The difficult clinical diagnosis of erythropoietic protoporphyria.

We give a short survey of the Swedish erythropoietic protoporphyria patients (EPP) with respect to the lapsed time between symptom debut and diagnosis. With two examples we illustrate the consequence of undiagnosed EPP for the patient and also the family. We recall efforts to spread information among health workers in order to investigate patients suffering from extreme sun-exposure intolerance for this uncommon kind of porphyria as well.

Liver transplantation for HCV cirrhosis at Karolinska University Hospital Huddinge, Stockholm.

Hepatitis C virus (HCV)-induced cirrhosis is the major indication for liver transplantation globally, and an increasing indication for liver transplantation in Sweden. We have retrospectively examined the 120 patients transplanted for HCV cirrhosis from 1987 through 2005, including 11 who received more than one graft. The 1-, 3-, and 5-year postoperative survivals for all patients transplanted for HCV with or without hepatocellular cancer (HCC) were 77%, 66%, and 53%, respectively. HCV patients without HCC had a 1-, 3-, and 5-year survivals of 78%, 73%, and 61%, compared with 84%, 79% and 74%, respectively, for patients transplanted with chronic liver diseases without cancer or HCV. The number of patients with HCV cirrhosis transplanted in our center is increasing. Compared with patients transplanted for other chronic liver diseases, we experienced inferior results among patients with HCV cirrhosis.

Antibodies to liver sinusoidal endothelial cells modulate immune responses in liver transplantation.

AIM: Liver sinusoidal endothelial cells (LSECs) have been implicated to play a role in the induction of liver allograft rejections. Here, we studied the clinical consequences of preformed LSEC-reactive antibodies and their functional capacity in modulating T-cell responses. METHODS: Pre- and posttransplant sera and T lymphocytes from 95 liver transplant patients were used in this study. LSECs were isolated from a normal healthy liver. Binding of antibodies to LSECs was detected using flow cytometric analysis. To study whether LSEC antibodies facilitated cell-mediated immunity, a mixed cell culture (MCC) assay was used. Cytokines in the supernatant of MCC were also measured by enzyme-linked immunosorbent assay. Immunohistochemical staining on liver biopsy sections was performed to detect deposition of immunoglobulins in LSEC during rejections. RESULTS: Significantly higher numbers of patients with rejections had LSEC antibodies (35/50, 70%) compared with 8/45 (18%) without rejections (P < .0001). Purified fractions of LSEC antibodies induced the expression of the costimulatory marker CD86 on LSECs. Significantly higher numbers of patients with LSEC antibodies and rejections had an increased proliferation of T cells and markedly decreased levels of transforming growth factor (TGF)-beta in the MCC as compared with those without antibodies and rejections (P < .0001, P < .0001, respectively). Deposition of antibodies in LSECs during rejection episodes was observed in the biopsies of patients with LSEC antibodies but not in those without LSEC antibodies. CONCLUSION: Our data suggest that antibodies to LSEC may facilitate acute liver allograft rejections by down-regulating the immune modulating cytokine TGF-beta and thus up-regulating alloreactive T-cell proliferation.

Malignant effusions are sources of fibronectin and other promigratory and proinvasive components.

Metastatic dissemination is the primary cause of death in ovarian cancer (OvCa) patients, and dissemination to pleural and peritoneal effusions is a common clinical event. Effusion samples were collected from 15 OvCa patients. Twenty-six samples were collected prospectively, two were archival, and eight were taken from patients with other malignancies. Twenty-nine samples were from malignant ascites, and seven specimens were pleural fluids. In addition, six ascites and two pleural fluids from noncancer patients were studied as effusion controls. Effusion supernatants were tested for migration-stimulation activity, using A2058 human melanoma cells as the index responder cell. Malignant samples induced a 400-1200% increase in migration. Sixty percent of the migration was inhibited by incubation of the malignant fluid with antifibronectin (FN) antibody, in contrast to 75% inhibition of control fluid-stimulated migration (P = 0.017). Gelatin zymography and Western blot analyses showed that latent and activated MMP-2 and MMP-9 collagenases, and tissue inhibitor of metalloproteinase-2 (TIMP-2) were present in all malignant fluids. Serial samples were taken from several patients, and a trend for correlation between MMPs and clinical behavior of the tumors was shown. Free TIMP-2 correlated with CA-125 levels in two patients for whom serial samples were available. The demonstration of promigratory and proinvasive activity in malignant effusions is consistent with their association with other metastatic disease in OvCa patients and their function as a haven for metastatic cells.

Clinical features in primary sclerosing cholangitis.

This article describes clinical features in primary sclerosing cholangitis, including clinical presentation and complications. The natural history of the disease is discussed, as well as the strong association to inflammatory bowel disease.

Hepatobiliary and extra-hepatic malignancies in primary sclerosing cholangitis.

The increased risk for cholangiocarcinoma in primary sclerosing cholangitis (PSC) is well established, but the factors responsible for the malignant development in the bile ducts in this disease are not known. The pathogenesis of cholangiocarcinoma in PSC including the role of chronic inflammation and oncogenic mutations will be discussed. Cholangiocarcinoma is a leading cause of death in PSC and the prognosis even after liver transplantation is poor, with a median survival after cancer diagnosis of 5 months. Therefore, it is of great importance to identify PSC patients who are at risk of developing cholangiocarcinoma in order to transplant them before cancer has developed.

Sampling variability of percutaneous liver biopsy in primary sclerosing cholangitis.

AIMS: To study sampling variability of percutaneous liver biopsy in primary sclerosing cholangitis (PSC). METHODS: One hundred and twelve biopsy specimens (that is, 56 pairs) from 44 patients with PSC, confirmed by cholangiography, were evaluated blindly. Six different features, qualitative grading of four other features and staging according to Ludwig were assessed. RESULTS: Quantitative sampling variability was confined mainly to just one grade or stage, although 11% (six of 56) of the biopsy specimen pairs differed by more than one stage (7% (one of 15) in pairs > 2 cm in length). Qualitative sampling variabilities were between 18 and 71%. Advanced disease (stages 3 or 4) was missed in 40% (two of five) of the biopsy specimens while cirrhosis was missed in 37%. CONCLUSION: Paired liver biopsy specimens should be taken in clinical studies of PSC using liver histology for evaluation or prognosis.

Detection of antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis: a comparison of the alkaline phosphatase and immunofluorescent techniques.

BACKGROUND: The reported prevalence of antineutrophil cytoplasmic antibodies (ANCA) in primary sclerosing cholangitis (PSC) varies considerably (26-85%). Part of this may reflect methodological differences but part may reflect the differences in the patient groups analysed. To resolve this issue we compared the sensitivity and specificity of the immunoalkaline phosphatase (IALP) and immunofluorescence (IF) techniques in four different populations. METHOD: Sera from four centres were tested blind on alcohol-fixed neutrophils using both techniques. PATIENTS: USA: 14 PSC, 14 primary biliary cirrhosis (PBC); Sweden: 32 PSC, 3 autoimmune hepatitis (AIH), 14 PBC, 11 chronic liver disease; Norway: 32 PSC, 14 AIH, 13 PBC, 1 hepatitis C. Italy: 8 PSC, 14 PBC, 8 viral hepatitis. Thirty-six normal healthy volunteers from Oxford, together with positive and negative controls, were also tested. RESULTS: The healthy controls were all ANCA negative. The diagnostic sensitivity and specificity, respectively, of ANCA for PSC using the IALP technique for the different test sera were: USA 71% and 93%, Sweden 66% and 96%, Norway 69% and 46%, Italy 50% and 95%. The diagnostic sensitivity and specificity, respectively, of the IF technique on the same sera were: USA 50% and 86%, Sweden 56% and 86%, Norway 47% and 61%, Italy 50% and 91%. Overall, combining all four groups, detection of ANCA using the IALP technique gave a diagnostic sensitivity of 66% with a specificity of 74% for PSC. In contrast, the IF technique gave an overall diagnostic of only 51% (P = 0.044, compared with IALP) with a specificity of 73%. Although overall the IALP technique was more sensitive than IF, the differences in sensitivity and specificity between the two techniques did not reach statistical significance for any individual group. Furthermore, the small differences in sensitivity between the four groups using either technique were not significant. However, the IALP technique had greater specificity in the US, Swedish and Italian groups compared with the Norwegian group (P < 0.05) whereas no statistically significant differences in specificity were noted between the groups using the IF technique. CONCLUSION: This study shows that the IALP method of ANCA detection is at least as sensitive as IF for the serological diagnosis of PSC. Indeed, combining data from all four centres, the IALP technique was significantly more sensitive than IF. We therefore recommend the use of the IALP technique, which is also easier to interpret and does not require the use of a specialist fluorescent microscope. The lack of a wide variation in sensitivity between IALP and IF for any individual patient group reported in this study suggests that the previously reported regional differences in ANCA prevalence in PSC of between 26% and 85% may be patient, related, rather than due to ethnic or methodological differences in ANCA detection, perhaps reflecting possible disease heterogeneity within PSC, or case selection bias. Further studies are needed to investigate this intriguing possibility. Such differences, if confirmed, will need to be taken into account when assessing the use of ANCA as a serological marker of PSC.

Spontaneous course of symptoms in primary sclerosing cholangitis: relationships with biochemical and histological features.

An analysis was made of the symptom diaries of 65 patients with primary sclerosing cholangitis (PSC) who recorded their symptoms of itching, pain and fever during a 3 year period. Symptoms occurred in 84% of the patients, with considerable individual variations in symptom load. Symptoms were usually intermittent. "Itching only" and "pain only" were the most frequent episode features. Most episodes lasted only 1-2 days. Fever seemed to be the most embarrassing symptom. Apart from close correlations between pruritus and serum ALP levels, there were no significant correlations between the symptom load and serum biochemistry or eleven different histological features. Even daily symptoms over a period of several months could disappear spontaneously. We conclude that most symptom episodes in PSC are mono-symptomatic and brief. Biochemical or histological data do not predict the appearance of symptoms.

Relations between clinical signs of right and left cardiac decompensation and radiological signs thereof.

Ten consecutive patients arriving at the emergency department for severe systemic cardiac decompensation were investigated in respect of 17 clinical and laboratory parameters indicative of right or left heart failure. Investigations were made at arrival to the hospital and after completed in-hospital care. In respect of left heart failure the presence of rales and signs of interstitial oedema had a similar sensitivity. Both were of diagnostic value. Right heart failure was best diagnosed with clinical parameters such as pitting oedema, filling of the jugular vein, and liver enlargement. The laboratory parameters were less sensitive and appeared to have not a diagnostic but well a confirmatory value.

[Hepatitis GBV isolated in acute liver failure. Successful outcome after liver transplantation]. / Hepatit GBV isolerades vid akut leversvikt. Lyckligt förlopp tack vare transplantation.

Fulminant hepatic failure is a life-threatening condition associated with a mortality of approximately 80 per cent. Liver transplantation may be the only life-saving recourse in such cases. The condition can be caused by any of a number of different agencies such as viral infection, or toxic, circulatory or metabolic factors, though in a large proportion of cases the aetiology is unknown. Recently, knowledge has accumulated of a new hepatitis virus, hepatitis GB virus (HGBV), a Flavivirus remotely related to hepatitis C. The clinical significance of this virus is unclear. It is found in 3-4 per cent of blood donors, and most HGBV-positive patients are asymptomatic though some develop fulminant hepatic failure. The article consists in a case report of fulminant hepatic failure in a 17-year-old woman where no possible aetiological factor could be identified, other than her HGBV-positivity. The patient underwent a successful liver transplantation and is now, 18 months later, in excellent condition. She is still HGBV-positive but manifests no hepatic effects. Whether HGBV infection was responsible for the hepatic failure remains unclear, however.

Human liver sinusoidal endothelial cells induce apoptosis in activated T cells: a role in tolerance induction.

BACKGROUND: The liver may have a role in peripheral tolerance, by serving as a site for trapping, apoptosis and phagocytosis of activated T cells. It is not known which hepatic cells are involved in these processes. It was hypothesised that liver sinusoidal endothelial cells (LSEC) which are strategically placed for participation in the regulation of sinusoidal blood flow, and express markers involved in recognition, sequestration and apoptosis, may contribute to peripheral tolerance by inducing apoptosis of activated T cells. METHODS: By using immunoassays and western blot analysis, the fate of activated T cells when incubated with human LSEC isolated from normal healthy livers was investigated. RESULTS: Evidence that activated (approximately 30%) but not non-activated T cells undergo apoptosis on incubation with human LSEC in mixed cell cultures is provided. No difference in the results was observed when unstimulated and cytokine-stimulated LSEC were used. T cell-LSEC contact is required for induction of apoptosis. Apoptosis induced by LSEC was associated with caspase 8 and 3 activity and strong expression of the proapoptotic molecule Bak. Transforming growth factor beta (TGFbeta) produced constitutively by LSEC is partly responsible for the caspase-induced apoptosis, as neutralising antibodies to TGFbeta markedly attenuated apoptosis, up regulated the antiapoptotic molecule Bcl-2 and partially blocked caspase-3 activity. CONCLUSION: These findings broaden the potential role of LSEC in immune tolerance and homeostasis of the immune system. This study may provide insight for exploring the mechanisms of immune tolerance by liver allografts, immune escape by some liver pathogens including hepatitis C and pathogenesis of liver diseases.