Prognosis and vascular co-morbidity in dementia a historical cohort study in general practice.

BACKGROUND: Disease management of dementia in general practice (GP) is hampered by a lack of data on the prognosis of dementia. AIM: To gain more insight into the life expectancy of and the effects of cardiovascular and cerebrovascular co-morbidity in dementia patients in GP. DESIGN OF STUDY: Historical cohort. SETTING: 4 general practices in Nijmegen, The Netherlands. POPULATION: All patients in these practices participating in the Continuous Morbidity Registration (CMR). METHODS: The patient cohort was diagnosed with dementia between January 1st 1985 and December 31st 2002. The control cohort consisted of patients matched one-to-one with demented patients on age, sex, and socio-economic status. Cardiovascular and cerebrovascular co-morbidity was studied from 5 years before the diagnosis of dementia till the endpoints of data collection. RESULTS: 251 couples of patients and controls were formed (79 men, 172 women, mean age 81.4+/-7.0 years). The median life expectancy after diagnosis was 2.3 years for the dementia patients, and 3.7 years for the controls. Median time from diagnosis till nursing home placement was 1.4 years. Cerebrovascular and cardiovascular morbidity preceding dementia diagnosis decreased survival of cases with dementia with a relative risk of 1.54 (95%CI: 1.13-2.09) and in controls with a relative risk of 1.91 (95%CI: 1.48-2.46). Obesity was associated with a lower risk of dementia (RR=0.77 (95%-CI 0.63-0.94)). Hypertension and obesity diagnosed after the dementia diagnosis were significantly associated with an increase in survival. CONCLUSION: In general practice, the diagnosis of dementia is made at a late stage, when patients will continue to live at home only for a short time. Moreover, life expectancy at diagnosis is very limited and prognosis is furthermore negatively influenced by preceding cardio- and cerebrovascular co-morbidity.

Erythropoietic protoporphyria. An overview with emphasis on the liver.

BACKGROUND: Erythropoietic protoporphyria (EPP) is an inherited disorder of heme synthesis, causing excess of protoporphyrin in blood, skin, liver and other organs. Protoporphyrin accumulation causes rapidly progressive liver failure in a minority of patients. Many questions concerning liver disease in EPP patients remain to be solved. METHODS: Review and update of the literature on EPP, protoporphyrin and hepatic involvement. RESULTS: The protoporphyrin molecule can be excited by absorbing light energy. This causes generation of free radicals and thereby photosensitivity of all tissues exposed to light. In the dark, several other toxic mechanisms have been described: deposition of protoporphyrin crystals in hepatocytes and bile canaliculi, interference with redox systems and, recently, formation of cytotoxic bile. Clinical manifestations of EPP are photosensitivity, insignificant hematological abnormalities and liver disease. The hepatic manifestations of the disease are diverse: mildly disturbed liver enzymes in 20% to fatal hepatic failure in less than 5%. End-stage protoporphyric liver failure and liver transplantation are complicated by severe photosensitivity, hemolysis, abdominal pains and neurological dysfunction. To make liver transplantation a safe procedure, special requirements have been proposed. Long-term survival after liver transplantation for EPP has been documented, but does not cure the disease.

Biliary fibrosis associated with altered bile composition in a mouse model of erythropoietic protoporphyria.

BACKGROUND & AIMS: Reduced activity of ferrochelatase in erythropoietic protoporphyria (EPP) results in protoporphyrin (PP) accumulation in erythrocytes and liver. Liver disease may occur in patients with EPP, some of whom develop progressive liver failure that necessitates transplantation. We investigated the mechanisms underlying EPP-associated liver disease in a mouse model of EPP. METHODS: Liver histology, indicators of lipid peroxidation, plasma parameters of liver function, and bile composition were studied in mice homozygous (fch/fch) for a point mutation in the ferrochelatase gene and in heterozygous (fch/+) and wild-type (+/+) mice. RESULTS: Microscopic examination showed bile duct proliferation and biliary fibrosis with portoportal bridging in fch/fch mice. PP content was 130-fold increased, and thiobarbituric acid-reactive substances (+30%) and conjugated dienes (+75%) were slightly higher in fch/fch than in fch/+ and +/+ livers. Levels of hepatic thiols (-12%) and iron (-52%) were reduced in fch/fch livers. Liver enzymes and plasma bilirubin were markedly increased in the homozygotes. Plasma bile salt levels were 80 times higher in fch/fch than in fch/+ and +/+ mice, probably related to the absence of the Na(+)-taurocholate cotransporting protein (Ntcp) in fch/fch liver. Paradoxically, bile flow was not impaired and biliary bile salt secretion was 4 times higher in fch/fch mice than in controls. Up-regulation of the intestinal Na(+)-dependent bile salt transport system in fch/fch mice may enhance efficiency of bile salt reabsorption. The bile salt/lipid ratio and PP content of fch/fch bile were increased 2-fold and 85-fold, respectively, compared with +/+, whereas biliary glutathione was reduced by 90%. Similar effects on bile formation were caused by griseofulvin-induced inhibition of ferrochelatase activity in control mice. CONCLUSIONS: Bile formation is strongly affected in mice with impaired ferrochelatase activity. Rather than peroxidative processes, formation of cytotoxic bile with high concentrations of bile salts and PP may cause biliary fibrosis in fch/fch mice by damaging bile duct epithelium.

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.

Type IIIb glycogen storage disease associated with end-stage cirrhosis and hepatocellular carcinoma. The Liver Transplant Group.

Type III glycogen storage disease (GSD) is a disorder of carbohydrate metabolism caused by a deficiency of debranching enzyme. Different subtypes with different clinical pictures have been recognized. During childhood and early adulthood, the symptoms generally regress, and normal adulthood appears possible in most patients without symptoms or signs of cirrhosis. We report on an adult patient with GSD who developed endstage cirrhosis and a small hepatocellular carcinoma. She had GSD subtype IIIb, i.e., there were no signs of cardiomyopathy, myopathy, or neuropathy. She underwent a successful transplantation, representing the first case treated this way for this indication to our knowledge, and she is doing well after 1 year. Debranching enzyme activity was absent both in the liver and in the leukocytes before transplantation. The debranching enzyme activity remained absent in the leukocytes after transplantation. We conclude that patients with GSD type III may develop end-stage cirrhosis and hepatocellular carcinoma and therefore need hepatological follow-up during adulthood.

Acute liver failure: spontaneous recovery or transplantation?

BACKGROUND: Decision-making in acute liver failure. Acute liver failure is a disease with multiple organ involvement and a high mortality rate. Conservative management alone will only partly influence the outcome. The option of emergency liver transplantation has greatly improved survival rates, but unables spontaneous recovery. A set of prognostic criteria enables selection of patients who will benefit the most from emergency liver transplantation. METHODS: Retrospective review and survey of the Groningen results. RESULTS: Of 52 patients (33 adults and 19 children) admitted for acute liver failure 2 were beyond recovery and died, 9 were treated conservatively and recovered and 41 were listed for emergency liver transplantation because of an estimated survival rate < 20%. Of these, 3 died and 1 recovered spontaneously while waiting and 37 were transplanted. Survival rate for 41 patients listed for transplantation was 23 (56%) and was similar for children and adults. CONCLUSIONS: In patients with acute liver failure, management and decision-making in a specialized liver unit with the possibility of emergency liver transplantation is mandatory.

Evidence for an increased rate of bacterial infections in liver transplant patients with cytomegalovirus infection.

It has been reported that cytomegalovirus (CMV) infections increase the susceptibility of transplant patients for other opportunistic infections. Most of these studies date back from a time when CMV infection was difficult to diagnose and antiviral treatment not available. We therefore analyzed CMV-related morbidity after OLT in 111 consecutive patients. CMV monitoring was done weekly using the antigenemia assay, a quantitative marker of the viral load, in addition to serology. CMV infection occurred in 66/95 (69%) evaluable patients. Antigenemia was detected in 94% of them. The number of CMV antigen-positive cells was helpful to monitor the course of infection and differentiate CMV disease from other complications. CMV infection was symptomatic in 48/66 (73%) patients. Mild disease occurred in 30 patients, and severe constitutional symptoms or organ involvement in 18. No patient died as a direct result of CMV infection, but mortality between day 30 and 180 tended to be higher in CMV-infected patients (15 vs. 0%, p < 0.1). CMV infection was associated with a 2.45-fold higher incidence of major infections between day 30 and 180 after OLT (p < 0.05). Most of these infections were caused by gram-positive cocci. We conclude that CMV not only causes substantial morbidity, but also increases the risk of bacterial infections.

Doppler ultrasound of the hepatic artery and vein performed daily in the first two weeks after orthotopic liver transplantation. Useful for the diagnosis of acute rejection?

RATIONALE AND OBJECTIVES: To analyze changes in Doppler ultrasound variables in relation to liver biopsy findings for the diagnosis of acute rejection after orthotopic liver transplantation (OLT), the authors performed in a prospective study 316 Doppler ultrasound examinations in the first 2 weeks after OLT on 23 patients. METHODS: Recordings were obtained daily from the hepatic artery (resistive index [RI]) and hepatic vein (damping index [DI]). Correlations were explored between the Doppler ultrasound findings and histologic data. The chi-square test was used to analyze differences in Doppler ultrasound variables in patients with and without acute rejection. RESULTS: Serial Doppler ultrasound examinations showed a significant increase in the RI in 11 of 22 patients (50%); the 23rd patient was excluded because of hepatic artery thrombosis. Despite an agreement in 15 of 22 patients (68%) no statistically significant correlation could be found (positive predictive value 6/11 = 55%; negative predictive value 9/11 = 82%; chi-square = 3.14; P > 0.05). A significant increase in the DI was observed in 14 of 23 patients (61%). However, no statistically significant correlation could be found as well with this parameter (positive predictive value 6/14 = 43%; negative predictive value 6/9 = 67%; chi-square = 0.00; P > 0.05). CONCLUSION: Serial Doppler ultrasound examinations were not helpful in predicting acute rejection.

Bone loss after liver transplantation is not prevented by cyclical etidronate, calcium and alphacalcidol. The Liver Transplant Group, Groningen.

After orthotopic liver transplantation (OLT) bone mass rapidly declines and vertebral fracture rate increases. We studied bone loss and parameters of bone turnover in 53 consecutive patients. In an attempt to reduce bone loss the patients were prophylactically treated with cyclical etidronate in addition to daily 1 alpha-hydroxyvitamin D3 and calcium. During the first 3 months after transplantation median lumbar spinal bone mineral density (BMD) decreased 4.5%; subsequently no significant changes occurred. Median hip BMD continued to fall during the first post-transplantation year and deteriorated 7% over the whole study period. New vertebral fractures were seen in 25% of the patients, which is not lower than previously reported rates in patients not receiving cyclical etidronate. Parathyroid hormone levels increased after OLT (p = 0.01), but remained within normal ranges. Urinary hydroxyproline levels were increased and normalized in the second half-year after OLT. Elevated fasting calciuria increased further after OLT. 1,25-Dihydroxy-vitamin D3 levels were lowered pre-OLT (25 vs 66 pmol/ 1, p < 0.001) and normalized at 3 months after OLT. Serum osteocalcin concentrations remained unchanged and were reduced compared with levels in healthy controls. In summary, increased bone resorption occurs after OLT with persistent decreased bone formation, leading to vertebral fracture in 25% of patients. Etidronate, 1 alpha-calcidol and calcium treatment did not prevent bone loss.

Determination of porphyrins in bile using high performance liquid chromatography and some clinical applications.

A simple and fast HPLC method for the determination of porphyrins in bile without extraction is described. Porphyrins were determined in bile from control subjects and from patients after orthotopic liver transplantation, including three patients with erythropoietic protoporphyria. It was found that: 1) coproporphyrin I is the predominant porphyrin in bile of controls, accompanied by some coproporphyrin III and protoporphyrin, whereas protoporphyrin mostly but not always is the predominant porphyrin in the bile of erythropoietic protoporphyria patients. In two of the three erythropoietic protoporphyria patients, the bile contained a hundred times more protoporphyrin than that of non-porphyric orthotopic liver transplantation patients. The third erythropoietic protoporphyria patient remained cholestatic and was unable to excrete sufficient amounts of protoporphyrin. 2) All investigated bile samples contained no secondary porphyrins derived from protoporphyrin, i.e. no deutero-, pempto-, or mesoporphyrin. Even when extracts of bile and serum were concentrated fifty to a hundred times, no traces of deutero-, pempto- and mesoporphyrin were detected. This complete absence of secondary porphyrins suggests that an enterohepatic circulation of dicarboxylic porphyrins from the distal gastrointestinal tract does not exist. 3) The HPLC chromatograms contain peaks from unknown compounds. No correlation between porphyrins and these compounds was found. Porphyrin profiles were followed in the bile of some orthotopic liver transplantation patients. Three episodes are recognizable. During the first three days after orthotopic liver transplantation there is a very high coproporphyrin excretion. There is then a lag of one to three weeks, in which no or very low porphyrin concentrations are detectable, followed by the restoration of normal biliary porphyrin patterns.

Neutrophil cytoplasmic autoantibodies after liver transplantation in patients with primary sclerosing cholangitis.

The immunopathogenic importance of neutrophil cytoplasmic autoantibodies in ulcerative colitis and primary sclerosing cholangitis is unknown. These autoantibodies were investigated before and after liver transplantation in 9 patients with primary sclerosing cholangitis. Sera from 10 patients transplanted for metabolic disorders or hemangioma served as controls. Before liver transplantation neutrophil cytoplasmic autoantibodies, producing a perinuclear pattern by indirect immunofluorescence on ethanol fixed neutrophils, were present in all patients with primary sclerosing cholangitis. A decline in titer was noted in the first months after liver transplantation. During long-term follow up, the autoantibodies remained present and most often the titer did not differ from before transplantation. They were not directed against proteinase 3, myeloperoxidase, elastase or lactoferrin. All but one of the control patients were negative for the autoantibody. No relation was seen, before or after transplantation, with ulcerative colitis or proctocolectomy. There was no recurrence of primary sclerosing cholangitis in any of the patients as judged by liver histology. We conclude that neutrophil cytoplasmic autoantibodies remain present after liver transplantation for primary sclerosing cholangitis and that its synthesis is not related to the presence of the diseased organ(s). The primary disease process in primary sclerosing cholangitis and ulcerative colitis may well be a disturbance of the immune system.