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{{CMG}}
__NOTOC__
{{SI}}                                                                 
{{CMG}} {{AE}} {{MV}},{{Rekha}}<br>
 
{{SK}} NRHL; Non-cirrhotic portal hypertension; NRH
==Overview==
 
Nodular regenerative hyperplasia (NRH) is described as a rare form of non-cirrhotic [[portal hypertension]] in the absence of a recognizable cause. NRH is associated with [[Organ transplant|solid organ transplant]] (eg. [[Renal transplantation|renal transplants]], [[Bone marrow transplantation|bone marrow transplants]]) and chronic use of medications. it may be classified into 2 subtypes: Pre-sinusoidal and sinusoidal. The pathogenesis of NRH is characterized by arterial hypervascularity secondary to loss of hepatic vein radicles and loss of central venule in the [[hepatic lobule]]. NRH is a rare disease. The estimated incidence of NRH is approximately 0.34 cases per 100,000 individuals. NRH is more commonly observed among patients between 25 and 65 years old. The majority of patients with NRH may be initially asymptomatic. Early clinical features include [[fatigue]], [[weight loss]], and [[abdominal distension]].  If left untreated, the majority of patients with NRH may progress to develop [[Acute liver failure|acute hepatic failure]] and death. The diagnosis of NRH is made with the following diagnostic criteria: Latency of more than 6 months, minimal or no elevations in serum [[Alanine transaminase|alanine transaminase (ALT)]], clinical, radiologic or endoscopic signs of [[portal hypertension]], and [[liver biopsy]]. Treatment includes cessation of offending agents and management of [[portal hypertension]] and [[variceal bleeding]].




==Historical Perspective==
* In 1953, the first case of NRH was described by Ranstrom in a patient with [[Felty's syndrome|Felty’s syndrome]], terming it as “miliary hepatocellular adenomatatosis”.<ref name="pmid22956964">{{cite journal |vauthors=Louwers LM, Bortman J, Koffron A, Stecevic V, Cohn S, Raofi V |title=Noncirrhotic Portal Hypertension due to Nodular Regenerative Hyperplasia Treated with Surgical Portacaval Shunt |journal=Case Rep Med |volume=2012 |issue= |pages=965304 |year=2012 |pmid=22956964 |pmc=3432362 |doi=10.1155/2012/965304 |url=}}</ref><ref name="pmid21472097">{{cite journal |vauthors=Hartleb M, Gutkowski K, Milkiewicz P |title=Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension |journal=World J. Gastroenterol. |volume=17 |issue=11 |pages=1400–9 |year=2011 |pmid=21472097 |pmc=3070012 |doi=10.3748/wjg.v17.i11.1400 |url=}}</ref>
* NRH was first described by Steiner in 1959.<ref name="pmid13834213">{{cite journal |vauthors=STEINER PE |title=Nodular regenerative hyperplasia of the liver |journal=Am. J. Pathol. |volume=35 |issue= |pages=943–53 |year=1959 |pmid=13834213 |pmc=1934844 |doi= |url=}}</ref>


==Overview==
==Classification==
{{SI}}
* Nodular regenerative hyperplasia may be classified into 2 subtypes:<ref name="pmid22956964">{{cite journal |vauthors=Louwers LM, Bortman J, Koffron A, Stecevic V, Cohn S, Raofi V |title=Noncirrhotic Portal Hypertension due to Nodular Regenerative Hyperplasia Treated with Surgical Portacaval Shunt |journal=Case Rep Med |volume=2012 |issue= |pages=965304 |year=2012 |pmid=22956964 |pmc=3432362 |doi=10.1155/2012/965304 |url=}}</ref>
'''Nodular regenerative hyperplasia''' is a form of liver hyperplasia associated with [[portal hypertension]].<ref name="pmid18417867">{{cite journal |author=Shelly D, Tevatia MS, Praharaj AK, Mehta A, Harish S, Baskaran V |title=Nodular regenerative hyperplasia of liver |journal=Indian J Pathol Microbiol |volume=51 |issue=1 |pages=78–80 |year=2008 |pmid=18417867 |doi= |url=http://www.ijpmonline.org/article.asp?issn=0377-4929;year=2008;volume=51;issue=1;spage=78;epage=80;aulast=Shelly}}</ref>
** Pre-sinusoidal
** Sinusoidal
* Another variant of NRH may be included in [[Banti's syndrome]], which is described as chronic splenic congestion chronic resulting in rapid destruction of [[Red blood cell|red blood cells (RBCs)]] prematurely.
 
==Pathophysiology==
* It is a poorly understood disease process thought to be mediated by chronic [[inflammatory]] and [[thrombotic]] processes leading to occlusion of hepatic microvascuature. [[Ischemic]] changes then lead to regeneration of [[hepatocytes]].<ref>{{Cite journal|last=Vispo|first=E|date=May 2010|title=Noncirrhotic portal hypertension in HIV-infected patients: unique clinical and pathological findings.|url=https://www.ncbi.nlm.nih.gov/pubmed/20299955|journal=AIDS.|volume=|pages=|via=}}</ref>
*The pathogenesis of NRH is characterized by:
**Arterial hypervascularity secondary to loss of hepatic vein radicles.
**Loss of central venule in the [[hepatic lobule]].
**Diffuse regeneration of [[hepatocytes]] in the parenchyma in the form of nodules.
* The RASSF1A gene has been associated with the development of NRH, involving the [[Apoptosis|pro-apoptotic pathway]].<ref name="librepato">Nodular regenerative hyperplasia.  Libre Pathology https://librepathology.org/wiki/Medical_liver_disease#Nodular_regenerative_hyperplasia Accessed on April 12, 2015 </ref>
* On gross pathology a diffuse nodularity may be seen.<ref name="librepato">Nodular regenerative hyperplasia.  Libre Pathology https://librepathology.org/wiki/Medical_liver_disease#Nodular_regenerative_hyperplasia Accessed on April 12, 2015 </ref>
* The most important findings on microscopic histopathological analysis:<ref name="librepato">Nodular regenerative hyperplasia.  Libre Pathology https://librepathology.org/wiki/Medical_liver_disease#Nodular_regenerative_hyperplasia Accessed on April 12, 2015 </ref>
** Plates of [[hepatocytes]] in the [[parenchyma]] set in thick curved nodules.
** "Plump" [[hepatocytes]] arranged in micronodules:
***Central hyperplasia with an atrophic rim.
** No fibrosis.
 
==Causes==
Common causes of NRH may include:<ref name="pmid214720972">{{cite journal| author=Hartleb M, Gutkowski K, Milkiewicz P| title=Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension. | journal=World J Gastroenterol | year= 2011 | volume= 17 | issue= 11 | pages= 1400-9 | pmid=21472097 | doi=10.3748/wjg.v17.i11.1400 | pmc=3070012 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21472097  }}</ref><ref name="pmid3140108">{{cite journal| author=Buffet C, Cantarovitch M, Pelletier G, Fabre M, Martin E, Charpentier B et al.| title=Three cases of nodular regenerative hyperplasia of the liver following renal transplantation. | journal=Nephrol Dial Transplant | year= 1988 | volume= 3 | issue= 3 | pages= 327-30 | pmid=3140108 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=3140108  }}</ref>
 
*[[Organ transplantation|Solid organ transplantation]]
*[[Autoimmune|Autoimmune diseases]]
* Infections like [[HIV]]<ref name="pmid17640321">{{cite journal| author=Schiano TD, Kotler DP, Ferran E, Fiel MI| title=Hepatoportal sclerosis as a cause of noncirrhotic portal hypertension in patients with HIV. | journal=Am J Gastroenterol | year= 2007 | volume= 102 | issue= 11 | pages= 2536-40 | pmid=17640321 | doi=10.1111/j.1572-0241.2007.01428.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17640321  }}</ref>
*[[Hematological]]
*[[Neoplastic]]
* Chronic use of medications, such as:
**[[Azathioprine]] <ref name="pmid17504943">{{cite journal| author=Vernier-Massouille G, Cosnes J, Lemann M, Marteau P, Reinisch W, Laharie D et al.| title=Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine. | journal=Gut | year= 2007 | volume= 56 | issue= 10 | pages= 1404-9 | pmid=17504943 | doi=10.1136/gut.2006.114363 | pmc=2000290 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17504943  }}</ref><ref>{{Cite journal|last=Dubinksy|first=MC|date=August 2003|title=6-thioguanine can cause serious liver injury in inflammatory bowel disease patients.|url=https://www.ncbi.nlm.nih.gov/pubmed/12891528/|journal=Gastroenterology|volume=125(2)|pages=298-303|via=}}</ref>
**[[Thioguanine]]
**[[Mercaptopurine]]
**[[Didanosine]]<ref name="pmid195890792">{{cite journal| author=Kovari H, Ledergerber B, Peter U, Flepp M, Jost J, Schmid P et al.| title=Association of noncirrhotic portal hypertension in HIV-infected persons and antiretroviral therapy with didanosine: a nested case-control study. | journal=Clin Infect Dis | year= 2009 | volume= 49 | issue= 4 | pages= 626-35 | pmid=19589079 | doi=10.1086/603559 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19589079  }}</ref>
**[[Stavudine]]
**[[Cisplatin|Isoplatin]]
**[[Vitamin A]]
**[[Methotrexate]]
**[[Trastuzumab]]<ref>{{Cite journal|last=Lepelley|first=Marion|date=November-December 2018|title=Nodular Regenerative Hyperplasia Induced by
Trastuzumab Emtansine: Role of Emtansine?|url=https://www.medigraphic.com/pdfs/hepato/ah-2018/ah186u.pdf|journal=Annals of Hepatology|volume=17|pages=1067-1071|via=}}</ref>
 
* NRH is commonly found in patients with Abernethy’s Syndrome.
 
==Differentiating nodular regenerative hyperplasia from other Diseases==
* NRH must be differentiated from other diseases that cause fatigue, hematemesis, and weight-loss such as:<ref name="pmid21472097">{{cite journal |vauthors=Hartleb M, Gutkowski K, Milkiewicz P |title=Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension |journal=World J. Gastroenterol. |volume=17 |issue=11 |pages=1400–9 |year=2011 |pmid=21472097 |pmc=3070012 |doi=10.3748/wjg.v17.i11.1400 |url=}}</ref>
**[[Hepatocellular carcinoma]]
** Hepatic adenoma,
**[[Focal nodular hyperplasia]]
**[[Cirrhosis]]
**[[Peptic ulcer]]
**[[Schistosomiasis]]
**[[Metastatic disease]]
 
==Epidemiology and Demographics==
* NRH is a rare disease.
* The prevalence of NRH is approximately 31 cases per 100,000 individuals in the United Kingdom.
* The estimated incidence of NRH is approximately 0.34 cases per 100,000 individuals.
===Age===
* More commonly observed among patients aged between 25 and 65 years old.<ref name="pmid21472097">{{cite journal |vauthors=Hartleb M, Gutkowski K, Milkiewicz P |title=Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension |journal=World J. Gastroenterol. |volume=17 |issue=11 |pages=1400–9 |year=2011 |pmid=21472097 |pmc=3070012 |doi=10.3748/wjg.v17.i11.1400 |url=}}</ref>
* More commonly observed among adults and elderly patients.
 
===Gender===
* It affects men and women equally, however in patients receiving Azathioprine, a weak association has been reported with the male sex.<ref name=":0">{{Cite journal|last=Seksik|first=P.|date=Feb 2011|title=Incidence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with azathioprine|url=https://www.ncbi.nlm.nih.gov/pubmed/20848502/|journal=Inflammatory Bowel Diseases|volume=|pages=|via=}}</ref>
===Race===
* There is no racial predilection for NRH.
 
==Risk Factors==
* Common risk factors in the development of NRH include chronic vascular and infectious complications such as in:
**Inflammatory bowel disease
**Crohn's disease
**Cystic fibrosis
**Common variable immune deficiency (CVID)
**Chronic granulomatous disease.
*Small bowel resection.<ref name=":0" />
 
== Natural History, Complications and Prognosis==
* Initially asymptomatic.
*An unexplained drop in platelets.
* Early clinical features include [[fatigue]], [[weight loss]], and [[abdominal distension]].
* If left untreated, the majority of patients with nodular regenerative hyperplasia may progress to develop [[Acute liver failure|acute hepatic failure]] or liver decompensation and eventually requiring liver transplantation.<ref name="pmid7665869">{{cite journal| author=Bernard PH, Le Bail B, Cransac M, Barcina MG, Carles J, Balabaud C et al.| title=Progression from idiopathic portal hypertension to incomplete septal cirrhosis with liver failure requiring liver transplantation. | journal=J Hepatol | year= 1995 | volume= 22 | issue= 4 | pages= 495-9 | pmid=7665869 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7665869  }}</ref><ref name="pmid17414109">{{cite journal| author=Isabel Fiel M, Thung SN, Hytiroglou P, Emre S, Schiano TD| title=Liver failure and need for liver transplantation in patients with advanced hepatoportal sclerosis. | journal=Am J Surg Pathol | year= 2007 | volume= 31 | issue= 4 | pages= 607-14 | pmid=17414109 | doi=10.1097/01.pas.0000213425.76621.f1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17414109  }}</ref>
* Screening for the hepatocellular carcinoma is not recommended in these patients.<ref name="pmid17530368">{{cite journal| author=Isobe Y, Yamasaki T, Yokoyama Y, Kurokawa F, Hino K, Sakaida I| title=Hepatocellular carcinoma developing six and a half years after a diagnosis of idiopathic portal hypertension. | journal=J Gastroenterol | year= 2007 | volume= 42 | issue= 5 | pages= 407-9 | pmid=17530368 | doi=10.1007/s00535-007-2025-0 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17530368  }}</ref><ref name="pmid15740501">{{cite journal| author=Hidaka H, Ohbu M, Kokubu S, Shibuya A, Saigenji K, Okayasu I| title=Hepatocellular carcinoma associated with idiopathic portal hypertension: review of large nodules in seven non-cirrhotic portal hypertensive livers. | journal=J Gastroenterol Hepatol | year= 2005 | volume= 20 | issue= 3 | pages= 493-4 | pmid=15740501 | doi=10.1111/j.1440-1746.2005.03771.x | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15740501  }}</ref><ref name="pmid8633575">{{cite journal| author=Nzeako UC, Goodman ZD, Ishak KG| title=Hepatocellular carcinoma and nodular regenerative hyperplasia: possible pathogenetic relationship. | journal=Am J Gastroenterol | year= 1996 | volume= 91 | issue= 5 | pages= 879-84 | pmid=8633575 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8633575  }}</ref>
* NRH severity may be classified by the [[Child-Pugh score]].
* Common complications of NRH, may include:<ref name="pmid20075739">{{cite journal |vauthors=Morris JM, Oien KA, McMahon M, Forrest EH, Morris J, Stanley AJ, Campbell S |title=Nodular regenerative hyperplasia of the liver: survival and associated features in a UK case series |journal=Eur J Gastroenterol Hepatol |volume=22 |issue=8 |pages=1001–5 |year=2010 |pmid=20075739 |doi=10.1097/MEG.0b013e3283360021 |url=}}</ref>
**Portal hypertension
**[[Variceal bleeding]]
**[[Peritonitis|Secondary peritonitis]]
**[[Encephalopathy]]
* The prognosis of NRH is related to the consequences of portal hypertension and the severity of the associated diseases.Prognosis is generally poor, and the mean survival rate of patients is approximately 8.1 years.<ref name="pmid20075739">{{cite journal |vauthors=Morris JM, Oien KA, McMahon M, Forrest EH, Morris J, Stanley AJ, Campbell S |title=Nodular regenerative hyperplasia of the liver: survival and associated features in a UK case series |journal=Eur J Gastroenterol Hepatol |volume=22 |issue=8 |pages=1001–5 |year=2010 |pmid=20075739 |doi=10.1097/MEG.0b013e3283360021 |url=}}</ref>
 
==Diagnosis ==
===Diagnostic Criteria===
* The diagnosis of nodular regenerative hyperplasia is made with a strict diagnostic criteria, all of the following must be present:<ref name="livertox">Nodular regenerative hyperplasia http://livertox.nih.gov/Phenotypes_nodular.html Accesed on April 12, 2016</ref>
** Clinical, radiologic or endoscopic signs of portal hypertension, such as:<ref name="livertox">Nodular regenerative hyperplasia http://livertox.nih.gov/Phenotypes_nodular.html Accesed on April 12, 2016</ref>
***[[Ascites]]
***[[Splenomegaly]]
*** Portovenous collaterals
***[[Varices]] (esophageal or gastric)
***[[Portal hypertensive gastropathy]]
** Liver biopsy excluding cirrhosis; showing nodularity with minimal or no fibrosis. Presence of fibrous septa definitely excludes NRH.
**Definite exclusion of all other causes of portal hypertension.
**Confirmation of patent hepatic venous system on imaging.
 
<br />
 
* The diagnosis is favoured by:
** Latency of more than 6 months of clinically associated drugs.
** Minimal or no elevations in serum ALT (<120 U/L: <3 times ULN)
**Alkaline phosphatase (<345 U/L: <3 times ULN)
 
=== Symptoms ===
 
* Symptoms of nodular regenerative hyperplasia may include the following:<ref name="livertox">Nodular regenerative hyperplasia. NIH Livertox Library. http://livertox.nih.gov/Phenotypes_nodular.html Accesed on April 12, 2016</ref>
** Fatigue
** Weight loss
** Abdominal distension
** Nausea
** Hematemesis
 
=== Physical Examination ===
* Patients with NRH may be well-appearing, lethargic, or confused.
* Physical examination of the abdomen may be remarkable for:
'''Inspection'''
* Caput medusae
** Appearance of distended and engorged superficial epigastric veins
'''Auscultation'''
* Positive liver scratch test for enlarged liver size.
* ''Cruveilhier-Baumgarten murmur''
** A venous hum in patients with portal hypertension
'''Percussion'''
* Dull percussion
'''Palpation'''
* Abdominal distention
* Tenderness in right upper quadrant 
* [[Hepatomegaly]]
* [[Splenomegaly]]
* Other physical signs for NRH may include:
* [[Pallor]]
* [[Jaundice]]
* Plantar and [[palmar erythema]]
* Dermatographic urticaria, or "scratching marks"
** Muehrcke nails
** Terry nails, or "luekonychia"


It can be a complication of [[azathioprine]] therapy.<ref name="pmid15980758">{{cite journal |author=Daniel F, Cadranel JF, Seksik P, ''et al'' |title=Azathioprine induced nodular regenerative hyperplasia in IBD patients |journal=Gastroenterol. Clin. Biol. |volume=29 |issue=5 |pages=600–3 |year=2005 |month=May |pmid=15980758 |doi= |url=http://linkinghub.elsevier.com/retrieve/pii/MDOI-GCB-05-2005-29-5-0399-8320-101019-200514077}}</ref><ref name="pmid17504943">{{cite journal |author=Vernier-Massouille G, Cosnes J, Lemann M, ''et al'' |title=Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine |journal=Gut |volume=56 |issue=10 |pages=1404–9 |year=2007 |month=October |pmid=17504943 |doi=10.1136/gut.2006.114363 |url=http://gut.bmj.com/cgi/pmidlookup?view=long&pmid=17504943}}</ref>
=== Laboratory Findings ===
* Laboratory findings consistent with the diagnosis of NRH,  may include:<ref name="pmid23419380">{{cite journal |vauthors=Seijo S, Lozano JJ, Alonso C, Reverter E, Miquel R, Abraldes JG, Martinez-Chantar ML, Garcia-Criado A, Berzigotti A, Castro A, Mato JM, Bosch J, Garcia-Pagan JC |title=Metabolomics discloses potential biomarkers for the noninvasive diagnosis of idiopathic portal hypertension |journal=Am. J. Gastroenterol. |volume=108 |issue=6 |pages=926–32 |year=2013 |pmid=23419380 |doi=10.1038/ajg.2013.11 |url=}}</ref>
** Anemia,Leucopenia and thrombocytopenia because of hypersplenism
** Abnormal AST/ALT ratio<ref name="pmid2007779">{{cite journal| author=Naber AH, Van Haelst U, Yap SH| title=Nodular regenerative hyperplasia of the liver: an important cause of portal hypertension in non-cirrhotic patients. | journal=J Hepatol | year= 1991 | volume= 12 | issue= 1 | pages= 94-9 | pmid=2007779 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=2007779  }}</ref>
*** Less than <345 U/L: <3 times upper limit of normal
** Decreased levels of vitamin B12<ref name="pmid22918688">{{cite journal| author=Goel A, Ramakrishna B, Muliyil J, Madhu K, Sajith KG, Zachariah U et al.| title=Use of serum vitamin B12 level as a marker to differentiate idiopathic noncirrhotic intrahepatic portal hypertension from cryptogenic cirrhosis. | journal=Dig Dis Sci | year= 2013 | volume= 58 | issue= 1 | pages= 179-87 | pmid=22918688 | doi=10.1007/s10620-012-2361-7 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=22918688  }}</ref>
**Liver biochemistry profile showing cholestasis, thought to be secondary to increased sinusoidal pressure.<ref>{{Cite journal|last=Pai|first=RK|date=2010|title=Aberrant expression of cytokeratin 7 in perivenular hepatocytes correlates with a cholestatic chemistry profile in patients with heart failure.|url=|journal=Modern pathology|volume=23|pages=1650-1656|via=}}</ref>


==References==
===Imaging Findings===
{{reflist}}
* Imaging studies useful for the diagnosis of NRH, may include:<ref name="pmid21472097">{{cite journal |vauthors=Hartleb M, Gutkowski K, Milkiewicz P |title=Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension |journal=World J. Gastroenterol. |volume=17 |issue=11 |pages=1400–9 |year=2011 |pmid=21472097 |pmc=3070012 |doi=10.3748/wjg.v17.i11.1400 |url=}}</ref>
** Ultrasound (doppler U/S modality of choice)
** CT scan
** MRI scan
* On ultrasound:
** May resemble the ring-shaped coral, an appearance first described in 2011.<ref name="pmid21697407">{{cite journal| author=Caturelli E, Ghittoni G, Ranalli TV, Gomes VV| title=Nodular regenerative hyperplasia of the liver: coral atoll-like lesions on ultrasound are characteristic in predisposed patients. | journal=Br J Radiol | year= 2011 | volume= 84 | issue= 1003 | pages= e129-34 | pmid=21697407 | doi=10.1259/bjr/17975057 | pmc=3473481 | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21697407  }}</ref><ref name="XiangHan2018">{{cite journal|last1=Xiang|first1=Hao|last2=Han|first2=Jason|last3=Ridley|first3=William E|last4=Ridley|first4=Lloyd J|title=Liver atoll sign: Nodular regenerative hyperplasia|journal=Journal of Medical Imaging and Radiation Oncology|volume=62|year=2018|pages=88–88|issn=17549477|doi=10.1111/1754-9485.35_12784}}</ref>
** Lesions usually smaller than 3mm
** Round isoechoic or hypoechoic lesions
** Thin hyper-echoic rim
* CT scan suggestive of nonspecific hypodense nodules without significant enhancement.
* MRI suggestive of Isointense nodules on T2-weighted images that contain foci of high intensity on T1-weighted images
=== Other Diagnostic Studies ===
* NRH is definitely diagnosed using biopsy.
** Findings include:<ref name="pmid21472097">{{cite journal |vauthors=Hartleb M, Gutkowski K, Milkiewicz P |title=Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension |journal=World J. Gastroenterol. |volume=17 |issue=11 |pages=1400–9 |year=2011 |pmid=21472097 |pmc=3070012 |doi=10.3748/wjg.v17.i11.1400 |url=}}</ref>
*** Diffuse fine nodularity of the liver
*** Nodule size between 1-3 mm
*** Mild hepatomegaly


== Treatment ==
=== Medical Therapy ===
* There is no specific treatment for NRH.
* Mainstay therapy is preventing the progression of the disease (e.g., cessation of causative medication, treatment of the underlying conditions)<ref name="pmid16607155">{{cite journal| author=Seiderer J, Zech CJ, Diebold J, Schoenberg SO, Brand S, Tillack C et al.| title=Nodular regenerative hyperplasia: a reversible entity associated with azathioprine therapy. | journal=Eur J Gastroenterol Hepatol | year= 2006 | volume= 18 | issue= 5 | pages= 553-5 | pmid=16607155 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16607155  }}</ref> <ref name="pmid8020909">{{cite journal| author=Gane E, Portmann B, Saxena R, Wong P, Ramage J, Williams R| title=Nodular regenerative hyperplasia of the liver graft after liver transplantation. | journal=Hepatology | year= 1994 | volume= 20 | issue= 1 Pt 1 | pages= 88-94 | pmid=8020909 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8020909  }}</ref> with acute management of complications, such as variceal bleeding. <ref name="pmid21472097">{{cite journal |vauthors=Hartleb M, Gutkowski K, Milkiewicz P |title=Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension |journal=World J. Gastroenterol. |volume=17 |issue=11 |pages=1400–9 |year=2011 |pmid=21472097 |pmc=3070012 |doi=10.3748/wjg.v17.i11.1400 |url=}}</ref>
* Variceal bleeding in NRH can be treated in the same manner as variceal bleeding in cirrhotic portal hypertension by:<ref name="pmid24155091">{{cite journal| author=Siramolpiwat S, Seijo S, Miquel R, Berzigotti A, Garcia-Criado A, Darnell A et al.| title=Idiopathic portal hypertension: natural history and long-term outcome. | journal=Hepatology | year= 2014 | volume= 59 | issue= 6 | pages= 2276-85 | pmid=24155091 | doi=10.1002/hep.26904 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24155091  }}</ref><ref name="pmid26799606">{{cite journal| author=Noronha Ferreira C, Seijo S, Plessier A, Silva-Junior G, Turon F, Rautou PE et al.| title=Natural history and management of esophagogastric varices in chronic noncirrhotic, nontumoral portal vein thrombosis. | journal=Hepatology | year= 2016 | volume= 63 | issue= 5 | pages= 1640-50 | pmid=26799606 | doi=10.1002/hep.28466 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26799606  }}</ref>
** Use of non selective B blockers
** Endoscopic variceal ligation


=== Surgery ===
* Surgery is the mainstay of therapy for NRH in case of failure of endoscopic sclerotherapy/endoscopic variceal ligation. Other indication of surgery include symptomatic hypersplenism.<ref name="pmid12084024">{{cite journal| author=Sarin SK, Kapoor D| title=Non-cirrhotic portal fibrosis: current concepts and management. | journal=J Gastroenterol Hepatol | year= 2002 | volume= 17 | issue= 5 | pages= 526-34 | pmid=12084024 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12084024  }}</ref>
* TIPS is more suitable to treat and prevent refractory gastric variceal bleed in patients with NRH, however it is avoided in certain conditions such as:<ref name="pmid26990687">{{cite journal| author=Bissonnette J, Garcia-Pagán JC, Albillos A, Turon F, Ferreira C, Tellez L et al.| title=Role of the transjugular intrahepatic portosystemic shunt in the management of severe complications of portal hypertension in idiopathic noncirrhotic portal hypertension. | journal=Hepatology | year= 2016 | volume= 64 | issue= 1 | pages= 224-31 | pmid=26990687 | doi=10.1002/hep.28547 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26990687  }}</ref>
** Renal failure
** Ascites
** Promthrombic conditions like malignancy
** Organ transplantation
* Surgical resection is usually performed for patients with persistent pain or for lesions that are suspicious on radiological findings.
* Splenectomy can be done if symptomatic hypersplenism.
* Liver transplantation is rarely considered.<ref name="pmid174141092">{{cite journal| author=Isabel Fiel M, Thung SN, Hytiroglou P, Emre S, Schiano TD| title=Liver failure and need for liver transplantation in patients with advanced hepatoportal sclerosis. | journal=Am J Surg Pathol | year= 2007 | volume= 31 | issue= 4 | pages= 607-14 | pmid=17414109 | doi=10.1097/01.pas.0000213425.76621.f1 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17414109  }}</ref><ref name="pmid7916934">{{cite journal| author=Elariny HA, Mizrahi SS, Hayes DH, Boudreaux JP, Hussey JL, Farr GH| title=Nodular regenerative hyperplasia: a controversial indication for orthotopic liver transplantation. | journal=Transpl Int | year= 1994 | volume= 7 | issue= 4 | pages= 309-13 | pmid=7916934 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7916934  }}</ref>


{{Digestive system neoplasia}}
=== Prevention ===
* There are no primary preventive measures available for nodular regenerative hyperplasia, however close surveillance of the patient with the risk factors is required for the early diagnosis and management of the condition.<ref name="Hartleb2011">{{cite journal|last1=Hartleb|first1=Marek|title=Nodular regenerative hyperplasia: Evolving concepts on underdiagnosed cause of portal hypertension|journal=World Journal of Gastroenterology|volume=17|issue=11|year=2011|pages=1400|issn=1007-9327|doi=10.3748/wjg.v17.i11.1400}}</ref>
*In patients receiving neo-adjuvant (downstaging) therapy before resection of malignancy, it is generally recommended to keep the duration of chemotherapy to a minimum number of cycles.


[[Category:Gastroenterology]]
==References==
[[Category:Oncology]]
{{Reflist|2}}
[[Category: Oncology]]
[[Category:Hepatology]]


{{WS}}
{{WH}}
{{WH}}
{{WS}}
[[Category:Up-To-Date]]
[[Category:Medicine]]
[[Category:Hepatology]]
[[Category:Gastroenterology]]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2],Rekha, M.D.

Synonyms and keywords: NRHL; Non-cirrhotic portal hypertension; NRH

Overview

Nodular regenerative hyperplasia (NRH) is described as a rare form of non-cirrhotic portal hypertension in the absence of a recognizable cause. NRH is associated with solid organ transplant (eg. renal transplants, bone marrow transplants) and chronic use of medications. it may be classified into 2 subtypes: Pre-sinusoidal and sinusoidal. The pathogenesis of NRH is characterized by arterial hypervascularity secondary to loss of hepatic vein radicles and loss of central venule in the hepatic lobule. NRH is a rare disease. The estimated incidence of NRH is approximately 0.34 cases per 100,000 individuals. NRH is more commonly observed among patients between 25 and 65 years old. The majority of patients with NRH may be initially asymptomatic. Early clinical features include fatigue, weight loss, and abdominal distension. If left untreated, the majority of patients with NRH may progress to develop acute hepatic failure and death. The diagnosis of NRH is made with the following diagnostic criteria: Latency of more than 6 months, minimal or no elevations in serum alanine transaminase (ALT), clinical, radiologic or endoscopic signs of portal hypertension, and liver biopsy. Treatment includes cessation of offending agents and management of portal hypertension and variceal bleeding.


Historical Perspective

  • In 1953, the first case of NRH was described by Ranstrom in a patient with Felty’s syndrome, terming it as “miliary hepatocellular adenomatatosis”.[1][2]
  • NRH was first described by Steiner in 1959.[3]

Classification

  • Nodular regenerative hyperplasia may be classified into 2 subtypes:[1]
    • Pre-sinusoidal
    • Sinusoidal
  • Another variant of NRH may be included in Banti's syndrome, which is described as chronic splenic congestion chronic resulting in rapid destruction of red blood cells (RBCs) prematurely.

Pathophysiology

  • It is a poorly understood disease process thought to be mediated by chronic inflammatory and thrombotic processes leading to occlusion of hepatic microvascuature. Ischemic changes then lead to regeneration of hepatocytes.[4]
  • The pathogenesis of NRH is characterized by:
    • Arterial hypervascularity secondary to loss of hepatic vein radicles.
    • Loss of central venule in the hepatic lobule.
    • Diffuse regeneration of hepatocytes in the parenchyma in the form of nodules.
  • The RASSF1A gene has been associated with the development of NRH, involving the pro-apoptotic pathway.[5]
  • On gross pathology a diffuse nodularity may be seen.[5]
  • The most important findings on microscopic histopathological analysis:[5]
    • Plates of hepatocytes in the parenchyma set in thick curved nodules.
    • "Plump" hepatocytes arranged in micronodules:
      • Central hyperplasia with an atrophic rim.
    • No fibrosis.

Causes

Common causes of NRH may include:[6][7]

  • NRH is commonly found in patients with Abernethy’s Syndrome.

Differentiating nodular regenerative hyperplasia from other Diseases

Epidemiology and Demographics

  • NRH is a rare disease.
  • The prevalence of NRH is approximately 31 cases per 100,000 individuals in the United Kingdom.
  • The estimated incidence of NRH is approximately 0.34 cases per 100,000 individuals.

Age

  • More commonly observed among patients aged between 25 and 65 years old.[2]
  • More commonly observed among adults and elderly patients.

Gender

  • It affects men and women equally, however in patients receiving Azathioprine, a weak association has been reported with the male sex.[13]

Race

  • There is no racial predilection for NRH.

Risk Factors

  • Common risk factors in the development of NRH include chronic vascular and infectious complications such as in:
    • Inflammatory bowel disease
    • Crohn's disease
    • Cystic fibrosis
    • Common variable immune deficiency (CVID)
    • Chronic granulomatous disease.
  • Small bowel resection.[13]

Natural History, Complications and Prognosis

  • Initially asymptomatic.
  • An unexplained drop in platelets.
  • Early clinical features include fatigue, weight loss, and abdominal distension.
  • If left untreated, the majority of patients with nodular regenerative hyperplasia may progress to develop acute hepatic failure or liver decompensation and eventually requiring liver transplantation.[14][15]
  • Screening for the hepatocellular carcinoma is not recommended in these patients.[16][17][18]
  • NRH severity may be classified by the Child-Pugh score.
  • Common complications of NRH, may include:[19]
  • The prognosis of NRH is related to the consequences of portal hypertension and the severity of the associated diseases.Prognosis is generally poor, and the mean survival rate of patients is approximately 8.1 years.[19]

Diagnosis

Diagnostic Criteria

  • The diagnosis of nodular regenerative hyperplasia is made with a strict diagnostic criteria, all of the following must be present:[20]
    • Clinical, radiologic or endoscopic signs of portal hypertension, such as:[20]
    • Liver biopsy excluding cirrhosis; showing nodularity with minimal or no fibrosis. Presence of fibrous septa definitely excludes NRH.
    • Definite exclusion of all other causes of portal hypertension.
    • Confirmation of patent hepatic venous system on imaging.


  • The diagnosis is favoured by:
    • Latency of more than 6 months of clinically associated drugs.
    • Minimal or no elevations in serum ALT (<120 U/L: <3 times ULN)
    • Alkaline phosphatase (<345 U/L: <3 times ULN)

Symptoms

  • Symptoms of nodular regenerative hyperplasia may include the following:[20]
    • Fatigue
    • Weight loss
    • Abdominal distension
    • Nausea
    • Hematemesis

Physical Examination

  • Patients with NRH may be well-appearing, lethargic, or confused.
  • Physical examination of the abdomen may be remarkable for:

Inspection

  • Caput medusae
    • Appearance of distended and engorged superficial epigastric veins

Auscultation

  • Positive liver scratch test for enlarged liver size.
  • Cruveilhier-Baumgarten murmur
    • A venous hum in patients with portal hypertension

Percussion

  • Dull percussion

Palpation

Laboratory Findings

  • Laboratory findings consistent with the diagnosis of NRH, may include:[21]
    • Anemia,Leucopenia and thrombocytopenia because of hypersplenism
    • Abnormal AST/ALT ratio[22]
      • Less than <345 U/L: <3 times upper limit of normal
    • Decreased levels of vitamin B12[23]
    • Liver biochemistry profile showing cholestasis, thought to be secondary to increased sinusoidal pressure.[24]

Imaging Findings

  • Imaging studies useful for the diagnosis of NRH, may include:[2]
    • Ultrasound (doppler U/S modality of choice)
    • CT scan
    • MRI scan
  • On ultrasound:
    • May resemble the ring-shaped coral, an appearance first described in 2011.[25][26]
    • Lesions usually smaller than 3mm
    • Round isoechoic or hypoechoic lesions
    • Thin hyper-echoic rim
  • CT scan suggestive of nonspecific hypodense nodules without significant enhancement.
  • MRI suggestive of Isointense nodules on T2-weighted images that contain foci of high intensity on T1-weighted images

Other Diagnostic Studies

  • NRH is definitely diagnosed using biopsy.
    • Findings include:[2]
      • Diffuse fine nodularity of the liver
      • Nodule size between 1-3 mm
      • Mild hepatomegaly

Treatment

Medical Therapy

  • There is no specific treatment for NRH.
  • Mainstay therapy is preventing the progression of the disease (e.g., cessation of causative medication, treatment of the underlying conditions)[27] [28] with acute management of complications, such as variceal bleeding. [2]
  • Variceal bleeding in NRH can be treated in the same manner as variceal bleeding in cirrhotic portal hypertension by:[29][30]
    • Use of non selective B blockers
    • Endoscopic variceal ligation

Surgery

  • Surgery is the mainstay of therapy for NRH in case of failure of endoscopic sclerotherapy/endoscopic variceal ligation. Other indication of surgery include symptomatic hypersplenism.[31]
  • TIPS is more suitable to treat and prevent refractory gastric variceal bleed in patients with NRH, however it is avoided in certain conditions such as:[32]
    • Renal failure
    • Ascites
    • Promthrombic conditions like malignancy
    • Organ transplantation
  • Surgical resection is usually performed for patients with persistent pain or for lesions that are suspicious on radiological findings.
  • Splenectomy can be done if symptomatic hypersplenism.
  • Liver transplantation is rarely considered.[33][34]

Prevention

  • There are no primary preventive measures available for nodular regenerative hyperplasia, however close surveillance of the patient with the risk factors is required for the early diagnosis and management of the condition.[35]
  • In patients receiving neo-adjuvant (downstaging) therapy before resection of malignancy, it is generally recommended to keep the duration of chemotherapy to a minimum number of cycles.

References

  1. ↑ 1.0 1.1 Louwers LM, Bortman J, Koffron A, Stecevic V, Cohn S, Raofi V (2012). "Noncirrhotic Portal Hypertension due to Nodular Regenerative Hyperplasia Treated with Surgical Portacaval Shunt". Case Rep Med. 2012: 965304. doi:10.1155/2012/965304. PMC 3432362. PMID 22956964.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Hartleb M, Gutkowski K, Milkiewicz P (2011). "Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension". World J. Gastroenterol. 17 (11): 1400–9. doi:10.3748/wjg.v17.i11.1400. PMC 3070012. PMID 21472097.
  3. ↑ STEINER PE (1959). "Nodular regenerative hyperplasia of the liver". Am. J. Pathol. 35: 943–53. PMC 1934844. PMID 13834213.
  4. ↑ Vispo, E (May 2010). "Noncirrhotic portal hypertension in HIV-infected patients: unique clinical and pathological findings". AIDS.
  5. ↑ 5.0 5.1 5.2 Nodular regenerative hyperplasia. Libre Pathology https://librepathology.org/wiki/Medical_liver_disease#Nodular_regenerative_hyperplasia Accessed on April 12, 2015
  6. ↑ Hartleb M, Gutkowski K, Milkiewicz P (2011). "Nodular regenerative hyperplasia: evolving concepts on underdiagnosed cause of portal hypertension". World J Gastroenterol. 17 (11): 1400–9. doi:10.3748/wjg.v17.i11.1400. PMC 3070012. PMID 21472097.
  7. ↑ Buffet C, Cantarovitch M, Pelletier G, Fabre M, Martin E, Charpentier B; et al. (1988). "Three cases of nodular regenerative hyperplasia of the liver following renal transplantation". Nephrol Dial Transplant. 3 (3): 327–30. PMID 3140108.
  8. ↑ Schiano TD, Kotler DP, Ferran E, Fiel MI (2007). "Hepatoportal sclerosis as a cause of noncirrhotic portal hypertension in patients with HIV". Am J Gastroenterol. 102 (11): 2536–40. doi:10.1111/j.1572-0241.2007.01428.x. PMID 17640321.
  9. ↑ Vernier-Massouille G, Cosnes J, Lemann M, Marteau P, Reinisch W, Laharie D; et al. (2007). "Nodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine". Gut. 56 (10): 1404–9. doi:10.1136/gut.2006.114363. PMC 2000290. PMID 17504943.
  10. ↑ Dubinksy, MC (August 2003). "6-thioguanine can cause serious liver injury in inflammatory bowel disease patients". Gastroenterology. 125(2): 298–303.
  11. ↑ Kovari H, Ledergerber B, Peter U, Flepp M, Jost J, Schmid P; et al. (2009). "Association of noncirrhotic portal hypertension in HIV-infected persons and antiretroviral therapy with didanosine: a nested case-control study". Clin Infect Dis. 49 (4): 626–35. doi:10.1086/603559. PMID 19589079.
  12. ↑ Lepelley, Marion (November–December 2018). "Nodular Regenerative Hyperplasia Induced by Trastuzumab Emtansine: Role of Emtansine?" (PDF). Annals of Hepatology. 17: 1067–1071. line feed character in |title= at position 44 (help)
  13. ↑ 13.0 13.1 Seksik, P. (Feb 2011). "Incidence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with azathioprine". Inflammatory Bowel Diseases.
  14. ↑ Bernard PH, Le Bail B, Cransac M, Barcina MG, Carles J, Balabaud C; et al. (1995). "Progression from idiopathic portal hypertension to incomplete septal cirrhosis with liver failure requiring liver transplantation". J Hepatol. 22 (4): 495–9. PMID 7665869.
  15. ↑ Isabel Fiel M, Thung SN, Hytiroglou P, Emre S, Schiano TD (2007). "Liver failure and need for liver transplantation in patients with advanced hepatoportal sclerosis". Am J Surg Pathol. 31 (4): 607–14. doi:10.1097/01.pas.0000213425.76621.f1. PMID 17414109.
  16. ↑ Isobe Y, Yamasaki T, Yokoyama Y, Kurokawa F, Hino K, Sakaida I (2007). "Hepatocellular carcinoma developing six and a half years after a diagnosis of idiopathic portal hypertension". J Gastroenterol. 42 (5): 407–9. doi:10.1007/s00535-007-2025-0. PMID 17530368.
  17. ↑ Hidaka H, Ohbu M, Kokubu S, Shibuya A, Saigenji K, Okayasu I (2005). "Hepatocellular carcinoma associated with idiopathic portal hypertension: review of large nodules in seven non-cirrhotic portal hypertensive livers". J Gastroenterol Hepatol. 20 (3): 493–4. doi:10.1111/j.1440-1746.2005.03771.x. PMID 15740501.
  18. ↑ Nzeako UC, Goodman ZD, Ishak KG (1996). "Hepatocellular carcinoma and nodular regenerative hyperplasia: possible pathogenetic relationship". Am J Gastroenterol. 91 (5): 879–84. PMID 8633575.
  19. ↑ 19.0 19.1 Morris JM, Oien KA, McMahon M, Forrest EH, Morris J, Stanley AJ, Campbell S (2010). "Nodular regenerative hyperplasia of the liver: survival and associated features in a UK case series". Eur J Gastroenterol Hepatol. 22 (8): 1001–5. doi:10.1097/MEG.0b013e3283360021. PMID 20075739.
  20. ↑ 20.0 20.1 20.2 Nodular regenerative hyperplasia http://livertox.nih.gov/Phenotypes_nodular.html Accesed on April 12, 2016
  21. ↑ Seijo S, Lozano JJ, Alonso C, Reverter E, Miquel R, Abraldes JG, Martinez-Chantar ML, Garcia-Criado A, Berzigotti A, Castro A, Mato JM, Bosch J, Garcia-Pagan JC (2013). "Metabolomics discloses potential biomarkers for the noninvasive diagnosis of idiopathic portal hypertension". Am. J. Gastroenterol. 108 (6): 926–32. doi:10.1038/ajg.2013.11. PMID 23419380.
  22. ↑ Naber AH, Van Haelst U, Yap SH (1991). "Nodular regenerative hyperplasia of the liver: an important cause of portal hypertension in non-cirrhotic patients". J Hepatol. 12 (1): 94–9. PMID 2007779.
  23. ↑ Goel A, Ramakrishna B, Muliyil J, Madhu K, Sajith KG, Zachariah U; et al. (2013). "Use of serum vitamin B12 level as a marker to differentiate idiopathic noncirrhotic intrahepatic portal hypertension from cryptogenic cirrhosis". Dig Dis Sci. 58 (1): 179–87. doi:10.1007/s10620-012-2361-7. PMID 22918688.
  24. ↑ Pai, RK (2010). "Aberrant expression of cytokeratin 7 in perivenular hepatocytes correlates with a cholestatic chemistry profile in patients with heart failure". Modern pathology. 23: 1650–1656.
  25. ↑ Caturelli E, Ghittoni G, Ranalli TV, Gomes VV (2011). "Nodular regenerative hyperplasia of the liver: coral atoll-like lesions on ultrasound are characteristic in predisposed patients". Br J Radiol. 84 (1003): e129–34. doi:10.1259/bjr/17975057. PMC 3473481. PMID 21697407.
  26. ↑ Xiang, Hao; Han, Jason; Ridley, William E; Ridley, Lloyd J (2018). "Liver atoll sign: Nodular regenerative hyperplasia". Journal of Medical Imaging and Radiation Oncology. 62: 88–88. doi:10.1111/1754-9485.35_12784. ISSN 1754-9477.
  27. ↑ Seiderer J, Zech CJ, Diebold J, Schoenberg SO, Brand S, Tillack C; et al. (2006). "Nodular regenerative hyperplasia: a reversible entity associated with azathioprine therapy". Eur J Gastroenterol Hepatol. 18 (5): 553–5. PMID 16607155.
  28. ↑ Gane E, Portmann B, Saxena R, Wong P, Ramage J, Williams R (1994). "Nodular regenerative hyperplasia of the liver graft after liver transplantation". Hepatology. 20 (1 Pt 1): 88–94. PMID 8020909.
  29. ↑ Siramolpiwat S, Seijo S, Miquel R, Berzigotti A, Garcia-Criado A, Darnell A; et al. (2014). "Idiopathic portal hypertension: natural history and long-term outcome". Hepatology. 59 (6): 2276–85. doi:10.1002/hep.26904. PMID 24155091.
  30. ↑ Noronha Ferreira C, Seijo S, Plessier A, Silva-Junior G, Turon F, Rautou PE; et al. (2016). "Natural history and management of esophagogastric varices in chronic noncirrhotic, nontumoral portal vein thrombosis". Hepatology. 63 (5): 1640–50. doi:10.1002/hep.28466. PMID 26799606.
  31. ↑ Sarin SK, Kapoor D (2002). "Non-cirrhotic portal fibrosis: current concepts and management". J Gastroenterol Hepatol. 17 (5): 526–34. PMID 12084024.
  32. ↑ Bissonnette J, Garcia-Pagán JC, Albillos A, Turon F, Ferreira C, Tellez L; et al. (2016). "Role of the transjugular intrahepatic portosystemic shunt in the management of severe complications of portal hypertension in idiopathic noncirrhotic portal hypertension". Hepatology. 64 (1): 224–31. doi:10.1002/hep.28547. PMID 26990687.
  33. ↑ Isabel Fiel M, Thung SN, Hytiroglou P, Emre S, Schiano TD (2007). "Liver failure and need for liver transplantation in patients with advanced hepatoportal sclerosis". Am J Surg Pathol. 31 (4): 607–14. doi:10.1097/01.pas.0000213425.76621.f1. PMID 17414109.
  34. ↑ Elariny HA, Mizrahi SS, Hayes DH, Boudreaux JP, Hussey JL, Farr GH (1994). "Nodular regenerative hyperplasia: a controversial indication for orthotopic liver transplantation". Transpl Int. 7 (4): 309–13. PMID 7916934.
  35. ↑ Hartleb, Marek (2011). "Nodular regenerative hyperplasia: Evolving concepts on underdiagnosed cause of portal hypertension". World Journal of Gastroenterology. 17 (11): 1400. doi:10.3748/wjg.v17.i11.1400. ISSN 1007-9327.

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