma (22), autoimmune disorder (3) and multiple organ malformation in fetuses (4). Unlike the other pediatric cases in the literature, our patient was asymptomatic (besides the mild abdominal pain on presentation), had no hepatosplenomegaly, and had no signs of portal hypertension or hypersplenism. The presence of antiplatelets antibodies and the bone marrow findings support the diagnosis of ITP. We could not demonstrate any of the primary conditions associated with NRH. It is possible that an autoimmune mechanism is responsible for both disorders including the low white blood cell count. The borderline lupus anticoagulant may suggest this possibility. The management of patients with NRH depends on the clinical presentation. Most patients have no symptoms attributable to NRH. The diagnosis is discovered incidentally during abdominal imaging performed for various reasons. In these patients, the symptoms of the underlying associated disease may predominate, and no further interventions are required other than reassuring the patient. In some instances, however, symptoms may develop. The most common problem is symptomatic portal hypertension, which may present as variceal bleeding requiring recurrent endoscopic therapy or portocaval shunt (2). In conclusion, NRH in pediatric patients is usually associated with primary diseases. This is the first case, to our knowledge, that is presented mainly by abnormal liver tests, mild thrombocytopenia, and leukopenia. It is possible that some of these cases are not diagnosed due to lack of symptoms of the patients and the use of liver needle biopsy for diagnosis. Wedge biopsy should be considered in these circumstances. Follow up of these children is mandated due to possible future complications mainly portal hypertension and possible malignant transformation of a long standing disease. NRH should feature in the differential diagnosis of abnormal liver enzymes in both pediatric and adult patients.