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research-article2015
IJSXXX10.1177/1066896915582264International Journal of Surgical PathologyLee et al
Original Articles
Histological Spectrum of Idiopathic Noncirrhotic Portal Hypertension in Liver Biopsies From Dialysis Patients
International Journal of Surgical Pathology 1–8 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896915582264 ijs.sagepub.com
Hwajeong Lee, MD1, Sanaz Ainechi, MD1, Mandeep Singh, MD1, Peter F. Ells, MD1, Christine E. Sheehan, MS1, and Jingmei Lin, MD, PhD2
Abstract Objectives. Liver biopsy is performed for various indications in dialysis patients. Being a less-common subset, the hepatic pathology in renal dialysis is not well documented. Idiopathic noncirrhotic portal hypertension (INCPH) is a clinical entity associated with unexplained portal hypertension and/or a spectrum of histopathological vascular changes in the liver. After encountering INCPH and vascular changes of INCPH in 2 renal dialysis patients, we sought to further investigate this noteworthy association. Materials and methods. A random search for patients on hemodialysis or peritoneal dialysis with liver biopsy was performed. Hematoxylin and eosin, reticulin, trichrome, and CK7 stains were performed on formalin-fixed, paraffin-embedded tissue sections. Histopathological features were reviewed, and the results were correlated with clinical findings. Results. In all, 13 liver biopsies were retrieved. The mean cumulative duration of dialysis was 50 months (range = 17 months to 11 years). All patients had multiple comorbidities. Indications for biopsy were a combination of abnormal liver function tests (6), portal hypertension (4), ascites (3), and possible cirrhosis (3). Two patients with portal hypertension underwent multiple liver biopsies for diagnostic purposes. All (100%) biopsies showed some histological features of INCPH, including narrowed portal venous lumen (9), increased portal vascular channels (8), shunt vessels (3), dilated sinusoids (9), regenerative nodule (5), and features of venous outflow obstruction (3). No cirrhosis was identified. Conclusion. Liver biopsies from patients on dialysis demonstrate histopathological vascular changes of INCPH. Some (31%) patients present with portal hypertension without cirrhosis. The histological changes may be reflective of underlying risk factors for INCPH in this group. Keywords portal hypertension, dialysis, liver biopsy, histopathology, noncirrhotic
Introduction Liver biopsy is performed to evaluate abnormal liver function tests in patients with unknown liver disease or to document cirrhosis in patients with signs of portal hypertension, such as ascites, hypersplenism, and esophageal varices. Patients on dialysis may undergo liver biopsies with the same indications. However, liver biopsy is uncommon in this population, and hepatic pathology in these patients is largely unknown. The biopsy may fail to reveal diagnostic features to explain the clinical manifestations and necessitate repeat biopsy or open-wedge biopsy, which is associated with potential complications, including pain, bleeding, pneumothorax, hemothorax, bile peritonitis, hemobilia, puncture of other organs, and infections.1 We encountered serial liver biopsies from a patient on dialysis with portal hypertension (case 11). Three consecutive needle core biopsies failed to show cirrhosis, and final open-wedge biopsy demonstrated diffuse nodular
regenerative hyperplasia—one of the histological manifestations of idiopathic noncirrhotic portal hypertension (INCPH). Subsequently, we came across another liver biopsy from a different patient on dialysis with hyperammonemia (case 12). This biopsy demonstrated portal vascular changes characterized by narrow portal vein branches and increased portal vascular profiles, which also can be seen in INCPH. The unusual association of these 2 index cases prompted us to retrieve and review liver biopsies from patients on dialysis to assess whether these biopsies
1
Albany Medical College, Albany, NY, USA Indiana University School of Medicine, Indianapolis, IN, USA
2
Corresponding Author: Hwajeong Lee, Anatomic Pathology, Albany Medical College, 47 New Scotland Ave, MC81, Albany, NY 12208, USA. Email: [email protected]
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exhibit histological features of INCPH, and whether these patients presented with portal hypertension. INCPH is a clinical entity in which the patient presents with portal hypertension and associated clinical manifestations such as esophageal varices and hypersplenism, without apparent causes of portal hypertension, such as cirrhosis, schistosomiasis, chronic liver disease, and portal vein thrombosis.2 Although pathognomonic histological features are not defined, the hepatic histopathology in INCPH consists of a spectrum of vascular changes, including obliterative portal vasculopathy with increased venous profiles per portal tract, narrowed venous lumen, and shunt vessels (herniated portal vessels into the surrounding liver parenchyma). In addition, increased number of hepatic venous branches per lobule, dilated sinusoids, nodular regenerative hyperplasia, and portal, periportal, and perisinusoidal fibrosis may be present.2-15 Previously, some of the morphological features were grouped together and categorized as distinct histological entities of INCPH, such as hepatoportal sclerosis, nodular regenerative hyperplasia, partial nodular transformation, incomplete septal cirrhosis, and noncirrhotic portal hypertension. However, subsequent studies using hepatic resection and autopsy specimens showed that gross and microscopic features cannot reliably distinguish these entities, suggesting that these entities may constitute a spectrum of histological manifestations of a unifying etiology, such as obliterative portal vasculopathy.5,10,13-18 INCPH has been reported in association with heterogeneous conditions, including immunological, infectious, medication and toxin related, genetic, and thrombophilic status.2,3,12-15,18,19 The goal of this series study is to review the hepatic pathology of patients on dialysis, concentrating on the vascular changes relevant to INCPH and, furthermore, to evaluate clinical presentations and conditions associated with the histopathology in this group.
Materials and Methods The study was approved by the institutional review board. A random search for patients who underwent liver biopsy while on peritoneal or hemodialysis was performed by the institutional Hospital Information System department. The diagnosis and procedure codes from the International Classification of Diseases, Ninth Revision (ICD-9), were used. For inpatients, codes 585 (chronic kidney disease), V45.11 (dialysis status), 50.11 (closed/percutaneous needle biopsy of liver), and 50.12 (open liver biopsy) were used. For outpatients, the Current Procedural Terminology (CPT) code 47 000 (percutaneous needle biopsy of liver) was used. Clinical history was obtained by review of medical records. Corresponding liver biopsy tissue blocks were retrieved. Hematoxylin and eosin, reticulin, and trichrome stains were performed on 5-µm-thick tissue sections from the formalin-fixed, paraffin-embedded
tissue blocks. Immunohistochemical staining for cytokeratin 7 (CK7) was performed by an automated method (Ventana Medical Systems, Inc, Tucson, AZ), utilizing an indirect biotin streptavidin diaminobenzidine (DAB) detection system (iVIEW DAB Detection Kit). Briefly, following deparaffinization, the antigenic determinant sites were unmasked; predilute CONFIRM anti-CK7 rabbit monoclonal primary antibody was applied for 20 minutes; after the development of the color with DAB, the slides were counterstained with hematoxylin. Positive controls were included, and CK7 expression was as expected. Expression of the CK7 protein was cytoplasmic.
Results Demographics and Clinical History of the Dialysis Patients In all, 13 liver biopsies from patients on hemodialysis or peritoneal dialysis were retrieved (2000-2013). As shown in Table 1, the 13 cases included 10 men and 3 women, with a mean age of 55 years (range = 22-74 years). At the time of liver biopsy, 12 patients were on hemodialysis, and 1 was on peritoneal dialysis; with mean cumulative duration of 50 months (range = 17 months to 11 years). Three patients had histories of failed renal transplant prior to dialysis. Comorbidities included hypertension (7 patients), diabetes mellitus (5 patients), congestive heart failure (5 patients), hepatitis C viral (HCV) infection (4 patients), and human immunodeficiency viral (HIV) infection (3 patients). Coagulopathy was documented in 4 patients: one with hypercoagulopathy caused by anticardiolipin antibody and functional protein C deficiency (case 3) and 3 with deepvein thrombosis and/or pulmonary embolism (cases 4, 9, and 12). No patient with HIV was on didanosine. Two patients (cases 12 and 13) were on immunosuppressants, including sirolimus, tacrolimus, and mycophenolate mofetil. No patient was taking drugs of the thiopurine family. Indications for liver biopsy were a combination of abnormal liver function tests (6 patients), portal hypertension (4 patients), ascites (3 patients), and suspicion of cirrhosis (3 patients). In case 3, the only documented biochemical abnormality was increased alkaline phosphatase, and the liver biopsy was performed during cholecystectomy without γ glutamyl transpeptidase test. Two patients with portal hypertension underwent 3 or more consecutive liver biopsies to rule out cirrhosis, and 7 patients had selective elevation of alkaline phosphatase (range = 146-484 IU/L).
Histopathological Features of the Liver Biopsies As illustrated in Table 2 and Figure 1, 10 biopsies showed aberrant portal vasculature, including narrowed lumen (9
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Lee et al Table 1. Demographics and Clinical History of the Patients. A/G
Duration
Causes of Renal Failure
Inf
1
55, F 2 years
2
22, F 2 years 3 Cystinosis months
3 4 5
49, M 9 years HIV, DM 56, M 4 years Unknown 66, M 1 year 10 Amyloidosis, HTN months
HCV, HIV HCV HCV
6
43, M 3 years
Unknown
HIV
7 8
53, M 4 years 47, M 8 years
Unknown Alport SD
HCV, HIV
9
68, M 1 year 6 DM months 56, F 1 year 6 Possible IgA months nephritis
10 11a 12
13
HTN, DM
Comorbidities
Abnormal Biochemistry
Ix for Bx
CHF, HTN, MV disorder Cystinosis, hypothyroidism, anemia
AlkP 470 IU/L
HC, DM, Anemia CHF, HC, DM Amyloidosis (heart and kidney), HTN, AR, anemia HTN
AlkP146 IU/L Unknown AST143 IU/L HCV LFT
HTN, DM Alport SD
LFT, ascites, r/o LC Portal HTN
AlkP193 IU/L LFT AST1306 IU/L, ALT1070 IU/L Ascites AlkP295 IU/L Portal HTN
Other h/o Failed renal transplant ×2
h/o Failed renal transplant, multiple liver biopsies
CMV (liver) CHF. HC, HTN, DM, AlkP220 IUL Portal HTN, LFT COPD, Anemia HTN, Crohn’s disease, AlkP283 IU/L LFT, r/o LC hyperthyroidism, h/o cervical cancer 70, M 1 year 5 HTN CHF, HTN, AlkP484 IU/L Portal HTN, Multiple liver months ascites biopsies 74, M 1 year 5 Toxin (calcineurin) HC, DM, a1-AT def Ammonia Hyperammonemia, h/o Liver months 133 µg/dL r/o LC transplant as a result of a1-AT def 52, M 11 years Segmental CHF, Wegener’s LFT, ascites h/o Failed glomerulosclerosis granulomatosis, renal hyperparathyroidism transplant
Abbreviations: A/G, age and gender; Duration, cumulative duration of dialysis; Inf, infection; Ix, indication; Bx, biopsy; F, female; M, male; HTN, hypertension; DM, diabetes mellitus; CHF, congestive heart failure; MV, mitral valve; AlkP, alkaline phosphatase; LFT, abnormal liver function test; r/o, rule out; LC, liver cirrhosis; h/o, history of; HIV, human immunodeficiency virus; HCV, hepatitis C virus; HC, hypercoagulability; AR, aortic regurgitation; SD, syndrome; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; Ig, immunoglobulin; a1-AT def, α1 antitrypsin deficiency. AST, aspartate aminotransferase; ALT, alanine aminotransferase. a This patient (case 11) was on peritoneal dialysis, and the rest were on hemodialysis.
cases; Figure 1A), increased vascular profiles in portal tracts (8 cases; Figure 1B), and shunt vessels (3 cases; Figure 1C). Dilated sinusoids (9 cases; Figure 1D) and pattern of venous outflow obstruction (VOO) with centrizonal dilated sinusoids and atrophic hepatocytes (3 cases; Figure 1E) were also noted. Increased central veins per lobule were arbitrarily defined as 4 or more central veins per lobule at medium (×100) magnification, which was seen in 2 cases (Figure 1F). A total of 9 cases showed portal (4), periportal (3), and bridging (2) fibrosis; 5 cases showed focal to
extensive perisinusoidal fibrosis; and no steatosis or cholestasis was seen. No cirrhosis was identified. Portal and lobular inflammation was minimal to mild. The necroinflammatory activity of the biopsies from patients with chronic hepatitis C was minimal to mild (Batts-Ludwig activity grade 1-2). Reticulin stain showed regenerative nodules in 5 cases (Figures 1G and 1H). CK7 immunostaining showed a variable degree of portal bile ductular proliferation in all 13 cases, and aberrant expression of CK7 in centrilobular hepatocytes in 7 cases (Figure 1I).
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Table 2. Histopathological Features of the Liver Biopsies.a Case
1
Narrow lumen + Increased vascular profile in portal tract − Shunt vessel − Bile ductular proliferation + Fibrosis B Perisinusoidal fibrosis +(e) Dilated sinusoids + VOO + Increased central veins per lobule − Regenerative nodule − Aberrant CK7 expression +
2
3
4
5
6
7
8
9
10
11
12
13
+ − − +(m) P − + − − +(f) −
+ + +(f) + − − − − − − −
− − − + PP − + − + − +
+ + − +(m) P − − − + +(f) −
− − + +(m) − +(f) + − − − +
+ + − + B − − − − + +
+ + − +(m) − − − − − +(f) +
− + + + PP + + + − − +
+ + − + PP +(f) + − − − +
+ + − +(m) P − + + − + n/a
+ + − +(m) P − + − − n/a n/a
− − − +(m) − + + + − − n/a
Abbreviations: +, present; −, not present; f, focal; m, mild; e, extensive; B, bridging fibrosis; P, portal fibrosis; PP, periportal fibrosis; VOO, features of venous outflow obstruction; n/a, not applicable. a Stains were not performed or were unavailable.
Discussion Portal hypertension is defined as increased resistance to portal blood flow, with wedged and free hepatic venous pressure gradients of ≥6 mm Hg.3,20 The causes of portal hypertension may be prehepatic (portal vein thrombosis or increased splenic venous blood flow), intrahepatic (cirrhosis, schistosomiasis, and chronic liver disease), or posthepatic (constrictive pericarditis and hepatic outflow obstruction). Liver cirrhosis remains the most common intrahepatic cause of portal hypertension in the Western world.3 If no cirrhosis is found in patients with portal hypertension, other prehepatic, intrahepatic, and posthepatic causes of noncirrhotic portal hypertension are sought. The diagnosis of INCPH is rendered when other causes of noncirrhotic portal hypertension are excluded. The nomenclature of INCPH is not standardized. It has been referred to as noncirrhotic portal fibrosis and idiopathic portal hypertension in the Eastern world.3 In the Western world, the liver histopathology of INCPH has been conventionally divided into 4 categories: hepatoportal sclerosis, incomplete septal cirrhosis, nodular regenerative hyperplasia, and partial nodular transformation.2-4,6,9,10,13,17,18,21-23 Some authors considered incomplete septal cirrhosis as a form of regressed cirrhosis.24 Nevertheless, given the multitude of morphological features overlapping in these entities, these may represent common entities of varying histology.4,6,8,23,25,26 Schouten et al3 addressed the overlapping morphological features and common associated conditions of these entities in their review article and proposed the term idiopathic noncirrhotic portal hypertension as a single entity. Several hypotheses exist for the etiology of INCPH, including obliterative portal vasculopathy, endothelial cell damage, septic emboli and thrombosis, immunological disturbances, and drug/toxin associations.2,10,15,18 Regardless
of postulated etiologies, the histology shows a spectrum of vasculopathy and variable portal and perisinusoidal fibrosis. In fact, ultrastructural studies showed that perisinusoidal fibrosis is observed in most of the INCPH cases.27,28 Also, regenerative nodules may be seen on reticulin stain.2-15 In the present study, all 13 patients on dialysis at the time of liver biopsy showed some histological components of INCPH. Narrowed lumen of the portal vein branches and dilated sinusoids were the most common histological findings, seen in 9 of 13 patients. In addition, increased vascular profiles per portal tract were noted in 8 of 13 patients. Bile ductular proliferation and variable fibrosis appear to be less specific; however, bile ductular proliferation was noted in all 13 cases and fibrosis in 11 cases. Although portal vasculopathy is conveyed as a dominating culprit in several published studies, periportal and perisinusoidal fibrosis in the absence of portal vasculopathy is frequently seen in Western INCPH.3 In our study, 2 cases (4 and 13) were devoid of portal vessel changes but showed periportal and perisinusoidal fibrosis, dilated sinusoids, and increased central veins per lobule. Histological features of VOO, characterized by central sinusoidal dilation with congestion, with or without perisinusoidal fibrosis, were seen in patients with congestive heart failure. It is well known that congestive hepatopathy shows features of VOO. However, other conditions, including nodular regenerative hyperplasia, portal venous insufficiency, inflammation, granulomatous disease, neoplasms, and open-wedge biopsies, may also show VOO-like histology.29 Thus, the VOO-like histology in these patients may be in part attributable to other etiologies. For example, case 11 with portal hypertension underwent 3 needle biopsies before the diagnostic open-wedge biopsy that showed diffuse nodular regenerative hyperplasia, and one of the prior needle biopsies showed VOO pattern injury.
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Figure 1. Histological spectrum of liver biopsies from patients on dialysis. A. Portal tract with narrowed portal venous branch (arrow; hematoxylin and eosin [H&E], ×200, case 12). B. Portal tract with multiple vascular profiles (arrows; H&E ×200, case 10). C. Shunt vessel directly connecting the periportal liver parenchyma (arrow; H&E ×200, case 5). D. Dilated sinusoids (H&E, ×200, case 9). E. Venous outflow obstruction pattern injury with perisinusoidal fibrosis (arrow; trichrome, ×200, case 13). F. Increased central veins per lobule (H&E, ×100, case 5). G. Regenerative nodules (nodular regenerative hyperplasia) (arrows; H&E, ×50, case 11). H. Regenerative nodules (nodular regenerative hyperplasia; arrows; reticulin, ×50, case 11). I. Aberrant expression of CK7 in centrilobular hepatocytes and mild bile ductular proliferation (CK7, ×100, case 9).
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CK7 immunostain is helpful in evaluating bile ductular proliferation in the portal tracts and aberrant expression of CK7 in the centrizonal hepatocytes. Although not specific, centrilobular cholangiolar metaplasia represented by aberrant CK7 expression is associated with centrilobular scarring and cholestatic biochemistry profile.30,31 It may represent an intermediate hepatobiliary phenotype of centrizonal hepatocytes undergoing metaplasia or dedifferentiation secondary to tissue hypoxia.32,33 In our study, 7 of 10 biopsies showed variable degree of centrilobular cholangiolar metaplasia by the CK7 immunostain. In addition, 7 patients showed selective elevation of alkaline phosphatase, suggesting ischemic centrilobular injury and a possible cholestatic component, in keeping with previous reports of INCPH.2,3 We postulate that heterogeneous perfusion resulting from intrahepatic vascular remodeling, similar to INCPH, and subsequent ischemic injury of the central zone may manifest as cholangiolar metaplasia of centrizonal hepatocytes in these cases. INCPH is associated with variable conditions, including infection, thrombophilic status, genetic disorder, connective tissue disorder, and immunological disturbances.2,3,12-15,18,19 In our study, 4 patients (cases 3, 4, 9, and 12) had thrombophilic conditions, 4 (cases 2, 5, 10, and 13) had potential immunological disorder, and 3 (cases 2, 8, and 12) had genetic disorders. Four patients (cases 2, 8, 12, and 13) had failed renal and liver allografts, indicative of an exposure to immunosuppressive reagents; 10 patients (cases 1, 3, 4, 5, 6, 7, 9, 10, 11, and 12) had hypertension and/or diabetes mellitus, which are prone to vasculopathy. Of note, 4 patients (cases 3, 4, 5, and 7) had chronic hepatitis C. Krasinskas et al34 explored portal vasculopathy of native and allograft liver biopsies with HCV and found that the biopsies from patients with HCV showed increased number of vascular channels per portal tract compared with non-HCV biopsies. Also, the portal vascular changes were positively correlated with the degree of portal inflammation. Thus, the portal vascular changes and fibrosis seen in these patients may partly be attributed to HCV hepatitis. However, the portal inflammation of these patients was minimal to mild (Batts-Ludwig grade 1-2), and the biopsies from 3 patients showed dilated sinusoids, increased central veins per lobule, and regenerative nodules, which were not studied in HCV biopsies but were described in INCPH. Therefore, it is also possible that the portal vascular changes in these 4 patients represent histological components of INCPH. In addition, 3 patients (cases 3, 6, and 7) had HIV infection. INCPH has been described in HIV patients, for which didanosine, an antiretroviral nucleoside analogue, is considered to be responsible.13,15 No patient in this study was on didanosine. Similarly, although all patients were on multiple medications at the time of the biopsy, a history of drugs that are reported to be associated with INCPH, such
as immunosuppressant of thiopurine family (azathioprine, 6-thioguanine), was not found. All patients were on dialysis at the time of the biopsy. Hence, the possibility that dialysis itself may have contributed to the histological changes is raised. Khurana et al20 studied portal venous pressure in patients with chronic hepatitis C, of whom 58 were on dialysis. The authors found that dialysis significantly decreases portal pressure, especially in those with advanced fibrosis. It was postulated that dialysis removes inflammatory mediators such as interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-α from the circulation, thereby mitigating the inflammatory component that may contribute to elevated portal venous pressure.20 Likewise, albumin dialysis temporarily reduced portal pressure in patients with acute alcoholic hepatitis with risk of variceal bleeding.35 Mysorekar et al36 studied liver biopsies of HCV patients on hemodialysis and reported that the necroinflammatory activity is mild in this group. Similarly, in our cases, the portal and lobular inflammation was minimal to mild. Although these studies did not address histological changes pertinent to INCPH, they appear to suggest that dialysis plays a beneficial role in controlling inflammation and portal hypertension. The fact that portal inflammation is positively associated with portal vasculopathy in chronic hepatitis C further supports the notion.34 Taken together, it seems unlikely that dialysis itself caused the histological changes in the liver biopsies. Hepatic pathology in patients on dialysis was rarely reported. Elariny et al10 reported a case of nodular regenerative hyperplasia in a patient on hemodialysis. This patient also had HCV and history of failed renal transplant.10 Loinaz et al17 reported 1 patient on dialysis in their study of 4 patients with portal hypertension without cirrhosis. This patient had Alport syndrome and had undergone a renal transplant.17 Given the multiple coexisting risk factors for INCPH in patients on dialysis, as demonstrated in our series and the previous reports, the histology of INCPH in these patients appears to be reflective of varying underlying clinical conditions that are known risk factors for INCPH. The specificity and significance of portal vascular changes outside the setting of cirrhosis and portal hypertension is unknown. Obliterative portal vasculopathy was described in patients with congestive heart failure and arterial thrombosis, and shunt vessels were described in liver biopsies with no portal hypertension.16,37 In the absence of a systemic review of “normal” liver biopsies pertaining to the histological features of INCPH, the significance of our observation remains unclear. However, the fact that 4 of 13 (31%) patients had documented portal hypertension without evidence of cirrhosis and 2 patients underwent multiple liver biopsies for suspicion of cirrhosis deserves attention. The histomorphological
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Lee et al changes may represent a chronological progression of INCPH, with clinical portal hypertension at one end of the spectrum. The report that only 5% of INCPH by histomorphology was associated with clinical portal hypertension further lends support to our hypothesis.5 In summary, histological features of INCPH were identified in liver biopsies from patients on dialysis and appear to be secondary to various underlying risk factors for INCPH in this group. Cognizance of these findings and the potential risk factors for INCPH in patients with a complicated medical history will enhance the diagnostic prowess of surgical pathologists and help avoid overdiagnosis of chronic hepatitis and cirrhosis, and redundant procedures. Acknowledgments The authors thank Natalya Colomb, Nicole Burrow, the Tumor Registry and Hospital Information System at the Albany Medical Center for their support.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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32. Desmet VJ. Ductal plates in hepatic ductular reactions: hypothesis and implications. I. Types of ductular reaction reconsidered. Virchows Arch. 2011;458:251-259. 33. Krings G, Can B, Ferrell L. Aberrant centrizonal features in chronic hepatic venous outflow obstruction: centrilobular mimicry of portal-based disease. Am J Surg Pathol. 2014;38:205-214. 34. Krasinskas AM, Goldsmith JD, Burke A, Furth EE. Abnormal intrahepatic portal vasculature in native and allograft liver biopsies: a comprehensive analysis. Am J Surg Pathol. 2005;29:1382-1388. 35. Sen S, Mookerjee RP, Cheshire LM, Davies NA, Williams R, Jalan R. Albumin dialysis reduces portal pressure acutely in patients with severe alcoholic hepatitis. J Hepatol. 2005;43:142-148. 36. Mysorekar VV, Rao SG, Mahadeva K. Liver histology in patients on hemodialysis with chronic hepatitis C viral infection. Indian J Pathol Microbiol. 2008;51:182-185. 37. Wanless I, Bernier V, Seger M. Intrahepatic portal vein sclerosis in patients without a history of liver disease: an autopsy study. Am J Pathol. 1982;106:63-70.
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research-article2015
IJSXXX10.1177/1066896915582264International Journal of Surgical PathologyLee et al
Original Articles
Histological Spectrum of Idiopathic Noncirrhotic Portal Hypertension in Liver Biopsies From Dialysis Patients
International Journal of Surgical Pathology 1–8 © The Author(s) 2015 Reprints and permissions: sagepub.com/journalsPermissions.nav DOI: 10.1177/1066896915582264 ijs.sagepub.com
Hwajeong Lee, MD1, Sanaz Ainechi, MD1, Mandeep Singh, MD1, Peter F. Ells, MD1, Christine E. Sheehan, MS1, and Jingmei Lin, MD, PhD2
Abstract Objectives. Liver biopsy is performed for various indications in dialysis patients. Being a less-common subset, the hepatic pathology in renal dialysis is not well documented. Idiopathic noncirrhotic portal hypertension (INCPH) is a clinical entity associated with unexplained portal hypertension and/or a spectrum of histopathological vascular changes in the liver. After encountering INCPH and vascular changes of INCPH in 2 renal dialysis patients, we sought to further investigate this noteworthy association. Materials and methods. A random search for patients on hemodialysis or peritoneal dialysis with liver biopsy was performed. Hematoxylin and eosin, reticulin, trichrome, and CK7 stains were performed on formalin-fixed, paraffin-embedded tissue sections. Histopathological features were reviewed, and the results were correlated with clinical findings. Results. In all, 13 liver biopsies were retrieved. The mean cumulative duration of dialysis was 50 months (range = 17 months to 11 years). All patients had multiple comorbidities. Indications for biopsy were a combination of abnormal liver function tests (6), portal hypertension (4), ascites (3), and possible cirrhosis (3). Two patients with portal hypertension underwent multiple liver biopsies for diagnostic purposes. All (100%) biopsies showed some histological features of INCPH, including narrowed portal venous lumen (9), increased portal vascular channels (8), shunt vessels (3), dilated sinusoids (9), regenerative nodule (5), and features of venous outflow obstruction (3). No cirrhosis was identified. Conclusion. Liver biopsies from patients on dialysis demonstrate histopathological vascular changes of INCPH. Some (31%) patients present with portal hypertension without cirrhosis. The histological changes may be reflective of underlying risk factors for INCPH in this group. Keywords portal hypertension, dialysis, liver biopsy, histopathology, noncirrhotic
Introduction Liver biopsy is performed to evaluate abnormal liver function tests in patients with unknown liver disease or to document cirrhosis in patients with signs of portal hypertension, such as ascites, hypersplenism, and esophageal varices. Patients on dialysis may undergo liver biopsies with the same indications. However, liver biopsy is uncommon in this population, and hepatic pathology in these patients is largely unknown. The biopsy may fail to reveal diagnostic features to explain the clinical manifestations and necessitate repeat biopsy or open-wedge biopsy, which is associated with potential complications, including pain, bleeding, pneumothorax, hemothorax, bile peritonitis, hemobilia, puncture of other organs, and infections.1 We encountered serial liver biopsies from a patient on dialysis with portal hypertension (case 11). Three consecutive needle core biopsies failed to show cirrhosis, and final open-wedge biopsy demonstrated diffuse nodular
regenerative hyperplasia—one of the histological manifestations of idiopathic noncirrhotic portal hypertension (INCPH). Subsequently, we came across another liver biopsy from a different patient on dialysis with hyperammonemia (case 12). This biopsy demonstrated portal vascular changes characterized by narrow portal vein branches and increased portal vascular profiles, which also can be seen in INCPH. The unusual association of these 2 index cases prompted us to retrieve and review liver biopsies from patients on dialysis to assess whether these biopsies
1
Albany Medical College, Albany, NY, USA Indiana University School of Medicine, Indianapolis, IN, USA
2
Corresponding Author: Hwajeong Lee, Anatomic Pathology, Albany Medical College, 47 New Scotland Ave, MC81, Albany, NY 12208, USA. Email: [email protected]
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exhibit histological features of INCPH, and whether these patients presented with portal hypertension. INCPH is a clinical entity in which the patient presents with portal hypertension and associated clinical manifestations such as esophageal varices and hypersplenism, without apparent causes of portal hypertension, such as cirrhosis, schistosomiasis, chronic liver disease, and portal vein thrombosis.2 Although pathognomonic histological features are not defined, the hepatic histopathology in INCPH consists of a spectrum of vascular changes, including obliterative portal vasculopathy with increased venous profiles per portal tract, narrowed venous lumen, and shunt vessels (herniated portal vessels into the surrounding liver parenchyma). In addition, increased number of hepatic venous branches per lobule, dilated sinusoids, nodular regenerative hyperplasia, and portal, periportal, and perisinusoidal fibrosis may be present.2-15 Previously, some of the morphological features were grouped together and categorized as distinct histological entities of INCPH, such as hepatoportal sclerosis, nodular regenerative hyperplasia, partial nodular transformation, incomplete septal cirrhosis, and noncirrhotic portal hypertension. However, subsequent studies using hepatic resection and autopsy specimens showed that gross and microscopic features cannot reliably distinguish these entities, suggesting that these entities may constitute a spectrum of histological manifestations of a unifying etiology, such as obliterative portal vasculopathy.5,10,13-18 INCPH has been reported in association with heterogeneous conditions, including immunological, infectious, medication and toxin related, genetic, and thrombophilic status.2,3,12-15,18,19 The goal of this series study is to review the hepatic pathology of patients on dialysis, concentrating on the vascular changes relevant to INCPH and, furthermore, to evaluate clinical presentations and conditions associated with the histopathology in this group.
Materials and Methods The study was approved by the institutional review board. A random search for patients who underwent liver biopsy while on peritoneal or hemodialysis was performed by the institutional Hospital Information System department. The diagnosis and procedure codes from the International Classification of Diseases, Ninth Revision (ICD-9), were used. For inpatients, codes 585 (chronic kidney disease), V45.11 (dialysis status), 50.11 (closed/percutaneous needle biopsy of liver), and 50.12 (open liver biopsy) were used. For outpatients, the Current Procedural Terminology (CPT) code 47 000 (percutaneous needle biopsy of liver) was used. Clinical history was obtained by review of medical records. Corresponding liver biopsy tissue blocks were retrieved. Hematoxylin and eosin, reticulin, and trichrome stains were performed on 5-µm-thick tissue sections from the formalin-fixed, paraffin-embedded
tissue blocks. Immunohistochemical staining for cytokeratin 7 (CK7) was performed by an automated method (Ventana Medical Systems, Inc, Tucson, AZ), utilizing an indirect biotin streptavidin diaminobenzidine (DAB) detection system (iVIEW DAB Detection Kit). Briefly, following deparaffinization, the antigenic determinant sites were unmasked; predilute CONFIRM anti-CK7 rabbit monoclonal primary antibody was applied for 20 minutes; after the development of the color with DAB, the slides were counterstained with hematoxylin. Positive controls were included, and CK7 expression was as expected. Expression of the CK7 protein was cytoplasmic.
Results Demographics and Clinical History of the Dialysis Patients In all, 13 liver biopsies from patients on hemodialysis or peritoneal dialysis were retrieved (2000-2013). As shown in Table 1, the 13 cases included 10 men and 3 women, with a mean age of 55 years (range = 22-74 years). At the time of liver biopsy, 12 patients were on hemodialysis, and 1 was on peritoneal dialysis; with mean cumulative duration of 50 months (range = 17 months to 11 years). Three patients had histories of failed renal transplant prior to dialysis. Comorbidities included hypertension (7 patients), diabetes mellitus (5 patients), congestive heart failure (5 patients), hepatitis C viral (HCV) infection (4 patients), and human immunodeficiency viral (HIV) infection (3 patients). Coagulopathy was documented in 4 patients: one with hypercoagulopathy caused by anticardiolipin antibody and functional protein C deficiency (case 3) and 3 with deepvein thrombosis and/or pulmonary embolism (cases 4, 9, and 12). No patient with HIV was on didanosine. Two patients (cases 12 and 13) were on immunosuppressants, including sirolimus, tacrolimus, and mycophenolate mofetil. No patient was taking drugs of the thiopurine family. Indications for liver biopsy were a combination of abnormal liver function tests (6 patients), portal hypertension (4 patients), ascites (3 patients), and suspicion of cirrhosis (3 patients). In case 3, the only documented biochemical abnormality was increased alkaline phosphatase, and the liver biopsy was performed during cholecystectomy without γ glutamyl transpeptidase test. Two patients with portal hypertension underwent 3 or more consecutive liver biopsies to rule out cirrhosis, and 7 patients had selective elevation of alkaline phosphatase (range = 146-484 IU/L).
Histopathological Features of the Liver Biopsies As illustrated in Table 2 and Figure 1, 10 biopsies showed aberrant portal vasculature, including narrowed lumen (9
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Lee et al Table 1. Demographics and Clinical History of the Patients. A/G
Duration
Causes of Renal Failure
Inf
1
55, F 2 years
2
22, F 2 years 3 Cystinosis months
3 4 5
49, M 9 years HIV, DM 56, M 4 years Unknown 66, M 1 year 10 Amyloidosis, HTN months
HCV, HIV HCV HCV
6
43, M 3 years
Unknown
HIV
7 8
53, M 4 years 47, M 8 years
Unknown Alport SD
HCV, HIV
9
68, M 1 year 6 DM months 56, F 1 year 6 Possible IgA months nephritis
10 11a 12
13
HTN, DM
Comorbidities
Abnormal Biochemistry
Ix for Bx
CHF, HTN, MV disorder Cystinosis, hypothyroidism, anemia
AlkP 470 IU/L
HC, DM, Anemia CHF, HC, DM Amyloidosis (heart and kidney), HTN, AR, anemia HTN
AlkP146 IU/L Unknown AST143 IU/L HCV LFT
HTN, DM Alport SD
LFT, ascites, r/o LC Portal HTN
AlkP193 IU/L LFT AST1306 IU/L, ALT1070 IU/L Ascites AlkP295 IU/L Portal HTN
Other h/o Failed renal transplant ×2
h/o Failed renal transplant, multiple liver biopsies
CMV (liver) CHF. HC, HTN, DM, AlkP220 IUL Portal HTN, LFT COPD, Anemia HTN, Crohn’s disease, AlkP283 IU/L LFT, r/o LC hyperthyroidism, h/o cervical cancer 70, M 1 year 5 HTN CHF, HTN, AlkP484 IU/L Portal HTN, Multiple liver months ascites biopsies 74, M 1 year 5 Toxin (calcineurin) HC, DM, a1-AT def Ammonia Hyperammonemia, h/o Liver months 133 µg/dL r/o LC transplant as a result of a1-AT def 52, M 11 years Segmental CHF, Wegener’s LFT, ascites h/o Failed glomerulosclerosis granulomatosis, renal hyperparathyroidism transplant
Abbreviations: A/G, age and gender; Duration, cumulative duration of dialysis; Inf, infection; Ix, indication; Bx, biopsy; F, female; M, male; HTN, hypertension; DM, diabetes mellitus; CHF, congestive heart failure; MV, mitral valve; AlkP, alkaline phosphatase; LFT, abnormal liver function test; r/o, rule out; LC, liver cirrhosis; h/o, history of; HIV, human immunodeficiency virus; HCV, hepatitis C virus; HC, hypercoagulability; AR, aortic regurgitation; SD, syndrome; CMV, cytomegalovirus; COPD, chronic obstructive pulmonary disease; Ig, immunoglobulin; a1-AT def, α1 antitrypsin deficiency. AST, aspartate aminotransferase; ALT, alanine aminotransferase. a This patient (case 11) was on peritoneal dialysis, and the rest were on hemodialysis.
cases; Figure 1A), increased vascular profiles in portal tracts (8 cases; Figure 1B), and shunt vessels (3 cases; Figure 1C). Dilated sinusoids (9 cases; Figure 1D) and pattern of venous outflow obstruction (VOO) with centrizonal dilated sinusoids and atrophic hepatocytes (3 cases; Figure 1E) were also noted. Increased central veins per lobule were arbitrarily defined as 4 or more central veins per lobule at medium (×100) magnification, which was seen in 2 cases (Figure 1F). A total of 9 cases showed portal (4), periportal (3), and bridging (2) fibrosis; 5 cases showed focal to
extensive perisinusoidal fibrosis; and no steatosis or cholestasis was seen. No cirrhosis was identified. Portal and lobular inflammation was minimal to mild. The necroinflammatory activity of the biopsies from patients with chronic hepatitis C was minimal to mild (Batts-Ludwig activity grade 1-2). Reticulin stain showed regenerative nodules in 5 cases (Figures 1G and 1H). CK7 immunostaining showed a variable degree of portal bile ductular proliferation in all 13 cases, and aberrant expression of CK7 in centrilobular hepatocytes in 7 cases (Figure 1I).
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Table 2. Histopathological Features of the Liver Biopsies.a Case
1
Narrow lumen + Increased vascular profile in portal tract − Shunt vessel − Bile ductular proliferation + Fibrosis B Perisinusoidal fibrosis +(e) Dilated sinusoids + VOO + Increased central veins per lobule − Regenerative nodule − Aberrant CK7 expression +
2
3
4
5
6
7
8
9
10
11
12
13
+ − − +(m) P − + − − +(f) −
+ + +(f) + − − − − − − −
− − − + PP − + − + − +
+ + − +(m) P − − − + +(f) −
− − + +(m) − +(f) + − − − +
+ + − + B − − − − + +
+ + − +(m) − − − − − +(f) +
− + + + PP + + + − − +
+ + − + PP +(f) + − − − +
+ + − +(m) P − + + − + n/a
+ + − +(m) P − + − − n/a n/a
− − − +(m) − + + + − − n/a
Abbreviations: +, present; −, not present; f, focal; m, mild; e, extensive; B, bridging fibrosis; P, portal fibrosis; PP, periportal fibrosis; VOO, features of venous outflow obstruction; n/a, not applicable. a Stains were not performed or were unavailable.
Discussion Portal hypertension is defined as increased resistance to portal blood flow, with wedged and free hepatic venous pressure gradients of ≥6 mm Hg.3,20 The causes of portal hypertension may be prehepatic (portal vein thrombosis or increased splenic venous blood flow), intrahepatic (cirrhosis, schistosomiasis, and chronic liver disease), or posthepatic (constrictive pericarditis and hepatic outflow obstruction). Liver cirrhosis remains the most common intrahepatic cause of portal hypertension in the Western world.3 If no cirrhosis is found in patients with portal hypertension, other prehepatic, intrahepatic, and posthepatic causes of noncirrhotic portal hypertension are sought. The diagnosis of INCPH is rendered when other causes of noncirrhotic portal hypertension are excluded. The nomenclature of INCPH is not standardized. It has been referred to as noncirrhotic portal fibrosis and idiopathic portal hypertension in the Eastern world.3 In the Western world, the liver histopathology of INCPH has been conventionally divided into 4 categories: hepatoportal sclerosis, incomplete septal cirrhosis, nodular regenerative hyperplasia, and partial nodular transformation.2-4,6,9,10,13,17,18,21-23 Some authors considered incomplete septal cirrhosis as a form of regressed cirrhosis.24 Nevertheless, given the multitude of morphological features overlapping in these entities, these may represent common entities of varying histology.4,6,8,23,25,26 Schouten et al3 addressed the overlapping morphological features and common associated conditions of these entities in their review article and proposed the term idiopathic noncirrhotic portal hypertension as a single entity. Several hypotheses exist for the etiology of INCPH, including obliterative portal vasculopathy, endothelial cell damage, septic emboli and thrombosis, immunological disturbances, and drug/toxin associations.2,10,15,18 Regardless
of postulated etiologies, the histology shows a spectrum of vasculopathy and variable portal and perisinusoidal fibrosis. In fact, ultrastructural studies showed that perisinusoidal fibrosis is observed in most of the INCPH cases.27,28 Also, regenerative nodules may be seen on reticulin stain.2-15 In the present study, all 13 patients on dialysis at the time of liver biopsy showed some histological components of INCPH. Narrowed lumen of the portal vein branches and dilated sinusoids were the most common histological findings, seen in 9 of 13 patients. In addition, increased vascular profiles per portal tract were noted in 8 of 13 patients. Bile ductular proliferation and variable fibrosis appear to be less specific; however, bile ductular proliferation was noted in all 13 cases and fibrosis in 11 cases. Although portal vasculopathy is conveyed as a dominating culprit in several published studies, periportal and perisinusoidal fibrosis in the absence of portal vasculopathy is frequently seen in Western INCPH.3 In our study, 2 cases (4 and 13) were devoid of portal vessel changes but showed periportal and perisinusoidal fibrosis, dilated sinusoids, and increased central veins per lobule. Histological features of VOO, characterized by central sinusoidal dilation with congestion, with or without perisinusoidal fibrosis, were seen in patients with congestive heart failure. It is well known that congestive hepatopathy shows features of VOO. However, other conditions, including nodular regenerative hyperplasia, portal venous insufficiency, inflammation, granulomatous disease, neoplasms, and open-wedge biopsies, may also show VOO-like histology.29 Thus, the VOO-like histology in these patients may be in part attributable to other etiologies. For example, case 11 with portal hypertension underwent 3 needle biopsies before the diagnostic open-wedge biopsy that showed diffuse nodular regenerative hyperplasia, and one of the prior needle biopsies showed VOO pattern injury.
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Figure 1. Histological spectrum of liver biopsies from patients on dialysis. A. Portal tract with narrowed portal venous branch (arrow; hematoxylin and eosin [H&E], ×200, case 12). B. Portal tract with multiple vascular profiles (arrows; H&E ×200, case 10). C. Shunt vessel directly connecting the periportal liver parenchyma (arrow; H&E ×200, case 5). D. Dilated sinusoids (H&E, ×200, case 9). E. Venous outflow obstruction pattern injury with perisinusoidal fibrosis (arrow; trichrome, ×200, case 13). F. Increased central veins per lobule (H&E, ×100, case 5). G. Regenerative nodules (nodular regenerative hyperplasia) (arrows; H&E, ×50, case 11). H. Regenerative nodules (nodular regenerative hyperplasia; arrows; reticulin, ×50, case 11). I. Aberrant expression of CK7 in centrilobular hepatocytes and mild bile ductular proliferation (CK7, ×100, case 9).
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CK7 immunostain is helpful in evaluating bile ductular proliferation in the portal tracts and aberrant expression of CK7 in the centrizonal hepatocytes. Although not specific, centrilobular cholangiolar metaplasia represented by aberrant CK7 expression is associated with centrilobular scarring and cholestatic biochemistry profile.30,31 It may represent an intermediate hepatobiliary phenotype of centrizonal hepatocytes undergoing metaplasia or dedifferentiation secondary to tissue hypoxia.32,33 In our study, 7 of 10 biopsies showed variable degree of centrilobular cholangiolar metaplasia by the CK7 immunostain. In addition, 7 patients showed selective elevation of alkaline phosphatase, suggesting ischemic centrilobular injury and a possible cholestatic component, in keeping with previous reports of INCPH.2,3 We postulate that heterogeneous perfusion resulting from intrahepatic vascular remodeling, similar to INCPH, and subsequent ischemic injury of the central zone may manifest as cholangiolar metaplasia of centrizonal hepatocytes in these cases. INCPH is associated with variable conditions, including infection, thrombophilic status, genetic disorder, connective tissue disorder, and immunological disturbances.2,3,12-15,18,19 In our study, 4 patients (cases 3, 4, 9, and 12) had thrombophilic conditions, 4 (cases 2, 5, 10, and 13) had potential immunological disorder, and 3 (cases 2, 8, and 12) had genetic disorders. Four patients (cases 2, 8, 12, and 13) had failed renal and liver allografts, indicative of an exposure to immunosuppressive reagents; 10 patients (cases 1, 3, 4, 5, 6, 7, 9, 10, 11, and 12) had hypertension and/or diabetes mellitus, which are prone to vasculopathy. Of note, 4 patients (cases 3, 4, 5, and 7) had chronic hepatitis C. Krasinskas et al34 explored portal vasculopathy of native and allograft liver biopsies with HCV and found that the biopsies from patients with HCV showed increased number of vascular channels per portal tract compared with non-HCV biopsies. Also, the portal vascular changes were positively correlated with the degree of portal inflammation. Thus, the portal vascular changes and fibrosis seen in these patients may partly be attributed to HCV hepatitis. However, the portal inflammation of these patients was minimal to mild (Batts-Ludwig grade 1-2), and the biopsies from 3 patients showed dilated sinusoids, increased central veins per lobule, and regenerative nodules, which were not studied in HCV biopsies but were described in INCPH. Therefore, it is also possible that the portal vascular changes in these 4 patients represent histological components of INCPH. In addition, 3 patients (cases 3, 6, and 7) had HIV infection. INCPH has been described in HIV patients, for which didanosine, an antiretroviral nucleoside analogue, is considered to be responsible.13,15 No patient in this study was on didanosine. Similarly, although all patients were on multiple medications at the time of the biopsy, a history of drugs that are reported to be associated with INCPH, such
as immunosuppressant of thiopurine family (azathioprine, 6-thioguanine), was not found. All patients were on dialysis at the time of the biopsy. Hence, the possibility that dialysis itself may have contributed to the histological changes is raised. Khurana et al20 studied portal venous pressure in patients with chronic hepatitis C, of whom 58 were on dialysis. The authors found that dialysis significantly decreases portal pressure, especially in those with advanced fibrosis. It was postulated that dialysis removes inflammatory mediators such as interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor-α from the circulation, thereby mitigating the inflammatory component that may contribute to elevated portal venous pressure.20 Likewise, albumin dialysis temporarily reduced portal pressure in patients with acute alcoholic hepatitis with risk of variceal bleeding.35 Mysorekar et al36 studied liver biopsies of HCV patients on hemodialysis and reported that the necroinflammatory activity is mild in this group. Similarly, in our cases, the portal and lobular inflammation was minimal to mild. Although these studies did not address histological changes pertinent to INCPH, they appear to suggest that dialysis plays a beneficial role in controlling inflammation and portal hypertension. The fact that portal inflammation is positively associated with portal vasculopathy in chronic hepatitis C further supports the notion.34 Taken together, it seems unlikely that dialysis itself caused the histological changes in the liver biopsies. Hepatic pathology in patients on dialysis was rarely reported. Elariny et al10 reported a case of nodular regenerative hyperplasia in a patient on hemodialysis. This patient also had HCV and history of failed renal transplant.10 Loinaz et al17 reported 1 patient on dialysis in their study of 4 patients with portal hypertension without cirrhosis. This patient had Alport syndrome and had undergone a renal transplant.17 Given the multiple coexisting risk factors for INCPH in patients on dialysis, as demonstrated in our series and the previous reports, the histology of INCPH in these patients appears to be reflective of varying underlying clinical conditions that are known risk factors for INCPH. The specificity and significance of portal vascular changes outside the setting of cirrhosis and portal hypertension is unknown. Obliterative portal vasculopathy was described in patients with congestive heart failure and arterial thrombosis, and shunt vessels were described in liver biopsies with no portal hypertension.16,37 In the absence of a systemic review of “normal” liver biopsies pertaining to the histological features of INCPH, the significance of our observation remains unclear. However, the fact that 4 of 13 (31%) patients had documented portal hypertension without evidence of cirrhosis and 2 patients underwent multiple liver biopsies for suspicion of cirrhosis deserves attention. The histomorphological
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Lee et al changes may represent a chronological progression of INCPH, with clinical portal hypertension at one end of the spectrum. The report that only 5% of INCPH by histomorphology was associated with clinical portal hypertension further lends support to our hypothesis.5 In summary, histological features of INCPH were identified in liver biopsies from patients on dialysis and appear to be secondary to various underlying risk factors for INCPH in this group. Cognizance of these findings and the potential risk factors for INCPH in patients with a complicated medical history will enhance the diagnostic prowess of surgical pathologists and help avoid overdiagnosis of chronic hepatitis and cirrhosis, and redundant procedures. Acknowledgments The authors thank Natalya Colomb, Nicole Burrow, the Tumor Registry and Hospital Information System at the Albany Medical Center for their support.
Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
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