HCV-related liver cancer in people with haemophilia.

The topic of this monograph is liver cancer associated with chronic HCV infection. We start with some background information on chronic HCV infection and its long-term sequelae, one of which is liver cancer. The rest of the article is concerned with liver cancer or hepatocellular carcinoma (HCC). Epidemiology, risk factors, treatment and outcomes are discussed. We focus on those aspects that are of specific interest in people with haemophilia: studies performed in haemophilia populations, the use of invasive diagnostic and therapeutic tools and the outcome of liver transplantation. Throughout the paper, recommendations are given on surveillance for and diagnosis of HCC and on the practical aspects of invasive procedures. These recommendations are based on professional guidelines, other published evidence and the authors' experience. In general, diagnostic and therapeutic options are the same in persons with and without haemophilia.

Liver transplantation: an update.

Liver transplantation has been an accepted treatment for end-stage liver disease since the 1980s. Currently it is a highly successful treatment for this indication. The aim of this review is to give a general update on recent developments in the field of liver transplantation. In the last decades considerable progress has been made in the care of liver transplant candidates and recipients. At present the one- and five-year patient survival rates are approximately 85 and 75%. The indications for liver transplantation are shifting and the number of absolute contraindications is decreasing. In the coming years, an increase in the number of transplant candidates can be expected. An important problem is the shortage of donor organs, for which many solutions are being explored. A recently introduced method for recipient selection is the MELD score using simple laboratory measurements. Perioperative care at the present time is characterised by a high degree of standardisation and rapidly declining blood loss during transplantation. Long-term care includes awareness and management of recurrent disease. Important causes of morbidity and mortality such as de novo malignancies and cardiovascular disease should be adequately screened for and managed. With the increasing success of liver transplantation, physicians should aim at reaching a normal life expectancy and quality of life for transplant recipients.

Current health status of patients who have survived for more than 15 years after liver transplantation.

BACKGROUND: Liver transplantation was started in our centre as early as 1979. We have studied the clinical outcome of patients surviving longer than 15 years, with special interest for the broad range of comorbidity and the self-perceived quality of life. METHODS: All patients who underwent a liver transplantation at an adult age, between March 1979 and February 1991, and who had survived at least 15 years were eligible for the study. Data were collected from the medical records. Health-related quality of life was assessed using the Six-Dimensional EuroQol test. RESULTS: The five-year survival of patients alive 15 years after transplantation was 78%. Thirty-seven patients are currently alive with a median follow-up of 18.8 years (range 15.0 to 26.8) after transplantation. Comorbidity consists predominantly of overweight (57%), osteoporosis (49%), de novo cancer (38%, mainly skin cancer), hypertension (38%), cardiovascular events (19%), diabetes mellitus (22%), cataract (24%), and renal clearance<50 ml/min (11%). The pattern of comorbidity seems to relate to the type of immunosuppression which consisted mainly of prednisolone and azathioprine. Quality of life was perceived as satisfactory (7 on a scale of 0 to 10). However, about half of the patients reported limitations in the domains mobility, usual activities and pain/discomfort. In addition a minority reported some anxiety or depression. CONCLUSION: The outcome of liver transplantation in this early cohort of patients is fairly good. Improvements may be achieved by adaptations in the immunosuppressive regimen.

Effects of different immunosuppressive regimens on regulatory T-cells in noninflamed colon of liver transplant recipients.

BACKGROUND: Regulatory T-cells (Treg) are natural suppressors of autoimmunity. Previous studies indicate that immunosuppressive drugs, especially calcineurin-inhibitors, may interfere with Treg homeostasis. Inflammatory bowel disease (IBD) can relapse or develop de novo after liver transplantation. IBD is associated with a relative deficiency of Treg. The aim of this study was to determine the effect of long-term immunosuppression on the presence of Treg in the noninflamed colonic mucosa of liver transplant recipients. METHODS: Colonic biopsies of normal mucosa of 36 liver transplant recipients on different types of immunosuppression and 11 controls were studied. Treg marker Foxp3 and Treg products transforming growth factor-beta (TGF-beta) and interleukin-10 (IL-10) were studied by quantitative polymerase chain reaction (Q-PCR) and immunohistochemistry. TGF-beta-induced Smad-protein 3 and 7 were studied by Q-PCR. RESULTS: No significant differences between controls and patients were observed in IL-10, TGF-beta, and Smad expression. Mucosal Foxp3 mRNA levels and Foxp3+CD3+ cells were significantly reduced in transplant recipients using prednisone/azathioprine/tacrolimus compared with controls but no direct relationship between Foxp3 expression and 1 specific drug was detected. CONCLUSIONS: These results challenge the hypothesis that calcineurin-induced reduction of Treg or TGF-beta expression predisposes nontransplanted tissue to inflammation, but indicate that combined immunosuppression hampers Treg development in the intestine.

The prognostic value of histology in the assessment of patients with Budd-Chiari syndrome.

BACKGROUND/AIMS: It is unclear whether treatment of patients with Budd-Chiari syndrome (BCS) should be based on liver histology, as large histopathological studies have not been performed. We investigated the relationship between the histopathological findings and survival. METHODS: We studied the clinical features and findings on biopsy specimens in 45 patients with BCS who were admitted to four tertiary referral medical centers. Histological findings, i.e. congestion, necrosis, inflammation and fibrosis, were graded. Survival was assessed in relation to histological findings and clinical features at the time of diagnosis as well as in relation to subsequent treatment with or without portosystemic shunting. RESULTS: Centrilobular congestion, centrilobular necrosis, lobular inflammation and portal inflammation were not significantly related to survival. In addition, there was no association between either pericentral or periportal fibrosis and survival. Univariate analysis revealed that the prothrombin time and Child-Pugh score were significantly related to survival (P = 0.005 and Ptrend = 0.02, respectively). Multivariate analysis yielded the Child-Pugh score, serum alanine aminotransferase (ALT) and treatment with portosystemic shunting as independent prognostic indicators. CONCLUSIONS: We found no evidence for a relationship between early liver pathology and survival. Child-Pugh score, serum ALT and portosystemic shunting appeared to be prognostic indicators for patients with BCS.

Extrahepatic portal vein thrombosis: aetiology and determinants of survival.

BACKGROUND: Malignancy, hypercoagulability, and conditions leading to decreased portal flow have been reported to contribute to the aetiology of extrahepatic portal vein thrombosis (EPVT). Mortality of patients with EPVT may be associated with these concurrent medical conditions or with manifestations of portal hypertension, such as variceal haemorrhage. PATIENTS AND METHODS: To determine which variables have prognostic significance with respect to survival, we performed a retrospective study of 172 adult EPVT patients who were followed over the period 1984-1997 in eight university hospitals. RESULTS: Mean follow up was 3.9 years (range 0.1-13.1). Overall survival was 70% (95% confidence interval (CI) 62-76%) at one year, 61% (95% CI, 52-67%) at five years, and 54% (95% CI, 45-62%) at 10 years. The one, five, and 10 year survival rates in the absence of cancer, cirrhosis, and mesenteric vein thrombosis were 95% (95% CI 87-98%), 89% (95% CI 78-94%), and 81% (95% CI 67-89%), respectively (n=83). Variables at diagnosis associated with reduced survival according to multivariate analysis were advanced age, malignancy, cirrhosis, mesenteric vein thrombosis, absence of abdominal inflammation, and serum levels of aminotransferase and albumin. The presence of variceal haemorrhage and myeloproliferative disorders did not influence survival. Only four patients died due to variceal haemorrhage and one due to complications of a portosystemic shunt procedure. CONCLUSION: We conclude that mortality among patients with EPVT is related primarily to concurrent disorders leading to EPVT and not to complications of portal hypertension.

Superior diagnostic strength of combined contrast enhanced MR-angiography and MR-imaging compared to intra-arterial DSA in liver transplantation candidates.

To evaluate the diagnostic value of combined contrast enhanced MRA (ce-MRA) and MRI compared to that of intra-arterial DSA (i.a.DSA) in liver transplantation, transjugular porto-systemic (TIPSS) and spleno-renal shunt candidates. 50 patients in the workup for liver transplantation underwent ce-MRA/MRI and i.a.DSA within a three days interval. Both examinations were assessed with respect to vessel anatomy and patency of the arterial, portal venous, porto-systemic collateral and systemic venous system. The results were compared with the intra-operative findings when available. Malignancy detection in ce-MRA/MRI and i.a.DSA were compared. There are no significant differences for the arterial part of the vascular supply to the liver that is important for transplantation. Although the differences for the portal system are not significant, the difference between the two techniques is of clinical importance because i.a.DSA failed to detect portal vein occlusion in 4 patients. Ce-MRA is significantly better for the detection of collaterals (p < 0.001) and the assessment of the inferior vena cava, the hepatic and the renal veins (p < 0.001). Although the detection of liver malignancy is poor in both techniques, ce-MRA/MRI is superior to i.a.DSA. This study shows that a one step diagnostic approach with a combination of ce-MRA and MRI is a valuable radiological tool with a superior diagnostic strength compared to i.a.DSA in the liver transplantation and shunt candidate. Therefore, ce-MRA/MRI should replace i.a.DSA in these patients groups.

Rapid decreases in donor-specific cytotoxic T lymphocyte precursor frequencies and graft outcome after liver and lung transplantation.

BACKGROUND: A decrease in donor-specific T cell precursor frequencies as seen late, one or more years, after transplantation is assumed to reflect transplantation tolerance, a condition important for long term acceptance of the allograft. However, such late decreases also occur in recipients that developed chronic transplant dysfunction questioning its relevance in transplantation tolerance. We investigated whether early, i.e., the first 6 months, decreases in donor-specific T cell precursor frequencies reflect transplantation tolerance and predict graft outcome after liver and lung transplantation. METHODS: Donor and third party specific cytotoxic (CTLp) and helper T lymphocyte precursor (HTLp) frequencies were analyzed in pretransplant and 1 (or 2) and 6-month blood samples taken from liver and lung recipients and were correlated with graft outcome. RESULTS: In liver allograft recipients with good graft function (n=7), mean donor-specific CTLp frequencies decreased as early as 1 month after transplantation and remained low thereafter. In contrast, mean CTLp frequencies did not decrease in liver allograft recipients with chronic transplant dysfunction (n=6). In lung allograft recipients, donor-specific CTLp frequencies remained relatively high and frequencies were not different between recipients without (n=6) or with (n=6) chronic transplant dysfunction. Donor-specific HTLp frequencies did not change significantly after liver or lung transplantation and did not differ between recipients without or with chronic transplant dysfunction. CONCLUSIONS: An early decrease in donor-specific CTLp correlates with good graft outcome after liver transplantation. Such rapid decreases in alloreactivity do not occur after lung transplantation illustrating the unique capacity of liver allografts to induce transplantation tolerance.

Increased cancer risk after liver transplantation: a population-based study.

BACKGROUND/AIMS: Development of de novo malignancies emerges as a serious long term complication after liver transplantation. METHODS: We reviewed the medical records of 174 adult one-year survivors for de novo malignancies. The observed cancer rates were compared with the expected cancer rates in the Dutch population. RESULTS: Twenty-one of the 174 patients developed 23 malignancies (12%). Skin and lip cancer accounted for 12 of the 23 malignancies (52%). Only one patient had a B-cell lymphoma. The cumulative risk for de novo malignancy was 6, 20, and 55% at 5, 10, and 15 years after transplantation, respectively. The overall relative risk (RR) as compared with the general population was 4.3 (95% confidence interval 2.4-7.1). Significantly increased RRs were observed for non-melanoma skin cancer (RR 70.0), non-skin solid cancer (RR 2.7), renal cell cancer (RR 30.0), and colon cancer (RR 12.5). Multivariate analysis showed that an age > 40 years and pretransplant use of immunosuppression were significant risk factors. CONCLUSIONS: An increased risk of cancer exists after liver transplantation, for both for skin/lip cancer, and other solid tumors. Older age and the use of immunosuppression are risk factors.

Transthyretin Val71Ala mutation in a Dutch family with familial amyloidotic polyneuropathy.

A Dutch family with familial amyloidotic polyneuropathy associated with the transthyretin mutation Val71Ala is described. This is the third reported family with this mutation, causing at the protein level an unstable TTR monomer and at the clinical level progressive wasting, polyneuropathy, autonomic dysfunction and vitreous opacities.

Subacute Budd-Chiari syndrome associated with polycythemia vera and factor V Leiden mutation.

We describe a 48-year-old caucasian woman with a subacute Budd-Chiari syndrome attributed to the presence of polycythaemia vera, heterozygosity for the factor V Leiden mutation and the use of an oral contraceptive pill. Two diagnostic pitfalls were encountered. First, on CT scanning of the abdomen the still normally vascularized central part of the liver was initially judged as a hypervascular tumour. Second, there was difficulty to recognize the thrombocytosis/leukocytosis in relation with portal hypertension and hypersplenism. Our case illustrates the obstacles which can be faced during the diagnostical process in a subacute form of Budd-Chiari syndrome. Furthermore, our case illustrates the need for routinely screening of the factor V Leiden mutation in patients with Budd-Chiari syndrome.

Liver transplantation for glycogen storage disease types I, III, and IV.

UNLABELLED: Glycogen storage disease (GSD) types I, III, and IV can be associated with severe liver disease. The possible development of hepatocellular carcinoma and/or hepatic failure make these GSDs potential candidates for liver transplantation. Early diagnosis and initiation of effective dietary therapy have dramatically improved the outcome of GSD type I by reducing the incidence of liver adenoma and renal insufficiency. Nine type I and 3 type III patients have received liver transplants because of poor metabolic control, multiple liver adenomas, or progressive liver failure. Metabolic abnormalities were corrected in all GSD type I and type III patients, while catch-up growth was reported only in two patients. Whether liver transplantation results in reversal and/or prevention of renal disease remains unclear. Neutropenia persisted in both GSDIb patients post liver transplantation necessitating continuous granulocyte colony stimulating factor treatment. Thirteen GSD type IV patients were liver transplanted because of progressive liver cirrhosis and failure. All but one patient have not had neuromuscular or cardiac complications during follow-up periods for as long as 13 years. Four have died within a week and 5 years after transplantation. Caution should be taken in selecting GSD type IV candidates for liver transplantation because of the variable phenotype, which may include life-limiting extrahepatic manifestations. It remains to be evaluated, whether a genotype-phenotype correlation exists for GSD type IV, which may aid in the decision making. CONCLUSION: Liver transplantation should be considered for patients with glycogen storage disease who have developed liver malignancy or hepatic failure, and for type IV patients with the classical and progressive hepatic form.

The value of Doppler ultrasound in cirrhosis and portal hypertension.

BACKGROUND: Cirrhosis and portal hypertension affect the flow profile of the liver vasculature. In these conditions Doppler ultrasound can provide important information on the hemodynamics of the portal venous system, the hepatic artery and the hepatic veins. METHODS: The value of Doppler ultrasound in the assessment of the patient with cirrhosis and portal hypertension was determined by reviewing the literature. RESULTS: Portal venous blood flow becomes reversed with advanced portal hypertension. Reversed flow is also demonstrated in patients with veno-occlusive disease and portosystemic shunts. Despite general agreement that portal flow velocity is decreased in cirrhotic patients, the absolute values of portal flow velocity in both healthy subjects and cirrhotic patients vary considerably. Errors in Doppler measurements, observer variability and collateral pathways contribute to these variations. Furthermore, portal blood flow is influenced by numerous factors such as changes in the body position, phase of respiration, timing of meals, exercise and cardiac output. Finally, portal flow may be unaltered due to a combination of high inflow from the splanchnic organs and increased resistance within the liver. High resistive index of the hepatic artery is seen in patients with end-stage liver disease, particularly in children with severe cirrhosis secondary to biliary atresia. However, hepatic artery flow remains normal in most patients. Abnormal hepatic vein flow profiles are seen in patients with cirrhosis, but dampening or flattening of the flow profile has a multifactorial origin (Budd-Chiari, metastases, ascites) and can be observed in healthy subjects. CONCLUSIONS: Although many factors may affect the accuracy of volume flow and velocity measurements and the flow profile of the liver vasculature may change in different situations, Doppler ultrasound is useful in the assessment of the patient with cirrhosis and portal hypertension.

Long-term follow-up after liver transplantation for erythropoietic protoporphyria.

OBJECTIVE: Erythropoietic protoporphyria (EPP) is an inherited disorder of haem synthesis, causing excess of protoporphyrin in blood, skin, liver and other organs. Protoporphyrin causes rapidly progressive liver failure in a minority of EPP patients. Long-term follow-up after liver transplantation for EPP is poorly documented. DESIGN: Two EPP patients were followed for 7 years after liver transplantation. Porphyrin levels were monitored and serial liver biopsies were taken. RESULTS: After transplantation, serum protoporphyrin levels remained elevated. In one patient, long periods with normal liver tests, low protoporphyrin levels and the absence of photosensitivity were followed by episodes of cholestasis and elevated protoporphyrin levels in blood, faeces and liver tissue. These episodes could be managed successfully with blood transfusions and changes in medication. The simultaneous rise of protoporphyrin concentration in both blood and faeces in this patient argues for increased protoporphyrin production as the cause of liver cell injury. The other patient acquired hepatitis B infection during the transplantation. From 3 months onwards she had continuously elevated liver tests, cholestasis, elevated protoporphyrin levels in blood, faeces and liver tissue, and photosensitivity. In this case, cholestasis and impaired protoporphyrin excretion may have played an important role in the persistent liver injury. Sequential liver biopsies of both patients showed various degrees of liver injury related to variations of the hepatic protoporphyrin concentrations. Eight and six months respectively after liver transplantation the livers of both patients showed fibrosis and hepatocellular protoporphyrin accumulation. CONCLUSIONS: The main cause of liver damage in EPP is overproduction of protoporphyrin in the bone marrow. Liver transplantation must be considered as symptomatic therapy with a high-risk for recurrent disease.

The assessment of autonomic function in patients with systemic amyloidosis: methodological considerations.

Autonomic neuropathy is a well-known and prognostically important feature of systemic amyloidosis. In other conditions, autonomic function is commonly assessed by cardiovascular reflex tests, described by Ewing, but the feasibility of these tests has not been investigated in patients with systemic amyloidosis. We studied autonomic function in amyloidotic patients using cardiovascular tests and assessed their feasibility. Patients with AA, AL and ATTR amyloidosis participated. In all patients, cardiovascular reflex testing (mental arithmetic stress test and head-up tilting, besides the Ewing-tests) was performed. Of the 46 patients included, only 28 patients could perform all 4 Ewing-tests. In particular, patients with AA amyloidosis secondary to rheumatoid arthritis could not perform standing up and the isometric handgrip test. However, when the mental stress test replaced the handgrip test and head-up tilting replaced standing up, in 45 of the 46 patients, autonomic function could be assessed with cardiovascular reflex tests. Half of the patients with AA amyloidosis had signs of autonomic neuropathy--which was more than expected. We propose to replace the isometric handgrip test with the mental arithmetic stress test and standing up with head-up tilting if a patient is not able to perform these tests.

Routine Doppler ultrasound for the detection of clinically unsuspected vascular complications in the early postoperative phase after orthotopic liver transplantation.

To assess the role of routine Doppler ultrasound in the detection of clinically unsuspected vascular complications in the early postoperative phase after orthotopic liver transplantation (OLT), the findings of 858 routinely performed Doppler ultrasound examinations were analyzed in 268 transplants. At various time intervals after OLT, we encountered 46 abnormal Doppler findings: hepatic artery (thrombosis), portal vein [anastomotic stenosis, (non)occlusive thrombosis or reversed flow], inferior vena cava [anastomotic stenosis with reversed flow, no flow, or (non)occlusive thrombosis], and hepatic veins (to-and-fro flow or stenosis with reversed flow) in 14, 20, 9, and 2 transplants, respectively. Most of these abnormal Doppler findings were confirmed by angiography, cavography, or surgery. The positive predictive value for hepatic artery thrombosis (HAT) was 12 out of 14, or 86%. In the first 2 weeks after OLT, routine Doppler ultrasound revealed 20 of the 46 abnormal findings (43%). Clinically unsuspected complications of the hepatic artery, portal vein, inferior vena cava, and hepatic veins were found in 9 of the 14 (64%), 6 of the 20 (30%), 3 of the 9 (33%), and 2 of the 2 (100%) transplants, respectively. The highest incidence--nine vascular complications--was found on the 1st day. On each of the remaining days (except for the 2nd and 9th days), one or two vascular complications were detected. HAT was found mainly in the 1st week. Vascular complications developed independently or concomitantly. We conclude that routine Doppler ultrasound is very important for the detection of clinically unsuspected vascular complications, particularly HAT, in the first 2 weeks after OLT. We recommend routine Doppler ultrasound of all hepatic vessels every 3 days in the early postoperative phase after OLT. Special attention should be paid to the 1st day.

Noninvasive metabolic assessment of human donor livers: prognostic value of 31P-magnetic resonance spectroscopy for early graft function.

BACKGROUND: The purpose of this study was to investigate whether phosphorus-31 magnetic resonance spectroscopy (31P-MRS) of the isolated donor liver can serve as a viability indicator with prognostic value for transplantation outcome. METHODS: Forty human donor livers preserved with University of Wisconsin solution were studied shortly before transplantation. The respective spectral peak areas of the isolated donor liver were correlated with the amount of hepatocellular graft damage and liver metabolic function shortly after implantation. RESULTS: The individual phosphomonoesters, inorganic phosphate, phosphodiesters, and nicotine adenine dinucleotide peaks were not prognostic for postoperative hepatocellular damage or liver metabolic capacity. The presence of adenosine triphosphate, however, predicts a significantly better metabolic capacity to eliminate bilirubin, to synthesize fibrinogen and antithrombin III, and to maintain a better prothrombin time after transplantation. Furthermore, this study is probably the first 31P-MRS demonstration in the human liver of phosphocreatine. CONCLUSIONS: In the clinical setting described, metabolic assessment using 31P-MRS did not result in a reliable noninvasive test to predict primary graft dysfunction. Study of the role of phosphocreatine in liver metabolism during cold storage is needed.

High prevalence of hepatitis G virus after liver transplantation without apparent influence on long-term graft function.

BACKGROUND/AIMS: Hepatitis G virus is a recently characterized transfusion-transmissible RNA virus. Its pathogenicity remains to be established. We studied its prevalence in liver transplant patients and assessed the long-term influence on the liver graft. METHODS: Thirty-nine adult patients without hepatitis B or C were included; median follow-up was 8 years (range 1-17). Serum samples from before and late after transplantation were investigated for the presence of HGV-RNA. HGV-RNA was detected by cDNA-PCR, using primers from the NS3 region of the viral genome. The latest available yearly liver biopsy was assessed in a coded fashion according to established histological criteria. The outcome in the HGV-positive patients was compared with the outcome in the HGV-negative patients with respect to liver tests and liver histology. RESULTS: The prevalence before and after transplantation was 15.4 and 43.6%, respectively. Liver test results and liver histology did not differ between the HGV and non-HGV groups. In both groups more than 50% of the patients showed normal histology. Mild portal and/or lobular inflammation tended to be more prevalent in the non-HGV group (no statistical difference). CONCLUSIONS: HGV infection is highly prevalent in liver transplant patients. In the absence of co-infection with hepatitis B or C virus, no long-term negative influence on the graft occurs.