Nodular regenerative hyperplasia: Difference between revisions
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*Early clinical features include [[fatigue]], [[weight loss]], and [[abdominal distension]]. | *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 de compensation 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> | *If left untreated, the majority of patients with nodular regenerative hyperplasia may progress to develop [[Acute liver failure|acute hepatic failure]] or liver de compensation 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> | ||
*Association between nodular regenerative hyperplasia and hepatocellular carcinoma,has been found in some case reports but still the data in unclear and therefore 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> | *Association between nodular regenerative hyperplasia and hepatocellular carcinoma,has been found in some case reports but still the data in unclear and therefore 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> | ||
*Nodular regenerative hyperplasia severity may be classified by the [[Child-Pugh score]]. | *Nodular regenerative hyperplasia severity may be classified by the [[Child-Pugh score]]. | ||
*Common complications of nodular regenerative hyperplasia, 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> | *Common complications of nodular regenerative hyperplasia, 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> | ||
Revision as of 04:28, 25 April 2019
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Maria Fernanda Villarreal, M.D. [2]
Synonyms and keywords: NRHL; Non-cirrhotic portal hypertension; NRH
Overview
Nodular regenerative hyperplasia is described as a rare form of non-cirrhotic portal hypertension. Nodular regenerative hyperplasia is associated with solid organ transplant (eg. renal transplants, bone marrow transplants) and chronic use of medications. Nodular regenerative hyperplasia may be classified into 2 subtypes: pre-sinusoidal and sinusoidal.[1] The pathogenesis of nodular regenerative hyperplasia is characterized by arterial hypervascularity secondary to loss of hepatic vein radicles and loss of central venule in the hepatic lobule. Nodular regenerative hyperplasia is a rare disease. The estimated incidence of nodular regenerative hyperplasia is approximately 0.34 cases per 100,000 individuals. Nodular regenerative hyperplasia is more commonly observed among patients between 25 and 65 years old.[2] The majority of patients with nodular regenerative hyperplasia may be initially asymptomatic. 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 and death. The diagnosis of nodular regenerative hyperplasia is made with the following diagnostic criteria: latency of more than 6 months, minimal or no elevations in serum ALT, clinical, radiologic or endoscopic signs of portal hypertension, and liver biopsy.
Historical Perspective
- In 1953, the first case of Nodular regenerative hyperplasia was described by Ranstrom in a patient with Felty’s syndrome,and termed it as “miliary hepatocellular adenomatatosis”.
- Nodular regenerative hyperplasia was first described by Steiner in 1959.[3]
Classification
- Nodular regenerative hyperplasia may be classified into 2 subtypes:[1]
- Pre-sinusoidal
- Sinusoidal
- Other variant of nodular regenerative hyperplasia may include Banti's syndrome.
Pathophysiology
- The pathogenesis of nodular regenerative hyperplasia is characterized by arterial hypervascularity secondary to loss of hepatic vein radicles and loss of central venule in the hepatic lobule.
- The RASSF1A gene has been associated with the development of nodular regenerative hyperplasia, involving the proapoptotic pathway.[4]
- On gross pathology findings of nodular regenerative hyperplasia, may include:[4]
- Diffuse nodularity
- On microscopic histopathological analysis findings of nodular regenerative hyperplasia, may include:[4]
- Diffuse hepatic micronodular transformation in groups without fibrous septa between the nodules
- "Plump" hepatocytes surrounded by atrophic ones
- No fibrosis
Causes
- Common causes of nodular regenerative hyperplasia, may include:[5][6]
- Solid organ transplantation
- Autoimmune
- Infectious
- Hematological
- Neoplastic
- Chronic use of medications, such as:
Differentiating nodular regenerative hyperplasia from other Diseases
- Nodular regenerative hyperplasia must be differentiated from other diseases that cause fatigue, hematemesis, and weight-loss such as:[2]
Epidemiology and Demographics
- Nodular regenerative hyperplasia is a rare disease.
- The prevalence of nodular regenerative hyperplasia is approximately 31 cases per 100,000 individuals in the United Kingdom.
- The estimated incidence of nodular regenerative hyperplasia is approximately 0.34 cases per 100,000 individuals.
Age
- Nodular regenerative hyperplasia is more commonly observed among patients aged between 25 and 65 years old.[2]
- Nodular regenerative hyperplasia is more commonly observed among adults and elderly patients
Gender
- Nodular regenerative hyperplasia affects men and women equally.
Race
- There is no racial predilection for nodular regenerative hyperplasia.
Risk Factors
- Common risk factors in the development of nodular regenerative hyperplasia are recurrent vascular and infectious complications such as in cystic fibrosis, common variable hypogammaglobulinemia, and chronic granulomatous disease.
Natural History, Complications and Prognosis
- The majority of patients with nodular regenerative hyperplasia may be initially asymptomatic
- 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 de compensation and eventually requiring liver transplantation.[8][9]
- Association between nodular regenerative hyperplasia and hepatocellular carcinoma,has been found in some case reports but still the data in unclear and therefore screening for the hepatocellular carcinoma is not recommended in these patients.[10][11][12]
- Nodular regenerative hyperplasia severity may be classified by the Child-Pugh score.
- Common complications of nodular regenerative hyperplasia, may include:[13]
- The prognosis of nodular regenerative hyperplasia 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 with nodular regenerative hyperplasia is approximately 8.1 years.[13]
Diagnosis
Diagnostic Criteria
- The diagnosis of nodular regenerative hyperplasia is made with the following diagnostic criteria:[14]
- Latency of more than 6 months
- Minimal or no elevations in serum ALT
- Alkaline phosphatase (<345 U/L: <3 times ULN)
- Clinical, radiologic or endoscopic signs of portal hypertension, such as:[14]
- Ascites
- Splenomegaly
- Abdominal venous collaterals
- Varices
- Portal hypertensive gastropathy
- Liver biopsy showing nodularity with minimal or no fibrosis
Symptoms
- Symptoms of nodular regenerative hyperplasia may include the following:[14]
- Fatigue
- Weight loss
- Abdominal distension
- Nausea
- Hematemesis
Physical Examination
- Patients with nodular regenerative hyperplasia 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 nodular regenerative hyperplasia 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 nodular regenerative hyperplasia, may include:[15]
- Abnormal AST/ALT ratio
- Less than <345 U/L: <3 times upper limit of normal
- Decreased levels of vitamin B12
Imaging Findings
- Imaging studies useful for the diagnosis of nodular regenerative hyperplasia, may include:[2]
- Ultrasound ( doppler ultrasound)
- CT scan
- MRI scan
- Ultrasound is the imaging modality of choice for nodular regenerative hyperplasia
- On ultrasound, findings of nodular regenerative hyperplasia, may include
- CT scan suggestive of nonspecifically 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
- Nodular regenerative hyperplasia may also be diagnosed using biopsy.
- Liver biopsy confirms the diagnosis of nodular regenerative hyperplasia
- On biopsy, findings of nodular regenerative hyperplasia, may 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 nodular regenerative hyperplasia.
- The mainstay of therapy for nodular regenerative hyperplasia is supportive care by preventing the progression of the disease (e.g., cessation of causative medication,treatment of the underlying conditions)[18] [19]and acute management of complications, such as variceal bleeding. [2]
- Variceal bleeding in nodular regenerative hyperplasia can be treated in the same manner as variceal bleeding in cirrhotic portal hypertension by:[20][21]
- use of non selective B blockers
- Endoscopic vaiceal ligation
Surgery
- Surgery is the mainstay of therapy for nodular regenerative hyperplasia in case of failure of endoscpic sclerotherapy/endoscopic variceal ligation.Other indication of surgery include symptomatic hypersplenism.[22]
- 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:[23]
- 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.[24][25]
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.[26]
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.
- ↑ 4.0 4.1 4.2 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.
- ↑ 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.
- ↑ 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.
- ↑ 13.0 13.1 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.
- ↑ 14.0 14.1 14.2 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.
- ↑ 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.