Nodular Regenerative Hyperplasia Research Articles

Idiopathic noncirrhotic portal hypertension: current perspectives.

The term idiopathic noncirrhotic portal hypertension (INCPH) has been recently proposed to replace terms, such as hepatoportal sclerosis, idiopathic portal hypertension, incomplete septal cirrhosis, and nodular regenerative hyperplasia, used to describe patients with a hepatic presinusoidal cause of portal hypertension of unknown etiology, characterized by features of portal hypertension (esophageal varices, nonmalignant ascites, porto-venous collaterals), splenomegaly, patent portal, and hepatic veins and no clinical and histological signs of cirrhosis. Physicians should learn to look for this condition in a number of clinical settings, including cryptogenic cirrhosis, a disease known to be associated with INCPH, drug administration, and even chronic alterations in liver function tests. Once INCPH is clinically suspected, liver histology becomes mandatory for the correct diagnosis. However, pathologists should be familiar with the histological features of INCPH, especially in cases in which histology is not only requested to exclude liver cirrhosis.

Spleen Histologic Appearance in Common Variable Immunodeficiency: Analysis of 17 Cases.

Histologic and phenotypic analyses of splenectomy samples from 17 patients with common variable immunodeficiency (CVID) showed the following nonspecific, evocative, white-pulp lesions: white-pulp hyperplasia (WPH) with reactive follicles, giant follicles (GFs), marginal zone hyperplasia, periarteriolar T-zone hyperplasia (PATH) and/or granulomas, which enabled us to discern 2 groups: the first (n=6) composed of WPH with reactive follicles without granulomas, and the second (n=9) characterized by the presence of granulomas with or without WPH. All specimens were Epstein-Barr virus negative by in situ hybridization. Molecular analyses revealed a polyclonal immunoglobulin heavy chain gene (IGH) rearrangement (n=12). WPH-only patients were mostly female individuals and younger at CVID onset, diagnosis, and splenectomy, but their interval between the first symptom and diagnosis was longer; they had more associated infectious events, autoimmune disease, pulmonary complications, and liver regenerative nodular hyperplasia; their IgG, IgA, and IgM concentrations were also higher. Granuloma-group patients were mostly male individuals; were older at CVID onset, diagnosis, and splenectomy; had disseminated granulomatous disease, but infectious events, autoimmune disease, pulmonary complications, and liver regenerative nodular hyperplasia were less common; their immunoglobulin concentrations were lower. Histologic comparisons between the WPH-only and granuloma groups showed more intense WPH and more intense marginal zone hyperplasia and fewer GFs in the former versus more developed PATH and more common GFs in the latter. The results of this novel comparative study of the histologic patterns of 17 CVID patients' evocative splenic lesions suggested different biological and clinical profiles.

Combined hepatocellular‐cholangiocarcinoma in a patient with Abernethy malformation and tetralogy of Fallot: A case report

Abernethy malformation is a rare congenital anomaly of the portal vein where the portal blood bypasses the liver. We report the first case of a patient with Abernethy malformation and tetralogy of Fallot associated with nodular regenerative hyperplasia and focal nodular hyperplasia (FNH), which finally evolved to a giant hepatocellular-cholangiocarcinoma (HCC-CC) of the liver, successfully resected. (Hepatology 2016;64:1800-1802).

PTH-079 6-Thioguanine as An Alternative Therapy in Inflammatory Bowel Disease? - Experience in A London District General Hospital

<h3>Introduction</h3> Conventional thiopurines (Azathioprine/6 Mercaptopurine) remain the cornerstone of maintaining remission in steroid-dependent inflammatory bowel disease (IBD). Despite the well-documented efficacy of these drugs, more than 50% of patients discontinue treatment due to adverse events or therapy resistance. Over the past decade, there has been renewed interest in the use of 6 thioguanine (TG), an agent historically used in haematological malignancy. With a shorter metabolic pathway, TG possesses a favourable side effect profile and it’s use as an alternative thiopurine in IBD is growing. We report our experience in tolerability, safety and efficacy of TG use in a London District General Hospital. <h3>Methods</h3> A retrospective review of electronic patient records including clinic letters, blood tests and endoscopic findings were carried out on patients commenced on TG between 2012 and 2015. Data was collected on patient demographics, indication and duration of therapy, response rates and reasons for treatment failure. <h3>Results</h3> A total of 28 patients received TG 20 mg once daily and median treatment duration was 14 months (range 1–40). Therapy was equally distributed amongst males and females (14:14), and mean age was 44 years (range 19–67). 14 (50%) patients had Ulcerative colitis (UC), 13 (46%) Crohn’s disease (CD) and 1 (4%) Indeterminate colitis. 24 patients (86%) received TG due to adverse reactions to conventional thiopurines vs. 3 patients (11%) who were non-responders. Treatment with TG resulted in clinical remission in 86% (19/22) patients at 6 months and 75% (12/16) at 12 months. In total, 6 patients (21%) discontinued TG – 4 failed treatment (2 continued alternative medical therapy and 2 had surgery) and 2 suffered adverse events (headaches and confusion). Tolerability and efficacy rates were similar in both UC and CD groups. All patients underwent blood monitoring and no abnormalities in liver function tests were detected. Of those who underwent MRI liver there was no evidence of nodular regenerative hyperplasia. <h3>Conclusion</h3> TG was well tolerated with comparable remission rates to conventional thiopurine therapy. We advocate the use of TG therapy in selected cases where conventional thiopurine therapy has failed or resulted in adverse reactions. Larger prospective trials are required to further evaluate the efficacy and safety of TG, with a view to potentially incorporate it’s use into clinical guidelines. <h3>Disclosure of Interest</h3> None Declared

Afectación hepática en enfermedades sistémicas de patogenia inmunológica

IntroductionLiver involvement in patients with autoimmune disease is not unusual. Clinical manifestationsSubclinical alterations in liver function tests (mild hypertransaminasemia and cholestasis), are the most frequent forms of presentation. Cirrhosis and fulminant hepatitis are infrequent in this group of diseases. The presence of Budd-Chiari syndrome and nodular regenerative hyperplasia are remarkable, and related to hepatic vein and small intrahepatic arteries thrombosis, respectively. HistopathologyLiver biopsy is not specific and may reveal a variety of subclinical diseases, such as viral hepatitis, steatosis and drug toxicity. TreatmentThere is no specific treatment for these alterations and the management should be directed toward the underlying disease.

Congenital Extrahepatic Portosystemic Shunt (Abernethy Malformation Type Ib) with Associated Hepatocellular Carcinoma: Case report and Literature Review

Abernethy malformation, also termed congenital portosystemic shunt and congenital absence of portal vein (CAPV) is the result of malformation of the splanchnic venous system. Congenital portosystemic shunts are divided into extra-and intrahepatic shunts. Two shunts have been defined: type I is characterized by the complete diversion of portal blood into the vena cava with an associated congenital absence of the portal vein. Type II is defined by an intact but diverted portal vein through a side-to-side, extrahepatic connection to the vena cava. The clinical manifestations of Abernethy malformation are diverse with a typical presentation consisting of hypoxia and hepto-pulmonary syndrome. Histologically, focal nodular hyperplasia, nodular regenerative hyperplasia, liver adenoma, hepatoblastoma, and hepatocellular carcinoma have all been reported. Herein we report a case of Abernethy malformation, type Ib, in a 12 month old male who was found to have a small hepatocellular carcinoma at the time of explant. The immunohistochemical characteristics in relation to the genetic aspects are discussed. To our knowledge, this is the first reported case of hepatocellular carcinoma developing in a patient who is under the age of 5 years old with Abernethy Malformation.

Changes in portal vein flow mean velocity after glucagon application measured by magnetic resonance imaging flowmetry indicates presence of severe sinusoidal injury in patients with colorectal liver metastases

Aims: Non-invasive methods like aspartate aminotransferase to platelets ratio index (APRI) score or spleen volume changes were proposed to identify patients with sinusoidal injury after preoperative chemotherapies for colorectal liver metastases. Magnetic resonance imaging flowmetry can be used to measure changes in portal vein hemodynamics in patients with sinusoidal injury. The present study evaluates the changes in portal vein flow mean velocity (VELO) after glucagon application and analyzes their ability to predict severe sinusoidal injury (SSI) in comparison to other methods. Methods: Magnetic resonance imaging flowmetry of portal vein was estimated in 28 fasting patients and repeated five minutes after 0.5 mg glucagon injection the day before liver surgery. APRI score was estimated the same day. Spleen volume changes were calculated from segmented spleen volumes on imaging before chemotherapy start and the day before surgery. Resected non-tumorous liver parenchyma was evaluated for sinusoidal injury; parenchymal extinction lesion or nodular regenerative hyperplasia was recognized as SSI. Results: SSI was observed in 6 of 28 patients. Patients with SSI demonstrated higher APRI score 0.65 vs. 0.36, p = 0.028; and non-significant change in spleen volume, 36% vs. 12%, p = 0.764. Percentage of change in VELO five minutes after glucagon in SSI patients was 11% vs. – 3%, p = 0.039. Change in VELO <= – 0.5% predicted SSI with 83% sensitivity and 73% specificity (cross-validated classification error rate 29%), similarly to APRI score >=0.43 with the same sensitivity and specificity but higher classification error rate 32%. Conclusions: Relative changes of VELO five minutes after glucagon administration showed lowered ability of portal system to react on glucagon stimuli in patients with SSI. Application of glucagon as a stress test of portal vein hemodynamic facilitates magnetic resonance imaging flowmetry ability to predict SSI non-invasively.

Prevalence of significant liver disease in human immunodeficiency virus-infected patients exposed to Didanosine: A cross sectional study.

AIMTo identify significant liver disease [including nodular regenerative hyperplasia (NRH)] in asymptomatic Didanosine (DDI) exposed human immunodeficiency virus (HIV) positive patients.METHODSPatients without known liver disease and with > 6 mo previous DDI use had liver stiffness assessed by transient elastography (TE). Those with alanine transaminase (ALT) above upper limit normal and/or TE > 7.65 kPa underwent ultrasound scan (U/S). Patients with: (1) abnormal U/S; or (2) elevated ALT plus TE > 7.65 kPa; or (3) TE > 9.4 kPa were offered trans-jugular liver biopsy (TJLB) with hepatic venous pressure gradient (HVPG) assessment.RESULTSNinety-nine patients were recruited, median age 50 years (range 31-70), 81% male and 70% men who have sex with men. Ninety-five percent with VL < 50 copies on antiretroviral therapy with median CD4 count 639 IU/L. Median DDI exposure was 3.4 years (range 0.5-14.6). Eighty-one had a valid TE readings (interquartile range/score ratio < 0.3): 71 (88%) < 7.65 kPa, 6 (7%) 7.65-9.4 kPa and 4 (6%) > 9.4 kPa. Seventeen (17%) met criteria for TJLB, of whom 12 accepted. All had HVPG < 6 mmHg. Commonest histological findings were steatosis (n = 6), normal architecture (n = 4) and NRH (n = 2), giving a prevalence of previously undiagnosed NRH of 2% (95%CI: 0.55%, 7.0%).CONCLUSIONA screening strategy based on TE, liver enzymes and U/S scan found a low prevalence of previously undiagnosed NRH in DDI exposed, asymptomatic HIV positive patients. Patients were more likely to have steatosis highlighting the increased risk of multifactorial liver disease in this population.

Trastuzumab emtansine associated nodular regenerative hyperplasia: A case report and review of literature

Abstract Background Trastuzumab emtansine (T-DM1), a novel drug-antibody conjugate, has shown promising activity in HER2-positive breast cancer and is the recommended agent of choice for second line therapy for advanced HER 2-positive breast cancer. Elevations in transaminase levels have been reported in up to 40% of patients treated with T-DM1 on phase I-III clinical studies. More serious hepatotoxicity can also result from this drug-antibody conjugate, but has been infrequently described in the literature. Case Presentation Here we report a 73 year old female with previously untreated metastatic HER 2-positive breast cancer who developed nodular regenerative hyperplasia and noncirrhotic portal hypertension while on treatment with single agent T-DM1. Liver biopsy demonstrated nodular regenerative hyperplasia, bile duct injury, and portal fibrosis. Conclusion A high index of suspicion for liver injury and NRH must be maintained for patients who develop liver test abnormalities and/or signs of portal hypertension during treatment with T-DM1. Abdominal imaging, liver biopsy, and prompt discontinuation of T-DM1 is recommended for patients with signs or symptoms of liver injury.

Clinical Characteristics and Outcomes of Transjugular Intrahepatic Portosystemic Shunt Procedure for Portal Hypertension Secondary to Myeloproliferative Neoplasms

▪Portal hypertension is a common complication of myeloproliferative neoplasms (MPN) and portends a poor prognosis. Arising in 7-18% of MPN patients, portal hypertension develops through several distinct mechanisms, including abdominal vein thrombosis, extramedullary hematopoiesis (EMH), and nodular regenerative hyperplasia (NRH). Similar to cirrhotic patients, MPN-associated portal hypertension presents with refractory ascites, gastrointestinal bleeding, hepatic encephalopathy, and susceptibility to infections. Transjugular intrahepatic portosystemic shunt (TIPS) procedure has been used empirically to treat refractory ascites and variceal bleeding in MPN-related portal hypertension; however, there is limited data in regards to TIPS effectiveness in MPN-associated portal hypertension. To assess the safety and efficacy of TIPS for treatment of portal hypertension in MPN, we performed a retrospective analysis of outcomes of TIPS procedure in patients with MPN in our institution.Using the University of Pennsylvania electronic medical record database, we identified nine patients with MPN who underwent TIPS procedure for treatment of refractory portal hypertension between 2005 and 2015. Patients with portal hypertension from causes other than MPN were excluded from the study. Clinical characteristics and long-term outcomes were analyzed.The mean age at time of TIPS was 47 years (range 30-67 years). Seven of nine patients were female (78%) and all seven carried a diagnosis of polycythemia vera (PV) or post-PV myelofibrosis (PV-MF); both male patients had a diagnosis of primary myelofibrosis (PMF) (Table 1). All nine patients were positive for JAK2V617F mutation, and one patient had a concurrent diagnosis of Philadelphia-chromosome positive CML. The most common etiology of portal hypertension was Budd-Chiari Syndrome (BCS) in six patients (67%), followed by NRH in five patients (56%), and EMH in two patients (22%); one patient had several distinct causes of MPN-related portal hypertension. Indications for TIPS included refractory ascites in five patients (63%), ascites and esophageal varices in three patients (33%), and ascites and hydrothorax in one patient. All patients demonstrated immediate normalization of portal pressures following TIPS without any reported periprocedural complications (Table 2). Additionally, all patients received indefinite anticoagulation (low molecular weight heparin, 3 patients; vitamin K antagonist, 2 patients; fondaparinux, 2 patients). TIPS intervention had 1-year patency rate of 89%. However, one third of patients required subsequent shunt revision at a median interval of 22.3 months (range 10-34 months) due to stent stenosis or thrombosis despite anticoagulation; one patient had radiographic evidence of TIPS dysfunction without clinical symptoms. Of note, all three patients who developed TIPS stenosis/thrombosis had BCS and NRH. The majority of patients (89%) experienced complete resolution of ascites, while the remaining patient had partial improvement in ascites but no longer required routine paracentesis. Grade 1 and 2 hepatic encephalopathy was the most common complication post-TIPS (67%), occurring in half of the patients with BCS and in all three patients with portal hypertension due to EMH. One patient had variceal bleeding in the setting of TIPS thrombosis. All patients were alive 2 years post-TIPS (excluding one patient with recent TIPS; range 2-5 years).Our study represents the first systematic analysis of outcomes of TIPS procedure for management of portal hypertension in MPN using data from a single-institution over a ten-year period. Our results suggest that TIPS procedure can be performed safely in this high-risk population, and can effectively mitigate the clinical consequences of portal hypertension in patients with MPN. However, the prevalence of TIPS complications, particularly of TIPS stenosis/thrombosis and hepatic encephalopathy, remains significant and must be balanced against the desired clinical benefits. Future studies with a larger number of patients are needed to delineate prognostic factors that identify MPN patients most likely to benefit from TIPS. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Indolent cytotoxic T cell lymphoproliferation associated with nodular regenerative hyperplasia: a common liver lesion in the context of common variable immunodeficiency disorder.

Patients with common variable immunodeficiency disorder (CVID) are subject to lymphoproliferative disorders and predisposed to lymphoma. Some patients may also develop liver lesions. The purpose of this study was to define clinical and histopathological features of patients with CVID presenting with liver lesions suspicious of lymphoma. Four CVID cases corresponding to these criteria were retrieved from our files. Liver biopsy specimens were subjected to morphologic, immunophenotypic and molecular analysis. All patients presented with hepatosplenomegaly and two furthermore with lymphadenopathy. The clinical working diagnosis in the four cases was lymphoma. All liver biopsies revealed nodular regenerative hyperplasia (NRH), associated with mild to marked sinusoid lymphocytic infiltrate consisting of "activated" cytotoxic T cells (CD8+, Tia1+, granzyme B+, TCRβF1+, CD56-). EBER was negative in all cases. T cell clonality was found in one of the two interpretable cases. All patients had an indolent course and clinical symptoms regressed with immunoglobulin replacement. This study suggests that indolent proliferation in the liver sinusoid of cytotoxic T cell associated with NRH is a specific liver lesion in the context of CVID. In CVID patients clinically suspected of lymphoma, pathologists should avoid a misdiagnosis of aggressive T cell lymphoma with a risk of over treatment.

Prevalence and clinical significance of nodular regenerative hyperplasia in liver biopsies.

Nodular regenerative hyperplasia (NRH) is a rare histological disorder associated with a wide variety of systemic diseases. We aimed (i) to report the prevalence of NRH in a database of liver biopsies (LBs) and the frequency of portal hypertension (PHT) at diagnosis, and (ii) to investigate whether associated diseases and/or specific histological lesions, including abnormalities of the microvasculature, were related to PHT. Patients with a histological diagnosis of NRH, referred by seven clinical departments, were retrospectively selected. Clinical, biological, radiological, haemodynamic and endoscopic data at diagnosis were recorded. LBs were reassessed for microvascular abnormalities. NRH was diagnosed in 4.4% of LBs (n = 159, male: 52%, mean age: 54). Among patients referred for unexplained liver enzyme abnormalities, 15% had NRH. PHT was present at diagnosis in 45 patients (38%), including 13 with portal thrombosis; 65% of patients had an associated disorder. Obliteration of portal vein branches, observed in the LBs of 17 patients (11%), was significantly associated with PHT (P = 0.02). Periportal angiomatosis, observed in 101 patients (63%), was associated with the absence of PHT (P < 10(-4) ). We suggest that NRH is a frequent histological lesion in the setting of unexplained liver enzyme abnormalities. PHT is present at the time of diagnosis in 1/3 of patients regardless of the presence of associated disease. The frequency of periportal angiomatosis in NRH without obliteration of portal vein branches, and its association with the absence of PHT suggest that obstructive portal venopathy would not represent the most frequent mechanism involved in NRH.

Nutmeg Liver: A Radiographic Manifestation of Non-cirrhotic Portal Hypertension Presenting as Chronic Abdominal Pain

Non-cirrhotic portal hypertension (NCPH) is the presence of portal hypertension in the absence of a cirrhotic liver. Insults to the liver lead to injury to endothelial cells of portal venules causing reactive changes in the liver including nodular regenerative hyperplasia (NRH) ultimately resulting in portal hypertension. The changes in hepatic vasculature lead to hepatic venous congestion and perfusion abnormalities most prominent in the liver periphery manifesting in a nutmeg liver appearance on Computed Tomography (CT) scan. A 36 year-old female with Helicobacter pylori negative gastritis presented to clinic with post prandial epigastric pain despite twice daily dosing of a proton-pump inhibitor. Review of systems was otherwise negative. No use of alcohol, illicit drugs, hepatotoxic medications or herbal supplements. No family history of liver disease. Physical examination and blood work revealed no abnormalities. An upper endoscopy showed no esophageal varices. A gastric emptying study to evaluate for gastroparesis revealed a normal gastric emptying time. A CT scan of the abdomen and pelvis displayed a diffusely heterogeneous appearance with a mottled attenuation most pronounced in the sub capsular region of the liver. Limited enhancement was seen of the hepatic veins. The findings were consistent with congestive hepatopathy and described as a nutmeg liver. An abdominal ultrasound ruled out veno-occlusive disease. Subsequently the patient developed a minimal elevation in her aminotransaminases. A needle liver biopsy was pursued showing herniated portal vein structures with inflammation, sinusoidal dilatation, portal fibrosis, thickened hepatic arteriole walls, and the presence of a megakaryocyte suggestive of extra medullary hematopoiesis (see images 1 and 2). No hepatitis or infiltrative disorder seen. These finding were most consistent with NRH and concomitant obliterative portal venopathy (OPV). Both entities are precursors for NCPH. A coagulopathy work-up was unrevealing and the patient was negative for the human immunodeficiency virus. Repeat CT scan and ultrasound of the liver have since shown resolution of all changes. To date the patient has no manifestations or complications of portal hypertension and is under close monitoring. The incidence of NCPH varies worldwide and its diagnosis is subtle. The majority of cases do not present with clinical symptoms of portal hypertension or even abnormal aminotransaminases on serological studies. Perfusion abnormalities most prominent in the liver periphery on CT scan is a key finding to indicate to physicians that a more in depth work-up is necessary. Ultimately, a timely liver biopsy is needed for definitive diagnosis. The pathognomonic CT findings lead to a more prompt diagnosis and consequently early management of the complications of portal hypertension.Figure 1Figure 2

Obliterative Portal Venopathy Masquerading Large Bile Duct Obstruction in a Patient on Oral Contraceptive Pills

Introduction: Oral contraceptives pills (OCP) are generally safe but can cause wide range of side effects. We report a case of obliterative portal venopathy (OPV) causing large bile duct obstruction picture from OCP use and slow resolution after discontinuation of the medication. Case: A 19-year-old woman with medical history of Down's syndrome and hypothyroidism presented with acute jaundice, pruritus and RUQ abdominal pain. She denied any fever, alcohol use, recent travel, sick contacts, new medications or herbal supplements. Her medications included levothyroxine, fexofenadine and OCP. Physical exam was remarkable for icterus and RUQ tenderness with positive Murphy's sign. Labs showed a total bilirubin of 8.0 with direct bilirubin of 5.1, alk phos of 245, AST of 50, ALT of 100 and lipase of 23. Acute and chronic hepatitis work up was negative for acetaminophen toxicity, viral hepatitis, EBV, CMV and HSV serologies, autoimmune hepatitis, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson disease, hemochromatosis, α1 antitrypsin deficiency, and HIV. Urine toxicology was negative. Ultrasound showed no evidence of cholecystitis, cholelithiasis or choledocholithiasis. There was no intra or extra hepatic biliary obstruction on EUS and MRCP. CT scan was unremarkable. Alk phos progressively increased to 500 and the bilirubin slowly improved. The liver biopsy showed histologic features of large bile duct obstruction, and features suggestive of OPV and nodular regenerative hyperplasia. This was most likely thought to be due to OCP use in the absence of other etiologies. OCP was discontinued and LFT's slowly improved with normalization in 5 months. Discussion: OCPs are currently prescribed to 62 million women of reproductive age in the US. While deemed mostly safe, they can cause hepatic and biliary dysfunction, and a small subset of women develop intrahepatic cholestasis. Liver biopsy shows bland cholestasis without significant inflammation. Obstructive picture with OPV has not been described. A prothrombotic state caused by OCP probably resulted in OPV-induced large duct injury and obstruction picture in the biopsy. This report highlights that OCP can present with OPV and secondary changes such as large duct injury due to their prothrombotic effects. OPV should be considered as a differential diagnosis if the labs and biopsy show findings suggestive of large bile duct obstruction before proceeding with invasive procedures like ERCP.

Hepatopulmonary Syndrome Is a Frequent Cause of Dyspnea in the Short Telomere Disorders

Telomere syndromes have their most common manifestation in idiopathic pulmonary fibrosis and emphysema. The short telomere defect in these patients may manifest systemically as bone marrow failure and liver disease. We sought to understand the causes of dyspnea in telomerase and telomere gene mutation carriers who have no parenchymal lung disease. Clinical and pathologic data were reviewed as part of a Johns Hopkins-based natural history study of short telomere syndromes including dyskeratosis congenita. Hepatopulmonary syndrome (HPS) was diagnosed in nine of 42 cases (21%). Their age at presentation was significantly younger than that of cases initially presenting with pulmonary fibrosis and emphysema (median, 25 years vs 55 years; P < .001). Cases had evidence of intra- and extrapulmonary arteriovascular malformations that caused shunt physiology. Nodular regenerative hyperplasia was the most frequent histopathologic abnormality, and it was seen in the absence of cirrhosis. Dyspnea and portal hypertension were progressive, and the median time to death or liver transplantation was 6 years (range, 4-10 years; n = 6). In cases that underwent liver transplantation, dyspnea and hypoxia improved, but pulmonary fibrosis subsequently developed. This report identifies HPS as a frequent cause of dyspnea in telomerase and telomere gene mutation carriers. While it usually precedes the development of parenchymal lung disease, HPS may also co-occur with pulmonary fibrosis and emphysema. Recognizing this genetic diagnosis is critical for management, especially in the lung and liver transplantation setting.

Chronic liver injury induced by drugs: a systematic review.

To examine the available literature and summarize what is known about chronic drug-induced liver injury. We reviewed PubMed/MEDLINE through March 2015. We developed a MEDLINE search strategy using PubMed medical subject heading terms chronic liver injury, hepatotoxicity, drug-induced liver injury, cirrhosis and chronic liver disease. We reviewed the reference list of included articles to identify articles missed in the database search. Chronic liver injury from drugs is more common than once thought with prevalence as high as 18% based on large national registries. Patients with cholestatic injury, age ≤65years, and a long latency period (>365days) are at increased risk. Of the most common drugs associated with drug-induced liver injury, antibiotics (amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, azithromycin) are most likely to cause chronic injury. The presence of autoantibodies is common with chronic DILI, however, it is not diagnostic nor is it specific to autoimmune-like drug-induced liver injury. Immunosuppressive therapy may be necessary for individual cases of autoimmune-like drug-induced liver injury where cessation of the drug alone does not result in resolution of injury, however, the lowest dose should be used for the shortest duration with careful attention to the development of side effects. The effectiveness of treament of cholestatic liver injury with corticosteroids or ursodiol remains unclear. Cases of drug-induced fatty liver, nodular regenerative hyperplasia and peliosis hepatitis are less common subtypes of chronic drug-induced liver injury that deserve special consideration. A high degree of clinical suspicion is required for the diagnosis of chronic drug-induced liver injury and should be suspected in any patient with liver associated enzyme abnormalities that persist out past 6months of initial presentation. Treatment with drug removal and/or immunosuppressive therapy appears to be effective for the majority of cases. More study into pharmacogenomics and personalized medicine may aid in predicting which patients will go on to develop chronic drug-induced liver injury.

Obliterative portal venopathy without portal hypertension: an underestimated condition

Obliterative portal venopathy without portal hypertension has been described by a single study in a limited number of patients, thus very little is known about this clinical condition. This study aimed to investigate the prevalence of obliterative portal venopathy and its clinical-pathological correlations in patients with cryptogenic chronic liver test abnormalities without clinical signs of portal hypertension. We analysed 482 liver biopsies from adults with non-cirrhotic cryptogenic chronic liver disorders and without any clinical signs of portal hypertension, consecutively enrolled in a 5-year period. Twenty cases of idiopathic non-cirrhotic portal hypertension diagnosed in the same period, were included for comparison. Histological findings were matched with clinical and laboratory features. Obliterative portal venopathy was identified in 94 (19.5%) of 482 subjects and in all 20 cases of idiopathic non-cirrhotic portal hypertension: both groups shared the entire spectrum of histological changes described in the latter condition. The prevalence of incomplete fibrous septa and nodular regenerative hyperplasia was higher in the biopsies of idiopathic non-cirrhotic portal hypertension (P = 0.006 and P = 0.002), a possible hint of a more advanced stage of the disease. The two groups also shared several clinical laboratory features, including a similar liver function test profile, concomitant prothrombotic conditions and extrahepatic autoimmune disorders. Obliterative portal venopathy occurs in a substantial proportion of patients with unexplained chronic abnormal liver function tests without portal hypertension. The clinical-pathological profile of these subjects suggests that they may be in an early (non-symptomatic) stage of idiopathic non-cirrhotic portal hypertension.

Pediatric multifocal liver lesions evaluated by MRI

Objective:The purpose of this study is to present our experience with MRI evaluation of multifocal liver lesions in children and describe the MRI characteristics of these lesions.Patients and Methods:A retrospective review of consecutive MRI exams performed for the evaluation of multiple liver lesions between 1 January 2007 and 31 December 2012 was done to note the number of lesions, the size of the largest lesion, MR signal characteristics, and background liver. Final diagnosis was assigned to each case based on pathology in the available cases and a combination of clinical features, imaging features, and follow-up in the remaining cases.Results:A total of 48 children (22 boys, 26 girls; age between 3 months and 18 years with average age 10.58 years and median age 11 years) were included in the study. Totally 51 lesion diagnoses were seen in 48 children that included 17 focal nodular hyperplasia (FNH), 8 hemangiomas, 7 metastases, 6 regenerative nodules, 3 adenomas, 3 abscesses, and one each of angiomyolipoma, epithelioid hemangioendothelioma, focal fatty infiltration, hepatocellular carcinoma, hepatic infarction, nodular regenerative hyperplasia, and hepatic cyst. Background liver was normal in 33, cirrhotic in 10, fatty in 3, and siderotic in 2 children. Most FNH, hemangiomas, and regenerative nodules showed characteristic MRI features, while metastases were variable in signal pattern.Conclusion:Many commonly seen multifocal liver lesions in children have characteristic MRI features. MRI can help to arrive at reasonable differential diagnoses for multifocal liver lesions in children and guide further investigation and management.

Diagnosing Nodular Regenerative Hyperplasia of the Liver Is Thwarted by Low Interobserver Agreement.

Background and AimsNodular regenerative hyperplasia (NRH) of the liver is associated with several diseases and drugs. Clinical symptoms of NRH may vary from absence of symptoms to full-blown (non-cirrhotic) portal hypertension. However, diagnosing NRH is challenging. The objective of this study was to determine inter- and intraobserver agreement on the histopathologic diagnosis of NRH.MethodsLiver specimens (n=48) previously diagnosed as NRH, were reviewed for the presence of NRH by seven pathologists without prior knowledge of the original diagnosis or clinical background. The majority of the liver specimens were from thiopurine using inflammatory bowel disease patients. Histopathologic features contributing to NRH were also assessed. Criteria for NRH were modified by consensus and subsequently validated. Interobserver agreement was evaluated by using the standard kappa index.ResultsAfter review, definite NRH, inconclusive NRH and no NRH were found in 35% (23-40%), 21% (13-27%) and 44% (38-56%), respectively (median, IQR). The median interobserver agreement for NRH was poor (κ = 0.20, IQR 0.14-0.28). The intraobserver variability on NRH ranged between 14% and 71%. After modification of the criteria and exclusion of biopsies with technical shortcomings, the interobserver agreement on the diagnosis NRH was fair (κ = 0.45).ConclusionsThe interobserver agreement on the histopathologic diagnosis of NRH was poor, even when assessed by well-experienced liver pathologists. Modification of the criteria of NRH based on consensus effort and exclusion of biopsies of poor quality led to a fairly increased interobserver agreement. The main conclusion of this study is that NRH is a clinicopathologic diagnosis that cannot reliably be based on histopathology alone.

WS16.5 Pathological analysis of native liver in cystic fibrosis (CF) with severe portal hypertension reveals a vascular liver disease without cirrhosis

The prevalence of CF related liver disease (CFLD) ranges from 26% to 45%. The pathogenesis is allegedly related to small bile duct obstruction leading to focal biliary cirrhosis and cirrhosis. Portal hypertension (PHT) without hepatocellular insufficiency is the main presentation of CFLD. The aim of this study was to establish the pathologic pattern in CFLD patients with severe PHT. Patients and Methods In 2 CF centers, all consecutive patients who underwent liver transplantation were retrospectively analysed. Results Eight patients (7 males; 14–32 y) were analysed. All presented with severe PHT: esophageal varices more than grade 2 (bleeding in 2 patients), splenomegaly 18–30 cm, collaterals or ascites. None had signs of hepatocellular insufficiency. Liver tests were less than 1.5 times elevated. Macroscopically, all explants (mean weight 1.6 kg) were dysmorphic with left atrophy and irregular macronodular aspect. There was no thrombosis of the large veins and large bile ducts were normal. Microscopically, all explants showed septal fibrosis without cirrhosis (F2 or F3 Metavir Score, n = 4 each). Diffuse obliterative portal venopathy with sinusoidal dilatation and regenerative nodular hyperplasia was observed in all, associated with frequent ductopenia in small portal tracts, without cholestasis or inflammation. Biliary plugs with ductular reaction were scarce, medium or large biliary ducts were normal. Conclusion According to histological examination of the native livers, CFLD with PHT is not related to biliary cirrhosis but responds to vascular damages as observed in idiopathic non-cirrhotic PHT. The mechanism leading to vascular lesion in CF is unknown.