Nodular regenerative hyperplasia
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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]
- Solid organ transplantation
- Autoimmune diseases
- Infections like HIV[8]
- Hematological
- Neoplastic
- Chronic use of medications, such as:
- 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:[2]
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]
- Portal hypertension
- Variceal bleeding
- 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.[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]
- 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.
- Clinical, radiologic or endoscopic signs of portal hypertension, such as:[20]
- 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
- 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"
Laboratory Findings
- Laboratory findings consistent with the diagnosis of NRH, may include:[21]
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:
- 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
- Findings include:[2]
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
- ↑ 1.0 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.
- ↑ 2.0 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.
- ↑ STEINER PE (1959). "Nodular regenerative hyperplasia of the liver". Am. J. Pathol. 35: 943–53. PMC 1934844. PMID 13834213.
- ↑ Vispo, E (May 2010). "Noncirrhotic portal hypertension in HIV-infected patients: unique clinical and pathological findings". AIDS.
- ↑ 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
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Dubinksy, MC (August 2003). "6-thioguanine can cause serious liver injury in inflammatory bowel disease patients". Gastroenterology. 125(2): 298–303.
- ↑ 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.
- ↑ 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) - ↑ 13.0 13.1 Seksik, P. (Feb 2011). "Incidence of nodular regenerative hyperplasia in inflammatory bowel disease patients treated with azathioprine". Inflammatory Bowel Diseases.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 19.0 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.
- ↑ 20.0 20.1 20.2 Nodular regenerative hyperplasia http://livertox.nih.gov/Phenotypes_nodular.html Accesed on April 12, 2016
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ Sarin SK, Kapoor D (2002). "Non-cirrhotic portal fibrosis: current concepts and management". J Gastroenterol Hepatol. 17 (5): 526–34. PMID 12084024.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.