Brief Communication Acta Haematol 2014;132:49–52 DOI: 10.1159/000356736
Received: July 29, 2013 Accepted: October 8, 2013 Published online: January 15, 2014
Nodular Regenerative Hyperplasia Causing Portal Hypertension in a Patient with Chronic Graft versus Host Disease: Response to Sirolimus Hannah Choe a Ibrahim Aldoss a Preeti Chaudhary a John Donovan b Lydia Petrovic c Vinod Pullarkat a a
Jane Ann Nohl Division of Hematology, b Division of Gastrointestinal and Liver Disease, and c Department of Pathology, Keck School of Medicine, University of Southern California, Los Angeles, Calif., USA
Nodular regenerative hyperplasia (NRH) of the liver is a rare, noncirrhotic liver disease characterized by diffuse replacement of normal hepatic parenchyma by multiple small nodules composed of regenerating hepatocytes with minimal or no fibrosis [1, 2]. In the Western world, it accounts for 14–27% of noncirrhotic portal hypertension (PH) cases . NRH is most commonly seen in association with rheumatologic diseases, exposure to chemotherapy, radiation and immunosuppressive therapy, and prothrombotic conditions including myeloproliferative and lymphoproliferative disorders [4, 5]. In the organ transplantation setting, NRH is mostly associated with solid organ transplantation and has rarely been reported as a complication of allogeneic hematopoietic stem cell transplant (HSCT). We report the development of PH secondary to NRH in a patient with chronic graft versus host disease (cGVHD) 3 years after allogeneic HSCT and review the literature on NRH associated with HSCT. We further demonstrate the rapid resolution of clinical features of PH in this patient after initiation of sirolimus therapy. A 61-year-old man with relapsed mantle cell lymphoma underwent allogeneic HSCT from a matched unrelated donor with reduced-intensity conditioning using fludarabine and melphalan. His posttransplant course © 2014 S. Karger AG, Basel 0001–5792/14/1321–0049$39.50/0 E-Mail [email protected]
was complicated by hypogammaglobulinemia, iron deficiency anemia and cGVHD involving the oral mucosa, the skin and the gastrointestinal tract. Three years after HSCT, the patient presented with new-onset ascites. He had no history of viral hepatitis, excessive alcohol use, hepatic sinusoidal obstruction syndrome (SOS) or GVHD involving the liver. There was no history of jaundice, encephalopathy or gastrointestinal bleeding. Physical examination showed an ill-appearing, wasted man with moderate abdominal distension. No hepatosplenomegaly, peripheral edema or stigmata of chronic liver disease was noticed. Laboratory values are reported in table 1. Viral hepatitis studies were negative. His immunosuppressive regimen at the time of presentation consisted of tacrolimus (1 mg daily) and prednisone (4 mg daily). Abdominal CT scan showed subtle liver surface nodularity with relative enlargement of the lateral left hepatic and caudate lobes and moderate ascites. Ascitic fluid was straw-colored, with a serum-ascites albumin gradient of 0.3, consistent with PH. Esophagoduodenoscopy showed grade II medium-sized esophageal varices and portal hypertensive gastropathy. Biopsies from the stomach and duodenum were negative for GVHD, infiltration or malignancy. A transjugular liver biopsy with hepatic vein pressure measurements was obtained. Normal right atriVinod Pullarkat, MD, MRCP Department of Hematology and Hematopoietic Cell Transplantation City of Hope Medical Center, 1500 East Duarte Road, Building 51A Duarte, CA 91010 (USA) E-Mail vpullarkat @ coh.org
Color version available online
Fig. 1. a NRH. The reticulin stain highlights the vague nodularity
of the liver parenchyma, with only mild focal thickening of the liver cell plates (2–3 cells thick). There is only mild portal fibrosis. Original magnification ×20. b Immunohistochemistry for CD3+
Table 1. Laboratory values
Value (range) Laboratory findings Total bilirubin, mg/dl Alkaline phosphatase, U/l Aspartate aminotransferase, U/l Alanine aminotransferase, U/l Serum total protein, g/dl Serum albumin, g/dl INR Serum-ascites albumin gradient Pressure measurements, mm Hg Wedge hepatic vein pressure Free hepatic vein pressure Corrected sinusoidal pressure Right atrial pressure Portosystemic gradient
0.6 (0.9 – 1.1) 461 (40 – 130) 36 (0 – 40) 32 (0 – 41) 4.5 (6.4 – 8.3) 2.9 (3.5 – 5.2) 0.9 (0.9 – 1.1) 0.3 18 9 9 6 12
al pressure, patent hepatic veins and a mildly elevated portosystemic gradient were reported (table 1). Liver biopsy showed NRH, mild portal fibrosis and a mild intrasinusoidal inflammatory infiltrate. Immunohistochemistry showed that the majority of the inflammatory cells, located intrasinusoidally in the liver parenchyma and within the portal tracts, were CD3+ T cells, with a few CD68+ cells. There was no evidence of light-chain clonal 50
Acta Haematol 2014;132:49–52 DOI: 10.1159/000356736
lymphocytes. The majority of the inflammatory cells are CD3+ T lymphocytes. Most of the lymphocytes were in the liver parenchyma, within sinusoids, and in portal tracts. Original magnification ×20.
restriction or B cell lymphoma (fig. 1). Diuretics were started with modest symptomatic relief but persistent ascites required periodic paracentesis for 4 months. Sirolimus 2 mg daily was added. Within 1 month, the patient’s ascites improved markedly. He required no further paracentesis, and diuretics were successfully tapered. He remains free of ascites at the present time. Liver function abnormalities, not uncommon after allogeneic HSCT, are often due to GVHD, SOS, drug toxicity and viral reactivation. The finding of noncirrhotic intrahepatic PH (NCIPH) following HSCT is, in contrast, extremely rare. Alternatively, NRH may be an underrecognized posttransplant complication that can lead to NCIPH after allogeneic HSCT. Studies evaluating biopsyproven NRH show that only approximately 50% of NRH patients have clinically apparent PH. NRH is characterized by benign nodular transformation of hepatic parenchyma, which requires biopsy for diagnosis. The pathogenesis of NRH is poorly understood but is thought to be incited by an obliterative portal venopathy resulting from endothelial injury or thrombotic occlusion causing hypoperfusion to small portal veins. In turn, this hypoperfusion causes a reactive regeneration in adjacent parenchyma . The regenerative nodules may compress adjacent sinusoids, resulting in sinusoidal PH [7, 8]. On histological examination, there are alternating areas of hyperplastic nodules and congested areas of atrophy. The absence of inflammation and fibroChoe /Aldoss /Chaudhary /Donovan / Petrovic /Pullarkat
sis distinguishes NRH from the regenerative nodules in cirrhotic liver diseases. The pathology also shows a compression of central veins by the regenerative nodules . Reticulin staining can be especially helpful in identifying NRH by defining increased thickness of the liver cell plates . Some studies have implicated T cell-induced autoimmune mechanisms leading to portal vein injury and subsequent portal venopathy . Ziol et al.  reported sinusoidal infiltration with CD8+ cytotoxic T cells in 32% of 44 patients with NRH. The T cells were located mainly in the atrophic areas and were adjacent to endothelial cells which showed evidence of apoptosis . Limited data suggest that NRH is associated with HSCT [5, 8, 12]. Early after HSCT, NRH is most likely due to conditioning regimen toxicities. When NRH is delayed, as in the described case, NRH is most likely a manifestation of cGVHD and, therefore, immune-mediated. T cell-mediated endothelial injury may be the trigger for the development of NRH in patients with cGVHD after HSCT. Since the diagnosis of NRH is only confirmed by histology, this condition may remain undiagnosed in patients with cGVHD without clinical findings indicating liver biopsy. A lack of clinical stigmata, abnormal laboratory findings or imaging results associated with chronic liver disease in a patient with evidence of PH suggests the diagnosis of NRH. Arguably, NRH may have little longterm significance in HSCT patients in whom there are no clinical manifestations. Early after allogeneic HSCT, it is important to distinguish NRH and SOS as they have disparate prognoses. In a retrospective study and review of histology in 103 HSCT patients, 8.8% had SOS and 22.5% had NRH . Unlike SOS, which was found to be associated with busulfan and younger age, NRH was not associated with age, underlying disease type, cytoreductive therapies or GVHD prophylaxis regimens. Eight of 9 SOS patients died, compared to 5 of 23 NRH patients. Each of the SOS-related deaths but none of the NRH-related deaths were attributed to liver disease. The study also points out that NRH is frequently misdiagnosed in this setting, as 5 of 11 patients diagnosed with SOS actually had NRH, and 9 of 9 with ‘possible SOS’ were ultimately diagnosed with NRH. In contrast to NRH, SOS demonstrates centrilobular sinusoidal congestion, central hepatocellular atrophy and/ or necrosis with or without obliteration of the central veins . In another series of 24 NRH patients with symptomatic PH, 4 of the patients had had hematological diseases, 3 of whom had undergone HSCT (for myelofibrosis, chronic myelogenous leukemia and acute myeloid leuke-
mia) . Two of these 3 patients had ascites on presentation . However, neither the timing of presentation in relation to HSCT nor the occurrence of GVHD was reported in this study. In another study of allogeneic (n = 11) and autologous (n = 5) bone marrow transplant recipients with liver abnormalities evaluated with color Doppler ultrasound and biopsy 3–10 months after HSCT, only 1 patient was diagnosed with NRH 9 months after allogeneic HSCT, suggesting that NRH is rare soon after HSCT . Pezullo et al.  described a patient with NRH in association with cGVHD. This patient had features of SOS immediately after HSCT and did not have PH when NRH was diagnosed . Immunosuppressants of the thiopurine class have been implicated in the pathogenesis of NRH. However, as they are rarely used in HSCT, they are more unlikely to be an etiologic factor in stem cell transplant patients than in solid organ recipients. Our patient was on tacrolimus, which has not been implicated as a cause of NRH. We added sirolimus (rapamycin) to the immunosuppressive regimen based on its known antiproliferative effects and, in particular, an inhibitory effect on liver regeneration . By inhibiting mTOR signaling, sirolimus has been shown to inhibit liver regeneration after mouse hepatectomy . Sirolimus has also been shown to decrease hepatocyte proliferation after living donor liver transplantation . These effects might explain the clinical improvements noted in this case after sirolimus introduction. Diuretic therapy alone would not explain the ultimate resolution of ascites in this case, which occurred only after addition of sirolimus. Due to the critical role of regenerative nodules in the pathophysiology of NRH, sirolimus requires further evaluation as a potential therapy. In conclusion, NRH should be considered in the differential diagnosis of NCIPH in allogeneic HSCT recipients. Given the association of NRH with autoimmune disorders, this pathology may be an unrecognized manifestation of cGVHD. Due to its inhibitory effects on hepatocyte proliferation and liver regeneration, sirolimus may have a role in the management of NRH.
Nodular Regenerative Hyperplasia in Chronic GVHD
Acta Haematol 2014;132:49–52 DOI: 10.1159/000356736
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