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1
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McCollum KJ, LeClair BF, Chen W, Shi C, Wegermann K, Pendse AA. Vascular flow alteration is a dominant pattern of liver pathology in patients with orthotopic lung transplants: a retrospective observational study. Histopathology 2025; 86:1001-1009. [PMID: 39829415 DOI: 10.1111/his.15409] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Revised: 11/20/2024] [Accepted: 12/21/2024] [Indexed: 01/22/2025]
Abstract
AIMS The number of orthotopic lung transplants (OLT) has skyrocketed since the 1960s, generating an ever-increasing cohort of post-OLT patients. Many challenges exist in the post-OLT timeframe, including donor graft dysfunction, infection, malignancy, and immunosuppression-related conditions. A rather elusive topic in the posttransplant setting remains the impact of the underlying disease process and donor lungs on other organ systems and the complications arising from the complex physiologic interactions. The liver represents a vital organ often impacted in many ways by the lung transplant procedure. Also, there is a higher likelihood of adverse outcomes in OLT recipients who have significant liver pathology. Yet little is known about the morphologic changes in liver after patients have received an OLT. In this study we retrospectively reviewed liver pathology cases obtained after the patient received an OLT. METHODS AND RESULTS Histology was reviewed by three pathologists and evaluated with a standardized checklist format. In our cohort, we found morphologic features of hepatic injury in the form of vascular outflow obstruction, nodular regenerative hyperplasia, portal vessel changes, and steatosis/steatohepatitis, but there was a striking absence of advanced fibrosis in our cohort. CONCLUSION Here we present the first comprehensive account of morphologic changes in livers of post-OLT patients. We believe that this information will aid clinical decision-making during monitoring of hepatic function and fibrosis in patients with OLT and other complex pulmonary diagnoses.
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Affiliation(s)
- Kasey J McCollum
- Department of Pathology, Duke University Health System, Durham, North Carolina, USA
| | | | - Wei Chen
- Department of Pathology, Duke University Health System, Durham, North Carolina, USA
| | - Chanjuan Shi
- Department of Pathology, Duke University Health System, Durham, North Carolina, USA
| | - Kara Wegermann
- Department of Pathology, Duke University Health System, Durham, North Carolina, USA
| | - Avani A Pendse
- Department of Pathology, Duke University Health System, Durham, North Carolina, USA
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2
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Shui Y, Geng Y, Naini BV, Wang HL. Nodular Regenerative Hyperplasia Is a Frequent Finding in Explanted Livers of Patients With Maple Syrup Urine Disease. Pediatr Dev Pathol 2025:10935266251333007. [PMID: 40243087 DOI: 10.1177/10935266251333007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/18/2025]
Abstract
BACKGROUND Maple syrup urine disease (MSUD) is an autosomal recessive inherited disorder characterized by deficiency of branched-chain α-keto acid dehydrogenase complex. The affected patients can experience severe metabolic intoxication and encephalopathy in the first few years of life. Liver transplantation is an effective long-term treatment. There has been a lack of histologic description of explanted livers from MSUD patients in the literature. METHODS A search of the medical record system was performed for cases carrying a diagnosis of MSUD between January 2003 and May 2024. Eight patients who underwent liver transplantation were identified. Their explanted livers were evaluated and their medical records were extensively reviewed. RESULTS The weights of explanted livers were within normal range for patients' age. Histologic examination demonstrated features of nodular regenerative hyperplasia (NRH) in 5 (62.5%) liver explants. Other histologic findings included minimal to mild lymphocytic portal inflammation seen in 6 cases and mild steatosis in 2 cases. A detailed review of clinical histories revealed no signs of portal hypertension or specific underlying conditions conducive to NRH development. CONCLUSION NRH is a frequent histologic finding in explanted livers from MSUD patients, although the underlying etiopathogenesis and clinical implication remain to be elucidated.
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Affiliation(s)
- Yuan Shui
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Yipeng Geng
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Bita V Naini
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
| | - Hanlin L Wang
- Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
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Li P, Schiano TD, Thung SN, Ward SC, Fiel MI. Shared Features of Obliterative Portal Venopathy, Normal Liver, and Chronic Liver Disease: A Histologic and Morphometric Analysis. Mod Pathol 2025; 38:100739. [PMID: 39986468 DOI: 10.1016/j.modpat.2025.100739] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 01/27/2025] [Accepted: 02/06/2025] [Indexed: 02/24/2025]
Abstract
Obliterative portal venopathy (OPV) is a cause of noncirrhotic portal hypertension, and its diagnosis is challenging, as the features are heterogeneous, subtle, and may be mistaken as "normal." We sought to compare OPV cases (n = 72; 326 total portal tracts [PT]) with 2 control groups: control group 1 comprised of normal liver (n = 40; 192 PTs) and control group 2 comprised of liver biopsies with chronic liver disease with OPV features (n = 40; 200 PTs). Morphometry was applied to determine the overall PT area and the luminal area of dystrophic portal veins (PVs). The frequency of absent native PVs was determined. Using trichrome-stained slides, approximately 5 PTs were randomly selected for morphometry utilizing Philips IntelliSite Pathology Solution 3.3. Clinical data were extracted from electronic health records. Of the 326 PTs in the OPV cases, phlebosclerosis was found in 31.6%, densely fibrotic PTs in 12.7%, dystrophic PVs in 31.4%, and absent native PVs in 44.5%. When comparing the OPV group with control group 1, dystrophic PVs, absent native PVs, phlebosclerosis, fibrotic PTs, greater luminal area of dystrophic PV, and a higher ratio of dystrophic PV area to PT area were more frequently found in the OPV group. No significant difference in overall PT area was found. When comparing control group 2 with OPV cases, densely fibrotic PTs were more frequent when compared with OPV cases. This study shows that absent native PVs are the most frequent feature in OPV. Other features that are less frequent but still significantly different from normal liver include dystrophic PVs, greater luminal area of dystrophic PVs, phlebosclerosis, and PT fibrosis. Except for densely fibrotic PTs in control group 2, all other features showed similar frequency as OPV. Pathologists should be aware that OPV features may be present in liver biopsies from both normal and chronic liver diseases.
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Affiliation(s)
- Peizi Li
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Thomas D Schiano
- Division of Liver Diseases, Recanati/Miller Transplantation Institute, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Swan N Thung
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Stephen C Ward
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York
| | - M Isabel Fiel
- Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, New York.
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Bihari C, Dhariwal S, Shasthry SM, Rastogi A, Sharma MK, Sarin SK. Dissociation in hepatic vein pressure gradient, liver stiffness measurement and complications in histological subtypes of porto-sinusoidal vascular disease. J Clin Pathol 2025; 78:169-176. [PMID: 38242555 DOI: 10.1136/jcp-2023-209321] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Accepted: 01/08/2024] [Indexed: 01/21/2024]
Abstract
BACKGROUND AND AIMS Portosinusoidal vascular disease (PSVD) is a broad term encompassing varied histological patterns with changes in portal tracts and sinusoids without cirrhosis. We aimed to assess whether there is any clinical and pathological difference among the various histological categories of PSVD. PATIENTS AND METHODS This study included liver biopsy cases classified as PSVD (2020-2022). Clinical and laboratory parameters were obtained from the electronic records. PSVD cases were histologically categorised as obliterative portal venopathy (OPV), OPV with fibrosis (OPV-F), incomplete septal cirrhosis (ISC), nodular regenerative hyperplasia (NRH), mega sinusoids with fibrosis (MSF) and unclassified. Follow-up complications were recorded. RESULTS PSVD categories were OPV (45 (26%)), OPV-F (37 (21.4%)), ISC (20 (11.6%)), NRH (19 (11%)), MSF (19 (11%)) and unclassified (33 (19%)). Elevated hepatic venous pressure gradient (HVPG) was noted in OPV-F (10 (IQR: 12-14.7)) and ISC (12 (IQR: 9-14)) mm Hg with higher fibrosis quantity in liver tissue and elevated procollagen III aminoterminal propeptide, which correlated with HVPG. On immunohistochemistry, OPV-F and ISC showed lesser expression of ADAMT13 in liver biopsies (p<0.001). On follow-up, ascites development was more in OPV-F and ISC than in other categories (p=0.001). Higher liver stiffness measurement (LSM) values were recorded in MSF and NRH, compared with other categories, but it did not correlate with fibrosis in liver biopsy. CONCLUSIONS OPV-F and ISC had higher HVPG, fibrosis, and more ascites development on follow-up than the other categories of PSVD, and all are not the same. In contrast, MSF and NRH have spuriously high LSM.
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Affiliation(s)
- Chhagan Bihari
- Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Sneha Dhariwal
- Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | | | - Archana Rastogi
- Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | | | - Shiv Kumar Sarin
- Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
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5
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Bartow BB, Dhall D, Lee G, Garapati M, Patel CR, Al Diffalha S. Nodular regenerative hyperplasia: The role of the CK7 immunohistochemistry pattern of expression in diagnosis. Am J Clin Pathol 2025; 163:196-204. [PMID: 39213447 DOI: 10.1093/ajcp/aqae110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2024] [Accepted: 08/07/2024] [Indexed: 09/04/2024] Open
Abstract
OBJECTIVES Nodular regenerative hyperplasia (NRH) is a rare vascular disorder of the liver. Clinically, patients present with portal hypertension with or without a cholestatic pattern of injury. Histologically, the liver parenchyma is composed of small nodules of hypertrophic hepatocytes surrounded by atrophic hepatocytes without significant fibrosis. Nodular regenerative hyperplasia is a difficult diagnosis on biopsy specimens, but biopsy remains the gold standard for diagnosis. In this retrospective review, cytokeratin 7 (CK7) immunohistochemistry (IHC) was used to aid in the diagnosis and further characterization of NRH and NRH-like changes. METHODS The H&E-stained slides, reticulin, and CK IHC were reviewed for 22 cases. The percentage of hepatocytes staining for CK7 (0%-100%), the location of staining (centrilobular hepatic progenitor cells vs periportal/bile ductular reaction), and the pattern of staining distribution (patchy or diffuse) were recorded for comparison. RESULTS Of the 22 cases, 9 were CK7 positive. Cases of NRH, however, expressed various degrees of CK7 positivity in centrilobular hepatic progenitor cells, unlike NRH-like changes, which were either CK7 negative or CK7 positive in periportal hepatocytes or in areas of bile ductular reaction. CONCLUSIONS In cases with the appropriate clinical history and histology, CK7 immunohistochemistry can be performed to distinguish nodular regenerative hyperplasia (primary) and NRH-like changes (secondary). In difficult cases, CK7 positivity in centrilobular hepatic progenitor cells can help confirm the diagnosis of NRH. These data support NRH as a true entity with a distinct pathophysiology from NRH-like changes.
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Affiliation(s)
- Brooke B Bartow
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, US
| | - Deepti Dhall
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, US
| | - Goo Lee
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, US
| | - Manjula Garapati
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, US
| | - Chirag R Patel
- Laboratory Medicine and Pathology, Mayo Clinic, Phoenix, AZ, US
| | - Sameer Al Diffalha
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, US
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6
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Shukla A, Rockey DC, Kamath PS, Kleiner DE, Singh A, Vaidya A, Koshy A, Goel A, Dökmeci AK, Meena B, Philips CA, Sharma CB, Payawal DA, Kim DJ, Lo GH, Han G, Qureshi H, Wanless IR, Jia J, Sollano JD, Al Mahtab M, Muthiah MD, Sonderup MW, Nahum MS, Merican MIB, Ormeci N, Kawada N, Reddy R, Dhiman RK, Gani R, Hameed SS, Harindranath S, Jafri W, Qi X, Chawla YK, Furuichi Y, Zheng MH, Sarin SK. Non-cirrhotic portal fibrosis/idiopathic portal hypertension: APASL recommendations for diagnosis and management. Hepatol Int 2024; 18:1684-1711. [DOI: https:/doi.org/10.1007/s12072-024-10739-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/28/2024] [Indexed: 04/13/2025]
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Kaze E, Baldin P, Piessevaux H, Dahlqvist G. Nodular Regenerative Hyperplasia: Report of 82 Patients and Systematic Review of Literature. United European Gastroenterol J 2024; 12:1404-1416. [PMID: 39569693 PMCID: PMC11652323 DOI: 10.1002/ueg2.12708] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2024] [Revised: 09/29/2024] [Accepted: 10/11/2024] [Indexed: 11/22/2024] Open
Abstract
BACKGROUND Data about the clinical significance and outcome of patients with nodular regenerative hyperplasia are limited. OBJECTIVE The aim of this study was to describe the clinical and histopathological characteristics of patients with nodular regenerative hyperplasia and compare our findings with the literature. METHODS From January 2015 to March 2021, patients with a diagnosis of nodular regenerative hyperplasia were included. They were extracted from the database of the pathology department of Cliniques universitaires Saint-Luc. Clinical and histological data were retrospectively recorded and complications of portal hypertension and mortality were analyzed. We also performed a systematic review of the literature. RESULTS Eighty-two histology-proven nodular regenerative hyperplasia were included. The mean age at diagnosis was 58 ± 14 years. At least one clinical sign of portal hypertension was present in 37 patients (45%), and liver tissue sampling was performed for 29 of them for evaluation of portal hypertension. Conversely, nodular regenerative hyperplasia was an incidental discovery in 27 patients (33%), mostly after liver resection for metastasis (n = 15) or protocol biopsy in liver-transplanted patients (n = 9). The 5-year liver-related mortality was 5%. The 5-year non-liver-related mortality was 20%. Patients diagnosed by clinical suspicion (n = 55) were compared to patients diagnosed incidentally (n = 27). Patients with an incidental diagnosis had more frequently a condition associated with nodular regenerative hyperplasia than patients diagnosed clinically (93% vs. 66%, p = 0.008) and they developed significantly lower liver-related complications (4% vs. 27%, p = 0.01). A systematic review allowed us to compare our patients with 10 case series in the literature. CONCLUSION The clinical spectrum of patients with nodular regenerative hyperplasia is heterogeneous, including patients with clinical liver manifestations and patients diagnosed incidentally who could remain free of liver-related complications. This suggests that nodular regenerative hyperplasia could be a histological epiphenomenon as well as a clinical entity.
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Affiliation(s)
- Edeline Kaze
- Department of Gastroenterology and HepatologyEurope HospitalsBrusselsBelgium
| | - Pamela Baldin
- Department of PathologyCliniques Universitaires Saint‐LucBrusselsBelgium
| | - Hubert Piessevaux
- Department of Gastroenterology and HepatologyCliniques Universitaires Saint‐LucBrusselsBelgium
| | - Géraldine Dahlqvist
- Department of Gastroenterology and HepatologyCliniques Universitaires Saint‐LucBrusselsBelgium
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8
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Shukla A, Rockey DC, Kamath PS, Kleiner DE, Singh A, Vaidya A, Koshy A, Goel A, Dökmeci AK, Meena B, Philips CA, Sharma CB, Payawal DA, Kim DJ, Lo GH, Han G, Qureshi H, Wanless IR, Jia J, Sollano JD, Al Mahtab M, Muthiah MD, Sonderup MW, Nahum MS, Merican MIB, Ormeci N, Kawada N, Reddy R, Dhiman RK, Gani R, Hameed SS, Harindranath S, Jafri W, Qi X, Chawla YK, Furuichi Y, Zheng MH, Sarin SK. Non-cirrhotic portal fibrosis/idiopathic portal hypertension: APASL recommendations for diagnosis and management. Hepatol Int 2024; 18:1684-1711. [PMID: 39546143 DOI: 10.1007/s12072-024-10739-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 09/28/2024] [Indexed: 11/17/2024]
Abstract
Since the Asian Pacific Association for the Study of the Liver (APASL) published guidelines on non-cirrhotic portal fibrosis/idiopathic portal hypertension in 2007, there has been a surge in new information, especially with the introduction of the term porto-sinusoidal vascular disorder (PSVD). Non-cirrhotic intra-hepatic causes of portal hypertension include disorders with a clearly identifiable etiology, such as schistosomiasis, as well as disorders with an unclear etiology such as non-cirrhotic portal fibrosis (NCPF), also termed idiopathic portal hypertension (IPH). This entity is being increasingly recognized as being associated with systemic disease and drug therapy, especially cancer therapy. An international working group with extensive expertise in portal hypertension was assigned with formulating consensus guidelines to clarify the definition, diagnosis, histological features, natural history, and management of NCPF/IPH, especially in the context of PSVD. The guidelines were prepared based on evidence from existing published literature. Whenever there was paucity of evidence, expert opinion was included after detailed deliberation. The goal of this manuscript, therefore, is to enhance the current understanding and help create global consensus on the issues surrounding NCPF/IPH.
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Affiliation(s)
- Akash Shukla
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Don C Rockey
- Digestive Disease Research Center, Medical University of South Carolina, 96 Jonathan Lucas Street, Suite 803, MSC 623, Charleston, SC, 29425, USA
| | | | | | - Ankita Singh
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Arun Vaidya
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Abraham Koshy
- Department of Gastroenterology, VPS Lakeshore Hospital, Kochi, Kerala, India
| | - Ashish Goel
- Department of Hepatology, CMC, Vellore, India
| | - A Kadir Dökmeci
- Department of Medicine, Ankara University School of Medicine, Ankara, Turkey
| | - Babulal Meena
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India
| | - Cyriac Abby Philips
- Department of Clinical and Translational Hepatology, The Liver Institute, Rajagiri Hospital, Aluva, Kerala, India
| | - Chhagan Bihari Sharma
- Department of Pathology, Institute of Liver and Biliary Sciences, New Delhi, Delhi, India
| | - Diana A Payawal
- Fatima University Medical Center Manila, Manila, Philippines
| | - Dong Joon Kim
- Department of Internal Medicine, Hallym University College of Medicine, Seoul, South Korea
| | - Gin-Ho Lo
- Department of Medical Research, E-Da Hospital, Kaohsiung, School of Medicine for International Students, I-Shou University, 1, Yi-Da Road, Kaohsiung, 824, Taiwan
| | - Guohong Han
- Department of Liver Disease and Digestive Interventional Radiology, National Clinical Research Center for Digestive Diseases and Xijing Hospital of Digestive Diseases, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China
| | | | - Ian R Wanless
- Department of Pathology, Dalhousie University, Halifax, Canada
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, 95 Yongan Road, Beijing, Mainland, China
| | - Jose D Sollano
- Department of Medicine, University of Santo Tomas, Manila, Philippines
| | - Mamun Al Mahtab
- Department of Hepatology, Bangabandhu Sheikh Mujib Medical University, Dhaka, Bangladesh
| | - Mark Dhinesh Muthiah
- Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
- Division of Gastroenterology and Hepatology, Department of Medicine, National University Hospital, Singapore, Singapore
- National University Centre for Organ Transplantation, National University Health System, Singapore, Singapore
| | - Mark W Sonderup
- Division of Hepatology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Mendez Sanchez Nahum
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
| | | | - Necati Ormeci
- İstanbul Health and Technology University, Istanbul, Turkey
| | - Norifumi Kawada
- Department of Hepatology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno-Ku, Osaka, 545-8585, Japan
| | - Rajender Reddy
- Division of Gastroenterology and Hepatology, 2 Dulles, Liver Transplant Office, University of Pennsylvania, 3400 Spruce Street, Philadelphia, PA, 19104, USA
| | - R K Dhiman
- Department of Hepatology, PGIMER, Chandigarh, India
| | - Rino Gani
- Division of Hepatobiliary, Department of Internal Medicine, Faculty of Medicine, Cipto Mangunkusumo Hospital, Universitas Indonesia, Jakarta, Indonesia
| | - Saeed S Hameed
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - Sidharth Harindranath
- Department of Gastroenterology, King Edward Memorial Hospital and Seth Gordhandas Sunderdas Medical College, Mumbai, India
| | - Wasim Jafri
- Department of Medicine, Aga Khan University and Hospital, Stadium Road, Karachi, 74800, Pakistan
| | - Xiaolong Qi
- Center of Portal Hypertension, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nurturing Center of Jiangsu Province for State Laboratory of AI Imaging & Interventional Radiology (Southeast University), Nanjing, China
| | - Yogesh Kumar Chawla
- Department of Hepatology and Gastroenterology, Kalinga Institute of MedicalSciences, KIIT University, Bhubaneshwar, India
| | - Yoshihiro Furuichi
- Department of Clinical Laboratory and Endoscopy, Tokyo Women's Medical University, Adachi Medical Center, Tokyo, Japan
| | - Ming-Hua Zheng
- MAFLD Research Center, Department of Hepatology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China
- Key Laboratory of Diagnosis and Treatment for The Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, 325000, China
| | - Shiv Kumar Sarin
- Department of Hepatology, Institute of Liver and Biliary Sciences, New Delhi, India.
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Hercun J, Asif B, Vittal A, Ahmed A, Gopalakrishna Pillai HK, Bergerson JRE, Holland S, Uzel G, Strober W, Fuss IJ, Koh C, Kleiner DE, Heller T. Development of hepatic fibrosis in common variable immunodeficiency-related porto-sinusoidal vascular disorder. Aliment Pharmacol Ther 2024; 60:888-896. [PMID: 39090843 DOI: 10.1111/apt.18180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2024] [Revised: 03/03/2024] [Accepted: 07/13/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND AND AIMS Liver involvement is an increasingly recognised complication of common variable immunodeficiency (CVID). Nodular regenerative hyperplasia (NRH), a subgroup of porto-sinusoidal vascular disorder, and manifestations of portal hypertension (PH) unrelated to cirrhosis are the most common findings. Nonetheless, the evolution of liver disease over time remains unknown. METHODS Retrospective review of patients followed at the National Institutes of Health with CVID-related liver disease and liver biopsy from 1990 to 2020. Clinical, imaging and histological follow-up were recorded as part of clinical research protocols. RESULTS Forty patients were included, with a median age of 37.5 years at initial biopsy, 73% presenting with clear evidence of NRH, and a median fibrosis stage of 1. At biopsy, median platelet count was 100 × 109/L, spleen size 19.5 cm, hepatic venous pressure gradient 9.5 mmHg and 37.5% of patients had signs of PH. Cumulative incidence of PH was 65% at 5 years. In a subgroup of 16 patients, a follow-up liver biopsy, performed at a median time of 3 years after the index biopsy, revealed an increase in fibrosis by ≥2 stages in 31% of cases and an increase to an overall stage of 2.2 (p = 0.001). No clinical or histological factors were associated with progression of fibrosis. CONCLUSIONS In this CVID cohort, NRH is the most common initial histological finding; however, unexpectedly fibrosis progresses over time in a subgroup of patients. A better understanding of the underlying causal process of liver disease CVID might lead to improved outcomes.
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Affiliation(s)
- Julian Hercun
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Bilal Asif
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Anusha Vittal
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Abdel Ahmed
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Harish Kumar Gopalakrishna Pillai
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - Jenna R E Bergerson
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
| | - Steven Holland
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
| | - Gulbu Uzel
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
| | - Warren Strober
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
| | - Ivan J Fuss
- Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland, USA
| | - Christopher Koh
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
| | - Theo Heller
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland, USA
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10
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Oshima SM, Chen W, Rege A, Barbas AS, Garbarino S. Rapid Development of Post-Liver Transplantation Nodular Regenerative Hyperplasia and Portal Hypertension After Perfusion Pump Use: A Case Series. Transplant Direct 2024; 10:e1688. [PMID: 39076519 PMCID: PMC11286241 DOI: 10.1097/txd.0000000000001688] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2024] [Revised: 05/17/2024] [Accepted: 06/10/2024] [Indexed: 07/31/2024] Open
Affiliation(s)
- Sachiko M. Oshima
- Department of Internal Medicine, Duke University School of Medicine, Durham, NC
| | - Wei Chen
- Department of Pathology, Duke University School of Medicine, Durham, NC
| | - Aparna Rege
- Department of Surgery, Duke University School of Medicine, Durham, NC
| | - Andrew S. Barbas
- Department of Surgery, Duke University School of Medicine, Durham, NC
| | - Stephanie Garbarino
- Division of Gastroenterology, Department of Internal Medicine, Duke University School of Medicine, Durham, NC
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Hirose K, Toshima T, Tobo T, Kai S, Hirakawa M, Higuchi S, Ofuchi T, Hosoda K, Yonemura Y, Hisamatsu Y, Masuda T, Aishima S, Mimori K. A rare case of liver regenerative and non-neoplastic lesion resembling a well-differentiated hepatocellular carcinoma. Surg Case Rep 2024; 10:30. [PMID: 38300348 PMCID: PMC10834926 DOI: 10.1186/s40792-024-01820-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Accepted: 01/11/2024] [Indexed: 02/02/2024] Open
Abstract
BACKGROUND Nodular regenerative hyperplasia (NRH) is a rare disease that presents pathologically as diffuse hepatic nodules without fibrous septa. It is believed to be caused by vasculopathy against a background of various systemic diseases, such as hematologic, autoimmune, and drug-induced diseases, with various symptoms. In spite of the recent imaging advances, various atypical cases of nodular lesions are observed in daily clinical practice. Cases that do not completely meet these criteria are referred to as -like or -similar lesions in clinical situations, making it difficult to understand their pathogenesis. We present a case in which two hepatic nodular lesions were noted and difficult to differentiate from malignancy preoperatively. The lesions were laparoscopically resected and a pathological diagnosis with non-neoplastic liver regenerative nodules resembling NRH was made. CASE PRESENTATION A 49-year-old man with no alcohol or drug intake and no past medical history was identified as having liver tumors on screening examination without any symptoms. Contrast-enhanced computed tomography (CT) showed two hepatic tumors; approximately 2-cm tumors at S7 and S8. Gadolinium-ethoxybenzyl-diethylenetriamine-pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) revealed fat inclusions in their contents. Ethoxybenzyl (EOB) uptake was also observed during the hepatobiliary phase. Based on preoperative examinations, we suspected well-differentiated hepatocellular carcinoma (HCC) and performed laparoscopic S7/8 partial resection for these lesions. Macroscopically, the resected specimens showed a non-cirrhotic yellowish-cut surface containing brownish, ill-defined lesions with irregular borders. Microscopically, these lesions showed zonal necrosis, congestion, and aggregation of hemosiderin-laden macrophages around the central vein. In these areas, the fatty deposition of hepatocytes was lower than that in the surrounding background hepatocytes. Histopathologically, neither neoplastic nor hyperplastic lesions were observed, and he was diagnosed as regenerative hepatic change with centrilobular necrosis. CONCLUSIONS Considering the pathological results, these lesions were thought to be a type of NRH-like lesion with possible hepatic vessel disorder. However, the lesion's cause and classification was difficult to determine. The accumulation of these regenerative changes accompanying fatty liver is needed to clarify the mechanism and its clinical significance.
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Affiliation(s)
- Kosuke Hirose
- Department of Surgery, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan
| | - Takeo Toshima
- Department of Surgery, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan
| | - Taro Tobo
- Department of Pathology, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan
| | - Satohiro Kai
- Department of Radiology, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan
| | - Masakazu Hirakawa
- Department of Radiology, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan
| | - Satoshi Higuchi
- Department of Surgery, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan
| | - Takashi Ofuchi
- Department of Surgery, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan
| | - Kiyotaka Hosoda
- Department of Surgery, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan
| | - Yusuke Yonemura
- Department of Surgery, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan
| | - Yuichi Hisamatsu
- Department of Surgery, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan
| | - Takaaki Masuda
- Department of Surgery, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan
| | - Shinichi Aishima
- Department of Pathology and Microbiology, Saga University, Nabeshima 5-1-1, Saga, 849-8501, Japan
| | - Koshi Mimori
- Department of Surgery, Kyushu University Beppu Hospital, 4546, Shoen, Beppu-Shi, Oita-Ken, 874-0838, Japan.
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12
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Halliday N, Eden N, Somers H, Burke N, Silva H, Brito CGX, Hall A, Quaglia A, Burns SO, Lowe DM, Thorburn D. Common variable immunodeficiency disorder-related liver disease is common and results in portal hypertension and an increased risk of death. Hepatol Commun 2024; 8:e0322. [PMID: 38099861 PMCID: PMC10727572 DOI: 10.1097/hc9.0000000000000322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Accepted: 09/28/2023] [Indexed: 12/18/2023] Open
Abstract
BACKGROUND Common variable immunodeficiency disorder (CVID) manifests with recurrent infections and inflammatory complications, including liver disease. We report the clinical features, natural history, and outcomes of patients with CVID-related liver disease (CVID-rLD) from a tertiary immunology and hepatology center. METHODS Two hundred eighteen patients were identified; CVID-rLD was defined by persistently abnormal liver function tests or evidence of chronic liver disease (CLD) or portal hypertension (PHTN) by radiological or endoscopic investigation, after exclusion of other causes. Patients with CVID-rLD were investigated and managed following a joint pathway between immunology and hepatology services. Data, including clinical parameters, investigations, and outcomes, were retrospectively collected. RESULTS A total of 91/218 (42%) patients had evidence of CVID-rLD, and 40/91 (44%) had PHTN. Patients with CVID-rLD were more likely to have other noninfectious complications of CVID (85/91, 93.4% vs. 75/127, 59.1%, p<0.001) including interstitial lung disease, gut disease, and autoimmune cytopenias. Nodular regenerative hyperplasia (NRH) was identified in 63.8% of liver biopsies, and fibrosis in 95.3%. Liver stiffness measurements (LSMs) were frequently elevated (median 9.95 kPa), and elevated LSM was associated with PHTN. All-cause mortality was higher in those with CVID-rLD (24/91, 26.4% vs. 14/127, 11%, p=0.003), which was the only organ complication associated with mortality (HR 2.24, 1.06-4.74, p=0.04). Factors predicting mortality in CVID-rLD included PHTN, increasing fibrosis, and LSM. CONCLUSIONS Liver disease is a common complication of CVID as part of complex, multi-organ involvement and is associated with high rates of PHTN and an increased hazard of mortality.
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Affiliation(s)
- Neil Halliday
- UCL Institute for Liver and Digestive Health, University College London, London, UK
- Sheila Sherlock liver centre, Royal Free London NHS Foundation Trust, London, UK
| | - Nadia Eden
- UCL Institute for Liver and Digestive Health, University College London, London, UK
- Sheila Sherlock liver centre, Royal Free London NHS Foundation Trust, London, UK
| | - Henry Somers
- UCL Institute for Liver and Digestive Health, University College London, London, UK
- Sheila Sherlock liver centre, Royal Free London NHS Foundation Trust, London, UK
| | - Niall Burke
- UCL Institute for Liver and Digestive Health, University College London, London, UK
- Sheila Sherlock liver centre, Royal Free London NHS Foundation Trust, London, UK
| | - Hiroshi Silva
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Camila GX Brito
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Andrew Hall
- Sheila Sherlock liver centre, Royal Free London NHS Foundation Trust, London, UK
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Alberto Quaglia
- UCL Institute for Liver and Digestive Health, University College London, London, UK
- Department of Cellular Pathology, Royal Free London NHS Foundation Trust, London, UK
| | - Siobhan O. Burns
- Institute of Immunity and Transplantation, University College London, UK
- Department of Immunology, Royal Free London NHS Foundation Trust, London, UK
| | - David M. Lowe
- Institute of Immunity and Transplantation, University College London, UK
- Department of Immunology, Royal Free London NHS Foundation Trust, London, UK
| | - Douglas Thorburn
- UCL Institute for Liver and Digestive Health, University College London, London, UK
- Sheila Sherlock liver centre, Royal Free London NHS Foundation Trust, London, UK
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13
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Kim J, Dwivedi G, Boughton BA, Sharma A, Lee S. Advances in cellular and tissue-based imaging techniques for sarcoid granulomas. Am J Physiol Cell Physiol 2024; 326:C10-C26. [PMID: 37955119 DOI: 10.1152/ajpcell.00507.2023] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2023] [Revised: 11/06/2023] [Accepted: 11/08/2023] [Indexed: 11/14/2023]
Abstract
Sarcoidosis embodies a complex inflammatory disorder spanning multiple systems, with its origin remaining elusive. It manifests as the infiltration of inflammatory cells that coalesce into distinctive noncaseous granulomas within afflicted organs. Unraveling this disease necessitates the utilization of cellular or tissue-based imaging methods to both visualize and characterize the biochemistry of these sarcoid granulomas. Although hematoxylin and eosin stain, standard in routine use alongside cytological stains have found utility in diagnosis within clinical contexts, special stains such as Masson's trichrome, reticulin, methenamine silver, and Ziehl-Neelsen provide additional varied perspectives of sarcoid granuloma imaging. Immunohistochemistry aids in pinpointing specific proteins and gene expressions further characterizing these granulomas. Finally, recent advances in spatial transcriptomics promise to divulge profound insights into their spatial orientation and three-dimensional (3-D) molecular mapping. This review focuses on a range of preexisting imaging methods employed for visualizing sarcoid granulomas at the cellular level while also exploring the potential of the latest cutting-edge approaches like spatial transcriptomics and matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), with the overarching goal of shedding light on the trajectory of sarcoidosis research.
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Affiliation(s)
- Junwoo Kim
- Department of Advanced Clinical and Translational Cardiovascular Imaging, Harry Perkins Institute of Medical Research, Murdoch, Western Australia, Australia
- School of Medicine, The University of Western Australia, Perth, Western Australia, Australia
| | - Girish Dwivedi
- Department of Advanced Clinical and Translational Cardiovascular Imaging, Harry Perkins Institute of Medical Research, Murdoch, Western Australia, Australia
- School of Medicine, The University of Western Australia, Perth, Western Australia, Australia
- Department of Cardiology, Fiona Stanley Hospital, Murdoch, Western Australia, Australia
| | - Berin A Boughton
- Australian National Phenome Centre, Murdoch University, Murdoch, Western Australia, Australia
| | - Ankur Sharma
- Onco-Fetal Ecosystem Laboratory, Harry Perkins Institute of Medical Research, Nedlands, Western Australia, Australia
- Curtin Medical School, Curtin University, Perth, Western Australia, Australia
| | - Silvia Lee
- Department of Advanced Clinical and Translational Cardiovascular Imaging, Harry Perkins Institute of Medical Research, Murdoch, Western Australia, Australia
- School of Medicine, The University of Western Australia, Perth, Western Australia, Australia
- Curtin Medical School, Curtin University, Perth, Western Australia, Australia
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14
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15
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Baumert LS, Shih A, Chung RT. Management of liver disease and portal hypertension in common variable immunodeficiency (CVID). JHEP Rep 2023; 5:100882. [PMID: 37869072 PMCID: PMC10585302 DOI: 10.1016/j.jhepr.2023.100882] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2023] [Revised: 06/30/2023] [Accepted: 07/22/2023] [Indexed: 10/24/2023] Open
Abstract
Patients with common variable immunodeficiency (CVID) frequently develop liver disease and associated complications, which represent an increasingly prevalent unmet medical need. The main hepatic manifestation of CVID is nodular regenerative hyperplasia (NRH), resulting in non-cirrhotic portal hypertension (NCPH). Liver disease is often underdiagnosed, leading to poor outcomes and decreased survival. The increasing numbers of patients with CVID who are diagnosed late with progressive liver disease underscores the importance of appropriate clinical management and treatment of liver complications. At the same time, specific guidelines for the clinical management of CVID-related liver disease are still lacking. Here, we review the epidemiology of CVID-related liver disease, reveal new insights into NRH and NCPH biology and highlight recently uncovered opportunities for NCPH diagnostics in CVID. Finally, we focus on current management of liver disease, portal hypertension and its complications - the key challenge in patients with CVID. Specifically, we review recent data regarding the role of transjugular intrahepatic portosystemic shunt and liver transplantation in clinical management. The role for anticoagulants and immunosuppressants targeting the pathogenesis of NRH will also be discussed. We propose an updated algorithm for the diagnostic work-up and treatment of NCPH in CVID. Finally, we consider future needs and therapeutic opportunities for CVID-related liver disease.
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Affiliation(s)
- Lukas S. Baumert
- Liver Center, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
- Faculty of Medicine, Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Angela Shih
- Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Raymond T. Chung
- Liver Center, Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
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16
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Fiordaliso M, Marincola G, Pala B, Muraro R, Mazzone M, Di Marcantonio MC, Mincione G. A Narrative Review on Non-Cirrohotic Portal Hypertension: Not All Portal Hypertensions Mean Cirrhosis. Diagnostics (Basel) 2023; 13:3263. [PMID: 37892084 PMCID: PMC10606323 DOI: 10.3390/diagnostics13203263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 10/17/2023] [Accepted: 10/18/2023] [Indexed: 10/29/2023] Open
Abstract
Non-cirrhotic portal hypertension (NCPH), also known as idiopathic non-cirrhotic portal hypertension (INCPH) and porto-sinusoidal vascular disorder (PSVD), is a rare disease characterized by intrahepatic portal hypertension (IPH) in the absence of cirrhosis. The precise etiopathogenesis of IPH is an area of ongoing research. NCPH diagnosis is challenging, as there are no specific tests available to confirm the disease, and a high-quality liver biopsy, detailed clinical information, and an expert pathologist are necessary for diagnosis. Currently, the treatment of NCPH relies on the prevention of complications related to portal hypertension, following current guidelines of cirrhotic portal hypertension. No treatment has been studied that aimed to modify the natural history of the disease; however, transjugular intrahepatic porto-systemic shunt (TIPS) placement, shunt and liver transplantation are considerable symptomatic options. In this review, we discuss the heterogeneity of NCPH as well as its etiopathogenesis, clinical presentation and management issues. Starting from the assumption that portal hypertension does not always mean cirrhosis, cooperative studies are probably needed to clarify the issues of etiology and the possible genetic background of this rare disease. This knowledge might lead to better treatment and perhaps better prevention.
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Affiliation(s)
- Michele Fiordaliso
- Department of Medicine and Ageing Sciences, University “G. D’Annunzio” of Chieti–Pescara, Via dei Vestini 29, 66100 Chieti, Italy;
| | - Giuseppe Marincola
- Bariatric and Metabolic Surgery Unit, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, 00168 Rome, Italy;
| | - Barbara Pala
- Division of Cardiology, Department of Clinical and Molecular Medicine, Sant’Andrea Hospital, Sapienza University of Rome, Via di Grottarossa, 1035/1039, 00189 Rome, Italy;
| | - Raffaella Muraro
- Department of Innovative Technologies in Medicine & Dentistry, University “G. D’Annunzio” of Chieti–Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (R.M.); (M.M.); (M.C.D.M.)
| | - Mariangela Mazzone
- Department of Innovative Technologies in Medicine & Dentistry, University “G. D’Annunzio” of Chieti–Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (R.M.); (M.M.); (M.C.D.M.)
| | - Maria Carmela Di Marcantonio
- Department of Innovative Technologies in Medicine & Dentistry, University “G. D’Annunzio” of Chieti–Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (R.M.); (M.M.); (M.C.D.M.)
| | - Gabriella Mincione
- Department of Innovative Technologies in Medicine & Dentistry, University “G. D’Annunzio” of Chieti–Pescara, Via dei Vestini 29, 66100 Chieti, Italy; (R.M.); (M.M.); (M.C.D.M.)
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17
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Numata Y, Sasaki S, Magara K, Takasawa A, Sugawara T, Ohara N, Akutsu N, Hasegawa T, Osanai M, Nakase H. Generalized crystal-storing histiocytosis with noncirrhotic portal hypertension: an autopsy case report. Clin J Gastroenterol 2023; 16:450-456. [PMID: 37014540 DOI: 10.1007/s12328-023-01782-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 03/06/2023] [Indexed: 04/05/2023]
Abstract
Crystal-storing histiocytosis (CSH) is a rare disease associated with the accumulation of histiocytes containing crystalline matter within their cytoplasm. Herein, we present the case of a female patient who was diagnosed with Tolosa-Hunt syndrome at 45 years of age and idiopathic retroperitoneal fibrosis when she was 48 years. She developed portal hypertension (PH), but did not present with cirrhosis; as such, the cause of PH was not identified. Her PH gradually worsened when she was 54 years, and at the age of 60 years, she died from an acute subdural hematoma. Autopsy revealed retroperitoneal fibrosis with severe fibrosis extending around the hepatic veins and into the porta hepatis. Histologically, the retroperitoneal tissue showed a dense infiltrate of eosinophilic histiocytes with crystal structures in the cytoplasm, which was pathologically diagnosed as CSH. Nodular regenerative hyperplasia was observed in the liver parenchyma, whereas cirrhosis was not. In the present case, CSH caused fibrosis, which was believed to be the cause of PH. In addition, we considered that nodular regenerative hyperplasia caused by the altered hepatic blood flow due to treatment of gastric varices contributed to worsening PH. Hence, CSH should be considered as an underlying disease in noncirrhotic portal hypertension.
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Affiliation(s)
- Yasunao Numata
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-Jo Nishi 16-Chome Chuo-Ku, Sapporo, 060-8543, Japan
| | - Shigeru Sasaki
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-Jo Nishi 16-Chome Chuo-Ku, Sapporo, 060-8543, Japan.
| | - Kazufumi Magara
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Akira Takasawa
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Taro Sugawara
- Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Naruki Ohara
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-Jo Nishi 16-Chome Chuo-Ku, Sapporo, 060-8543, Japan
| | - Noriyuki Akutsu
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-Jo Nishi 16-Chome Chuo-Ku, Sapporo, 060-8543, Japan
| | - Tadashi Hasegawa
- Department of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiroshi Nakase
- Department of Gastroenterology and Hepatology, Sapporo Medical University School of Medicine, Minami 1-Jo Nishi 16-Chome Chuo-Ku, Sapporo, 060-8543, Japan
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18
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Yang AH, Sullivan B, Zerbe CS, De Ravin SS, Blakely AM, Quezado MM, Marciano BE, Marko J, Ling A, Kleiner DE, Gallin JI, Malech HL, Holland SM, Heller T. Gastrointestinal and Hepatic Manifestations of Chronic Granulomatous Disease. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY. IN PRACTICE 2023; 11:1401-1416. [PMID: 36646382 DOI: 10.1016/j.jaip.2022.12.039] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 12/02/2022] [Accepted: 12/20/2022] [Indexed: 01/15/2023]
Abstract
Chronic granulomatous disease (CGD) is a rare inborn error of immunity, resulting from a defect in nicotinamide adenine dinucleotide phosphate oxidation and decreased production of phagocyte reactive oxygen species. The main clinical manifestations are recurrent infections and chronic inflammatory disorders. Current approaches to management include antimicrobial prophylaxis and control of inflammatory complications. Hematopoietic stem cell transplantation or gene therapy can provide definitive treatment. Gastrointestinal and hepatic manifestations are common in CGD and include structural changes, dysmotility, CGD-associated inflammatory bowel disease, liver abscesses, and noncirrhotic portal hypertension. The findings can be heterogeneous, and the management is complex in light of the underlying immune dysfunction. This review describes the various clinical findings and the latest studies in management of gastrointestinal and hepatic manifestations in CGD, as well as the management experience at the National Institutes of Health.
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Affiliation(s)
- Alexander H Yang
- Digestive Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md
| | - Brigit Sullivan
- Office of the Director, National Institutes of Health, Bethesda, Md
| | - Christa S Zerbe
- Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Suk See De Ravin
- Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Andrew M Blakely
- Surgical Oncology Program, National Cancer Institute, National Institutes of Health, Bethesda, Md
| | - Martha M Quezado
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Md
| | - Beatriz E Marciano
- Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Jamie Marko
- Department of Radiology, Clinical Center, National Institutes of Health, Bethesda, Md
| | - Alexander Ling
- Department of Radiology, Clinical Center, National Institutes of Health, Bethesda, Md
| | - David E Kleiner
- Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Md
| | - John I Gallin
- Clinical Pathophysiology Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Harry L Malech
- Genetic Immunotherapy Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Steven M Holland
- Immunopathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md
| | - Theo Heller
- Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Md.
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19
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Sharma D, Ben Yakov G, Kapuria D, Viana Rodriguez G, Gewirtz M, Haddad J, Kleiner DE, Koh C, Bergerson JRE, Freeman AF, Heller T. Tip of the iceberg: A comprehensive review of liver disease in Inborn errors of immunity. Hepatology 2022; 76:1845-1861. [PMID: 35466407 DOI: 10.1002/hep.32539] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 03/30/2022] [Accepted: 04/17/2022] [Indexed: 12/08/2022]
Abstract
Inborn errors of immunity (IEIs) consist of numerous rare, inherited defects of the immune system that affect about 500,000 people in the United States. As advancements in diagnosis through genetic testing and treatment with targeted immunotherapy and bone marrow transplant emerge, increasing numbers of patients survive into adulthood posing fresh clinical challenges. A large spectrum of hepatobiliary diseases now present in those with immunodeficiency diseases, leading to morbidity and mortality in this population. Awareness of these hepatobiliary diseases has lagged the improved management of the underlying disorders, leading to missed opportunities to improve clinical outcomes. This review article provides a detailed description of specific liver diseases occurring in various inborn errors of immunity. A generalized approach to diagnosis and management of hepatic complications is provided, and collaboration with hepatologists, immunologists, and pathologists is emphasized as a requirement for optimizing management and outcomes.
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Affiliation(s)
- Disha Sharma
- Department of Internal MedicineMedStar Washington Hospital Center & Georgetown UniversityWashingtonDCUSA.,Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
| | - Gil Ben Yakov
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA.,26744Center for Liver DiseaseSheba Medical CenterTel HaShomerIsrael
| | - Devika Kapuria
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA.,Department of GastroenterologyUniversity of New MexicoAlbuquerqueNew MexicoUSA
| | - Gracia Viana Rodriguez
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
| | - Meital Gewirtz
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
| | - James Haddad
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
| | - David E Kleiner
- 3421Laboratory of PathologyNational Cancer InstituteBethesdaMarylandUSA
| | - Christopher Koh
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
| | - Jenna R E Bergerson
- Laboratory of Clinical Immunology and MicrobiologyNIAID, NIHBethesdaMarylandUSA
| | - Alexandra F Freeman
- Laboratory of Clinical Immunology and MicrobiologyNIAID, NIHBethesdaMarylandUSA
| | - Theo Heller
- Liver Diseases Branch, Translational Hepatology SectionNational Institute of Diabetes and Digestive and Kidney Diseases, NIHBethesdaMarylandUSA
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20
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Lima FMS, Toledo-Barros M, Alves VAF, Duarte MIS, Takakura C, Bernardes-Silva CF, Marinho AKBB, Grecco O, Kalil J, Kokron CM. Liver disease accompanied by enteropathy in common variable immunodeficiency: Common pathophysiological mechanisms. Front Immunol 2022; 13:933463. [PMID: 36341360 PMCID: PMC9632424 DOI: 10.3389/fimmu.2022.933463] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 09/29/2022] [Indexed: 11/16/2022] Open
Abstract
Common variable immunodeficiency (CVID) is one of the inborn errors of immunity that have the greatest clinical impact. Rates of morbidity and mortality are higher in patients with CVID who develop liver disease than in those who do not. The main liver disorder in CVID is nodular regenerative hyperplasia (NRH), the cause of which remains unclear and for which there is as yet no treatment. The etiology of liver disease in CVID is determined by analyzing the liver injury and the associated conditions. The objective of this study was to compare CVID patients with and without liver–spleen axis abnormalities in terms of clinical characteristics, as well as to analyze liver and duodenal biopsies from those with portal hypertension (PH), to elucidate the pathophysiology of liver injury. Patients were divided into three groups: Those with liver disease/PH, those with isolated splenomegaly, and those without liver–spleen axis abnormalities. Clinical and biochemical data were collected. Among 141 CVID patients, 46 (32.6%) had liver disease/PH; 27 (19.1%) had isolated splenomegaly; and 68 (48.2%) had no liver–spleen axis abnormalities. Among the liver disease/PH group, patients, even those with mild or no biochemical changes, had clinical manifestations of PH, mainly splenomegaly, thrombocytopenia, and esophageal varices. Duodenal celiac pattern was found to correlate with PH (p < 0.001). We identified NRH in the livers of all patients with PH (n = 11). Lymphocytic infiltration into the duodenal mucosa also correlated with PH. Electron microscopy of liver biopsy specimens showed varying degrees of lymphocytic infiltration and hepatocyte degeneration, which is a probable mechanism of lymphocyte-mediated cytotoxicity against hepatocytes and enterocytes. In comparison with the CVID patients without PH, those with PH were more likely to have lymphadenopathy (p < 0.001), elevated β2-microglobulin (p < 0.001), low B-lymphocyte counts (p < 0.05), and low natural killer-lymphocyte counts (p < 0.05). In CVID patients, liver disease/PH is common and regular imaging follow-up is necessary. These patients have a distinct immunological phenotype that may predispose to liver and duodenal injury from lymphocyte-mediated cytotoxicity. Further studies could elucidate the cause of this immune-mediated mechanism and its treatment options.
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Affiliation(s)
- Fabiana Mascarenhas Souza Lima
- Division of Clinical Immunology and Allergy, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
- *Correspondence: Fabiana Mascarenhas Souza Lima,
| | - Myrthes Toledo-Barros
- Division of Clinical Immunology and Allergy, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | | | - Maria Irma Seixas Duarte
- Laboratory of the Discipline of Pathology of Transmissible Diseases, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Cleusa Takakura
- Laboratory of the Discipline of Pathology of Transmissible Diseases, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Carlos Felipe Bernardes-Silva
- Department of Gastroenterology, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | | | - Octavio Grecco
- Division of Clinical Immunology and Allergy, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
| | - Jorge Kalil
- Division of Clinical Immunology and Allergy, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
- iii-Institute for Investigation in Immunology, Instituto Nacional de Ciência e Tecnologia (INCT), Sao Paulo, Brazil
| | - Cristina Maria Kokron
- Division of Clinical Immunology and Allergy, Hospital das Clinicas HCFMUSP, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo, Brazil
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21
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Angiosarcoma in Long-Standing Nodular Regenerative Hyperplasia. ACG Case Rep J 2022; 9:e00863. [PMID: 36277737 PMCID: PMC9584196 DOI: 10.14309/crj.0000000000000863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2022] [Accepted: 08/04/2022] [Indexed: 01/24/2023] Open
Abstract
Nodular regenerative hyperplasia (NRH) is an uncommon chronic liver disease associated with noncirrhotic portal hypertension. A 29-year-old man with X-linked agammaglobulinemia and NRH complicated by noncirrhotic portal hypertension was followed. Laboratory test results showed pancytopenia and elevated transaminases. Magnetic resonance imaging showed innumerable hepatic lesions. Liver biopsy showed angiosarcoma (hepatic angiosarcoma). He was not a candidate for medical or surgical intervention because of extensive disease and died. Liver histology at autopsy showed infiltrating foci of angiosarcoma. This report extends the literature on a link between malignancy and NRH.
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22
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Tan YB, Teh JGX, Gwee YY, Ng YK. A Review and Case Discussion on a Rare Cause of Non-cirrhotic Portal Hypertension. Cureus 2022; 14:e30252. [DOI: 10.7759/cureus.30252] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/12/2022] [Indexed: 11/07/2022] Open
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23
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Ozturk NB, Fiel MI, Schiano TD. Identification and clinical significance of nodular regenerative hyperplasia in primary sclerosing cholangitis. JGH Open 2022; 6:607-611. [PMID: 36091322 PMCID: PMC9446399 DOI: 10.1002/jgh3.12795] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 01/27/2022] [Accepted: 07/04/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND AND AIM Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease characterized by inflammation and fibrosis of intrahepatic and extrahepatic bile ducts. PSC is frequently associated with inflammatory bowel disease (IBD). Nodular regenerative hyperplasia (NRH) can occur in IBD with the use or even in the absence of thiopurine treatment. We aimed to study the significance of the presence of NRH and obliterative portal venopathy (OPV), both causes of non-cirrhotic portal hypertension (NCPH), in patients having PSC. METHODS Patients with PSC and concurrent NRH on liver biopsy were identified from the digital pathology database covering the period 2003-2019. Evaluation of liver biopsy and the original diagnoses were confirmed on review based on standard histological features diagnostic for NRH and OPV. Clinical and laboratory data were obtained from electronic medical records. RESULTS Thirty-one patients (21 male, 10 female; median age at biopsy 40.1 years) were included in the study. Twelve (38.7%) patients had OPV in addition to NRH on the liver biopsy. Nineteen (61.2%) patients had IBD including 11 with Crohn's disease (CD), 7 with ulcerative colitis (UC), and 1 with indeterminate colitis. Thirteen (41.9%) patients had evidence of portal hypertension, 10 (32.2%) with esophageal varices, 4 (12.9%) with history of variceal bleeding, 6 (19.3%) with ascites, and 14 (12.9%) with splenomegaly. Eleven (35.4%) patients had a cirrhotic-appearing liver on imaging. Twelve (38.7%) patients had a history of prior or current thiopurine use. CONCLUSIONS The current study suggests that NRH with or without OPV independently occurs in patients having PSC and may lead to NCPH, even in the absence of concurrent IBD and/or thiopurine therapy.
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Affiliation(s)
- Nazli Begum Ozturk
- Division of Liver Diseases and Recanati‐Miller Transplantation InstituteIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Maria Isabel Fiel
- Department of Pathology, Molecular and Cell‐Based MedicineIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Thomas D. Schiano
- Division of Liver Diseases and Recanati‐Miller Transplantation InstituteIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
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24
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Choi SJ, Lee SS, Jung KH, Lee JB, Kang HJ, Park HJ, Choi SH, Kim DW, Jang JK. Noncirrhotic Portal Hypertension after Trastuzumab Emtansine in HER2-positive Breast Cancer as Determined by Deep Learning-measured Spleen Volume at CT. Radiology 2022; 305:606-613. [PMID: 35943338 DOI: 10.1148/radiol.220536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Background Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate approved for use in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Case reports have suggested an association between T-DM1 and portal hypertension. Purpose To evaluate the association of T-DM1 therapy with spleen volume changes and portal hypertension on CT scans and clinical findings compared with lapatinib and capecitabine therapy. Materials and Methods Patients with HER2-positive breast cancer who were administered at least two cycles of T-DM1 or lapatinib and capecitabine (controls) in a tertiary institution from 2001 to 2020 and who underwent CT before initial treatment and at least once during treatment were retrospectively enrolled. Spleen volume changes and the signs of portal hypertension (gastroesophageal varix [GEV], spontaneous portosystemic shunt [SPSS], and ascites) were evaluated at contrast-enhanced CT. Patients were followed until treatment ended or for 2 years after the start of treatment. Spleen volume changes were measured with a deep learning algorithm and evaluated by using a linear mixed model. The incidences of splenomegaly and portal hypertension were compared between the T-DM1 and control groups by using a χ2 test or Fisher exact test. Results The T-DM1 group included 111 patients (mean age, 54 years ± 11 [SD]; 111 women) and the control group included 122 patients (mean age, 50 years ± 9; 121 women). Spleen volume progressively increased with T-DM1 therapy but was constant in the control group (104% ± 5 vs -1% ± 6 at the 33rd treatment cycle, respectively; P < .001). Incidences of splenomegaly (46% [51 of 111] vs 3% [four of 122] of patients; P < .001), GEV (11% [12 of 111] vs 1% [one of 122] of patients; P < .001), and SPSS (27% [30 of 111] vs 1% [one of 122] of patients; P < .001) were higher in the T-DM1 group than in the control group. Conclusion Trastuzumab emtansine therapy was associated with noncirrhotic portal hypertension at CT, with higher incidences of splenomegaly, gastroesophageal varix, and spontaneous portosystemic shunt than those with lapatinib and capecitabine therapy. © RSNA, 2022 Online supplemental material is available for this article.
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Affiliation(s)
- Se Jin Choi
- From the Departments of Radiology and Research Institute of Radiology (S.J.C., S.S.L., H.J.P., S.H.C., D.W.K., J.K.J.), Oncology (K.H.J.), Clinical Epidemiology and Biostatistics (J.B.L.), and Pathology (H.J.K.), University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Seung Soo Lee
- From the Departments of Radiology and Research Institute of Radiology (S.J.C., S.S.L., H.J.P., S.H.C., D.W.K., J.K.J.), Oncology (K.H.J.), Clinical Epidemiology and Biostatistics (J.B.L.), and Pathology (H.J.K.), University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Kyung Hae Jung
- From the Departments of Radiology and Research Institute of Radiology (S.J.C., S.S.L., H.J.P., S.H.C., D.W.K., J.K.J.), Oncology (K.H.J.), Clinical Epidemiology and Biostatistics (J.B.L.), and Pathology (H.J.K.), University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Jung Bok Lee
- From the Departments of Radiology and Research Institute of Radiology (S.J.C., S.S.L., H.J.P., S.H.C., D.W.K., J.K.J.), Oncology (K.H.J.), Clinical Epidemiology and Biostatistics (J.B.L.), and Pathology (H.J.K.), University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Hyo Jeong Kang
- From the Departments of Radiology and Research Institute of Radiology (S.J.C., S.S.L., H.J.P., S.H.C., D.W.K., J.K.J.), Oncology (K.H.J.), Clinical Epidemiology and Biostatistics (J.B.L.), and Pathology (H.J.K.), University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Hyo Jung Park
- From the Departments of Radiology and Research Institute of Radiology (S.J.C., S.S.L., H.J.P., S.H.C., D.W.K., J.K.J.), Oncology (K.H.J.), Clinical Epidemiology and Biostatistics (J.B.L.), and Pathology (H.J.K.), University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Sang Hyun Choi
- From the Departments of Radiology and Research Institute of Radiology (S.J.C., S.S.L., H.J.P., S.H.C., D.W.K., J.K.J.), Oncology (K.H.J.), Clinical Epidemiology and Biostatistics (J.B.L.), and Pathology (H.J.K.), University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Dong Wook Kim
- From the Departments of Radiology and Research Institute of Radiology (S.J.C., S.S.L., H.J.P., S.H.C., D.W.K., J.K.J.), Oncology (K.H.J.), Clinical Epidemiology and Biostatistics (J.B.L.), and Pathology (H.J.K.), University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
| | - Jong Keon Jang
- From the Departments of Radiology and Research Institute of Radiology (S.J.C., S.S.L., H.J.P., S.H.C., D.W.K., J.K.J.), Oncology (K.H.J.), Clinical Epidemiology and Biostatistics (J.B.L.), and Pathology (H.J.K.), University of Ulsan College of Medicine, Asan Medical Center, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Republic of Korea
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25
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Penrice DD, Thakral N, Kezer CA, Lennon R, Moreira RK, Graham RP, Kamath PS, Simonetto DA. Outcomes of idiopathic versus secondary nodular regenerative hyperplasia of the liver: A longitudinal study of 167 cases. Liver Int 2022; 42:1379-1385. [PMID: 35187783 DOI: 10.1111/liv.15202] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 12/11/2021] [Accepted: 12/29/2021] [Indexed: 02/13/2023]
Abstract
BACKGROUND Nodular regenerative hyperplasia (NRH) is a rare condition characterized clinically by the development of non-cirrhotic portal hypertension. NRH is the histopathological result in the liver of various systemic disease processes including autoimmune disorders, haematological malignancies and medications. However, natural history of this condition has been limited to small case series while patient outcomes pertaining to different aetiologies of NRH are largely unknown. METHODS A retrospective cohort of consecutive patients diagnosed with pathology-confirmed NRH at Mayo Clinic between 2002 and 2017 was identified. The histological diagnosis of NRH was determined by expert liver pathologists. Patients with metastatic liver disease, history of liver transplantation or younger than 18 were excluded. Potential aetiologies of NRH were classified as haematological, rheumatological, drug-associated, miscellaneous or idiopathic. Long-term mortality was analysed using Kaplan-Meier estimation and Cox regression models. RESULTS One hundred and sixty-seven consecutive patients with pathology-confirmed NRH were analysed over a 15-year period and followed for a median time of 50 months (1-306 months). The mean age at diagnosis was 53 years. No aetiology or risk factor for NRH was identified in the majority of patients (94, 56.3%), whereas an associated, possibly causal, condition was found in 73 patients (secondary NRH). The most common presenting feature was elevated liver tests (80%), but no significant differences in laboratory tests were seen based on aetiology of NRH. Compared to idiopathic NRH, those with an identified cause had a higher rate of splenomegaly at presentation (54% vs. 27%, p = 0.002). Portal hypertension-related complications at diagnosis were common, with ascites present in one-third of patients. Overall transplant-free survival was 63% at 5 years. Median survival in idiopathic NRH was 9.4 years compared to 7.3 years in secondary NRH. Age, renal function and volume status at presentation were significantly associated with survival; however, MELD score was not. CONCLUSIONS The rates of liver-related complications and mortality in NRH are low, and only a small number of patients ultimately require liver transplantation. Most patients do not have an identified risk factor or aetiology for NRH, and liver-related outcomes do not appear to differ based on associated, possibly causal, conditions.
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Affiliation(s)
- Daniel D Penrice
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Nimish Thakral
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Camille A Kezer
- Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Ryan Lennon
- Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota, USA
| | - Roger K Moreira
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Rondell P Graham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA
| | - Patrick S Kamath
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
| | - Douglas A Simonetto
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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26
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Garrido I, Magalhães A, Lopes J, Macedo G. Trastuzumab Emtansine-Induced Nodular Regenerative Hyperplasia: Is Dose Reduction Enough as a Preventable Measure? Dig Dis 2022; 40:787-792. [PMID: 35078201 DOI: 10.1159/000521933] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 01/12/2022] [Indexed: 02/02/2023]
Abstract
INTRODUCTION Trastuzumab emtansine (T-DM1) is a novel antibody-drug conjugate targeting the human epidermal growth factor receptor 2, used in some recurrent metastatic cancers. It was linked to modest increases in serum aminotransferase elevations and bilirubin. More recently, some cases of noncirrhotic portal hypertension have been described in patients on long-term T-DM1. The underlying liver condition is usually nodular regenerative hyperplasia (NRH) with elements of sinusoidal obstruction. CASE REPORT We report the case of a 52-year-old woman who started T-DM1 therapy for recurrent metastatic lung adenocarcinoma. Although a progressive reduction in lung nodules was noticed, there was a new-onset cytocholestasis and elevation in bilirubin. A reduction in platelet count was also apparent over several months during the T-DM1 therapy. Liver biopsy revealed NRH and so the dose of T-DM1 was reduced. Thereafter, the patient had normalization of liver tests and platelet count. T-DM1 was continued for more than 9 months with no signs of portal hypertension or cancer progression. CONCLUSIONS We presented a rare case of NRH induced by T-DM1 in a patient with lung adenocarcinoma. 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. This is the first report of a successful dose reduction in a patient with NRH induced by T-DM1, suggesting that it is possible to maintain the drug while it is being effective for lung cancer treatment.
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Affiliation(s)
- Isabel Garrido
- Gastroenterology and Hepatology Department, Centro Hospitalar Universitário de São João, Porto, Portugal.,World Gastroenterology Organization (WGO) Porto Training Center, Porto, Portugal
| | - Adriana Magalhães
- Department of Pulmonology, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Joanne Lopes
- Pathology Department, Centro Hospitalar Universitário de São João, Porto, Portugal
| | - Guilherme Macedo
- Gastroenterology and Hepatology Department, Centro Hospitalar Universitário de São João, Porto, Portugal.,World Gastroenterology Organization (WGO) Porto Training Center, Porto, Portugal
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Abstract
INTRODUCTION There is a wide spectrum of noninfectious gastrointestinal pathology, causing considerable morbidity and mortality in CVID, where both etiology and effective therapy are under debate. AREAS COVERED This review will focus on the noninfectious inflammation in the GI tract in CVID patients, covering the both the upper and lower GI tract inflammation, including the liver. The controversy of the CVID enteropathy definition and that of gluten-free diet for celiac-like disease in CVID will be discussed. Furthermore, the review will cover the link between GI inflammation and GI cancer. Finally, the role of gut microbiota, IgA, and genetics and its relationship with CVID enteropathy is scrutinized. The authors reviewed literature from PubMed. EXPERT OPINION The heterogeneity and the unknown mechanism behind CVID enteropathy, and thereby the lack of effective treatment, is one of the key challenges in the field of CVID. Celiac-like disease in CVID is due to immune dysregulation, and a gluten-free diet is therefore not indicated. Gut microbial dysbiosis and mucosal IgA can initiate systemic and local inflammation and is involved in the immune dysregulation in CVID. Considering the heterogeneity of CVID enteropathy, personalized medicine is probably the future for these patients.
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Affiliation(s)
- I M Andersen
- Section of Clinical Immunology and Infectious Diseases, Department of Rheumatology, Dermatology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Norway
| | - S F Jørgensen
- Section of Clinical Immunology and Infectious Diseases, Department of Rheumatology, Dermatology and Infectious Diseases, Oslo University Hospital, Rikshospitalet, Norway.,Research Institute of Internal Medicine, Division of Surgery, Inflammatory Diseases and Transplantation, Oslo University Hospital, Rikshospitalet, Norway
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28
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Nunes-Santos CJ, Koh C, Rai A, Sacco K, Marciano BE, Kleiner DE, Marko J, Bergerson JRE, Stack M, Rivera MM, Constantine G, Strober W, Uzel G, Fuss IJ, Notarangelo LD, Holland SM, Rosenzweig SD, Heller T. Nodular regenerative hyperplasia in X-linked agammaglobulinemia: An underestimated and severe complication. J Allergy Clin Immunol 2022; 149:400-409.e3. [PMID: 34087243 PMCID: PMC8633079 DOI: 10.1016/j.jaci.2021.05.028] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 04/30/2021] [Accepted: 05/14/2021] [Indexed: 01/03/2023]
Abstract
BACKGROUND Late-onset complications in X-linked agammaglobulinemia (XLA) are increasingly recognized. Nodular regenerative hyperplasia (NRH) has been reported in primary immunodeficiency but data in XLA are limited. OBJECTIVES This study sought to describe NRH prevalence, associated features, and impact in patients with XLA. METHODS Medical records of all patients with XLA referred to the National Institutes of Health between October 1994 and June 2019 were reviewed. Liver biopsies were performed when clinically indicated. Patients were stratified into NRH+ or NRH- groups, according to their NRH biopsy status. Fisher exact test and Mann-Whitney test were used for statistical comparisons. RESULTS Records of 21 patients with XLA were reviewed, with a cumulative follow-up of 129 patient-years. Eight patients underwent ≥1 liver biopsy of whom 6 (29% of the National Institutes of Health XLA cohort) were NRH+. The median age at NRH diagnosis was 20 years (range, 17-31). Among patients who had liver biopsies, alkaline phosphatase levels were only increased in patients who were NRH+ (P = .04). Persistently low platelet count (<100,000 per μL for >6 months), mildly to highly elevated hepatic venous pressure gradient and either hepatomegaly and/or splenomegaly were present in all patients who were NRH+. In opposition, persistently low platelet counts were not seen in patients who were NRH-, and hepatosplenomegaly was observed in only 1 patient who was NRH-. Hepatic venous pressure gradient was normal in the only patient tested who was NRH-. All-cause mortality was higher among patients who were NRH+ (5 of 6, 83%) than in the rest of the cohort (1 of 15, 7% among patients who were NRH- and who were classified as unknown; P = .002). CONCLUSIONS NRH is an underreported, frequent, and severe complication in XLA, which is associated with increased morbidity and mortality.
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Affiliation(s)
- CJ Nunes-Santos
- Immunology Service, Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, MD, USA
| | - C Koh
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, Bethesda, MD, USA
| | - A Rai
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, Bethesda, MD, USA
| | - K Sacco
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - BE Marciano
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - DE Kleiner
- Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD, USA
| | - J Marko
- Department of Radiology and Imaging Sciences, Clinical Center, NIH, Bethesda, MD
| | - JRE Bergerson
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - M Stack
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - MM Rivera
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, Bethesda, MD, USA
| | - G Constantine
- National Institute of Allergy and Infectious Diseases Allergy and Immunology Fellowship Program, NIH, Bethesda, Maryland
| | - W Strober
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - G Uzel
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - IJ Fuss
- Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - LD Notarangelo
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - SM Holland
- Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD, USA
| | - SD Rosenzweig
- Immunology Service, Department of Laboratory Medicine, National Institutes of Health (NIH) Clinical Center, Bethesda, MD, USA, corresponding authors Sergio D. Rosenzweig, MD, PhD, ; Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, Building 10, Room 2C306, 10 Center Drive, Bethesda, MD, 20892 and Theo Heller, MD, ; Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, 10 Center Drive, Bethesda, MD 20892
| | - T Heller
- Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, Bethesda, MD, USA, corresponding authors Sergio D. Rosenzweig, MD, PhD, ; Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, Building 10, Room 2C306, 10 Center Drive, Bethesda, MD, 20892 and Theo Heller, MD, ; Translational Hepatology Section, Liver Diseases Branch, National Institute of Diabetes & Digestive & Kidney Diseases, NIH, 10 Center Drive, Bethesda, MD 20892
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Sintusek P, Phewplung T, Sanpavat A, Poovorawan Y. Liver tumors in children with chronic liver diseases. World J Gastrointest Oncol 2021; 13:1680-1695. [PMID: 34853643 PMCID: PMC8603454 DOI: 10.4251/wjgo.v13.i11.1680] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/27/2021] [Accepted: 08/23/2021] [Indexed: 02/06/2023] Open
Abstract
Liver tumors are rare in children, but the incidence may increase in some circumstances and particularly in chronic liver diseases. Most liver tumors consequent to chronic liver diseases are malignant hepatocellular carcinoma. Other liver tumors include hepatoblastoma, focal nodular hyperplasia, adenoma, pseudotumor, and nodular regenerative hyperplasia. Screening of suspected cases is beneficial. Imaging and surrogate markers of alpha-fetoprotein are used initially as noninvasive tools for surveillance. However, liver biopsy for histopathology evaluation might be necessary for patients with inconclusive findings. Once the malignant liver tumor is detected in children with cirrhosis, liver transplantation is currently considered the preferred option and achieves favorable outcomes. Based on the current evidence, this review focuses on liver tumors with underlying chronic liver disease, their epidemiology, pathogenesis, early recognition, and effective management.
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Affiliation(s)
- Palittiya Sintusek
- Thai Pediatric Gastroenterology, Hepatology and Immunology Research Unit, Department of Pediatrics, Division of Gastroenterology, Faculty of Medicine, King Chulalongkorn Memorial Hospital, Chulalongkorn University, Bangkok 10330, Thailand
| | - Teerasak Phewplung
- Department of Radiology, Faculty of Medicine, Chulalongkorn University, King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand
| | - Anapat Sanpavat
- Department of Pathology, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
| | - Yong Poovorawan
- Center of Excellence in Clinical Virology, Chulalongkorn University, Bangkok 10330, Thailand
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Navale P, Gonzalez RS. Mild changes of hepatic nodular regenerative hyperplasia may cause portal hypertension and be visible on reticulin but not hematoxylin and eosin staining. Virchows Arch 2021; 479:1145-1152. [PMID: 34435237 DOI: 10.1007/s00428-021-03195-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 08/16/2021] [Accepted: 08/18/2021] [Indexed: 01/05/2023]
Abstract
Nodular regenerative hyperplasia (NRH) can manifest as alternating parenchymal compression/expansion on hematoxylin and eosin (H&E) staining and as reticulin collapse/nodularity on reticulin staining. Histologic diagnosis can be challenging, especially when there is mild disease and on limited biopsy samples. We reviewed clinical and histologic parameters in a large series of NRH. We identified 60 liver specimens convincingly showing changes of NRH and reviewed them for clinical (age, sex, symptoms, lab values, portal hypertension [PHTN], NRH etiology) and histologic (inflammation, sinusoidal dilation, cholestasis, architectural change, portal vascular abnormalities, degree of changes on reticulin) parameters. The cases came from 28 women and 32 men (median age: 54 years). Most (55, 92%) were biopsies. Thirty patients were symptomatic. Forty-five cases showed mild NRH changes on reticulin; 24 of these (53%) showed them on H&E as well. Fifteen demonstrated well-developed changes on reticulin, which were always seen on H&E as well. Sinusoidal dilation was commonly observed in both of these subgroups (88% overall). Portal vascular abnormalities were seen in 33%. Well-developed NRH was diffuse more often than mild NRH (53% vs. 4%, P < 0.0001). Twenty-nine patients had clinically confirmed or likely PHTN. Of these, 21 showed mild and 8 showed well-developed NRH changes; only 3 had concomitant advanced fibrosis. Chemotherapy was the most frequent known cause of NRH; 30 patients lacked any definite etiology. NRH can be difficult to diagnose on biopsy, particularly since mild changes may be visible on reticulin but not H&E; even these patients can have PHTN. Additionally, NRH is often idiopathic, potentially lowering clinical and pathologic suspicion. Pathologists should have a low threshold for ordering reticulin stains, especially when a patient is known to have PHTN. Sinusoidal dilation, while nonspecific, commonly accompanies NRH.
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Affiliation(s)
- Pooja Navale
- Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO, USA
| | - Raul S Gonzalez
- Department of Pathology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA.
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Yamamoto A, Matsuda H, Hiramatsu K, Tsuji A, Midori Y, Murata Y, Tanaka T, Tohda G, Nosaka T, Takahashi K, Naito T, Ofuji K, Ohtani M, Imamura Y, Nakamoto Y. A case of idiopathic portal hypertension accompanying multiple hepatic nodular regenerative hyperplasia in a patient with systemic sclerosis. Clin J Gastroenterol 2021; 14:820-826. [PMID: 33886104 DOI: 10.1007/s12328-021-01348-z] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 01/16/2021] [Indexed: 11/24/2022]
Abstract
Idiopathic portal hypertension (IPH) is one of the background diseases causing nodular regenerative hyperplasia (NRH). Furthermore, IPH patients accompanied with autoimmune diseases, such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc), are more likely to form NRH in the liver. A 76-year-old woman had been aware of the Raynaud's phenomenon and scleroderma for the past 30 years. In this case, she presented with abdominal fullness, and her imaging analysis revealed ascites and multiple liver nodules. On Gd-EOB-DTPA enhanced magnetic resonance imaging (EOB-MRI), donut-like uptake was observed in the nodules in the hepatobiliary phase. Liver biopsy of a nodule demonstrated that it was composed of hyperplastic hepatocytes without fibrous septa, and dilated sinusoids were observed beside the nodule. Conversely, background liver showed that peripheral portal veins appeared stenotic with dense fibrosis in the portal area. The final diagnosis was that multiple NRH of the liver developed in SSc patient accompanying IPH. This case suggests that NRH may be unexpectedly diagnosed in patients with autoimmune diseases accompanying IPH.
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Affiliation(s)
- Arisa Yamamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Hidetaka Matsuda
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Katsushi Hiramatsu
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Arisa Tsuji
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Yohei Midori
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Yosuke Murata
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Tomoko Tanaka
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Gen Tohda
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Takuto Nosaka
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Kazuto Takahashi
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Tatsushi Naito
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Kazuya Ofuji
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Masahiro Ohtani
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Yoshiaki Imamura
- Department of Pathology, University of Fukui Hospital, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan
| | - Yasunari Nakamoto
- Second Department of Internal Medicine, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka Shimoaizuki, Eiheiji-cho, Yoshida-gun, Fukui, 910-1193, Japan.
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Globig AM, Heeg M, Larsen CS, Ferreira RD, Kindle G, Goldacker S, Strohmeier V, Silva SL, Cunningham-Rundles C, Quinti I, Thimme R, Bettinger D, Schultheiß M, Warnatz K. International multicenter experience of transjugular intrahepatic portosystemic shunt implantation in patients with common variable immunodeficiency. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:2931-2935.e1. [PMID: 33722695 DOI: 10.1016/j.jaip.2021.02.056] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Revised: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 12/18/2022]
Affiliation(s)
- Anna-Maria Globig
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Maximilian Heeg
- Institute for Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | | | - Ruben Duarte Ferreira
- Serviço de Imunoalergologia, Centro Hospitalar Universitário de Lisboa Norte, Lisboa, Portugal
| | - Gerhard Kindle
- Institute for Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sigune Goldacker
- Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Valentina Strohmeier
- Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Susana L Silva
- Serviço de Imunoalergologia, Centro Hospitalar Universitário de Lisboa Norte, Lisboa, Portugal
| | - Charlotte Cunningham-Rundles
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY
| | - Isabella Quinti
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Robert Thimme
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Dominik Bettinger
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Michael Schultheiß
- Department of Medicine II, Gastroenterology, Hepatology, Endocrinology, and Infectious Diseases, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Klaus Warnatz
- Center for Chronic Immunodeficiency, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany; Department of Rheumatology and Clinical Immunology, Medical Center-University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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Jain P, Patel S, Simpson HN, Silver RM, Lewin DN, Campbell RC, Guimaraes M, Silver KC. Nodular Regenerative Hyperplasia of the Liver in Rheumatic Disease: Cases and Review of the Literature. J Investig Med High Impact Case Rep 2021; 9:23247096211044617. [PMID: 34514900 PMCID: PMC8436301 DOI: 10.1177/23247096211044617] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/25/2021] [Accepted: 08/19/2021] [Indexed: 12/05/2022] Open
Abstract
Nodular regenerative hyperplasia (NRH) is a rare disease that is characterized by benign transformation of the hepatic parenchyma into small nodules with little to no fibrosis. Nodular regenerative hyperplasia is a cause of noncirrhotic portal hypertension. Symptoms can range from asymptomatic disease to more serious complications of portal hypertension such as esophageal varices and ascites. Nodular regenerative hyperplasia has been described in association with a variety of different rheumatologic, hematologic, and oncologic diseases, as well as in immune deficiency states and with exposures to certain toxins. Diagnosis is made by histology, and the treatment involves addressing the underlying disease. The first description of this rare disease was actually described in a patient with rheumatoid arthritis, neutropenia, and splenomegaly (Felty's Syndrome). We describe 2 cases of NRH associated with underlying rheumatic disorders, in one of which NRH was actually the presenting feature of the patient's underlying autoimmune condition. Subsequently, we provide a brief review of the literature of NRH in autoimmune disease with respect to epidemiology, cause, clinical manifestations, diagnosis, and treatment.
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Affiliation(s)
| | - Sagar Patel
- Medical University of South Carolina, Charleston, USA
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Wadehra A, Chokshi B, Buechler CR, Singh MM. Rapidly Progressive Acute Liver Failure in Relapsed Multiple Myeloma. Cureus 2020; 12:e12346. [PMID: 33520541 PMCID: PMC7837634 DOI: 10.7759/cureus.12346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Multiple myeloma affects upwards of 30,000 people every year and has significant morbidity and mortality. Common complications of the disease involve lytic bone lesions, hypercalcemia, anemia, and acute renal failure. A rare, yet serious, complication includes acute liver failure secondary to hepatic plasma cell infiltration. While this is reported seldom in living patients, it is found in upwards of 40% of patients incidentally on imaging or during autopsy. Conscientious and meticulous monitoring of liver function tests allows for early detection of liver failure in multiple myeloma; thus, allowing for broader therapeutic options overall.
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Affiliation(s)
- Anshu Wadehra
- Internal Medicine, Wayne State University/Detroit Medical Center, Detroit, USA
| | - Bhavin Chokshi
- Internal Medicine, Wayne State University/Detroit Medical Center, Detroit, USA
| | - Connor R Buechler
- Internal Medicine, Wayne State University/Detroit Medical Center, Detroit, USA
| | - Manmeet M Singh
- Internal Medicine, Wayne State University/Detroit Medical Center, Detroit, USA
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Abstract
This review covers a spectrum of pathologic changes and diseases involving hepatic sinusoids. In the majority of patients, clinical findings are rather uncharacteristic such as hepatomegaly, portal hypertension, or lingering liver failure of unknown origin. In contrast to more common hepatic disorders, characteristic clinical, serological, immunoserological, and radiographical findings are lacking. In these cases, biopsy findings may be crucial to guide treatment decisions. This review covers a variety of hepatic disorders that practicing pathologists may encounter in their clinical routine.
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Affiliation(s)
- Diane Goltz
- Pathologisches Institut Koblenz, Franz-Weis-Str. 13, 56073, Koblenz, Deutschland.
| | - Hans-Peter Fischer
- Institut für Pathologie, Universitätsklinikum Bonn, Sigmund-Freud-Str. 25, 53127, Bonn, Deutschland
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36
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Borisovsky G, Goldstein DA, Eliakim-Raz N, Tamir SR. Transitional Cell Carcinoma and Pseudocirrhosis— A Case Report and Review of the Literature. JOURNAL OF GASTROINTESTINAL AND ABDOMINAL RADIOLOGY 2020. [DOI: 10.1055/s-0040-1713829] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022] Open
Abstract
AbstractPseudocirrhosis is the occurrence of capsular retraction in patients with metastatic liver disease, usually of breast origin. It usually appears in these patients following chemotherapy and may result from shrinkage of the tumor, with scarring and nodular regeneration. In this article, we describe the first case of pseudocirrhosis, following treatment of transitional cell carcinoma metastatic to the liver. Portal vein thrombosis, a rare complication in pseudocirrhosis, was also detected in this patient.
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Affiliation(s)
- Gilad Borisovsky
- Radiology Department, Rabin Medical Center, Petah Tikva, Israel, affliated to the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Daniel A. Goldstein
- Davidoff Cancer Center, Rabin Medical Center, Petah Tikva, Israel, affliated to the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Noa Eliakim-Raz
- Internal Medicine E, Rabin Medical Center, Petah Tikva, Israel, affliated to the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Shlomit R. Tamir
- Radiology Department, Rabin Medical Center, Petah Tikva, Israel, affliated to the Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
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Abstract
Common variable immunodeficiency (CVID) has a heterogenous clinical presentation and can be challenging to diagnose. Distinct histologic changes have been linked with CVID in several organ systems, which can help identify the correct diagnosis. In this study we review a cohort of hepatic CVID biopsies, to better define the spectrum of histologic and biochemical alterations. We reviewed 26 liver biopsies from 24 patients with CVID, obtained at 4 institutions between 2010 and 2019. Histologic slides were examined, and pathologic, biochemical, and clinical features were recorded. A control cohort of 21 patients with nodular regenerative hyperplasia (NRH) but lacking CVID was also examined. Liver function tests were frequently abnormal, especially alkaline phosphatase (median: 193 IU/L) and aspartate transaminase (median: 56 U/L), elevated in 23 and 17 of 25 biopsies, respectively. Fifteen patients had CVID involvement of other organs. Histologic features of primary biliary cholangitis were present in 2 patients, with florid duct lesions and prominent bile duct injury, in association with positive antimitochondrial antibodies. Among the other 24 biopsies, mild to moderate portal and lobular inflammation were present in 18 and 17 of 24 biopsies, respectively. Overall, 22 of 24 biopsies showed NRH-like changes. Plasma cell were absent. A distinct pattern of pericellular fibrosis was present in 23 of 26 biopsies overall. Involvement ranged from focal centrizonal fibrosis to bridging fibrosis and was accompanied by increased intrasinusoidal lymphocytes in 13 of 24 biopsies. Pericellular fibrosis was identified in 1 of 21 biopsies in the control cohort. Additional findings included granulomatous inflammation or nonhepatocellular foreign body-type multinucleate giant cells, identified in 4 biopsies. Three of 6 examined biopsies also demonstrated focal hepatocellular copper deposition. Hepatic disease in CVID is often associated with elevated alkaline phosphatase and aspartate transaminase and is characterized histologically by the mild nonspecific portal and lobular hepatitis, absence of plasma cells, NRH-like changes, and less commonly, typical histologic features of primary biliary cholangitis. We have also identified a distinctive pattern of delicate pericellular fibrosis that is a helpful clue to the diagnosis of hepatic disease in CVID, especially when accompanied by NRH-like changes.
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Costa AF, Clarke SE, Stueck AE, McInnes MDF, Thipphavong S. Benign Neoplasms, Mass-Like Infections, and Pseudotumors That Mimic Hepatic Malignancy at MRI. J Magn Reson Imaging 2020; 53:979-994. [PMID: 32621572 DOI: 10.1002/jmri.27251] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/20/2020] [Accepted: 05/20/2020] [Indexed: 12/14/2022] Open
Abstract
A variety of conditions may mimic hepatic malignancy at MRI. These include benign hepatic tumors and tumor-like entities such as focal nodular hyperplasia-like lesions, hepatocellular adenoma, hepatic infections, inflammatory pseudotumor, vascular entities, and in the cirrhotic liver, confluent fibrosis, and hypertrophic pseudomass. These conditions demonstrate MRI features that overlap with hepatic malignancy, and can be challenging for radiologists to diagnose accurately. In this review we discuss the MRI manifestations of various conditions that mimic hepatic malignancy, and highlight features that may allow distinction from malignancy. Level of Evidence 5 Technical Efficacy Stage 3.
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Affiliation(s)
- Andreu F Costa
- Department of Diagnostic Radiology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada
| | - Sharon E Clarke
- Department of Diagnostic Radiology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada
| | - Ashley E Stueck
- Department of Anatomical Pathology, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, Nova Scotia, Canada
| | - Matthew D F McInnes
- Department of Radiology, The Ottawa Hospital and University of Ottawa, Ottawa, Ontario, Canada
| | - Seng Thipphavong
- Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital, Women's College Hospital, and University of Toronto, Toronto, Ontario, Canada
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Seo JW, Kim ES, Han MH, Kweon YO. Non-cirrhotic portal hypertension related to azathioprine therapy in a patient with Crohn's disease. Intest Res 2020; 19:247-251. [PMID: 32610890 PMCID: PMC8100374 DOI: 10.5217/ir.2020.00016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 04/09/2020] [Indexed: 12/14/2022] Open
Abstract
Azathioprine is widely used for the treatment of Crohn’s disease (CD). Few cases from Western countries have reported idiopathic non-cirrhotic portal hypertension (NCPH) related to thiopurine therapy in patients with inflammatory bowel disease. Idiopathic NCPH is a rare hepatic condition with intrahepatic portal hypertension but no evidence of cirrhosis or chronic liver disease. Patients with idiopathic NCPH present with symptoms of portal hypertension such as thrombocytopenia, splenomegaly and esophageal varices. We report a case of idiopathic NCPH in a 51-year-old male patient with CD who had been taking azathioprine for 5 years. He was admitted due to esophageal variceal bleeding along with splenomegaly and thrombocytopenia. Evaluation of cirrhosis or chronic liver disease showed normal-range results as estimated by FibroScan evaluation, laboratory examination for autoimmune hepatitis or viral hepatitis, and liver biopsy. This case may suggest the need for careful monitoring for manifestations of portal hypertension in Asian patients with inflammatory bowel disease receiving thiopurine treatment.
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Affiliation(s)
- Jong Won Seo
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Eun Soo Kim
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Man-Hoon Han
- Department of Pathology, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Young Oh Kweon
- Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea
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40
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Zhang X, Thomas C, Schiano TD, Thung SN, Ward SC, Fiel MI. Aberrant von Willebrand factor expression of sinusoidal endothelial cells and quiescence of hepatic stellate cells in nodular regenerative hyperplasia and obliterative portal venopathy. Histopathology 2020; 76:959-967. [PMID: 31994248 DOI: 10.1111/his.14083] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 01/20/2020] [Accepted: 01/25/2020] [Indexed: 02/06/2023]
Abstract
AIMS Nodular regenerative hyperplasia (NRH) and obliterative portal venopathy (OPV), entities that comprise idiopathic non-cirrhotic portal hypertension (INCPH), are under-recognised diseases of uncertain aetiology and the diagnosis can be easily missed on liver biopsy. The expression of CD34 and von Willebrand factor (vWF) in liver sinusoidal endothelial cells (LSEC) and alpha-smooth muscle actin (ASMA) in hepatic stellate cells (HSCs) is unknown in NRH and OPV. We sought to investigate the pathogenesis and potential immunomarkers that might aid in making the diagnosis of NRH and OPV. METHODS AND RESULTS Immunohistochemical (IHC) staining for CD34, vWF and ASMA was performed in clinically and histologically well-characterised NRH (n = 15) and OPV (n = 47) liver specimens. Among the 47 OPV cases, 37 (78.7%) had concurrent features of NRH. CD34 positive staining was mainly confined to small vessels in the portal tracts and LSECs in periportal areas, a finding similar to that in non-NRH/OPV livers. However, expression of vWF in LSECs was positive in the compressed sinusoids of NRH and in a patchy or geographic pattern, particularly prominent in the perivenular areas and dilated sinusoids of OPV cases. HSCs were negative for ASMA in all NRH and OPV cases. CONCLUSION Our findings indicate that NRH may be a subtle but common concurrent morphological feature in OPV. The aberrant expression of vWF in LSECs suggests that endothelial injury may play a role in the pathogenesis, which may thus aid in the recognition and diagnosis of NRH and OPV, particularly when confronted with otherwise apparent normal liver histology on needle biopsy.
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Affiliation(s)
- Xuchen Zhang
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Courtney Thomas
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Thomas D Schiano
- Department of Medicine - Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Swan N Thung
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Stephen C Ward
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - M Isabel Fiel
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
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41
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Pecoraro A, Crescenzi L, Varricchi G, Marone G, Spadaro G. Heterogeneity of Liver Disease in Common Variable Immunodeficiency Disorders. Front Immunol 2020; 11:338. [PMID: 32184784 PMCID: PMC7059194 DOI: 10.3389/fimmu.2020.00338] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Accepted: 02/11/2020] [Indexed: 12/13/2022] Open
Abstract
Common variable immunodeficiency (CVID) is the most frequent primary immunodeficiency (PID) in adulthood and is characterized by severe reduction of immunoglobulin serum levels and impaired antibody production in response to vaccines and pathogens. Beyond the susceptibility to infections, CVID encompasses a wide spectrum of clinical manifestations related to a complex immune dysregulation that also affects liver. Although about 50% CVID patients present persistently deranged liver function, burden, and nature of liver involvement have not been systematically investigated in most cohort studies published in the last decades. Therefore, the prevalence of liver disease in CVID widely varies depending on the study design and the sampling criteria. This review seeks to summarize the evidence about the most relevant causes of liver involvement in CVID, including nodular regenerative hyperplasia (NRH), infections and malignancies. We also describe the clinical features of liver disease in some monogenic forms of PID included in the clinical spectrum of CVID as ICOS, NFKB1, NFKB2, CTLA-4, PI3Kδ pathway, ADA2, and IL21-R genetic defects. Finally, we discuss the clinical applications of the various diagnostic tools and the possible therapeutic approaches for the management of liver involvement in the context of CVID.
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Affiliation(s)
- Antonio Pecoraro
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Ludovica Crescenzi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.,Center for Basic and Clinical Immunology Research, WAO Center of Excellence, University of Naples Federico II, Naples, Italy
| | - Giancarlo Marone
- Department of Public Health, University of Naples Federico II, Naples, Italy.,Monaldi Hospital, Naples, Italy
| | - Giuseppe Spadaro
- Department of Translational Medical Sciences, University of Naples Federico II, Naples, Italy.,Center for Basic and Clinical Immunology Research, WAO Center of Excellence, University of Naples Federico II, Naples, Italy
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Bayoumy AB, Simsek M, Seinen ML, Mulder CJJ, Ansari A, Peters GJ, De Boer NK. The continuous rediscovery and the benefit-risk ratio of thioguanine, a comprehensive review. Expert Opin Drug Metab Toxicol 2020; 16:111-123. [PMID: 32090622 DOI: 10.1080/17425255.2020.1719996] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2019] [Accepted: 01/16/2020] [Indexed: 12/11/2022]
Abstract
Introduction: In the 1950s, thioguanine (TG), a thiopurine-derivative together with azathioprine (AZA) and mercaptopurine (MP), were developed for the treatment of childhood leukemia. Over the years, the use of TG was also explored for other, mainly immune-mediated and inflammatory, diseases such as in the field of dermatology and rheumatology (e.g. psoriasis, systemic lupus erythematosus (SLE)) and gastroenterology and hepatology (e.g. inflammatory bowel diseases (IBD), autoimmune hepatitis).Areas covered: This review provides a comprehensive overview of all the clinical uses of TG and describes its mechanism of action, pharmacokinetic/pharmacodynamic features, and toxicity.Expert opinion: Thioguanine has shown beneficial clinical effects in hematological (particularly leukemia) and several immune-inflammatory diseases including psoriasis, SLE, polycythemia vera, Churg-Strauss syndrome, IBD, collagenous sprue, refractory celiac disease, and autoimmune hepatitis. Thioguanine is not effective in treating solid-cancers. At relatively low dosages, i.e. 0.2- 0.3mg/kg/day or 20 mg/day, TG has a favorable risk-benefit ratio and is a safe and effective drug in the long-term treatment of amongst other IBD patients. Thioguanine toxicity, especially myelotoxicity, and hepatotoxicity, including nodular regenerative hyperplasia (NRH) of the liver, is limited when dosed adequately. The occurrence of NRH appears dose-dependent and has been especially described during high dose TG above 40 mg/day.
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Affiliation(s)
- Ahmed B Bayoumy
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Melek Simsek
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, AG&M Research Institute, Amsterdam, Netherlands
| | - Margien L Seinen
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Chris J J Mulder
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, Amsterdam, Netherlands
| | - Azhar Ansari
- Department of Gastroenterology, Surrey and Sussex NHS, Easy Surrey Hospital, Surrey, UK
| | - Godefridus J Peters
- Amsterdam UMC, VU University Medical Center, Laboratory Medical Oncology, Cancer Center Amsterdam, Amsterdam, Netherlands
- Department of Biochemistry, Medical University of Gdansk, Gdansk, Poland
| | - Nanne K De Boer
- Amsterdam UMC, Department of Gastroenterology and Hepatology, VU University Medical Center, AG&M Research Institute, Amsterdam, Netherlands
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Cannella R, Minervini MI, Rachakonda V, Bollino G, Furlan A. Liver stiffness measurement in patients with nodular regenerative hyperplasia undergoing magnetic resonance elastography. Abdom Radiol (NY) 2020; 45:373-383. [PMID: 31834457 DOI: 10.1007/s00261-019-02367-8] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
PURPOSE Nodular regenerative hyperplasia (NRH) may mimic cirrhosis at imaging. We aim to investigate the effect of NRH on liver stiffness measurement (LSM) obtained with magnetic resonance elastography (MRE). METHODS This retrospective, Institutional Review Board-approved study included 37 subjects with NRH (Group 1) and no or minimal fibrosis (F0-F1), a control group (Group 2) made of 30 subjects with non-advanced fibrosis (F0-F2), and a control group (Group 3) made of 30 subjects with advanced fibrosis (F3-F4), all with available MRE. LSM was measured in each subject along with assessment of hepatic morphological features of cirrhosis and signs of portal hypertension. The significance of the difference in mean LSM between Group 1 and 2 and between Group 1 and 3 was evaluated using the Mann-Whitney U test. The difference in distribution of imaging features among groups was assessed using the Pearson χ2 or Fisher exact test. RESULTS The mean ± SD LSM in Group 1 (3.56 ± 1.10 kPa) was significantly higher compared to Group 2 (2.91 ± 0.52 kPa, P = 0.019) and significantly lower compared to Group 3 (7.18 ± 2.08 kPa, P < 0.001). Twelve (32%) patients with NRH had LSM ≥ 4.11 kPa, and 6 (16%) patients had LSM ≥ 4.71 kPa. Surface nodularity (P = 0.032) and caudate lobe hypertrophy (P = 0.004) were more commonly visualized in Group 1 than in Group 2. At least one feature of portal hypertension was observed in 16 (43%) NRH subjects. CONCLUSION NRH may increase the LSM obtained with MRE and may represent a confounding factor when using liver stiffness for the non-invasive diagnosis of fibrosis.
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Affiliation(s)
- Roberto Cannella
- Abdominal Imaging Division, Department of Radiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA
- Section of Radiology - BiND, University Hospital "Paolo Giaccone", Via del Vespro 129, 90127, Palermo, Italy
| | - Marta I Minervini
- Division of Transplantation Pathology UPMC Montefiore, Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Vikrant Rachakonda
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
| | - Gideon Bollino
- Abdominal Imaging Division, Department of Radiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA
| | - Alessandro Furlan
- Abdominal Imaging Division, Department of Radiology, University of Pittsburgh, 200 Lothrop Street, Pittsburgh, PA, 15213, USA.
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Bakshi N, Gulati N, Rastogi A, Chougule A, Bihari C, Jindal A. Nodular regenerative hyperplasia - An under-recognized vascular disorder of liver. Pathol Res Pract 2020; 216:152833. [PMID: 32164988 DOI: 10.1016/j.prp.2020.152833] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2019] [Revised: 12/24/2019] [Accepted: 01/18/2020] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Nodular regenerative hyperplasia (NRH) is a rare hepatic vascular disorder which is often associated with wide variety of systemic diseases. Intrahepatic microvascular injury and subsequent altered perfusion state leads to development of non-cirrhotic portal hypertension in many of these patients. Diagnosis of NRH often remains unsuspected clinically and liver biopsy is essential for the diagnosis and exclusion of fibrosis. We herein, present clinicopathological features of 22 NRH cases. In addition we assessed CK7 and CD34 expression in hepatocytes and sinusoidal endothelial cells respectively. RESULTS Most of the cases were associated with systemic disorders, predominantly immunological, inflammatory and drug-related injuries. Signs and symptoms of portal hypertension were found in 86.4 % patients. Majority of the patients showed a predominant mild cholestatic pattern of liver function tests. Nearly all the (21/22) cases showed CK7 positivity in centrizonal hepatocytes which ranged from <10 % cells to diffuse perivenular positivity extending into the midzonal areas. CD34 positivity in sinusoidal endothelial cells was seen in all the cases, which was prominent in periportal areas in all cases; while perivenular (n = 20) and midzonal (n = 14) areas also showed CD34 positive sinusoidal endothelial cells. CONCLUSION This study highlights the role of pathologist in the diagnosis of NRH and stresses upon the need for awareness of NRH as a cause of unexplained portal hypertension in patients with underlying systemic diseases. The altered perfusion state in NRH leads to phenotypic shift in centrizonal atrophic hepatocytes and sinusoidal endothelial cells (as depicted by IHC) which may be responsible for development of portal hypertension.
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Affiliation(s)
- Neha Bakshi
- Department of Pathology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India.
| | - Natasha Gulati
- Department of Pathology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Archana Rastogi
- Department of Pathology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India.
| | - Abhijit Chougule
- Department of Pathology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
| | - Chhagan Bihari
- Department of Pathology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India.
| | - Ankur Jindal
- Department of Hepatology, Institute of Liver and Biliary Sciences, Vasant Kunj, New Delhi, India
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Noncirrhotic Portal Hypertension Secondary to Nodular Regenerative Hyperplasia Postrenal Transplant. ACG Case Rep J 2019; 6:e00257. [PMID: 32042840 PMCID: PMC6946204 DOI: 10.14309/crj.0000000000000257] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 09/20/2019] [Indexed: 01/05/2023] Open
Abstract
Noncirrhotic portal hypertension (NCPH) is a well-known clinical entity, but often underdiagnosed. One of the common causes of NCPH is nodular regenerative hyperplasia (NRH) that presents as nodularity with features of portal hypertension and thus often diagnosed as cirrhosis. Although NRH has no histologic fibrosis, the liver synthetic function remains intact; thus, clinical diagnosis is essential because management may differ from cirrhosis. We were asked to consult in this series of 4 patients who had new-onset ascites after kidney transplantation and were diagnosed with NCPH from NRH.
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Bell PD, Thung S, Weiss S, Levstik M, Zhang D, Liu X, Liao X. Hepatocellular adenoma(s) arising in nodular regenerative hyperplasia in a patient with systemic lupus erythematosus. Pathol Res Pract 2019; 216:152770. [PMID: 31810588 DOI: 10.1016/j.prp.2019.152770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2019] [Revised: 11/14/2019] [Accepted: 11/27/2019] [Indexed: 11/24/2022]
Abstract
Hepatocellular adenoma (HCA) is a rare benign tumor of the liver with low risk of malignant transformation. It is associated with oral contraceptives/anabolic steroid use, metabolic disease, and rarely, vascular abnormalities. We report an interesting case of HCA arising in a background of diffuse hepatic nodular regenerative hyperplasia (NRH) in a 40-year-old female patient with systemic lupus erythematosus (SLE). She presented with sudden-onset refractory ascites, elevated liver enzymes, diffuse hepatic nodularity and mass lesions on imaging concerning for malignancy. Targeted biopsies of the mass lesion were performed with inconclusive diagnoses. The patient ultimately underwent resection of the mass, which was confirmed as HCA, inflammatory type, arising in a background of NRH. It is not uncommon for SLE patients to have liver manifestations such as NRH, but HCA arising in NRH has not been previously reported. Our case reveals an unusual relationship between HCA and hepatic vasculopathy in the clinical context of a systemic inflammatory condition, the mechanism by which is not fully understood.
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Affiliation(s)
- Phoenix D Bell
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Swan Thung
- Department of Pathology, Icahn Medical Center at Mount Sinai, New York, NY, USA
| | - Stan Weiss
- Department of Radiology, University of Rochester Medical Center, Rochester, NY, USA
| | - Mark Levstik
- Department of Gastroenterology/Hepatology, University of Rochester Medical Center, Rochester, NY, USA
| | - Dongwei Zhang
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA
| | - Xiuli Liu
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida College of Medicine, Gainesville, FL, USA
| | - Xiaoyan Liao
- Department of Pathology and Laboratory Medicine, University of Rochester Medical Center, Rochester, NY, USA.
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Abstract
Mycobacterium chimaera was identified as a species within the Mycobacterium avium complex in 2004. Until recently, it was predominantly seen in immunocompromised patients. In 2015, an outbreak of disseminated M. chimaera disease was described in European patients after undergoing open-heart surgery in which contaminated heater-cooler water units were used. Using whole genomic sequencing and phylogenetic analysis, investigators found a highly clonal outbreak from the German manufacturing site of the heater-cooler water units. This outbreak has now proven to be world-wide. Patients present with fever, fatigue, and weight loss months to many years after surgery. They are found to have systemic manifestations, including endocarditis, pancytopenia, renal dysfunction, chorioretinitis, and hepatitis. Preliminary reports suggest a high mortality rate despite aggressive treatment. In some patients, the predominant laboratory abnormalities are elevations in liver function tests, leading to diagnostic hepatobiliary work-ups, including liver biopsy. The pathologic changes in the liver have not yet been described. Herein, we report the clinicopathologic findings of the largest series of M. chimaera liver disease in the United States to date: 7 cases within a large, multihospital health care network. Five (71%) patients died of disease, despite aggressive treatment. Liver function test abnormalities were predominantly biliary: mean values of alkaline phosphate 288 U/L, aspartate aminotransferase 79 U/L, alanine aminotransferase 64 U/L. All 7 biopsies showed a consistent and characteristic dual pattern of injury: small, ill-formed collections of sinusoidal histiocytes with rare multinucleated giant cells, and scattered architectural changes of venous outflow obstruction. Two (29%) cases showed mild pericellular fibrosis. Nodular regenerative hyperplasia was seen in 2 (29%) cases, consistent with a sinusoidal/venous obstructive pattern of injury. We postulate that the sinusoidal location of the granulomas contributes to the venous obstructive changes. Recognition of this characteristic dual pattern of injury can allow pathologists to suggest the diagnosis and prompt the appropriate diagnostic and therapeutic interventions.
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González I, Lu HC, Ritter JH, Maluf HM, Dehner LP, He M. Clinicopathologic characteristics of de novo nodular regenerative hyperplasia in pediatric liver transplant. Pediatr Transplant 2019; 23:e13471. [PMID: 31124197 DOI: 10.1111/petr.13471] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 04/02/2019] [Accepted: 04/15/2019] [Indexed: 12/23/2022]
Abstract
Liver NRH is seen in all patients age; however, more frequently in those over the age of 60 years and associated with multiple systemic diseases. In liver allograft recipients, the development of DnNRH has been linked with the use of azathioprine or vascular abnormalities. We present the clinicopathologic characteristics of 17 pediatric patients who underwent liver transplantation and subsequently developed DnNRH. The patients were divided into early and late onset depending if DnNRH was diagnosed within or beyond 4 years after transplant. Eight patients (47%) presented as early onset, of which two had normal ultrasound at time of diagnosis. One patient (12.5%) with early onset lost the graft secondary to DnNRH. Nine patients (53%) presented as late onset, of which two (22%) had normal ultrasound at time of diagnosis. Two patients (25%) of the late onset lost their graft secondary to chronic rejection and DnNRH. Two patients (12%) died secondary to cytomegalovirus pneumonitis and pancolitis. Furthermore, both groups presented with symptoms differing from the adult population in prior studies and were not associated with the use of azathioprine or vascular abnormalities. Interestingly, episodes of acute cellular rejection were more common in the early-onset group compared to the late-onset group. In conclusion, DnNRH in the pediatric age group has a different clinical presentation, possibly reflecting a different pathogenesis compared to the adult population.
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Affiliation(s)
- Iván González
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri
| | - Hsiang-Chih Lu
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri
| | - Jon H Ritter
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri
| | - Horacio M Maluf
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri
| | - Louis P Dehner
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri
| | - Mai He
- Department of Pathology and Immunology, Washington University School of Medicine, Saint Louis, Missouri
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Nodular Regenerative Hyperplasia: Expression Pattern of Glutamine Synthetase and a Potential Role for Hepatic Progenitor Cells. Appl Immunohistochem Mol Morphol 2019; 28:243-248. [PMID: 31335486 DOI: 10.1097/pai.0000000000000793] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Nodular regenerative hyperplasia (NRH) is one of the most frequent causes of noncirrhotic intrahepatic hypertension, but is a difficult histologic diagnosis. The expression of glutamine synthetase (GS) and cytokeratin 7 (CK7) has been reported to be increased in other regenerative/vascular conditions, while CK7 and BerEP4 are also markers of hepatic progenitor cells. The aims of this study were to investigate the use of GS, CK7, and BerEP4 as the potential markers for NRH. This is a retrospective case series of NRH at Centre Hospitalier de l'Universite de Montreal between 1993 and 2013. Normal liver from partial hepatectomies for tumors were used as controls. GS, CK7, CK19, and BerEP4 immunohistochemical stains were performed on all specimens. Immunohistochemical staining patterns were scored from 0 to 3+. NRH was identified in 46 samples obtained from 26 patients. Liver chemistry profile was cholestatic in 45% of the patients. In 93% of the NRH cases, there was abnormal zone 2 expression of GS. Weak panacinar GS staining was seen in all the NRH cases. Aberrant CK7 expression was present in all cases of NRH, but were not associated with cholestasis. BerEP4 was overexpressed in 47% of the NRH cases (P<0.05); all cases with diffuse BerEP4 staining also showed extensive CK7 expression (P<0.01). NRH showed increased immunohistochemical GS staining that may support its morphologic diagnosis. Our findings suggest that there is an activation of hepatic progenitor cells in NRH.
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