Diagnostic Problems in Hepatology

Drug-Induced Nodular Regenerative Hyperplasia Marwan Ghabril, MD1

Raj Vuppalanchi, MD1

1 Department of Medicine, Indiana University School of Medicine,

Indianapolis, Indiana

Address for correspondence Raj Vuppalanchi, MD, Department of Medicine, Indiana University School of Medicine, 1050 Wishard Blvd, RG 4100, Indianapolis, IN 46202 (e-mail: [email protected]).

Semin Liver Dis 2014;34:240–245.

Abstract

Keywords

► nodular regenerative hyperplasia ► drug-induced liver injury

Drug-induced nodular regenerative hyperplasia is an uncommon injury with unique pathophysiology, clinical, and diagnostic considerations. This injury is characteristically asymptomatic in its early phases with only mild elevations in transaminases (< 3 upper limit of normal [ULN]). The latency period is typically more than 6 months. Once clinically apparent, it is marked by complications of portal hypertension, including hypersplenism, ascites, and variceal bleeding, with little or no hepatic dysfunction. Hence, it is an important cause of noncirrhotic portal hypertension. The most commonly associated drugs include thiopurines, chemotherapeutic agents, and antiretroviral agents. Diagnosis is aided by the recognition of noncirrhotic portal hypertension, a detailed history of prior drug exposure, and exclusion of the other causes of nodular regenerative hyperplasia. Clinical history, abdominal imaging, and hepatic hemodynamic studies provide important diagnostic clues, but histologic examination remains the diagnostic gold standard. Therapeutic intervention is aimed at earliest discontinuation of the offending agent and of portal hypertension complications. The natural history varies widely, and portal hypertension can progresses despite drug discontinuation.

Drug-induced liver injury (DILI) is often acute and presents with hepatocellular, cholestatic, or mixed biochemical and histological injury patterns.1,2 However, some drugs can induce venous and sinusoidal injuries to the liver, resulting in adaptive parenchymal changes due to abnormalities in portal and/or central veins. Nodular regenerative hyperplasia (NRH) of the liver is one such abnormality that can present with noncirrhotic portal hypertension (NCPH).3,4 NRH was first described by Ranstrom in 1953 in a patient with Felty syndrome.5 However, it was Steiner in 1959 who first coined the term “nodular regenerative hyperplasia,” emphasizing that hepatocyte hyperplasia or regeneration took place in the absence of fibrous tissue proliferation resulting in a nodular liver simulating cirrhosis.3 It is believed that intrahepatic vasculitis from certain drugs, autoimmune diseases, or recurrent microembolization from the portal system results in portal obliterative venopathy. The subsequent alterations in perfusion are felt to cause local hepatocyte ischemia with compensatory hypertrophy of unaffected adjacent hepatocytes leading to NRH. Recent demonstration

Issue Theme Drug-Induced Liver Injury; Guest Editors, Naga Chalasani, MD, and Paul H. Hayashi, MD, MPH

of downregulation of Notch1, delta-like 4, and ephrinB2, genes involved in vascular differentiation, suggest that NRH is indeed caused by a sinusoidal injury.6,7 NRH can develop in all age groups, but more commonly affects older individuals.8 There is a reporting bias with most cases in the literature having significant portal hypertension, representing the advanced phenotype of the disease spectrum.4 The majority of patients with milder forms of NRH presumably remain unidentified, and their disease course is rarely characterized.9 Survival is highly variable and is associated with age and the underlying cause of NRH (►Table 1), and typically not with severity of portal hypertension.10

Clinical Phenotype Clinically apparent drug-induced NRH is relatively uncommon, but it is an important diagnosis that needs to be considered in patients presenting with NCPH without hepatic dysfunction. The clinical presentation is variable, but the published reports are biased toward overt portal

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DOI http://dx.doi.org/ 10.1055/s-0034-1375963. ISSN 0272-8087.

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Drug-Induced Nodular Regenerative Hyperplasia

Autoimmune Inflammatory bowel disease Myasthenia gravis Celiac disease Primary biliary cirrhosis Scleroderma/CREST Sarcoidosis Rheumatoid arthritis / Felty syndrome Systemic lupus erythematosus Polyarteritis nodosa Behçet disease Antiphospholipid syndrome

Vascular Portal vein agenesis Cardiac abnormalities Congestive heart failure Portal vein thrombosis Budd-Chiari syndrome Malignancy Metastatic breast cancer via portal vein metastasis Carcinoid31 Lymphoproliferative and myeloproliferative disorders32 Castleman disease

Poisoning Arsenic Toxic oil syndrome

Other Common variable deficiency Sickle cell anemia Tuberculosis

Source: Collated from multiple sources including Reshamwala et al,33 Hartleb et al,9 and Schiff, Diseases of the Liver, 9th ed.39 Additional associated agents are referenced individually.

hypertension with ascites or variceal bleed.11 A diagnosis of drug-induced NRH requires consideration of a broad array of competing etiologies, including malignant, prothrombotic, or rheumatologic conditions (►Table 1). The absence of any of these associated conditions should prompt a detailed drug history, including remote exposure to immunosuppressants and chemotherapeutic drugs (►Table 2) to make the diagnosis. The most commonly reported agents in drug-induced NRH include the thiopurines (azathioprine and thioguanine), oxaliplatin and didanosine, although multiple other agents have been implicated (►Table 2). The clinical characteristics and risk factors for NRH associated with these drugs are summarized in ►Table 3. The majority of published cases and case series describing drug-induced NRH report mainly on specific populations targeted for that particular drug. Of these agents, thiopurines have the least specific indication, as they are commonly used in several immunosuppressive regimens. Nodular regenerative hyperplasia has been described with thiopurine use for autoimmune disorders, and following solid-organ transplantation, but is most commonly reported in individuals receiving therapy for inflammatory bowel disease (IBD).12 It is important to recognize that IBD itself is associated with NRH, and was incidentally found in 6% of thiopurine naive IBD patients undergoing bowel resection.13 A common feature of drug induced NRH is the relatively long latency (interval from initial drug exposure to recognition of injury). This is likely explained by a long asymptomatic phase without significantly increased liver biochemistries, the hallmark of most DILI. The range of latencies for thiopurine induced NRH was 5 months to 6 years, and the median latency for didanosine induced NRH was 4 years. In contrast, the median latency for non-NRH idiosyncratic DILI is 40 days

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Table 2 List of drugs implicated to cause nodular regenerative hyperplasia Well-described agents

Other reported agents

Immunosuppressive agents Azathioprine Mercaptopurine Thioguanine Antiretroviral agents Didanosine Stavudine Antineoplastic agents Oxaliplatin

Antineoplastic agents Isoplatin Busulfan4 Cytosine arabinoside / daunorubicin Chlorambucil Cyclophosphamide Bleomycin Carmustine Doxorubicin Phenytoin4 Gold and penicillamine4 Other agents Interleukin 2 therapy34 Thorotrast35 Methotrexate Birth control pills4 Oxymetholone4 Trastuzumab emtansine19

Source: Collated from multiple sources including Reshamwala et al,33 Hartleb et al,9 www.livertox.com; and Schiff, Diseases of the Liver, 9th ed.39 Additional agents were referenced individually.

(interquartile range, 19–117).1,12,14 Oxaliplatin induced NRH can manifest either with a short15 or very long (several years) latency with an incidence of up to 12%.16 As a result of these varied latencies with short or long asymptomatic phases and clinician's unfamiliarity with NRH, the disorder is often overlooked and certainly underreported in the literature. Moreover, NRH can be a difficult diagnosis to make even after a clinician suspects it.

Diagnostic Challenges During or immediately after exposure to the offending drug, there may be mild elevations in liver enzymes or thrombocytopenia related to splenic sequestration.17–19 Patients are asymptomatic in this early phase of the disease and health care providers may not recognize ongoing liver injury or remodeling.19 Moreover, regenerative nodules are very small (< 0.5 cm in diameter) and none of the conventional imaging techniques reveal any changes other than hepatic enlargement and/ or parenchymal heterogeneity. This may lead to prolonged exposure to the offending drug until the onset of NCPH.19 With advanced NRH, imaging studies show a small liver and coarse nodules with areas of capsular retraction.4 These nodules are numerous and can sometimes coalesce to form a large nodule spanning several centimeters.4 Imaging features using ultrasound (US) are generally varied and nonspecific with hypoechoic, isoechoic or hyperechoic nodules.4 However, a group recently described an “atoll sign” using latest generation US with contrast enhancement.20 The technique showed small, round isoechoic lesions with a thin hyperechoic rim resembling the ring-shaped coral-reef configuration of an atoll. On contrast-enhanced computed tomography, these nodules are isodense or hypodense in both Seminars in Liver Disease

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Table 1 Differential diagnosis of nondrug-related causes of nodular regenerative hyperplasia

Ghabril, Vuppalanchi

0.6 - 1.28% at 5 and 10 y

0–27%

Up to 33%

8 per 10,000 patient years

0.4%

Azathioprine12

Thioguanine12

Oxaliplatin36

Didanosine14

Trastuzumab Emtansine19

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Unknown

Age Cumulative exposure to didanosine and stavudine

3.6 mg/kg IV infusion over 90 min every 3 wk

Not specified

Not specified

20–80 mg/d

100–200 mg/d

Daily dose

203–441 days

Median of 4 y

Not specified, however sinusoidal injury is reported after 6–8 cycles of chemotherapy37

1–6 y

0.5–5 y

Latency

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HER2-positive, metastatic breast cancer

Human immunodeficiency virus infection

Severity of sinusoidal injury Increased risk with difficult surgery Risk reduction with bevacizumab therapy

Daily dose >40 mg/d

Older age Male gender Small bowel resection

Risk factors

Regression of portal hypertension has been described.

Undefined, both regression and progression of portal hypertension have been described38

Undefined, both regression and progression of portal hypertension have been described.

Undefined, both regression and progression of portal hypertension have been described.

Undefined Normalization of platelet count can occur after 12–36 mo; however, portal hypertension may persist

Natural history after drug cessation

Drug-Induced Nodular Regenerative Hyperplasia

Metastatic colorectal cancer

Inflammatory bowel disease

Inflammatory bowel disease

Indication

Table 3 Clinical phenotype and outcomes of select drugs that cause nodular regenerative hyperplasia. The ranges of reported values are described.

242 Ghabril, Vuppalanchi

arterial and portal venous phases, while on contrast-enhanced magnetic resonance imaging, they are hypertense on T1- and iso- to hypointense on T2-weighted images.21,22 Notably, the imaging abnormalities of NRH may persist for years after stopping the offending agent.23 Although imaging may be helpful, diagnosis of NRH requires histologic examination that is characterized by partial or complete transformation of the liver parenchyma into diffuse, benign, small regenerative nodules with little to no associated periportal or perisinusoidal fibrosis/septae.8 A reticulin stain is a useful aid. This preparation may highlight areas of focal hepatocyte atrophy and sinusoidal dilation from compression due to adjacent areas of regenerative, hypertrophic hepatocytes without intervening fibrosis (►Fig. 1). Increased CD34 expression in NRH biopsies appears to be related to the severity of portal hypertension.6 However, histologic diagnosis can still be difficult on percutaneous needle biopsy due to inadequate tissue sampling. The regenerative nodules may not be readily apparent on a thin core sample. A laparoscopically guided wedge biopsy may be necessary, but may not be feasible, particularly in the setting of severe portal hypertension. Assessment of portal hypertension by measuring the hepatic venouspressure gradient (HVPG) in patients with NRH has yielded conflicting data due to occurrence of both pre-sinusoidal and sinusoidal portal hypertension.24 It has been suggested that the presinusoidal portal hypertension is related to obliterative portal venopathy while the sinusoidal portal hypertension is related to sinusoidal obstruction due to compression by regenerative nodules.24 It is therefore conceivable that early in the course of NRH, the HVPG as measured by transjugular venous catheter may be less than 10 mm Hg due to presinusoidal portal hypertension. Alternatively, HVPG may depend upon the predominant mechanism causing portal hypertension for that particular patient (obliterative portal venopathy versus compression by regenerative nodules).24 The use of transient elastography for noninvasive assessment of NRH may hold promise with one study showing a low median liver stiffness of 7.9 kPa despite evidence of portal hypertension.25 Such a finding would at least suggest underlying noncirrhotic portal hypertension. However, this study also showed a wide range in the median liver stiffness values (range, 3.5–16.8 kPa).25 It is possible that the variation in liver stiffness again reflects variability in the predominant mechanism of injury (i.e., low liver stiffness in presinusoidal versus high liver stiffness in sinusoidal portal hypertension). In summary, a high index of suspicion must be maintained to make a diagnosis of NRH in patients with NCPH. Diagnosis depends on using an array of subtle, but important clues obtained through a careful history, imaging studies, liver biopsy with reticulin stain, and the HVPG measurements. For the latter two diagnostic data, we recommend liver biopsy by transjugular approach to obtain core needle samples and HVPG readings. The relatively small gauge of biopsy needle used during the transjugular approach often limits the specimen size needed to identify the histologic features of NRH. If the core sample is not adequate or diagnostic, and NRH is still

Ghabril, Vuppalanchi

Fig. 1 Liver histology in patients with NRH. (A) Reticulin stain highlights thinned out plates (arrows) alternating with thickened plates () creating a nodular hepatic parenchyma in the absence of fibrosis. (B) Immunohistochemical stain for the endothelial marker CD34 highlights endothelial cells around portal tract (arrows) in normal liver. CD34 diffusely marks sinusoidal cells in liver biopsy from patient 1. Arrows point to a portal tract. (C) Reticulin stain highlights thinned out plates (arrows) alternating with thickened plates ( ) creating a nodular hepatic parenchyma in the absence of fibrosis. (Reproduced with permission from Journal of Clinical Oncology19)

suspected, more invasive laparoscopic wedge biopsy may be considered and pursued on a case-by-case basis. NRH of the liver is an established pathologic entity and an important diagnosis to make. It must not be confused with focal nodular hyperplasia, hepatocellular adenoma, or the regenerative nodules associated with cirrhosis.4 Correct diagnosis will prevent an unnecessary hepatic lobectomy should NRH be Seminars in Liver Disease

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Drug-Induced Nodular Regenerative Hyperplasia

Drug-Induced Nodular Regenerative Hyperplasia

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mistaken for hepatocellular adenoma. Correct diagnosis is also important because the prognosis in patients with NRH and portal hypertension is better than in patients with portal hypertension due to cirrhosis. Most of all, early recognition can lead to discontinuation of the offending agent and prevent worsening of this atypical DILI.19

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Management Issues The primary goal in the management of drug-induced NRH is earlydetection and cessation of the causative medication. Classic examples for this situation include azathioprine, didanosine,23 trastuzumab emtansine,19 where cessation of therapy may either result in regression of NRH or at least help prevent progression of NRH.26 However, in chemotherapy-induced NRH, symptoms of NCPH are often recognized well after the exposure. Therefore, treatment is primarily geared toward management of portal hypertension. There are anecdotal reports of improvement in liver tests and function with use of ursodeoxycholic acid or low-molecular-weight heparin in a patient with NRH induced by antiretroviral therapy in an HIV patient with thrombophilia respectively.27,28 However, there are no prospective or controlled studies regarding therapeutics for NRH. The prognosis is generally good with prevention and treatment of portal hypertension complications. A transjugular intrahepatic portosystemic shunt (TIPS) may offer significant benefit in cases of refractory ascites or recurrent variceal bleeding despite endoscopic band ligation. Importantly, TIPS appears to benefit even those patients with predominantly presinusoidal portal hypertension (portal venous pressure gradient > 12 mm Hg, and HVPG by transjugular reading < 11 mg Hg).11 In centers with expertise, surgical portacaval shunt could also be considered in specific cases with preserved synthetic function when non-surgical management fails.29 Finally, liver transplantation may be offered to those rare cases that progress to hepatic failure despite cessation of the offending drug.30

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References 1 Chalasani N, Fontana RJ, Bonkovsky HL, et al; Drug Induced Liver

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Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008;135(6):1924–1934, e1–e4 Kleiner DE, Chalasani NP, Lee WM, et al; Drug-Induced Liver Injury Network (DILIN). Hepatic histological findings in suspected druginduced liver injury: systematic evaluation and clinical associations. Hepatology 2014;59(2):661–670 Steiner PE. Nodular regenerative hyperplasia of the liver. Am J Pathol 1959;35:943–953 Dachman AH, Ros PR, Goodman ZD, Olmsted WW, Ishak KG. Nodular regenerative hyperplasia of the liver: clinical and radiologic observations. AJR Am J Roentgenol 1987;148(4):717–722 Ranstrom S. Miliary hepatocellular adenomatosis. Acta Pathol Microbiol Scand 1953;33(3):225–229 Rothweiler S, Terracciano L, Tornillo L, Dill MT, Heim MH, Semela D. Downregulation of the Endothelial Genes Notch1 and EphrinB2 in Patients with Nodular Regenerative Hyperplasia. Liver Int 2014; 34(4):594–603

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plasia in a patient with generalized essential telangiectasia: Endotheliopathy as causal factor. Hepatology 2013 Wanless IR. Micronodular transformation (nodular regenerative hyperplasia) of the liver: a report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules. Hepatology 1990;11(5):787–797 Hartleb M, Gutkowski K, Milkiewicz P. Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension. World J Gastroenterol 2011;17(11):1400–1409 Morris JM, Oien KA, McMahon M, et al. Nodular regenerative hyperplasia of the liver: survival and associated features in a UK case series. Eur J Gastroenterol Hepatol 2010;22(8):1001–1005 Bissonnette J, Généreux A, Côté J, et al. Hepatic hemodynamics in 24 patients with nodular regenerative hyperplasia and symptomatic portal hypertension. J Gastroenterol Hepatol 2012;27(8): 1336–1340 Musumba CO. Review article: the association between nodular regenerative hyperplasia, inflammatory bowel disease and thiopurine therapy. Aliment Pharmacol Ther 2013;38(9):1025–1037 De Boer NK, Tuynman H, Bloemena E, et al. Histopathology of liver biopsies from a thiopurine-naïve inflammatory bowel disease cohort: prevalence of nodular regenerative hyperplasia. Scand J Gastroenterol 2008;43(5):604–608 Cotte L, Bénet T, Billioud C, et al. The role of nucleoside and nucleotide analogues in nodular regenerative hyperplasia in HIV-infected patients: a case control study. J Hepatol 2011; 54(3):489–496 Hubert C, Sempoux C, Horsmans Y, et al. Nodular regenerative hyperplasia: a deleterious consequence of chemotherapy for colorectal liver metastases? Liver Int 2007;27(7):938–943 Nguyen-Khac E, Lobry C, Chatelain D, et al. A Reappraisal of Chemotherapy-Induced Liver Injury in Colorectal Liver Metastases before the Era of Antiangiogenics. Int J Hepatol 2013;2013:314868 Naber AH, Van Haelst U, Yap SH. Nodular regenerative hyperplasia of the liver: an important cause of portal hypertension in noncirrhotic patients. J Hepatol 1991;12(1):94–99 Wicherts DA, de Haas RJ, Sebagh M, et al. Regenerative nodular hyperplasia of the liver related to chemotherapy: impact on outcome of liver surgery for colorectal metastases. Ann Surg Oncol 2011;18(3):659–669 Force J Sr, Schneider B, Storniolo A, Sledge GW, Chalasani N, Vuppalanchi R. Nodular Regenerative Hyperplasia After Treatment With Trastuzumab Emtansine. J Clin Oncol 2014; [Epub ahead of print] Caturelli E, Ghittoni G, Ranalli TV, Gomes VV. Nodular regenerative hyperplasia of the liver: coral atoll-like lesions on ultrasound are characteristic in predisposed patients. Br J Radiol 2011;84(1003): e129–e134 Siegelman ES, Outwater EK, Furth EE, Rubin R. MR imaging of hepatic nodular regenerative hyperplasia. J Magn Reson Imaging 1995;5(6):730–732 Ames JT, Federle MP, Chopra K. Distinguishing clinical and imaging features of nodular regenerative hyperplasia and large regenerative nodules of the liver. Clin Radiol 2009;64(12):1190–1195 Hofmaenner D, Kovari H, Weber A, Weishaupt D, Speck RF. Nodular regenerative hyperplasia of the liver associated with didanosine persists for years even after its interruption. BMJ Case Rep 2011; 2011; Duseja A, Chawla Y. Portal hypertension in nodular regenerative hyperplasia: a mixed bag!. J Gastroenterol Hepatol 2012;27(8): 1260–1262 Laharie D, Vergniol J, Bioulac-Sage P, et al. Usefulness of noninvasive tests in nodular regenerative hyperplasia of the liver. Eur J Gastroenterol Hepatol 2010;22(4):487–493 Gane E, Portmann B, Saxena R, Wong P, Ramage J, Williams R. Nodular regenerative hyperplasia of the liver graft after liver transplantation. Hepatology 1994;20(1 Pt 1):88–94

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Successful use of ursodeoxycholic acid in nodular regenerative hyperplasia of the liver. Ann Pharmacother 2011;45(4): e20 Bihl F, Janssens F, Boehlen F, Rubbia-Brandt L, Hadengue A, Spahr L. Anticoagulant therapy for nodular regenerative hyperplasia in a HIV-infected patient. BMC Gastroenterol 2010;10:6 Louwers LM, Bortman J, Koffron A, Stecevic V, Cohn S, Raofi V. Noncirrhotic Portal Hypertension due to Nodular Regenerative Hyperplasia Treated with Surgical Portacaval Shunt. Case Rep Med 2012;2012:965304 Manzia TM, Gravante G, Di Paolo D, et al. Liver transplantation for the treatment of nodular regenerative hyperplasia. Dig Liver Dis 2011;43(12):929–934 Al-Hamoudi WK, Pasieka JL, Urbanski SJ, Lee SS. Hepatic nodular regenerative hyperplasia in a patient with advanced carcinoid tumor. Eur J Gastroenterol Hepatol 2009;21(9):1083–1085 Al-Mukhaizeem KA, Rosenberg A, Sherker AH. Nodular regenerative hyperplasia of the liver: an under-recognized cause of portal hypertension in hematological disorders. Am J Hematol 2004;75(4): 225–230

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33 Reshamwala PA, Kleiner DE, Heller T. Nodular regenerative hyperpla-

sia: not all nodules are created equal. Hepatology 2006;44(1):7–14 34 Podevin P, Spiridon G, Terris B, et al. Nodular regenerative hyper-

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plasia of the liver after IL-2 therapy in an HIV-infected patient. AIDS 2006;20(2):313–315 Beer TW, Carr NJ, Buxton PJ. Thorotrast associated nodular regenerative hyperplasia of the liver. J Clin Pathol 1998;51(12):941–942 Rubbia-Brandt L, Lauwers GY, Wang H, et al. Sinusoidal obstruction syndrome and nodular regenerative hyperplasia are frequent oxaliplatin-associated liver lesions and partially prevented by bevacizumab in patients with hepatic colorectal metastasis. Histopathology 2010;56(4):430–439 Robinson SM, Wilson CH, Burt AD, Manas DM, White SA. Chemotherapy-associated liver injury in patients with colorectal liver metastases: a systematic review and meta-analysis. Ann Surg Oncol 2012;19(13):4287–4299 Scourfield A, Waters L, Holmes P, et al. Non-cirrhotic portal hypertension in HIV-infected individuals. Int J STD AIDS 2011; 22(6):324–328 Schiff ER, Sorrell MF, Maddrey WC, eds. Schiff’s diseases of the liver. 9th ed. Philadelphia: Lippincott Williams & Wilkins; 2003:1152–1155

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27 Ranucci G, Cirillo F, Della Corte C, Vecchione R, Vallone G, Iorio R.

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Drug-induced nodular regenerative hyperplasia.

Drug-induced nodular regenerative hyperplasia is an uncommon injury with unique pathophysiology, clinical, and diagnostic considerations. This injury ...
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