Krister Höckerstedt

Dietary phytoestrogens and cancer: in vitro and in vivo studies

Thirty postmenopausal women (11 omnivores, 10 vegetarians and 9 apparently healthy women with surgically removed breast cancer) were investigated with regard to the association of their urinary excretion of estrogens, lignans and isoflavonoids (all diphenols) with plasma sex hormone binding globulin (SHBG). A statistically significant positive correlation between urinary total diphenol excretion and plasma SHBG was found which remained statistically significant after elimination of the confounding effect of body mass determined by body mass index (BMI). Furthermore we found a statistically significant negative correlation between plasma SHBG and urinary excretion of 16 alpha-hydroxyestrone and estriol which also remained significant after eliminating the effect of BMI. Furthermore we observed that enterolactone (Enl) stimulates the synthesis of SHBG by HepG2 liver cancer cells in culture acting synergistically with estradiol and at physiological concentrations. Enl was rapidly conjugated by the liver cells, mainly to its monosulfate. Several lignans and the isoflavonoids daidzein and equol were found to compete with estradiol for binding to the rat uterine type II estrogen binding site (the s.c. bioflavonoid receptor). It is suggested that lignans and isoflavonoids may affect uptake and metabolism of sex hormones by participating in the regulation of plasma SHBG levels and in this way influence their biological activity and that they may inhibit cancer cell growth like some flavonoids by competing with estradiol for the type II estrogen binding sites.

Mutations in SEC63 cause autosomal dominant polycystic liver disease

Mutations in PRKCSH, encoding the β-subunit of glucosidase II, an N-linked glycan-processing enzyme in the endoplasmic reticulum (ER), cause autosomal dominant polycystic liver disease. We found that mutations in SEC63, encoding a component of the protein translocation machinery in the ER, also cause this disease. These findings are suggestive of a role for cotranslational protein-processing pathways in maintaining epithelial luminal structure and implicate noncilial ER proteins in human polycystic disease.

Liposomal amphotericin B prevents invasive fungal infections in liver transplant recipients. A randomized, placebo-controlled study.

Eighty-six consecutive liver transplant recipients were prospectively randomized in a double-blind, placebo-controlled antifungal prophylaxis study. Seventy-seven patients received 5 days of prophylaxis starting during the transplantation with either liposomal amphotericin B (AmBisome) 1 mg/kg/day or placebo. Among 40 AmBisome-treated patients, no invasive Candida infection was seen during the first month, compared with 5 invasive Candida albicans infections among 37 control patients (P < 0.05). Furthermore, 1 placebo patient experienced Aspergillus niger pneumonia. Thus, the overall incidence of invasive fungal infections was 0/40 (0%) in the AmBisome group versus 6/37 (16%) in the placebo group (P < 0.01). Patient survival at 30 days was 92% versus 94% for AmBisome- and placebo-treated patients, respectively. One patient experienced backache related to AmBisome infusion. Two patients had transient thrombocytopenia possibly caused by AmBisome treatment. AmBisome was otherwise well tolerated. The total cost for all antifungal drugs used in both groups was equal. However, prophylaxis with AmBisome was

Risk of Malignant Neoplasms After Liver Transplantation: A Population-Based Study

5000 less expensive than treatment of proven invasive fungal infections among placebo patients.

High-volume plasma exchange in patients with acute liver failure: An open randomised controlled trial.

Posttransplant malignancies have become a serious long‐term complication after liver transplantation. Our aim was to compare the incidence of posttransplant cancers with national cancer incidence rates. The study included all Finnish liver transplant patients transplanted at the Helsinki University Central Hospital between 1982 and 2005. The cohort was linked with the nationwide Finnish Cancer Registry. Observed numbers of cancers were compared to site‐specific expected numbers based on national cancer incidence rates stratified by age, sex, and calendar time. The standardized incidence ratios (SIRs) were calculated as observed‐to‐expected ratios. Thirty‐nine posttransplant de novo cancers and 11 basal cell carcinomas were found in the cohort of 540 patients during 3222 person years of follow‐up. The overall SIR was 2.59 (95% confidence interval 1.84‐3.53). SIR was higher for males (SIR 4.16) than for females (SIR 1.74), higher among children (SIR 18.1) than among adults (SIR 5.77 for ages of 17‐39 years and 2.27 for ages ≥ 40 years), and more elevated in the immediate posttransplant period (SIR 3.71 at < 2 years) compared to later periods (SIR 2.46 at 2‐10 years and 1.53 at >10 years). The most common cancer types were nonmelanoma skin cancer (SIR 38.5) and non‐Hodgkin lymphoma (SIR 13.9). Non‐Hodgkin lymphoma was associated with male gender, young age, and the immediate posttransplant period, whereas old age and antibody induction therapy increased skin cancer risk. In conclusion, cancer incidence is increased among liver transplant patients compared to the general population. This study points out the importance of cancer surveillance after liver transplantation. Liver Transpl 14:1428–1436, 2008.

Cytomegalovirus infection and development of biliary complications after liver transplantation

BACKGROUND & AIMS Acute liver failure (ALF) often results in cardiovascular instability, renal failure, brain oedema and death either due to irreversible shock, cerebral herniation or development of multiple organ failure. High-volume plasma exchange (HVP), defined as exchange of 8-12 or 15% of ideal body weight with fresh frozen plasma in case series improves systemic, cerebral and splanchnic parameters. METHODS In this prospective, randomised, controlled, multicentre trial we randomly assigned 182 patients with ALF to receive either standard medical therapy (SMT; 90 patients) or SMT plus HVP for three days (92 patients). The baseline characteristics of the groups were similar. The primary endpoint was liver transplantation-free survival during hospital stay. Secondary-endpoints included survival after liver transplantation with or without HVP with intention-to-treat analysis. A proof-of-principle study evaluating the effect of HVP on the immune cell function was also undertaken. RESULTS For the entire patient population, overall hospital survival was 58.7% for patients treated with HVP vs. 47.8% for the control group (hazard ratio (HR), with stratification for liver transplantation: 0.56; 95% confidence interval (CI), 0.36-0.86; p=0.0083). HVP prior to transplantation did not improve survival compared with patients who received SMT alone (CI 0.37 to 3.98; p=0.75). The incidence of severe adverse events was similar in the two groups. Systemic inflammatory response syndrome (SIRS) and sequential organ failure assessment (SOFA) scores fell in the treated group compared to control group, over the study period (p<0.001). CONCLUSIONS Treatment with HVP improves outcome in patients with ALF by increasing liver transplant-free survival. This is attributable to attenuation of innate immune activation and amelioration of multi-organ dysfunction.

Human herpesvirus-6 antigenemia after liver transplantation.

Background. Cytomegalovirus (CMV) infection is known to cause ulceration and mucosal hemorrhage in the gastrointestinal tract. Gastroduodenal and biliary complications were prospectively evaluated in 100 consecutive liver transplant patients in whom CMV was monitored during the first posttransplant year. Method. Gastroduodenal biopsy specimens were taken from 36 patients by endoscopies and in 28 patients by endoscopic retrograde cholangiopancreatography, and bile duct specimens were taken from three patients who underwent surgical reconstruction because of biliary complication. CMV was demonstrated from blood by the pp65 antigenemia test and from frozen sections of tissue specimens by immunohistochemistry and in situ hybridization. Results. Symptomatic CMV infection, treated with ganciclovir, developed in 49 recipients: 13 (100%) of CMV seropositive donor (D+) seronegative recipient (R−) cases, 29 (45%) D+/R+ cases, and 7 (32%) D−/R+ cases. Duodenal ulcer developed in three and hemorrhagic gastritis in three recipients. CMV antigens were found from the gastroduodenal mucosa in 37 (69%) of the 54 studied recipients. The biliary complication rate was 24%. Preceding or concomitant CMV antigenemia was demonstrated in 75% of patients with a biliary complication (68% in CMV D+/R+ or D−/R+ and 100% in D+/R− recipients). The biliary complication rate was higher among recipients with CMV antigenemia, compared with recipients without (P <0.05). CMV antigenemia, CMV infection, or both in the duodenal mucosa was found in 96% of patients with a biliary complication. In two patients who underwent surgical reconstruction, CMV antigens and DNA were demonstrated in the bile ducts. Conclusions. Liver transplant patients are at risk of developing biliary complications after CMV infection, especially those with primary CMV infection.

Diet and Breast Cancer

BACKGROUND Human herpesvirus (HHV)-6 has recently been reported in liver transplant patients. It infects and causes dysfunction in hepatic transplants, which provides serious differential diagnostic problems between allograft rejection and viral infection. The diagnosis of posttransplantation HHV-6 infection is usually based on serology or on polymerase chain reaction detection of viral DNA in peripheral blood specimens. However, serology does not tell the exact time of the infection, and detection of viral DNA by polymerase chain reaction may also indicate a latent infection in seropositive patients. Here we report the diagnostic use of frequent monitoring of HHV-6 antigenemia after liver transplantation. METHODS Altogether 622 blood specimens from 51 consecutive adult liver transplant patients were analyzed. The diagnosis was based on demonstration of HHV-6-specific antigens in peripheral blood mononuclear cells using immunoperoxidase staining and monoclonal antibodies and on serology. RESULTS During the first year (7-280 days) after transplantation, HHV-6 infection was diagnosed in 11 (22%) of 51 patients. HHV-6 early antigens, as well as HHV-6 variant B antigens, were detected in all 11 patients. HHV-6 diagnosis was confirmed by serology. The episode of HHV-6 antigenemia usually lasted for several weeks together with mild, if any, clinical signs of the infection. A significant graft dysfunction was associated with HHV-6 antigenemia in 8 of 11 patients, and viral antigens were also detected in the liver biopsy specimens of 3 of these patients. CONCLUSIONS An active HHV-6 infection can be diagnosed from peripheral blood by detection of virus-specific antigens in mononuclear cells. HHV-6 antigenemia correlated with seroresponse.

Health-Related Quality of Life and Employment Status of Liver Transplant Patients

It is a general opinion that the Western diet plays a significant role in increasing the risk of breast cancer in the Western World. Recently some likely mechanisms involved in increasing the risk have been disclosed. It has been found that a Western-type diet elevates plasma levels of sex hormones and decreases the sex hormone binding globulin concentration, increasing the availability of these steroids for peripheral tissues. The same diet results in low formation by intestinal bacteria of mammalian lignans and isoflavonoid phyotestrogens from plant precursors. These diphenolic compounds seem to affect hormone metabolism and production and cancer cell growth by many different mechanisms making them strong candidates for a role as cancer protective substances. The sex hormone pattern found in connection with a Western-type diet combined with low lignan and isoflavonoid excretion was found particularly in postmenopausal breast cancer patients and omnivores living in high-risk areas, and to a lesser degree in areas with less risk. However, the pattern observed was not entirely due to diet.

Pharmacokinetics and ventilatory effects of oxycodone before and after liver transplantation

Health‐related quality of life (HRQoL) is one preferable outcome measure of medical interventions such as liver transplantation (LT). The aim of this study was to compare HRQoL of LT patients with that of the general population and to assess the employment status of LT patients. HRQoL was measured with the 15D instrument, a validated, non–disease‐specific, 15‐dimensional, self‐administered HRQoL instrument. The questionnaire was sent to all adult LT patients in Finland (401 patients) alive in June 2007. The response rate was 89% (353 patients). The results were compared to those of 6050 age‐standardized and gender‐standardized controls from the general population. LT patients (mean age, 55 years; range, 20‐82) had slightly worse HRQoL scores than the general population (mean 15D score, 0.889 versus 0.907; P < 0.002). Survival time and retransplantation did not affect HRQoL significantly in age‐adjusted and gender‐adjusted analyses. HRQoL decreased with increasing age (P < 0.0001). Patients transplanted for acute liver failure (ALF) or chronic liver disease (CLD) had significantly worse HRQoL than the general population (P = 0.014 and P = 0.040). Forty‐four percent of working‐age patients were employed at the time of the study. Persons that were employed had significantly better HRQoL than those unemployed (15D scores, 0.934 versus 0.859; P < 0.0001). Eighty‐seven percent of patients experienced improved working capacity after LT. Early retirement was the most common cause of unemployment (56% of unemployed patients), and those patients presented with worse HRQoL than patients unemployed for other reasons. In conclusion, HRQoL of LT patients is very close to that of the general population. Older age, CLD, and ALF impair HRQoL. Employment is an indicator of HRQoL. Liver Transpl 15:64–72, 2009.