Liver histology in benign biliary stricture: Fibrosis to cirrhosis . . . and reversal?

Background: Secondary biliary cirrhosis is a potential complication of post‐cholecystectomy bile duct stricture (PCBDS). This study addresses the factors that determine the severity of pathological changes on liver biopsy and the correlation with long‐term outcome following repair. Methods: Liver biopsies obtained at surgery for repair of PCBDS in 71 patients were reviewed and pathological changes were scored from 0 to 3. Patients with fibrosis score 0–2 were categorized as the non‐cirrhotic group and those with score 3 (secondary biliary cirrhosis) were categorized as the cirrhotic group. Clinical and biochemical parameters, stricture type and outcome were analyzed by univariate and multivariate analysis for correlation with degree of fibrosis. Follow‐up liver biopsies (3–60 months) after stricture repair were obtained in five patients. Results: There were 58 patients in the non‐cirrhotic group and 13 in the cirrhotic group. On univariate analysis, portal hypertension and prolonged injury‐repair duration correlated with secondary biliary cirrhosis. Patients with a fair outcome in the cirrhotic group (4/13) had derangements in liver function tests but had patent biliary enteric anastomosis on evaluation. Of the five patients in whom liver biopsies were obtained at follow up, two had regression, two were static, and one had progression. Conclusion: All patients with PCBDS had varying degrees of fibrosis. Prolonged injury‐repair interval and portal hypertension were the important parameters correlating with secondary biliary cirrhosis. Early repair of biliary stricture is recommended to prevent liver fibrosis. A successful relief of biliary obstruction may halt and/or reverse pathological changes in the liver.     

Expectant management of patients with unilateral hepatic duct stricture and liver atrophy.

Three patients with postcholecystectomy unilateral hepatic duct stricture and subsequent liver atrophy were treated conservatively, with a successful outcome of up to three years follow up. A better understanding of the pathophysiological sequelae of segmental hepatic duct obstruction suggests that in such circumstances reconstructive surgery, with its attendant risks, may not invariably be necessary.     

Myeloid metaplasia, perisinusoidal fibrosis, and nodular regenerative hyperplasia of the liver

We describe two patients with myeloid metaplasia in whom portal hypertension resulted, not from infiltration of the liver sinusoids by myeloid cells, but from perisinusoidal fibrosis and nodular regenerative hyperplasia of the liver. We hypothesize that myeloid metaplasia induced the development of perisinusoidal fibrosis, which resulted in heterogeneous hepatic tissue blood perfusion, with atrophy of the liver cells in the underperfused areas and nodular regenerative hyperplasia in the normally perfused areas.     

Intrahepatic portal venopathy and related disorders of the liver

Intrahepatic portal venopathy leads to various entities that are important causes of portal hypertension. Noncirrhotic portal fibrosis (NCPF) occurs in the Indian subcontinent, whereas idiopathic portal hypertension (IPH) occurs in Japan although the pathogenesis and presentation of both are similar. NCPF presents mainly with upper gastrointestinal bleeding; IPH presents with massive splenomegaly. The liver functions are preserved. Wedged hepatic venous pressure is normal, but portal venous pressure is high indicating a presinusoidal block. Patients are best managed with endoscopic therapy or surgery, with better results than in patients with cirrhosis. Nodular regenerative hyperplasia is a histological diagnosis characterized by development of nodules in the liver due to uneven perfusion of the portal venous blood. These patients may develop portal hypertension and if they bleed would require treatment as in NCPF/IPH. Schistosomiasis produces portal hypertension by the development of fibrous tissue around the portal veins as a response to schistosome eggs. Gratifying results have been reported with praziquantel therapy. Rarely sarcoidosis and chronic biliary obstruction may also produce portal venopathy.     

Portal hypertension in primary biliary cirrhosis: Relationship with histological features

The prevalence and type of portal hypertension (PH) in primary biliary cirrhosis (PBC) and their relationship with liver lesions have been investigated in 32 patients with the disease. Portal hypertension was considered when oesophageal or gastric varices were observed by endoscopy and/or when hepatic venous pressure gradient measured by hepatic vein catheterization was greater than 6 mmHg. Within 3 days of endoscopy, a liver biopsy was performed for histological staging and semiquantitative grading (0 to 3+) of portal and sinusoidal fibrosis, portal inflammation, piecemeal necrosis, lobular necrosis, cholestasis, as well as the presence of granulomas and Mallory's hyaline. Twenty patients (62.5%) had portal hypertension, five of them showing presinusoidal PH (15.5%) and the remaining 15 (47%) with sinusoidal component. The four patients in stage IV had sinusoidal PH and the only patient in stage I had no PH. The prevalence of portal hypertension was similar in patients in stage II (57%) and stage III (55%), but presinusoidal PH was only observed in patients in stage II. Patients with PH showed significantly higher portal inflammation and piecemeal necrosis than patients without PH. By contrast, there were no differences in portal and sinusoidal fibrosis, nor in the other histologic features. These results indicate that portal hypertension is common in PBC and it may be present in the early stages of the disease. The fact that presinusoidal PH was only observed in patients in stage II suggests that portal hypertension is initially of presinusoidal type, and then as the disease progresses is joined by a sinusoidal component.     

Non-cirrhotic portal hypertension versus idiopathic portal hypertension

Portal hypertension occurs in a number of disorders other than cirrhosis and they are collectively called non-cirrhotic portal hypertension (NCPH). The common causes of NCPH include idiopathic portal hypertension (IPH), non-cirrhotic portal fibrosis (NCPF) and extrahepatic portal venous thrombosis (EHPVT). Other causes include schistosomiasis, hepatic venous outflow tract obstruction, veno-occlusive disease and congenital hepatic fibrosis. Patients with IPH and EHPVT present with upper gastrointestinal bleeding, splenomegaly, ascites after gastrointestinal bleeding, features of hypersplenism, growth retardation and jaundice due to portal biliopathy. The diagnosis is usually made by abdominal ultrasound, upper gastrointestinal endoscopy, normal liver function tests and normal liver histology. Variceal bleeding in NCPH has lower mortality as compared with cirrhosis because of better liver functions in NCPH. Treatment for NCPH includes primary prophylaxis for variceal bleeding and prevention of repeat bleeding using drugs like beta-blockers, endoscopic sclerotherapy and endoscopic band ligation of varices. In patients with uncontrolled variceal bleeding or symptomatic hypersplenism, porto-systemic shunt surgery or splenectomy are required.     

Biliary stricture caused by portal biliopathy: case report and literature review

Portal biliopathy is a rare condition that is usually not diagnosed and only in few cases causes symptoms. Those symptoms are caused by vascular obstruction of the biliary tree in patients with portal hypertension. We report a case of a 29 years man who presented with history of intermittent jaundice, persistent elevation of hepatic function test and hematemesis as a manifestation of portal hypertension without liver damage. We present the clinical, radiological and pathological characteristics and literature review of the cases that had been reported, their diagnoses, treatment and clinical implication.     

Analysis of abnormal recovery pattern of liver function tests after surgical repair of bile duct strictures

BACKGROUND: Gradual normalization of conventional liver function tests occurs in a majority of patients with extrahepatic biliary obstruction following adequate biliary drainage. Abnormal recovery pattern of liver function has been reported in up to 70% of these patients and there is scarcity of relevant information about this. The purpose of the present paper was to identify variables predictive of abnormal recovery pattern of liver function tests after surgical repair of benign biliary stricture. METHODS: Patient data, disease-related characteristics and serial liver function tests were prospectively collected in 64 patients with post-cholecystectomy bile duct strictures undergoing hepaticojejunostomy. Hepatic histology (fibrosis, portal inflammation, ductular proliferation and cholestasis) was independently graded by two pathologists using a previously validated scale. A cut-off limit of longer than 2 weeks for normalization of liver function tests following definitive surgical repair was considered abnormal. The patients were accordingly dichotomized into groups. Univariate and multivariate analysis was performed. RESULTS: Fourteen patients (22%) each had abnormal recovery pattern of serum bilirubin and serum alanine aminotransferase (ALT) levels while 13 (20%) had abnormal recovery pattern of serum alkaline phosphatase (SAP) levels. Multivariate analysis revealed basal serum bilirubin level was an independent predictor of abnormal recovery pattern of serum bilirubin level while basal ALT level as well as degree of hepatic fibrosis were independent predictors of abnormal recovery of serum ALT level. Similarly, basal SAP level and degree of hepatic fibrosis were independent predictors of abnormal recovery of SAP level. CONCLUSIONS: Basal values of liver function tests and degree of hepatic fibrosis are the most important predictors of abnormal recovery pattern of liver function following adequate biliary decompression in patients with post-cholecystectomy bile duct stricture.     

Portal hypertension in primary biliary cirrhosis

Evidence of portal hypertension was found in 50 out of 109 patients (47%) with primary biliary cirrhosis, and of these 32 bled from oesophageal varices. In four patients portal hypertension was the initial manifestation of the disease and this complication was recognized in a further 17 within two years of the first symptom of primary biliary cirrhosis. The development of portal hypertension was associated with a poor prognosis and death could frequently be attributed to variceal bleeding; the mean duration of survival from the time that portal hypertension was recognized was 14.9 months. Portal decompression operations may have improved the immediate prognosis in some patients but did not otherwise influence the progression of the disease. In 47 patients the histological findings in wedge biopsy or necropsy material were correlated with the presence or absence of varices. An association between nodular regeneration of the liver and varices was confirmed, but, in the absence of nodules, no other histological cause for portal venous obstruction could be found.     

Portal hypertension in systemic mastocytosis

We report the case of a 66-year-old male patient with portal hypertension related to systemic mastocytosis. The liver was enlarged; microscopic examination showed portal mast cell infiltration and fibrosis. Portal hypertension was evidenced by splenomegaly, esophageal varices, and increased wedged-free hepatic venous pressure gradient. Arteriography showed that portal vein was patent. Portal hypertension could be the consequence of intrahepatic block due to mast cell infiltration and/or fibrosis of the liver.     

Massive vitamin A intoxication with ascites and pleural effusion

Vitamin A intoxication was diagnosed in a 14-year-old girl who presented with massive exudative ascites and right pleural effusion, impaired liver enzymes, and hypertriglyceridemia. Electron microscopy of liver biopsy material demonstrated numerous perisinusoidal lipid-filled Ito cells. The patient had taken 100-200,000 I.U. vitamin A per day for 15 months. Serum vitamin A level remained elevated for 4 months after vitamin discontinuation. The unusual severity of portal hypertension was documented by a high wedged hepatic vein pressure level. The ascites occurred 2 months after vitamin A had been discontinued, probably owing to particularly slow mobilization of large hepatic stores of vitamin A. Portal hypertension disappeared after a 6-month low vitamin A diet, but the liver biopsy failed to demonstrate any decrease in number or size of Ito cells, suggesting that lipid venous obstruction is unlikely to be the only mechanism responsible for portal hypertension in vitamin A-induced liver disease.     

Nodular regenerative hyperplasia of the liver: an under-recognized cause of portal hypertension in hematological disorders

Portal hypertension has been described in a wide variety of hematological disorders, especially myeloproliferative and lymphoproliferative disorders. Its clinical manifestations may include bleeding esophageal varices, ascites, or hepatic encephalopathy. In patients with hematological disorders, there are a number of potential causes of portal hypertension, including nodular regenerative hyperplasia of the liver (NRH). This lesion is characterized by diffuse replacement of normal hepatic parenchyma by multiple small nodules composed of regenerating hepatocytes with minimal or no fibrosis. This lack of fibrosis distinguishes NRH from cirrhosis. Unlike cirrhosis, NRH only rarely results in compromised hepatic synthetic function. The major manifestation is portal hypertension related to increased resistance to blood flow within hepatic sinusoids. NRH has been linked to a variety of systemic diseases including collagen vascular diseases, myeloproliferative and lymphoproliferative disorders, as well as various medications. Although NRH is commonly associated with blood dyscrasias, the diagnosis is overlooked because of the complexity and wide differential diagnosis of liver diseases in the setting of hematological malignancy. We review herein nodular regenerative hyperplasia of the liver, including aspects of epidemiology, pathogenesis, differential diagnosis, clinical course, and treatment. We highlight its association with different forms of hematological disease, aiming to increase the awareness of this entity to the internist and the treating hematologist/oncologist.     

Liver resection for the treatment of post-cholecystectomy biliary stricture with vascular injury

AIM:To report experience with liver resection in a select group of patients with postoperative biliary stricture associated with vascular injury.METHODS:From a prospective database of patients treated for benign biliary strictures at our hospital,cases that underwent liver resections were reviewed.All cases were referred after one or more attempts to repair bile duct injuries following cholecystectomy(open or laparoscopic).Liver resection was indicated in patients with Strasberg E3/E4(hilar stricture)bile duct lesions associated with vascular damage(arterial and/or portal),ipsilateral liver atrophy/abscess,recurrent attacks of cholangitis,and failure of previous hepaticojejunostomy.RESULTS:Of 148 patients treated for benign biliary strictures,nine(6.1%)underwent liver resection;eight women and one man with a mean age of 38.6 years.Six patients had previously been submitted to open cholecystectomy and three to laparoscopic surgery.The mean number of surgical procedures before definitive treatment was 2.4.All patients had Strasberg E3/E4injuries,and vascular injury was present in all cases.Eight patients underwent right hepatectomy and one underwent left lateral sectionectomy without mortality.Mean time of follow up was 69.1 mo and after longterm follow up,eight patients are asymptomatic.CONCLUSION:Liver resection is a good therapeutic option for patients with complex postoperative biliary stricture and vascular injury presenting with liver atrophy/abscess in which previous hepaticojejunostomy has failed.     

Bile duct stricture due to caused by portal biliopathy: Treatment with one-stage portal-systemic shunt and biliary bypass

Portal biliopathy is a rare complication of extrahepatic portal vein obstruction. Jaundice occurs in symptomatic patients with fibrotic strictures. Short-term improvement in such patients can be achieved with endoscopic retrograde cholangio-pancreatography with balloon dilatation and stent placement. Surgery in these patients is traditionally two staged. We report the results of a one-stage procedure combining non-selective portal-systemic shunt surgery with biliary bypass, performed successfully on a 24-year-old man with a tight biliary stricture resulting from portal biliopathy. At 18-month follow up, the patient shows he is doing well, with normal liver function tests.     

Non-cirrhotic portal hypertension in HIV mono-infected patients

Background and Aim: Unexplained liver injury including fibrosis and portal hypertension has rarely been reported among patients with HIV in the absence of co‐infection with hepatitis B (HBV) or hepatitis C (HCV). We describe a series of HIV mono‐infected patients with evidence of non‐cirrhotic portal hypertension. Methods: HIV‐infected patients with evidence of portal hypertension who were anti‐HBV and anti‐HCV negative and HBV and HCV RNA polymerase chain reaction (PCR) negative were identified from patients managed by the Victorian statewide HIV referral service located at The Alfred Hospital, Melbourne. Portal hypertension was defined as either radiological or endoscopic evidence of varices, portal vein flow obstruction, or elevated hepatic venous pressure gradient (HPVG). Results: Five patients were found to have portal hypertension. These patients were male, aged 41 to 65 years, with known duration of HIV infection between 11 to 25 years. All had been treated with antiretroviral therapy, including didanosine. Tests for metabolic, autoimmune, and hereditary causes of liver disease failed to establish an etiology for the liver injury. All had radiological or endoscopic findings of varices, and four patients had radiological features of portal vein obstruction or flow reversal. Only one patient underwent HPVG measurement, which was elevated. Non‐invasive fibrosis assessment revealed increased liver stiffness in three (out of four) patients, and no cirrhotic features were found on those who underwent liver biopsy. Conclusions: To our knowledge, this is the largest published series of non‐cirrhotic portal hypertension in HIV mono‐infected patients in Australia. Further research is needed to understand what relationship, if any, HIV or its treatments might have on liver injury over time.     

Is portal vein cavernous transformation a component of congenital hepatic fibrosis？

Congenital hepatic fibrosis （CHF） is an autosomal recessive disorder that belongs to the family of fibropolycystic liver diseases. This family includes a spectrum of disorders which are usually found in combination with each other and are usually inherited. Clinically fibropolycystic diseases have three effects being present in different proportions, those of a space occupying lesion, of portal hypertension and of cholangitis. In most patients, the first manifestations of CHF are signs and symptoms related to portal hypertension such as splenomegaly and varices. Portal hypertension in these patients has been attributed to the hypoplasia or compression of the portal vein radicles in the fibrous bands. Cavernous transformation of the portal vein （CTPV） is a relatively rare condition resulting from extrahepatic portal vein obstruction with recanalization or collateral vein formation to bypass the obstruction. It has been found that patients with CHF having an accompanying CTPV have relatively large splenomegaly and suffers more frequent episodes of bleeding from esophageal varices.We believe that CTPV is a congenital component of CHF and also one of the important causative factors of portal hypertension in these patients.     

Rabbit model of non-cirrhotic portal fibrosis with repeated immunosensitization by rabbit splenic extract

BACKGROUND: Non-cirrhotic portal fibrosis (NCPF) or idiopathic portal hypertension, a disease of unknown etiology, is a common cause of portal hypertension in developing countries. Attempts to understand the etiopathogenesis of NCPF by developing animal models have been made. We describe a novel approach using repeated injections of rabbit splenic extract that were obtained from a previously primed rabbit, to develop a model of NCPF. METHODS: Twenty-eight rabbits (1.5-2.0 kg) were divided into the control (group I, n = 13) and the experimental (group II, n = 15) groups. The supernatant obtained after centrifugation of a 20% splenic homogenate, containing 6 mg protein/mL, was mixed with Freund's complete adjuvant (1:1 ratio) and injected intramuscularly to the recipient rabbits every 2 weeks for 3 months. Portal pressure was measured by inserting a cannula into the gastrosplenic vein. RESULTS: The mean portal pressure in group II was significantly (P < 0.05) higher than group I at 1 (19.4 +/- 2.9 vs 10.4 +/- 2.2 mmHg), 3 (16.7 +/- 1.1 vs 7.2 +/- 3.6 mmHg), and 6 (20.3 +/- 5.4 vs 10.3 +/- 4.8 mmHg) months. The mean splenic weight in group II was significantly (P < 0.05) greater than group I at 1, 3 and 6 months. Histopathology of spleen showed medullary congestion, hemosidrin laden macrophages and mild fibrosis. Liver showed normal hepatocytes with mild portal lymphocytic infiltrates and Kupffer cell hyperplasia. No significant anomalies were observed in the tests of liver function at 1 and 6 months. CONCLUSIONS: This animal model showed significant splenomegaly, with persistent rise in portal pressure without hepatic parenchymal injury, quite akin to NCPF seen in humans. This study also proposes that repeated immunostimulation may have an important role in the pathogenesis of NCPF.     

Effect of losartan,an angiotensin II antagonist,on secondary biliary cirrhosis

BACKGROUND/AIMS: Chronic bile duct obstruction leads to biliary cirrhosis and portal hypertension. The hepatic stellate cells are involved in this process and can be activated by angiotensin II. The aim of the present study was to determine the effect of losartan, an angiotensin II antagonist, on experimental biliary cirrhosis. METHODOLOGY: Wistar rats were allocated to one of three groups: bile duct ligation (BDL), bile duct ligation and losartan treatment (BDLL), and sham-operated animals (SHAM). After 28 days, liver and spleen weight, hepatic volume, portal flow, and hepatocytes, bile ducts, hepatic stellate cell population and collagen IV volume fraction were evaluated. RESULTS: The portal flow was lower in the BDL group than in the BDLL group, and lower in both groups than in the SHAM group. Hepatocyte volume fraction was higher in the BDLL group than in the BDL group, and lower in both groups than in the SHAM group. Liver and spleen weight, hepatic volume, hepatic stellate cells population and collagen IV were higher in the BDL group than in the BDLL group, and higher in both groups than in the SHAM group. CONCLUSIONS: These results suggest that losartan can inhibit both the liver fibrosis and portal hypertension occurring in secondary biliary cirrhosis.     

Hepatic vascular side effects of styrene maleic acid neocarzinostatin in the treatment of hepatocellular carcinoma

Styrene-maleic acid neocarzinostatin (SMANCS) sometimes causes hepatic vascular side effects, including arterial stricture, obstruction, and arterio-portal shunt. A total of 128 intra-arterial SMANCS injection treatments, performed for 89 patients with hepatocellular carcinoma, were analyzed to determine the relationship between angiographic findings and subsequent hepatic vascular injuries. After SMANCS therapy, hepatic arterial stricture or obstruction occurred in 5 patients (5/128; 3.9%), arterio-portal shunting in 12 (12/128; 9.4%), liver shrinkage in 4 (4/128; 3.1%), and cholangitis or biloma in 2 (2/128; 1.6%). Among 23 patients whose plain abdominal X-ray films just after SMANCS injection showed Lipiodol retention in the hepatic artery, 5 patients developed arterial obstruction, 10 developed arterio-portal shunt, and 2, cholangitis or biloma. Among 26 patients with Lipiodol retention in the portal vein, 4 developed hepatic lobe atrophy with aggravation of liver function. Among 3 patients with Lipiodol retention in both the hepatic artery and the portal vein, 1 developed arterio-portal shunt. In 76 treatments without excessive Lipiodol retention, only 1 of the patients developed arterio-portal shunt. Excessive retention of Lipiodol in hepatic vascular beds just after SMANCS therapy was significantly associated with future vascular side effects (22/52 vs 1/76; P < 0.0001). Lipiodol retention in arteries just after SMANCS injection was closely associated with subsequent arterial obstruction or arterio-portal shunt, and Lipiodol retention in the portal vein was related to subsequent hepatic lobe atrophy. Received: April 28, 1999 / Accepted: November 26, 1999     

Nature and Incidence of Liver Involvement in Agnogenic Myeloid Metaplasia

Clinical, biochemical and histopathological data of 33 patients with agnogenic myeloid metaplasia (AMM) were examined with reference to liver disease and dysfunction. Clinical manifestations of hepatic or portal system involvement included hepatomegaly, jaundice, hepatitis, gall stones, ascites and bleeding esophageal varices. The liver was smooth and firm; it became larger with progression of the disease, but to a lesser degree than the spleen. Mild indirect bilirubinaemia occurred in the course of the disease in about half of the patients. Hepatitis was diagnosed in 5 (15 %) patients and in 3 (10 %) cases it was the cause of death. Cholelithiasis was found in 4 (12 %) patients. Biochemical liver dysfunction occurred in 22 (66 %) patients. A progressive increase in serum alkaline phosphatase and a gradual decrease in serum albumin were observed in 4 patients, who were followed for 5 to 15 years. Hepatic myeloid metaplasia was found in all 20 patients examined histologically. The liver architecture was grossly distorted in 4 cases: in 2 this was due to impaction of the sinusoid with haemopoietic cells, and in the remaining 2 to necrosis and haemorrhage following viral hepatitis. Periportal fibrosis was observed in 6 (30 %) of the liver specimens. Ascites, portal hypertension, or both, were found in 7 (64 %) of the 11 autopsies and in 5 (22 %) of the remaining patients. Liver histology, examined in 11 patients, revealed periportal fibrosis in 5 cases and myeloid metaplasia only, in the remaining 5. Patients with ascites or portal hypertension exhibited more frequently increased levels of serum alkaline phosphatase and vitamin B₁₂, and lower levels of plasma prothrombin and serum albumin. The pathogenesis of the hepatic and portal system involvement in agnogenic myeloid metaplasia (AMM) remains uncertain. Mechanical pressure by foci of myeloid metaplasia, chronic passive congestion, hepatitis or combinations of the above may lead to atrophy or necrosis of the parenchyma, followed by reparative fibrosis. Portal hypertension and ascites, a common complication of advanced AMM, could be due to the combined effect of an increased blood flow in the portal system, hypoalbuminaemia and sinusoidal obstruction.