Nodular regenerative hyperplasia of the liver in rheumatic diseases: report of seven cases and review of the literature

Nodular regenerative hyperplasia (NRH) of the liver is an uncommon pathologic finding associated, in most cases, with rheumatic and hematologic diseases. Although its pathogenesis remains unclear, NRH probably results from liver regeneration to maintain its functional capacity after ischemia-induced injury. An intrahepatic microvascular occlusive mechanism has been considered most likely pathogenetically. NRH may lead to portal hypertension. Thus, the diagnosis of Felty's syndrome must be considered with caution in patients with rheumatoid arthritis (RA) and NRH of the liver. We report seven additional cases of NRH in patients with rheumatic disorders and review the literature to determine the patterns of clinical presentation and natural history of this condition. We also report four patients (three systemic lupus erythematosus [SLE] and one primary antiphospholipid syndrome [PAPS]) in whom antiphospholipid antibodies may have played a role in the genesis of NRH.     

Hepatoportal sclerosis as a cause of noncirrhotic portal hypertension in patients with HIV

BACKGROUND: Hepatoportal sclerosis (HPS) is a cause of noncirrhotic portal hypertension, with patients typically presenting with variceal bleeding. It is idiopathic in nature but is felt to be due to an abnormality of the intrahepatic vasculature. HPS is characterized by varying degrees of portal fibrosis, sclerosis of portal vein branches and dilatation of sinusoidal spaces. Nodular regenerative hyperplasia (NRH), another cause of noncirrhotic portal hypertension, has also been recently described in HIV patients initially diagnosed as having cryptogenic liver disease. METHODS/RESULTS: We describe four cases of HIV+ patients presenting with noncirrhotic portal hypertension; liver biopsies were reviewed by an experienced liver pathologist and found to be consistent with HPS. No other etiologies for their liver disease were found. CONCLUSIONS: HPS has been recently identified as a cause of noncirrhotic portal hypertension in patients with HIV. It should be considered in the differential diagnosis of HIV patients presenting with variceal bleeding. We postulate that it may be due to intrahepatic microthrombosis or an altered hepatic fibrogenesis related to highly active antiretroviral therapy or due to HIV itself.     

The pathogenesis of nodular regenerative hyperplasia of the liver associated with rheumatoid vasculitis.

Nodular regenerative hyperplasia (NRH) is an uncommon liver disease that typically develops in the setting of a chronic illness such as Felty's syndrome. Although the pathogenesis of NRH has not been defined, vasculitis has been postulated to play an important pathogenetic role in some cases of NRH, even though the association of NRH and vasculitis has been reported rarely. We describe two unusual cases of NRH in patients with Felty's syndrome complicated by rheumatoid vasculitis. Morphometric analysis demonstrated evidence of injury to the hepatic vasculature in the form of loss of small intrahepatic arteries and portal spaces, findings that support the hypothesis that hepatic arteritis plays a role in the development of NRH in cases associated with systemic vasculitis.     

Biliary diversion for progressive familial intrahepatic cholestasis: improved liver morphology and bile acid profile

BACKGROUND AND AIMS: Progressive familial intrahepatic cholestasis (PFIC) is characterized by pruritus, intrahepatic cholestasis, low serum gamma-glutamyltransferase levels, and characteristic "Byler bile" on electron microscopy. Many patients require liver transplantation, but partial external biliary diversion (PEBD) has shown therapeutic promise. However, the effect of PEBD on liver morphology and bile composition has not been evaluated. METHODS: We reviewed liver biopsy specimens from 3 children with low gamma-glutamyltransferase PFIC before and after PEBD. Follow-up liver biopsies were performed 9-60 months after PEBD. Light and electron microscopic features were scored blindly. Biliary bile acid composition was analyzed by gas chromatography-mass spectrometry before and after PEBD in 1 patient and after PEBD in 2 patients. RESULTS: Following PEBD, all patients improved clinically. Preoperative biopsy specimens showed characteristic features of PFIC, including portal fibrosis, chronic inflammation, cholestasis, giant cell transformation, and central venous mural sclerosis. Ultrastructural findings included coarse, granular canalicular Byler bile, effaced canalicular microvilli, and proliferative pericanalicular microfilaments. Following diversion, histology showed almost complete resolution of cholestasis, portal fibrosis, and inflammation with resolution of ultrastructural abnormalities. Biliary bile acids before PEBD consisted predominantly of cholic acid. After PEBD, the proportion of chenodeoxycholic acid increased significantly in 1 patient and was above the PFIC range in a second patient. CONCLUSIONS: The resolution of hepatic morphologic abnormalities following PEBD supports PEBD as an effective therapy for PFIC. The improved biliary bile acid composition suggests enhanced bile acid secretion after PEBD, perhaps by induction of alternative canalicular transport proteins.     

Diagnostic problems in nodular regenerative hyperplasia (nodular transformation) of the liver. Review of the literature and report of two cases.

Nodular regenerative hyperplasia (NRH) is a rare lesion of the liver associated with portal hypertension in more than half of patients. We present two cases demonstrating complications and diagnostic problems of NRH and review the pathogenesis, clinical, radiologic, and pathologic features of 240 cases in the literature. Patient 1 died from variceal bleeding as a complication of NRH. Patient 2 presented with ascites. Sonographic, computed-tomographic and magnetic resonance findings did not differ from liver cirrhosis. Three needle biopsies showed nonspecific reactive hepatitis. Wedge liver biopsy provided the correct diagnosis of NRH and a shunt operation was performed. Non-Hodgkin's lymphoma (centroblastic type) was diagnosed three years after NRH. At present there is no clinical or radiologic evidence of progression of NRH in this patient. The diagnosis of NRH cannot be made without histologic examination. Correct diagnosis is difficult in percutaneous needle biopsy. Therefore, laparoscopically guided liver biopsy or wedge biopsy is often necessary for diagnosis. NRH should be included in the differential diagnosis of portal hypertension. Portal diversion can be considered.     

Nodular regenerative hyperplasia: the main liver disease in patients with primary hypogammaglobulinemia and hepatic abnormalities

BACKGROUND/AIMS: Liver lesions associated with primary hypogammaglobulinemia have been poorly described. We aimed to assess the clinical, histological and immune features and outcome of hepatic injury in patients with primary hypogammaglobulinemia. METHODS: The medical records of 51 patients (23 patients with liver biopsy) with primary hypogammaglobulinemia and liver abnormalities were retrospectively reviewed. Forty-three controls with primary hypogammaglobulinemia but with no hepatic manifestations were analyzed in parallel. RESULTS: Cholestasis (65%), mainly anicteric, and portal hypertension (50%) were the main hepatic manifestations. Histological analysis revealed non-fibrosing architectural abnormalities consistent with nodular regenerative hyperplasia (NRH) in 84% of CVID patients and in all HIGM and XLA patients. Intrasinusoidal lymphocytic infiltration, abnormalities of portal vessels and epithelioid granulomas were observed in 90%, 43% and 44% of patients, respectively. NRH was associated with portal hypertension in 75% of the cases. These patients more often presented with autoimmune diseases and peripheral lymphocytic abnormalities than control patients (p < 0.05). CONCLUSIONS: Liver involvement in primary hypogammaglobulinemia mainly consists of NRH leading to chronic cholestasis and portal hypertension. Association with intrasinusoidal T cell infiltration, portal vein endotheliitis, autoimmune diseases and peripheral lymphocytic abnormalities suggests an autoimmune mechanism.     

Partial external diversion of bile for the treatment of intractable pruritus associated with intrahepatic cholestasis

Partial diversion of bile flow to an external stoma was performed in 6 patients with chronic intrahepatic cholestasis with severe pruritus that had been refractory to medical measures. Four patients with progressive intrahepatic cholestasis and 2 with arteriohepatic dysplasia were treated. Follow-up has been 3-8 yr. Patients with progressive intrahepatic cholestasis have been free of itching since surgery. Serum bile salt concentrations fell from 218-275 microM (normal less than 10) before to less than 10 microM after surgery. Biochemical tests of liver function and histology returned to normal or near normal. Patients with arteriohepatic dysplasia had persistent mild pruritus after surgery. Serum bile salt concentrations fell from 153-317 to 25-37 microM. There was little or no improvement in biochemical tests or histology. Bile volume and bile salt diverted were higher in patients with progressive intrahepatic cholestasis (7.3-13.0 ml/kg.day and 83-137 mumol/kg.day, respectively) than those with arteriohepatic dysplasia (3.2-4.5 ml/kg.day and 21-36 mumol/kg.day). The quality of life since surgery has been excellent in patients with progressive intrahepatic cholestasis, but not as optimal in those with arteriohepatic dysplasia. These findings suggest that partial external biliary diversion can provide effective relief from pruritus and perhaps reversal of liver disease in patients with progressive intrahepatic cholestasis. It should be used in patients with arteriohepatic dysplasia only in those with disabling pruritus.     

Primary biliary cirrhosis in adults

Primary biliary cirrhosis (PBC) is a chronic, autoimmune, cholestatic liver disease. It is characterized by slow destruction of small intrahepatic bile ducts, impaired biliary secretion and stasis of toxic endogenous bile acids within the liver with progression to liver fibrosis and cirrhosis. It has an increasing prevalence worldwide. It occurs more commonly in women than men at a ratio of 10:1. In most cases, diagnosis relies on a positive antimitochondrial antibody in the context of chronic cholestasis, without the need for a liver biopsy. Ursodeoxycholic acid improves survival even in patients with advanced liver disease. Certain findings such as fatigue, anti-nuclear antibodies, anti-centromere antibodies and the GP210 antinuclear antibody predict a poor outcome. Up to 40% of patients do not respond satisfactorily to ursodeoxycholic acid therapy and should be considered for adjunctive therapies. Several adjunctive and newer therapies are being tested and some appear promising. We provide a review of PBC with a focus on advances in therapies that may impact the management of PBC in the near future.     

Anticoagulant therapy for nodular regenerative hyperplasia in a HIV-infected patient

Background  

Nodular regenerative hyperplasia (NRH) has been recently recognized as an emergent cause of liver disease in HIV-infected patients. NRH may cause non-cirrhotic portal hypertension with potentially severe consequences such as refractory ascites, variceal bleeding and hypersplenism. Obliteration of the small intrahepatic portal veins in association with prothrombotic disorders linked to HIV infection itself or anti-retroviral therapy seem to be the causes of NRH and thus the term HIV-associated obliterative portopathy has been proposed.     

Significance of magnetic resonance imaging in the diagnosis of nodular regenerative hyperplasia of the liver complicated with systemic lupus erythematosus: a case report and review of the literature

Nodular regenerative hyperplasia of the liver (NRH), characterized by multiple hepatic nodules in the absence of fibrosis, is a rare but important complication of systemic lupus erythematosus (SLE) associated with non-cirrhotic portal hypertension. The diagnosis of NRH is based on the pathological examination, and radiological findings of NRH are poorly documented. We report a case of a 40-year-old woman with SLE complicated with NRH. Sixteen years after diagnosis of SLE, esophageal varices were incidentally found and diagnosis of portal hypertension due to NRH was made by magnetic resonance imaging (MRI) and confirmed by needle liver biopsy. Although MRI showed the lesions as significant nodules, neither computed tomography nor ultrasonography could demonstrate the nodules. However, serial MRI showed significant enlargement of the nodules for 2 years Because NRH may lead to portal hypertension with life-threatening variceral haemorrhage in patients with SLE, MRI is a useful, non-invasive examination to screen the patients for its presence and follow-up. We reviewed the literature regarding NRH in SLE and discuss the management of the affected patients.     

Jaundice in non-cirrhotic primary biliary cirrhosis: the premature ductopenic variant

The clinical and pathological findings of four females with primary biliary cirrhosis (PBC) with an unusual and hitherto not well recognised course are reported. Patients suffered severe pruritus and weight loss with progressive icteric cholestasis which did not respond to such treatments as ursodeoxycholic acid and immunosuppressives. In all cases liver histology revealed marked bile duct loss without however significant fibrosis or cirrhosis. Further diagnostic studies and repeat biopsies confirmed the absence of liver cirrhosis as well as other potential causes of hyperbilirubinaemia. Comparison of the fibrosis-ductopenia relationship for our cases with that for a group of 101 non-cirrhotic PBC patients indicated that in the former the severity of bile duct loss relative to the amount of fibrosis was significantly higher. The proportion of portal triads containing an interlobular bile duct was 3%, 4%, 6%, and 10% compared with 45% (median; range 8.3--100%) for controls (p<0.001). Three patients received a liver transplant 6--7 years after the first manifestation of PBC because of progressive cholestasis, refractory pruritus, and weight loss, while the fourth patient is considering this option. In one case cirrhosis had developed at the time of transplantation while the others still had non-cirrhotic disease. These cases suggest that cholestatic jaundice in non-cirrhotic PBC may be secondary to extensive "premature" or accelerated intrahepatic bile duct loss. Although the extent of fibrosis may be limited initially, progression to cirrhosis appears to be inevitable in the long run. Despite intact protein synthesis and absence of cirrhotic complications, liver transplantation in the pre-cirrhotic stage for preventing malnutrition and to improve quality of life should be considered for these patients.     

Diagnostic and therapeutic approach to cholestatic liver disease.

When cholestatic liver disease is present, liver ultrasound should be performed to ascertain if cholestasis is extrahepatic or intrahepatic. If bile ducts appear dilated and the probability of interventional treatment is high, endoscopic retrograde cholagio-pancreatography (ERCP) or trans-hepatic cholangiography (THC) should be the next step. If the probability of interventional therapeutics is low, cholangio-MRI should be performed. Once bile duct dilation and space occupying lesions are excluded, a work up for intrahepatic cholestasis should be started. Some specific clinical situations may be helpful in the diagnostic strategy. If cholestasis occurs in the elderly, drug-induced cholestatic disease should be suspected, whereas if it occurs in young people with risk factors, cholestatic viral hepatitis is the most likely diagnosis. During the first trimester of pregnancy cholestasis may occur in hyperemesis gravidorum, and in the third trimester of gestation cholestasis of pregnancy should be suspected. A familial history of recurrent cholestasis points to benign recurrent intrahepatic cholestasis. The occurrence of intrahepatic cholestasis in a middle-aged woman is a frequent presentation of primary biliary cirrhosis, whereas primary sclerosing cholangitis should be suspected in young males with inflammatory bowel disease. The presence of vascular spider nevi, ascites, and a history of alcohol abuse should point to alcoholic hepatitis. Neonatal cholestasis syndromes include CMV, toxoplasma and rubinfections or metabolic defects such as cystic fibrosis, alpha1-antitrypsin deficiency, bile acid synthesis defects, or biliary atresia. The treatment of cholestasis should include a management of complications such as pruritus, osteopenia and correction of fat soluble vitamin deficiencies. When hepatocellular failure or portal hypertension-related complications occur, liver transplantation should be considered.     

Recurrent intrahepatic cholestasis of pregnancy and chain-like choledocholithiasis in a female patient with stop codon in the ABDC4-gene of the hepatobiliary phospholipid transporter

We report the case of a 40-years-old female patient with recurrent cholestatic liver disease who presented twice with severe intrahepatic cholestasis of pregnancy and pronounced choledocholithiasis between pregnancies. Bile duct stones were removed endoscopically and a laparoscopic cholecystectomy was performed after the second pregnancy. Liver histology revealed intrahepatic cholestasis with portal inflammation and fibrosis, resembling progressive familial intrahepatic cholestasis (PFIC). Molecular genetic studies identified the heterozygous mutation c.957C > T in the ABCB4 gene encoding the hepatobiliary phospholipid transporter. This is the first report of this mutation that introduces a stop codon in an index patient with intrahepatic cholestasis of pregnancy and multiple bile duct stones. In addition, we detected the ABCB11 polymorphism V 444A, which is associated with a decreased expression of the bile salt export pump. Whereas homozygous carriers of the ABCB4 mutation develop PFIC type 3, the heterozygous ABC transporter mutations represent genetic risk factors for cholelithiasis and recurrent cholestatic hepatitis upon challenge with oral contraceptives or during pregnancy. Of note, the patient presented with normal serum gamma-glutamyltranspeptidase activities during pregnancy-associated cholestatic episodes but normal liver enzymes after delivery, whereas choledocholithiasis was associated with high gamma-glutamyl transpeptidase levels. It is unknown whether ursodeoxycholic acid prevents cholestasis or gallstones in patients with ABCB4 deficiency.     

特发性门脉高压肝移植术后随访第3年再发1例报告及文献复习

目的 复习1例特发性门脉高压(IPH)患者接受肝移植(LT)后第3年出现病情“再发”,并进行了相关文献复习,以提高对该病的认识。方法 报道1例我们诊治的IPH患者的病例资料,并检索MEDLINE、EMBASE、万方等数据库经LT治疗的IPH患者的研究报道,分析其治疗和转归。结果 本文报道的病例为57岁女性,因消化道出血、腹水行LT术,组织病理学检查诊断为IPH;术后随访第3年病情复发,行经皮肝穿刺活检术,病理学检查提示结节性再生性增生(NRH)、轻度汇管区炎症及纤维化,提示IPH再发;文献检索到81例LT治疗的IPH患者,其中42例在LT前诊断为肝硬化;LT后最长随访时间为248个月,8例死亡,其中5例分别在首次LT后3.5月～14年进行肝活检,组织病理学检查提示NRH,3例分别于LT后第7月、第3年和第14年出现具有门脉高压表现的NRH。结论 具有严重的门脉高压或肝功能衰竭的IPH患者需要LT治疗。少数患者在LT后可能出现IPH“再发”。     

Diagnosis of primary sclerosing cholangitis

Primary sclerosing cholangitis is a progressive chronic hepatobiliary disorder of unknown aetiology for which no effective medical therapy currently exists. This syndrome occurs most commonly in young men and is frequently associated with ulcerative colitis. Primary sclerosing cholangitis should be considered in the differential diagnosis of all patients presenting with chronic cholestasis. The diagnosis is based on a combination of the clinical features and cholestatic biochemical profile accompanied by typical cholangiographic abnormalities and is supported by liver histology findings. The major diagnostic criterion is the finding at cholangiography of irregularly distributed multifocal strictures within both the intrahepatic and extrahepatic bile ducts. The most characteristic histological feature of primary sclerosing cholangitis is periductal concentric obliterative fibrosis of small interlobular bile ducts with or without proliferation of bile ducts in portal tracts, but liver biopsy findings alone are infrequently diagnostic. Nevertheless, liver histology remains important to exclude other causes of chronic cholestasis and in staging the disease.     

慢性病毒性肝炎肝组织病变的形态学特征

目的：探讨慢性病毒性肝炎肝组织炎症活动度,纤维化程度和肝细胞病变形态学特征的差异,方法：按1995年全国慢性肝炎诊断标准,对224例慢性肝炎患者的肝穿刺组织进行炎症活动度分级和纤维化分期;采用免疫组化法检测组织切片的乙型肝炎表面抗原（HBsAg),乙型肝炎核心抗原（HBcAg)及丙型肝炎病毒（HCV）核心抗原（CP10）,并据此将患者分为乙型肝炎病毒（HBV）组,HCV组及HBV＋HCV组,比较各组患者炎症活动度分级,纤维化分期,肝细胞脂肪变性,细胞内胆,嗜酸小体及毛玻璃样肝细胞的差异。结果：HCV组患者的炎症活动度,纤维化程度及肝细胞内淤胆均较HBV组重,HBV＋HCV组患者的炎症活动度及纤维化程度介于HVB和HCV组之间,而肝细胞内淤胆比单独感染组轻,毛玻璃样肝细胞仅出现于HBV感染者中,脂肪变性及嗜酸小体在各组间无显著差异。结论：HCV引起的肝脏炎症活动度及纤维化程度较HBV重,合并感染的病变不比单独感染重;肝细胞内淤胆可能是肝损伤加重的重要因素之一。     

Hepatoportal sclerosis (obliterative portal venopathy) and nodular regenerative hyperplasia in a patient with myasthenia gravis: A case report and review of the published work

Nodular regenerative hyperplasia (NRH) and hepatoportal sclerosis, also known as obliterative portal venopathy (OPV), are two causes of non‐cirrhotic portal hypertension (NCPH). NCPH is an increasingly recognized entity that can be seen in association with collagen vascular diseases and with the use of medications such as azathioprine and didanosine, but oftentimes the etiology remains unidentified. We herein report a case of NCPH occurring due to OPV and NRH in a 64‐year‐old woman with myasthenia gravis (MG), status post‐thymectomy. Portal hypertension was diagnosed incidentally on computed tomography in the absence of predisposing factors. Extensive work‐up to determine the etiology of any underlying liver disease was unrevealing. NRH and OPV were identified on liver biopsy. Subsequently, the patient had variceal bleeding that necessitated transjugular intrahepatic portosystemic shunt placement. A few similar cases of NCPH occurring in the setting of MG have been previously reported, suggesting that the immunological mechanisms involved in the pathogenesis of myasthenia may also have contributed to the development of NCPH.     

Benign recurrent intrahepatic cholestasis progressing to progressive familial intrahepatic cholestasis: low GGT cholestasis is a clinical continuum

Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease, characterised by intermittent attacks of cholestasis, which can start at any age and last for several weeks to months. Characteristically serum GGT activity is low and normal liver structure is preserved. Progressive familial intrahepatic cholestasis (PFIC) is another liver disease, characterised by severe cholestasis, starting almost invariably before 6 months of age. All patients progress to cirrhosis, liver failure and death, unless a liver transplantation is performed. We now identified four patients who presented in childhood with recurrent attacks of cholestasis, while in the course of the disease the cholestasis gradually became permanent. Although liver biopsies performed in the early stages of the disease showed normal liver architecture, late stage biopsies revealed evident fibrosis with porto-portal septa formation. In conclusion, the disease of these patients started with the clinical and histopathological characteristics of BRIC but progressed to PFIC.     

Analysis of the histologic features in the differential diagnosis of intrahepatic neonatal cholestasis

AIM： To compare the histologic features of the liver in intrahepatic neonatal cholestasis （IHNC） with infectious, genetic-endocrine-metabolic, and idiopathic etiologies. METHODS： Liver biopsies from 86 infants with IHNC were evaluated. The inclusion criteria consisted of jaundice beginning at 3 mo of age and a hepatic biop- sy during the 1st year of life. The following histologic features were evaluated： cholestasis, eosinophilia, giant cells, erythropoiesis, siderosis, portal fibrosis, and the presence of a septum. RESULTS： Based on the diagnosis, patients were classified into three groups： group 1 （infectious; n = 18）, group 2 （genetic-endocrine-metabolic; n = 18）, and group 3 （idiopathic; n = 50）. There were no significant differences with respect to the following variables： cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and presence of a septum. A significant dif- ference was observed with respect to erythropoiesis, which was more severe in group 1 （Fisher＇s exact test, P = 0.016）. CONCLUSION： A significant difference was observed in IHNC of infectious etiology, in which erythropoiesis was more severe than that in genetic-endocrine-meta- bolic and idiopathic etiologies, whereas there were no significant differences among cholestasis, eosinophilia, giant cells, siderosis, portal fibrosis, and the presence of a septum.     

Congenital cholestatic syndromes: what happens when children grow up?

Although advances in the management of children with congenital cholestasis have enabled many to survive into adulthood with their native livers, even the most common of these conditions remains rare in adult hepatology practice. Among four congenital cholestatic syndromes (biliary atresia, Alagille syndrome, Caroli disease and congenital hepatic fibrosis, and progressive familial intrahepatic cholestasis), the published data on outcomes of the syndromes into adulthood suggest that a spectrum of severity of liver disease can be expected, from cirrhosis (almost universal in adults with biliary atresia who have not required liver transplantation) to mild and subclinical (eg, in the previously undiagnosed affected parent of an infant with Alagille syndrome). Complications associated with portal hypertension and nutritional deficiencies are common, and other associated features of the cholestatic syndrome may require appropriate attention, such as congenital heart disease in Alagille syndrome. Indications for liver transplantation include synthetic failure, progressive encephalopathy, intractable pruritus, recurrent biliary sepsis and recurrent complications of portal hypertension. Improved understanding of biliary physiology will hopefully translate into improved therapy for children and adults with cholestasis.