Pediatr Transplantation 2014: 18: E157–E160
© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd
Pediatric Transplantation DOI: 10.1111/petr.12281
Hepatopulmonary syndrome associated with nodular regenerative hyperplasia after liver transplantation in a child Alhosh R, Genyk Y, Alexopoulos S, Thomas D, Zhou S, Yanni G, Kerkar N. Hepatopulmonary syndrome associated with nodular regenerative hyperplasia after liver transplantation in a child.
Rabea Alhosh1, Yuri Genyk2, Sophoclis Alexopoulos2, Daniel Thomas1, Shengmei Zhou3, George Yanni1,4 and Nanda Kerkar1
Abstract: HPS is a signiﬁcant complication of portal hypertension in children with chronic liver disease and is an established indication for LT. It is characterized clinically by the triad of pulmonary vascular dilatation causing hypoxemia in the setting of advanced liver disease. NRH, a cause of non-cirrhotic portal hypertension, is characterized by diﬀuse benign transformation of the hepatic parenchyma into small regenerative nodules with minimal or no ﬁbrosis. Development of NRH and HPS in pediatric LT recipients has not been reported, although occasional cases have been reported in adult LT recipients. In this report, we discuss a case of a three-yr-old male who developed HPS, two yr after LT. Pulmonary and cardiac causes for hypoxemia were ruled out by appropriate investigations including a chest X ray, echocardiogram, cardiac catheterization, and a CT angiographic study. The diagnosis of HPS was conﬁrmed via bubble echocardiogram that demonstrated intrapulmonary shunting. Open liver biopsy revealed marked NRH. The patient underwent liver retransplantation that resulted in complete reversal of his pulmonary symptoms and normal oxygen saturations within three months after LT.
Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Children‘s Hospital Los Angeles/Keck School of Medicine of USC, Los Angeles, CA, USA, 2Division of Hepatobiliary Surgery and Abdominal Organ Transplantation, Department of Surgery, Children‘s Hospital Los Angeles/Keck School of Medicine of USC, Los Angeles, CA, USA, 3Department of Pathology, Children‘s Hospital Los Angeles/Keck School of Medicine of USC, Los Angeles, CA, USA, 4 Loma Linda University Children‘s Hospital (LLUCH), Loma Linda, CA, USA Key words: hepatopulmonary syndrome – nodular regenerative hyperplasia – liver transplantation Rabea Alhosh, 4650 Sunset Blvd, MS # 78, Los Angeles, CA 90027, USA Tel.: +319 631 2079 (cell) Fax: +323 361 3718 E-mail: [email protected]
Accepted for publication 1 April 2014
A three-yr-old Hispanic American male underwent his initial LT at the age of seven months for fulminant liver failure of unknown etiology. He was the result of a full-term pregnancy with no medical concerns after birth. He was not receiving any prescribed medications or any herbal supplements. It was reported that he had a mild systemic illness with low-grade fever, rhinorrhea, and mild cough for few days prior to his presen-
Abbreviations: CVVH, continuous veno-venous hemoﬁltration; ET-1, endothelin-1; FNH, focal nodular hyperplasia; HHV 6, herpes human virus 6; HPS, hepatopulmonary syndrome; LT, liver transplant; NO, nitric oxide; NRH, nodular regenerative hyperplasia; PPH, porto-pulmonary hypertension; RSV, respiratory syncytial virus; TIPS, transjugular intrahepatic portosystemic shunt; TNFa, tumor necrosis factor a.
tation with jaundice at a local hospital. He had clinical and laboratory evidence of acute liver failure and was then transferred to our hospital. He underwent an extensive workup, but no infectious, metabolic, toxic or autoimmune etiology for his acute liver failure was found. He had a liver biopsy shortly after admission that showed severely necrotic liver parenchyma. INR peaked at 3.6, while his ALT was 500 U/L with total bilirubin of 33.8 mg/dL. He was evaluated and listed for liver transplantation. He required ICU admission for CVVH to manage his worsening liver failure and associated encephalopathy (his blood ammonia peaked at 151 lM). Patient underwent living-related LT from his aunt. His explant showed extensive conﬂuent necrosis without evidence of NRH (Fig. 1a,b). His induction at transplant consisted of Thymoglobulin with steroids, and his maintenance immunosuppressant regimen included tacrolimus E157
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Fig. 1. (a) Native liver: The basic architecture is intact; however, the portal tracts are seen closely approximating each other as a result of striking hemorrhagic conﬂuent necrosis (H&E). (b) Native liver: PAS staining shows almost complete loss of the hepatocytes with few left over (purple staining). Original magniﬁcation 910 for (a) and (b). (c) Wedge biopsy: A small regenerative nodule composed of cytologically benign hepatocytes and arranged in irregularly aligned hepatic trabeculae (H&E). (d) Wedge biopsy: Reticulin staining shows the cords within the nodule are two-cell thick cords in contrast with the one-cell thick cords adjacent to the nodule. Original magniﬁcation 910 for (c) and (d).
and prednisone. Within a week after LT, he underwent a needle liver biopsy secondary to elevated transaminases. The histology showed no evidence of rejection. He was subsequently found to have HHV 6 viremia, and his immunosuppression was appropriately decreased resulting in improvement in graft function. He was maintained on tacrolimus and prednisone and did well except for recurrent concerns for pancytopenia that was evaluated by hematology. No evidence of any hematologic malignancy or aplastic anemia was found. The pancytopenia improved with time. At two yr post-transplantation, he was admitted to LLUCH for an upper respiratory tract infection and was found to have RSV bronchiolitis. Following his recovery from his RSV bronchiolitis (documented by negative repeat RSV test), he started suﬀering from increased shortness of breath associated with perioral cyanosis during physical activities. His oxygen saturation was in the low 90s while asleep, and it dropped further to the mid-80s while awake and active. He underwent an extensive multidisciplinary evaluation including cardiology and pulmonary services to assess the etiology of his hypoxia. A plain chest X-ray ﬁlm and an echocardiogram were within normal range for age. Doppler studies showed normal directional ﬂow in the portal vein. A CT angiography showed no evidence of E158
pulmonary arteriovenous malformation or portal vein abnormalities. He had a bubble echocardiogram that revealed a shunt in the late phase (after 3–5 heart beats). He also underwent a cardiac catheterization study that showed intrapulmonic arterio-venous shunting. He had normal pulmonary artery pressures (LPA 16/7 mmHg—mean 12, RPA 18/7 mmHg—mean 13), ruling out pulmonary hypertension and supporting the diagnosis of HPS. Oxygen supplementation was needed mainly while awake. At that time, splenomegaly and thrombocytopenia also were present, consistent with portal hypertension. A needle biopsy was performed and was concerning for NRH. To conﬁrm this ﬁnding, a wedge biopsy was then performed and it clearly showed NRH and focal sinusoidal dilatation and congestion (Fig. 1c,d). His immunosuppression regimen was modiﬁed by switching tacrolimus to sirolimus due to a report of adult patients developed NRH post-LT while receiving tacrolimus (1). Retransplantation was then considered and discussed with the family. PELD exception was submitted to UNOS given the HPS, and the patient was listed for his second LT with a PELD score of 28. The patient then underwent retransplantation using a left lateral segment of a deceased donor. Induction at transplant included methylprednisolone 10 mg/kg, which was tapered gradually per protocol. His maintenance
HPS associated with NRH post-liver transplantation
immunosuppression regimen included tacrolimus, prednisone, and mycophenolate mofetil. The liver explant evaluation showed diﬀuse NRH and early bridging ﬁbrosis with no evidence of cellular rejection or malignancy. The size and the distribution of these nodules were typical for NRH. The patient suﬀered postoperatively from signiﬁcant hypoxia. NO inhalation treatment was started while he was ventilated postoperatively and allowed weaning oﬀ the ventilator with signiﬁcant improvement in his oxygenation. NO was weaned oﬀ within 10 days post-transplant, but patient continued to require supplemental oxygen via nasal cannula. His postoperative course was also complicated by elevated transaminases that led to a liver biopsy to rule out rejection. The biopsy was negative for rejection and showed no evidence of viral hepatitis or NRH. Patient was then discharged home after adjusting his immunosuppression regimen and achieving stable graft function. Oxygen saturation monitor was provided for home monitoring. Close follow-up in the clinic was arranged. At his third clinic visit (around eight wk post-retransplant), he had stable liver graft function. It was also clear that his HPS had improved and his parents reported normal oxygen saturation levels on pulse oximetry most of the time even when the patient was awake and active. He was completely weaned oﬀ oxygen at 12 wk post-retransplantation. Discussion
This report describes the unusual development of HPS after LT in a little boy who was found to have NRH in his explant. HPS is an established and well-known complication of portal hypertension in children and adults. While it has been described in adults post-LT, HPS is extremely unusual in pediatric LT recipients, with just one report (2). The development of HPS after LT in association with NRH in children has not been reported to the best of our knowledge. Two types of pulmonary syndromes are noted in patients with liver disease and have been associated with the presence of portal hypertension, HPS, and PPH. HPS is a signiﬁcant complication of portal hypertension and occurs in 10–30% of cirrhotic patients (3). It is clinically manifested by oxygen desaturation due to intrapulmonic right-to-left shunting. No deﬁnite etiology has been identiﬁed, but many authors have proposed the role of vasoactive substances in the hyperdynamic state, especially NO, TNFa, and ET-1 (4).
The diagnosis of HPS is made by conﬁrming the presence of intrapulmonary right-to-left shunting. Bubble echocardiogram is the study of choice. Saline containing micro-air bubbles is usually injected in a peripheral intravenous access. The rapid detection of these bubbles in the left atrium conﬁrms the intrapulmonary shunting (in the absence of intracardiac shunting). Another diagnostic tool is a radioactive lung perfusion scan using macro-aggregated albumin. Although less sensitive, it gives quantiﬁcation of the degree of shunting (3). The principle of both tests is that either micro-bubbles or albumin aggregates can pass through dilated pulmonary vessels. HPS increases the mortality signiﬁcantly in chronic liver disease. Screening for HPS by measurement of peripheral oxygen saturations in supine and upright positions is an eﬀective tool. LT is the current standard treatment for HPS (5). Medical therapies have been investigated and mainly targeted NO, ET-1, and TNFa pathways. So far, the results of these experimental treatments have been disappointing, although they have occasionally worked (5). The role of TIPS remains unproven (6). NRH is a relatively rare condition characterized by a widespread transformation of the hepatic parenchyma into benign small regenerative nodules that can lead to the development of non-cirrhotic portal hypertension (7). NRH may develop in many autoimmune (e.g., SLE and celiac disease), hematologic (e.g., lymphomas), infectious (e.g., HIV), neoplastic, or drug-related (e.g., thiopurines) disorders (8). The diﬀerential diagnosis for NRH includes multiple liver cell adenomas (hepatocellular adenomatosis), cirrhotic nodules, and FNH. NRH occurs as multiple small nodules (1 cm in diameter) and have an irregular distribution (9). In the medical literature, very few cases of NRH following LT are reported and mainly in adult patients. There is one report of a pediatric (4.8 yr old) recipient who was diagnosed with NRH 48 months following LT, and he required retransplantation (1). The indication for his initial transplant was biliary atresia. Histologically, cirrhotic nodules are surrounded by thick ﬁbrous bands, while NRH shows no ﬁbrous band or focal mild ﬁbrous tissue. FNH has characteristic central radiating ﬁbrous septa exhibiting a lymphocytic inﬁltrate with numerous small vascular channels. NRH has no ﬁbrous septa at all (9). E159
Alhosh et al. Conclusion
Non-cirrhotic NRH is recognized as an established cause of portal hypertension in pediatric patients. This is the ﬁrst report of HPS associated with NRH in a pediatric LT recipient. Liver retransplantation has been curative for HPS in the subject of this report. Authors’ contributions Kerkar N and Genyk Y initiated the writing of the case report. Alhosh R wrote the ﬁrst draft and the subsequent revisions. Kerkar N and Thomas D critically reviewed the drafts and provided input for discussion. Genyk Y, Alexopoulox S, and Yanni G critically reviewed the case report. Zhou S provided the histology ﬁgures and critically edited the report from pathology perspective.
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