Age characteristics of formation of the hematopoietic microenvironment by stromal progenitors from the bone marrow of thymectomized mice

BACKGROUND: Portopulmonary hypertension, defined as mean pulmonary artery pressure >25 mmHg in the presence of a normal pulmonary capillary wedge pressure and portal hypertension, is a known complication of end-stage liver disease that has been associated with high morbidity and mortality at the time of liver transplantation. We have recently reported the successful treatment of portopulmonary hypertension with chronic intravenous epoprostenol and now report the first patient with severe portopulmonary hypertension successfully treated with epoprostenol who subsequently underwent successful liver transplantation. METHODS: A patient with severe portopulmonary hypertension was treated with intravenous epoprostenol, 23 ng/kg/min, for a 4-month period, after which the portopulmonary hypertension resolved and the patient underwent successful liver transplantation. RESULTS: The patient was discharged, continues to do well, and at 3 months is off epoprostenol with near normal pulmonary artery pressures. CONCLUSIONS: Chronic epoprostenol, in conjunction with a multidisciplinary, well-planned perioperative evaluation and treatment plan, may be the answer to a heretofore untreatable disease.     

Extrahepatic portal hypertension following liver transplantation: a rare but challenging problem

This study reports our experience of 8 cases of extrahepatic portal hypertension after 273 orthotopic liver transplantations in 244 adult patients over a 10-year period. The main clinical feature was ascites, and the life-threatening complication was variceal bleeding. Extrahepatic portal hypertension was caused by portal vein stenosis in 6 patients, and left-sided portal hypertension in 2 patients after inadventent ligation of portal venous tributaries or portasystemic shunts. All patients with portal vein stenosis had complete relief of portal hypertension after percutaneous transhepatic venoplasty (n = 4) or surgical reconstruction (n = 2), after a median follow-up of 33 (range: 6-62) months. Of the 2 patients with left-sided portal hypertension, one died after splenectomy and one rebled 6 months after left colectomy. This study suggests that extrahepatic portal hypertension is a series complication after liver transplantation that could be prevented by meticulous portal anastomosis and closure of portal tributaries or portasystemic shunts to improve the portal venous flow. However, any ligation has to be performed under ultrasound guidance to avoid inadventent venous ligations.     

Subacute cutaneous lupus erythematosus induced by radiation therapy

The authors describe for the first time a case of splenic infarction in a 7-year-old boy with portal hypertension and biliary cirrhosis secondary to biliary atresia. This rare complication may cause serious acceleration of chronic liver failure.     

Can clamping of splenic vessels prevent abrupt increase of portal vein pressure and migration of transplanted hepatocytes to the liver after intrasplenic hepatocyte transplantation?

BACKGROUND/AIMS: It is well known that hepatocyte transplantation can retain some proper functions, significantly improve the survival rate of rats with different models of acute fulminant hepatic failure, correct some congenital genetic disorders, and improve liver function in cirrhosis. Portal hypertension and hepatic embolization have been described following intrasplenic hepatocyte transplantation. We evaluated the effect of temporary occlusion of splenic vessels on changes in portal vein pressure and on distribution of transplanted hepatocytes after hepatocyte transplantation into the spleen in normal rats. METHODOLOGY: Liver cirrhosis has been induced in rats by 1% dimethylnitrosamine (Sigma, St. Louis, Mo) dissolved in normal saline at the dose of 10 ml of DMN/Kg, i.p., 3 consecutive days a week for 4 weeks. Donor hepatocytes were harvested by in situ ethylenediaminetetraacetic acid (EDTA) perfusion. Changes in portal vein pressures were monitored by a pressure monitor and distribution of transplanted hepatocytes was assayed by measurement of radioactivity of 51Cr-labeled transplanted hepatocytes according to clamping or non-clamping during intrasplenic hepatocyte transplantation. RESULTS: The changes in portal pressure remained significantly high 10 min after hepatocyte transplantation in the nonocclusion groups compared to the occlusion groups. However, the changes in portal vein pressures in cirrhotic rats returned to normal faster than in normal rats after cell transplantation in the nonocclusion groups. The distribution of 51Cr-labeled transplanted hepatocytes into the spleen significantly diminished radioactivity of the liver at 10 min, 2 hours, and 24 hours in the occlusion groups compared to the nonocclusion groups. Also, duration of clamping time of splenic vessels did not influence the initial distribution of transplanted hepatocytes at the time of intrasplenic hepatocyte injection. CONCLUSIONS: These results suggested that temporary occlusion of splenic vessels should be routinely used during intrasplenic hepatocyte transplantation.     

Refractory ascites due to portal vein thrombosis in liver cirrhosis--report of two cases

Portal vein thrombosis as a complication of liver cirrhosis has been reported to be extremely rare in Japan, as compared with European countries. There are few reports discussing the correlation of portal vein thrombosis with refractory ascites. Between January 1994 and December 1995, 20 cases (91%) of 22 patients with liver cirrhosis with ascites admitted to our hospital responded well within 2 months to a combination therapy of diuretics and albumin infusion, and the other two cases (9%) with refractory ascites were associated with portal vein thrombosis. The ascites in the first patient continued for 1 year, despite diuretics and albumin infusion therapy, and portal vein thrombosis was confirmed by autopsy. The ascites in the other patient continued for more than 4 months, and portal vein thrombosis was detected by ultrasound. Portal vein thrombosis was not found in the other 20 cirrhotic patients with ascites. These two cases suggest that portal vein thrombosis may be a contributing factor to refractory ascites in patients with decompensated liver cirrhosis.     

Optimal recovery of cytomegalovirus from urine as a function of specimen preparation

BACKGROUND/AIMS: Early liver transplantation is crucial in children with liver disease and pulmonary artery hypertension. Some severe pulmonary vascular anomalies associated with portal hypertension disappear after isolated liver transplantation. Evolution of pulmonary artery hypertension due to plexogenic arteriopathy is controversial, as this association is still considered a contraindication to isolated liver transplantation. Outcome of pulmonary hypertension after isolated liver transplantation is reported in three patients with portal hypertension. METHODS: After echocardiographic diagnosis, the patients had a complete hemodynamic exploration, and two had a lung biopsy. After liver transplantation, the survivors had echocardiographic follow up and a second hemodynamic exploration. RESULTS: In two children, pulmonary pressures and resistances returned to near-normal values 1 and 6 years after successful isolated liver transplantation. The third patient, with the most severe arteriopathy, had to wait 1 year for a donor, and the attempted transplantation was complicated by ventricular tachycardia; death occurred 2 days after surgery. CONCLUSIONS: Liver transplantation can reverse pulmonary artery hypertension due to high pulmonary resistances complicating liver disease with portal hypertension, provided it is carried out at an early stage. Early detection of pulmonary hypertension by systematic echocardiography may thus be crucial in these children with portal hypertension.     

Synthesis and dopamine receptor selectivity of the benzyltetrahydroisoquinoline, (R)-(+)-nor-roefractine

Colonic variceal bleeding is a rarity and is most commonly due to portal hypertension. The present report describes a patient with portal hypertension due to portal vein thrombosis who, following esophageal transection and successful sclerotherapy, developed a massive lower gastrointestinal bleeding from colonic varices. The literature is reviewed, and the pathophysiology of this complication is discussed. Possible etiologies of this condition may be esophageal transection and devascularization, successful sclerotherapy, and extensive thrombosis of the portal vein resulting in obliteration of the coronary-azygous anastomotic system. In such a situation other potential sites of portosystemic anastomoses, such as the colon, may be opened up, resulting in the development of colonic varices. Indeed, the incidence of colonic varices in two series after sclerotherapy for esophageal varices was 60-100%. Of 33 candidates evaluated for liver transplantation, colonic varices were found in 1.     

Cerebral oedema and increased intracranial pressure in chronic liver disease

BACKGROUND: Cerebral oedema is a cause of morbidity and mortality in fulminant hepatic failure but has not been well documented as a complication of chronic liver diseases. We report here the development of cerebral oedema and increased intracranial pressure in 12 patients with chronic liver disease. METHODS: Between July 1, 1987, and Dec 31, 1993, we studied 12 patients aged 29-67 years with end-stage chronic liver disease. All the patients had cirrhosis, portal hypertension, hypoprothrombinaemia, hepatic encephalopathy, and decreased serum concentrations of albumin (<25 g/L). During the study, the patients developed signs of increased intracranial pressure and had documented intracranial hypertension, cerebral oedema, or both. Intracranial hypertension was suspected on physical examination and confirmed by epidural catheters. We detected cerebral oedema by computed axial tomography of the head and necropsy of the brain when possible. FINDINGS: All the patients had intracranial hypertension and cerebral oedema. Two patients had successful treatment of cerebral hypertension with improvement of intracranial pressure such that orthotopic liver transplantation was undertaken. Both patients became neurologically normal after transplantation. Eight patients had only a transient response to treatment and died of cerebral oedema before a transplant could be done. INTERPRETATION: Cerebral oedema and increased intracranial pressure can occur in chronic liver disease and presents as neurological deterioration. Treatment guided by monitoring of intracranial pressure can lead to the reversal of intracranial hypertension, but in most patients cerebral oedema contributes to death or places them at too high a risk for liver transplantation.     

Inferolateral retraction reduces the risk of thermal injury to biliary structures

A liver transplant technique is described in a patient with a thrombosed portal vein and a functioning surgically created renal-lieno shunt. Permanent portal inflow to the graft was provided by division of the left renal vein (LRV) at its junction with the inferior vena cava and anastomosis of the LRV end-to-end with the donor portal vein. Although this results in splanchnic blood traversing a 360 degree roundabout from the superior mesenteric vein via the splenic and disconnected left renal veins to the donor portal vein, the anastomosis lay well and the procedure was successful.     

The middle colic vein: an alternative source of portal inflow in orthotopic liver transplantation complicated by portal vein thrombosis

BACKGROUND: Portal vein thrombosis (PVT) was previously considered a contraindication to orthotopic liver transplantation (OLT) since adequate portal blood supply is mandatory for graft function and patient survival. Improvements in surgical technique, however, have meant that this problem now can be circumvented in most instances. Nevertheless portal vein thrombosis remains an obstacle in OLT and is associated with increased incidence of primary non-function and long-term liver failure. METHODS: A 55-yr-old patient underwent OLT for secondary biliary cirrhosis associated with hepatitis C infection and complicated by long standing PVT. Involvement of the portal, mesenteric, and splenic veins prevented standard portal venous reconstruction. Portal inflow was accomplished by a side-to-end anastomosis between the middle colic vein and the donor portal vein. RESULTS: Hepatic reperfusion and subsequent liver function were excellent. Portal blood flow, as measured by color-enhanced Doppler ultrasound, was normal following surgery until discharge. The post-operative course was complicated by abdominal wound dehiscence and recurrent cytomegalovirus (CMV) infection. The patient was discharged in good clinical condition, with excellent liver function and patent portal vein 89 d after OLT. CONCLUSIONS: The middle colic vein is a novel, not previously described, source of portal venous inflow for OLT complicated by extensive splanchnic venous inflow thrombosis.     

Management of esophageal varices in children by endoscopic variceal ligation

Endoscopic variceal sclerotherapy (EVS) has been considered the mainstay of therapy for bleeding esophageal varices in adults. However, recent data have shown that endoscopic variceal ligation (EVL) is just as efficacious and has fewer complications than EVS. Although there are many reports concerning EVL in adults, only a few studies have been done in children. This report describes experience with EVL in 22 children with esophageal variceal hemorrhage. Eighty-seven EVL procedures were performed during a 9-year period in 22 children. The causes of portal hypertension were biliary atresia (10), portal vein thrombosis (8), chronic active hepatitis (1), cirrhosis secondary to cystic fibrosis (2), and primary sclerosing cholangitis (1). The age range at the onset of variceal bleeding was 8 months to 19 years. Twelve patients had EVS before EVL treatment was begun. Distal esophageal varices (one to four per session) were mechanically ligated using an elastic band ligature device attached to a flexible endoscope. The aim of therapy was obliteration of distal esophageal varices by EVL, every 2 to 4 weeks, until eradication. Subsequent EVL was dictated by the status of the varices. Outcome was assessed with respect to survival, rebleeding, status of varices, and complications. The patients underwent a mean of four sessions of EVL (range, one to eight). Four patients subsequently underwent liver transplantation. Of the 18 patients remaining (average follow-up period, 5.3 years), 12 had their varices eradicated (average of four EVL sessions), four are still in treatment, one has not been evaluated in the past 4 years, and one died of liver failure. Complications included bleeding between sessions (6 patients), cervical esophageal perforation (1 patient), and transient fever (2 patients). No child has experienced symptoms of esophageal stenosis or gastroesophageal reflux. Two patients died of liver disease, unrelated to bleeding from portal hypertension. EVL is effective in controlling variceal hemorrhage in children with portal hypertension, regardless of etiology. The complication rate is low, and EVL is an acceptable and perhaps preferable alternative to EVS in children with esophageal varices.     

The efficacy of organ-preserving operations on the spleen in portal hypertension in children

Under analysis are results of treatment of 38 children with liver cirrhosis. Operations were performed in 25 patients, in 13 children decompensating shunts were put between the vessels of the splenic and left renal veins. Based on the assessment of the clinical effect the authors made a conclusion that in children with portal hypertension and symptoms of hypersplenism the creation of a spleno-renal anastomosis with the retained spleen is an effective measure and considerably reduced risk of postoperative complications.     

Splenic artery aneurysms in liver transplant patients. Liver Transplant Group

BACKGROUND/AIMS: The purpose of the study was to investigate the incidence of and risk factors for splenic artery aneurysms in liver transplant patients. METHODS: Medical records and the pre- and 1-year postoperative angiograms of 337 liver transplant patients were reviewed to assess the presence and characteristics of these aneurysms. RESULTS: Forty-five patients with aneurysms were identified (13%): 41 cases in 242 adult patients (17%) and four (4%) in 95 children (p<0.01). The female-to-male ratio was 2:1. The majority of the aneurysms (87%) were located in the distal third of the splenic artery and the majority (87%) of the patients presented multiple aneurysms. In patients without portal hypertension no aneurysms were identified, whereas in 16% of the patients with portal hypertension aneurysms were found (p<0.001). In adult patients the incidence of splenic artery aneurysms was significantly higher in patients with parenchymal diseases than in patients with cholestatic diseases (p<0.0001). Two patients (4%) died due to rupture of the aneurysms. Control angiographies, 1 year after liver transplantation, showed no changes in size and number of the aneurysms, and no new aneurysms were identified. CONCLUSIONS: The incidence of splenic artery aneurysms in liver transplant patients is 13%. They are generally multiple and located in the distal third of the splenic artery. The incidence is higher in women and in patients with parenchymal liver disease and portal hypertension. The incidence of rupture was 4%.     

Domino hepatic transplantation using the liver from a patient with familial amyloid polyneuropathy

BACKGROUND: In transplantation, novel methods are required to augment the supply of donor organs. We report the first domino liver transplant in which a patient with familial amyloid polyneuropathy (FAP) received an orthotopic split liver graft, and her explanted liver was donated to another patient. Three successful liver transplants were thus achieved from the one cadaver liver. PATIENTS AND METHODS: A cadaveric donor liver was split and the left lobe was grafted into a child with biliary atresia. The right lobe was transplanted into a woman with FAP associated with the transthyretin Met30 variant. Her own otherwise healthy liver was donated to a patient with cirrhosis and hepatocellular carcinoma. RESULTS: Fifteen months after transplantation, all three recipients are well with normal liver function. The domino recipient developed inferior vena cava stricturing at the level of anastomosis after surgery with resultant ascites, requiring dilatation and LeVeen shunt insertion. Serum amyloid P component scintigraphy showed amyloid regression in the domino donor and to date has not identified any amyloid deposits in the recipient, who also remains free of tumor recurrence. CONCLUSIONS: Domino transplantation using the livers from patients with FAP may be justified for patients whose disease condition precludes a long spell on the waiting list, including those with hepatic malignancies and those for whom palliation rather than long-term cure is the aim.     

Primary biliary cirrhosis. Histological evidence of disease recurrence after liver transplantation

Histological evidence of primary biliary cirrhosis (PBC) recurring after orthotopic liver transplantation (OLT) was looked for in a 'blinded' study of 353 biopsies from 188 patients, 12-100 months post-transplant. Biopsies (172) were obtained from 83 patients transplanted for PBC and 181 biopsies from 105 patients with other liver diseases. Sixteen biopsies from 13 PBC patients (16%) had features suggestive of recurrent disease. The main diagnostic findings were: mononuclear portal inflammatory infiltration (n = 16), portal lymphoid aggregates (n = 14), portal epithelioid granulomas (n = 14) and bile duct damage (n = 15). This combination of changes was not seen in any biopsy from the non-PBC group. Additional features supporting a diagnosis of recurrent disease were ductopenia (n = 7), bile ductular proliferation (n = 7), portal fibrosis (n = 6) and copper deposition (n = 5). Thirteen biopsies from 12 patients were classified as stage I or II histologically. The other patient developed progressive damage in three serial biopsies resulting in an early micronodular cirrhosis, 5 years post-transplant. These observations provide further evidence that PBC recurs after OLT. More studies are required to determine the natural history and clinical significance of the predominantly early histological changes documented so far.     

Chronic liver failure induced by long-term administration of tegafur: a case report

A 55 year-old man was admitted with massive ascites. Although the laboratory data on admission were compatible with hepatic cirrhosis and remarkable esophageal varices were observed during endoscopy, the imaging findings such as computed tomography and ultrasonographic examination did not confirm hepatic cirrhosis. The patient had no history of alcohol abuse, blood transfusions or acute hepatitis. Serological markers related to viral and autoimmune hepatitis were all negative. Seven years ago, the patient had undergone an operation for colon cancer and has been taking tegafur since then for a total of 55 months. Tegafur was suspected as the causative agent for the liver dysfunction of this patient and the administration of tegafur was stopped. His laboratory data improved gradually and the ascites vanished. The first liver biopsy performed 6 months after discontinuation of tegafur still revealed chronic active hepatitis. However, at the liver biopsy performed 18 months after withdrawal of tegafur, inflammatory activity had subsided and the third liver biopsy, performed 34 months thereafter, revealed further improvement of the pathological changes that had occurred in the liver. We therefore conclude that the administration of tegafur may have caused chronic active liver injury with portal hypertension manifested as ascites and esophageal varices.     

Liver transplantation resolves the hyperdynamic circulation in hereditary hemorrhagic telangiectasia with hepatic involvement

BACKGROUND & AIMS: Hepatic involvement in hereditary hemorrhagic telangiectasia is common but often asymptomatic. However, in some cases, the vascular lesions that involve the liver may lead to high-output cardiac failure and pulmonary hypertension that is predominant over hepatobiliary manifestations. Liver transplantation and treatment of these complications are described and discussed in this article. METHODS: Three patients with hereditary hemorrhagic telangiectasia and hepatic involvement received transplants. They had pulmonary hypertension and chronic right-sided heart failure caused by disseminated intrahepatic telangiectasias with shunts between the hepatic artery and hepatic veins or portal vein. Left-to-right intrahepatic shunt output was estimated to range between 51% and 57.5% of cardiac output. RESULTS: Hyperdynamic circulation disappeared after liver transplantation in all patients. Results of computed tomography and right-sided heart catheterization performed 6 months later were normal. Follow-up periods currently are 65, 53, and 29 months, and each patient continues to be asymptomatic. CONCLUSIONS: This report suggests that liver transplantation can be considered as an alternative and successful curative treatment that may prevent the irreversible evolution of cardiopulmonary disease.     

High-output congestive heart failure following transjugular intrahepatic portal-systemic shunting

A hyperdynamic circulatory state with elevated cardiac output, decreased peripheral vascular resistance, and sodium retention occurs in patients with portal cirrhosis. Surgical portal-systemic shunts and transjugular intrahepatic portal-systemic shunts (TIPS) have been shown to worsen the high-output state in these patients. However, clinical evidence of high-output congestive heart failure has been reported only rarely to complicate cirrhosis. We describe a patient who developed high-output congestive heart failure with markedly elevated filling pressures after TIPS and had complete resolution of heart failure after liver transplantation.     

Neurological findings in the normal elderly: prevalence and relationships with memory performance

Portal hypertension is a result of chronic liver disease in the majority of cases. Rare, potentially curable causes of portal hypertension include vascular conditions such as hepatic or portal venous thrombosis and arterio-portal fistulas. We present the rare case of a spontaneous splenic arterio-venous fistula in a 40 year old multiparous woman. The young woman presented with massive diarrhea, ascites, abdominal pain, and an abdominal machinery type bruit and represents the second ever reported case with diarrhea as presenting symptom of splenic arterio-venous fistula. The diagnosis was confirmed by color Doppler ultrasound. Transfemoral aortography was performed to assess the possibility of catheter embolization. Surgical intervention was initially complicated by collateral arterial tributaries of the fistula and finally resulted in a dramatic recovery with persistent resolution of all symptoms. This case report demonstrates a curable form of portal hypertension that must be considered in acute onset portal hypertension in multiparous women and in the absence of liver disease. A machinery type bruit in the upper left abdominal quadrant represents an important and simple diagnostic symptom found by auscultation. Color Doppler ultrasound represents a non invasive, universally applicable and fast method of establishing the diagnosis. The literature and management of splenic arterio-venous fistulas are reviewed.     

Reducing the addictiveness of cigarettes. Council on Scientific Affairs, American Medical Association

Biliary atresia is a disorder of infants in which there is obliteration or discontinuity of the extrahepatic biliary system, resulting in obstruction of bile flow. Untreated, the resulting cholestasis leads to progressive conjugated hyperbilirubinemia, cirrhosis, and hepatic failure. Biliary atresia has an incidence of approximately one in 10,000 live births worldwide. Evidence to date supports a number of pathogenic mechanisms for the development of biliary atresia. An infectious cause, such as by a virus, would seem most pausible in many cases. The clinical observation that biliary atresia is rarely encountered in premature infants would support an agent acting late in gestation. However, no infectious or toxic agent has been conclusively implicated in biliary atresia. Genetic mechanisms likely play important roles, even regarding susceptibility to other specific causes, but no gene whose altered function would result in obstruction or atresia of the biliary tree has been identified. The variety of clinical presentations support the notion that the proposed mechanisms are not mutually exclusive but may play roles individually or in combination in certain patients. Biliary atresia, when untreated, is fatal within 2 years, with a median survival of 8 months. The natural history of biliary atresia has been favorably altered by the Kasai portoenterostomy. Approximately 25 to 35% of patients who undergo a Kasai portoenterostomy will survive more than 10 years without liver transplantation. One third of the patients drain bile but develop complications of cirrhosis and require liver transplantation before age 10. For the remaining one third of patients, bile flow is inadequate following portoenterostomy and the children develop progressive fibrosis and cirrhosis. The portoenterostomy should be done before there is irreversible sclerosis of the intrahepatic bile ducts. Consequently, a prompt evaluation is indicated for any infant older than 14 days with jaundice to determine if conjugated hyperbilirubinemia is present. If infectious, metabolic, endocrine disorders are unlikely and if the child has findings consistent with biliary atresia, then exploratory laparotomy and intraoperative cholangiogram should be done expeditiously by a surgeon who has experience doing the Kasai portoenteostomy. Biliary atresia represents the most common indication for pediatric liver transplantation, representing more than 50% of cases in most series. Transplantation is indicated when symptoms of end stage liver disease occur, including recurrent cholangitis, progressive jaundice, portal hypertension complications, ascites, decreased synthetic function, and growth/nutritional failure.