Diminished erythroid ferrochelatase activity in protoporphyria.

In two patients with protoporphyria the enzymatic synthesis of aminolevulinic acid and prophobilinogen in erythroid tissue was normal. Boine marrow ferrochelatase activity was less than one-fourth of the mean activity in normal control subjects. Ferrochelatase activity in peripheral blood reticulocytes was less than 10% of controls. This metabolic abnormality provides one biochemical explanation for the increased concentrations of blood protoporphyrin in protoporphyria and clarifies the apparent minimally impaired hemoglobin synthesis in the two case studies.     

Erythropoietic protoporphyria in the house mouse. A recessive inherited ferrochelatase deficiency with anemia, photosensitivity, and liver disease.

A viable autosomal recessive mutation (named fch, or ferrochelatase deficiency) causing jaundice and anemia in mice arose in a mutagenesis experiment using ethylnitrosourea. Homozygotes (fch/fch) display a hemolytic anemia, photosensitivity, cholestasis, and severe hepatic dysfunction. Protoporphyrin is found at high concentration in erythrocytes, serum, and liver. Ferrochelatase activity in various tissues is 2.7-6.3% of normal. Heterozygotes (+/fch) are not anemic and have normal liver function; they are not sensitive to light exposure; ferrochelatase activity is 45-65% of normal. Southern blot analysis using a ferrochelatase cDNA probe reveals no gross deletion of the ferrochelatase gene. This is the first spontaneous form of erythropoietic protoporphyria in the house mouse. Despite the presence in the mouse of clinical and biochemical features infrequent in the human, this mutation may represent a model for the human disease, especially in its severe form.     

Treatment options for osteoporosis in chronic liver disease patients requiring liver transplantation

As patient life expectancy rises after liver transplantation, osteoporosis becomes a significant contributor to morbidity and mortality. Patients who undergo liver transplant have an increased risk of bone fractures secondary to osteoporosis, relative to the general population. Risk factors (pre- and posttransplant) include treatment with steroids, alcohol abuse, smoking, poor nutritional status, immobility, reduced muscle mass, menopause, and hypogonadism. The role of cholestatic liver disease is well recognized, but as of yet, the underlying etiology is unknown. The role of immunosuppressants is also evident, but their exact contribution remains to be established. Currently, there are no established therapies for osteoporosis secondary to liver transplantation. Most of the therapeutic options have been extrapolated from usual treatment options for osteoporosis in the general population. It is reasonable to attempt to lower steroid dosages, especially with the availability of new and more potent immunosuppressants such as mycophenolate mofetil and tacrolimus. Potentially, high-risk patients could be identified early with BMD screening. Preventive measures could be instituted and patients could be monitored more closely for objective signs of osteoporosis, such as decline in BMD and early fractures. Calcium and vitamin D supplementation may be helpful in those with deficiencies or poor nutritional intake, as well as in women older than 25 years. The role of bisphosphonates and hormone replacement therapy remains equivocal as studies in transplant patients are currently lacking. Risk versus benefit must be weighed on an individual basis. Lifestyle measures should be instituted in all patients if possible.     

Studies in porphyria: functional evidence for a partial deficiency of ferrochelatase activity in mitogen-stimulated lymphocytes from patients with erythropoietic protoporphyria.

In this paper we show that the ferrochelatase defect in erythropoietic protoporphyria (EPP) can readily be identified in mitogen-stimulated lymphocytes since such cells from patients with EPP accumulate approximately twice as much protoporphyrin IX as cells from normal subjects when incubated with a porphyrin precursor, gamma-aminolevulinic acid (ALA). Treatment of cultures with ALA and with the iron chelator, CaMgEDTA significantly increased the level of protoporphyrin IX in mitogen-stimulated lymphocytes from normal subjects, while the same treatment failed to produce an increase in protoporphyrin IX in cell preparations from EPP patients. In contrast to the results with the chelator treatment, supplementation of the cultures with iron and ALA reduced the level of protoporphyrin IX in normal cells, but not in EPP cells. These findings are compatible with a partial deficiency of ferrochelatase in EPP lymphocytes. The gene defects of acute intermittent porphyria and hereditary coproporphyria have previously been identified using lymphocyte preparations from the gene carriers of these diseases. The present study demonstrates that EPP represents another form of human porphyria in which the gene defect of the disease can now be identified in lymphocyte preparations.     

A new ferrochelatase mutation combined with low expression alleles in a Japanese patient with erythropoietic protoporphyria

We investigated the molecular defect of the ferrochelatase gene in a Japanese patient with erythropoietic protoporphyria (EPP), and identified a novel 16 base pair (574-589) deletion within exon 5. This deletion resulted in a frame-shift mutation and created a premature stop codon at amino acid position 198. The same molecular defect was also identified in his mother and a brother who had symptomatic EPP, but not in his father who was asymptomatic. The subjects with EPP were homozygous for the low expression haplotype, while his father was heterozygous for this haplotype. These results indicate that the combination of a 16 base pair deletion and low expression of the wild-type allelic variant is responsible for EPP in this pedigree.     

Molecular adsorbent recirculating system dialysis in patients with acute liver failure who are assessed for liver transplantation

Objective To assess the usefulness of dialysis with the molecular adsorbent recirculating system (MARS) in patients with acute liver failure who fulfil criteria for liver transplantation.Design Observational cohort study.Setting ICU at a liver transplantation centre.Patients Twenty-two patients (23 episodes) received MARS dialysis. They were either listed for LT (n = 14), delayed (n = 1), or not listed (contra-indication, n = 7).Interventions A total of 56 MARS treatments (median per patient 2; mean duration 7.6 ± 2.6 h) were performed on haemodialysis.Measurements and results Clinical and biological variables were assessed before and 24 h after MARS therapy. The rate of recovery of liver function without transplantation was compared with an expected rate and survival was analysed.Following MARS dialysis, we observed an improvement in the grade of hepatic encephalopathy (P = 0.02) and the Glasgow coma score (P = 0.02), a decrease in conjugated bilirubin (P = 0.05) and INR (P = 0.006), and an increase in prothrombin index (P = 0.005). Overall, liver function improved in seven patients (32%): four listed patients in whom transplantation could be avoided and three patients among those not listed due to contra-indications. The transplant-free recovery rate in listed patients was 29% (vs. expected 9%, P = 0.036). Listed patients (n = 14) had a higher 30-day survival rate [86% (12/14) vs 38% (3/8), P = 0.05] and a higher long-term survival rate (P = 0.02).Conclusions A statistically significant improvement of liver function was observed after MARS therapy. Transplant-free recovery was more frequent than expected. The apparent benefit of MARS dialysis to treat acute liver failure needs to be confirmed by a controlled study.     

Outcome of bone marrow transplantation patients requiring mechanical ventilation

OBJECTIVE: To identify outcome predictors in bone marrow transplantation (BMT) patients admitted to the intensive care unit (ICU) of The University of Texas M. D. Anderson Cancer Center who required endotracheal intubation and mechanical ventilation. DESIGN: Retrospective, comparative study. SETTING: A 16-bed medical intensive care unit in a university teaching cancer center. PATIENTS: The records of 60 consecutive BMT patients who developed respiratory failure requiring mechanical ventilation were reviewed. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The most frequent complication leading to respiratory failure was pneumonia (41%) followed by diffuse alveolar hemorrhage (37%). Eighteen percent of the patients were extubated and discharged from the ICU, but only 5% were alive at 6 months. Graft vs. host disease was a predictor of a poor outcome (p < .05). Breast cancer as an underlying disease and pulmonary edema as a complication were favorable predictive factors (p < .05). Five of 26 patients with diffuse alveolar hemorrhage and four of 33 patients with pneumonia survived. We found no relationship between survival and age, gender, BMT type, or Acute Physiology and Chronic Health Evaluation II score. Prolonged mechanical ventilation (> or =15 days) and late development of respiratory failure (>30 days after BMT) were associated with poor prognosis. CONCLUSIONS: The ICU survival rate of BMT patients who developed pulmonary complications and required mechanical ventilation was 18%. Prognostic factors were described identifying patients with a substantial survival rate as well as those in whom mechanical ventilation was futile.     

Metabolic effects of liver transplantation in cirrhotic patients.

To assess whether liver transplantation (LTx) can correct the metabolic alterations of chronic liver disease, 14 patients (LTx-5) were studied 5+/-1 mo after LTx, 9 patients (LTx-13) 13+/-1 mo after LTx, and 10 patients (LTx-26) 26+/-2 months after LTx. Subjects with chronic uveitis (CU) and healthy volunteers (CON) were also studied. Basal plasma leucine and branched-chain amino acids were reduced in LTx-5, LTx-13, and LTx-26 when compared with CU and CON (P < 0.01). The basal free fatty acids (FFA) were reduced in LTx-26 with respect to CON (P < 0.01). To assess protein metabolism, LTx-5, LTx-13, and LTx-26 were studied with the [1-14C]leucine turnover combined with a 40-mU/m2 per min insulin clamp. To relate changes in FFA metabolism to glucose metabolism, eight LTx-26 were studied with the [1-14C]palmitate and [3-3H]glucose turnovers combined with a two-step (8 and 40 mU/m2 per min) euglycemic insulin clamp. In the postabsorptive state, LTx-5 had lower endogenous leucine flux (ELF) (P < 0.005), lower leucine oxidation (LO) (P < 0.004), and lower non-oxidative leucine disposal (NOLD) (P < 0.03) with respect to CON (primary pool model). At 2 yr (LTx-26) both ELF (P < 0.001 vs. LTx-5) and NOLD (P < 0.01 vs. LTx-5) were normalized, but not LO (P < 0.001 vs. CON) (primary and reciprocal pool models). Suppression of ELF by insulin (delta-reduction) was impaired in LTx-5 and LTx-13 when compared with CU and CON (P < 0.01), but normalized in LTx-26 (P < 0.004 vs. LTx-5 and P = 0.3 vs. CON). The basal FFA turnover rate was decreased in LTx-26 (P < 0.01) and CU (P < 0.02) vs. CON. LTx-26 showed a lower FFA oxidation rate than CON (P < 0.02). Tissue glucose disposal was impaired in LTx-5 (P < 0.005) and LTx-13 (P < 0.03), but not in LTx-26 when compared to CON. LTx-26 had normal basal and insulin-modulated endogenous glucose production. In conclusion, LTx have impaired insulin-stimulated glucose, FFA, and protein metabolism 5 mo after surgery. Follow-up at 26 mo results in (a) normalization of insulin-dependent glucose metabolism, most likely related to the reduction of prednisone dose, and, (b) maintenance of some alterations in leucine and FFA metabolism, probably related to the functional denervation of the graft and to the immunosuppressive treatment.     

肝硬化患者肝移植前后心电图改变的分析

目的研究肝硬化患者肝移植术前及术后心电图改变,从而探讨肝移植对心电生理的影响。方法选取2007～2010年住院行肝移植术的患者37例,对其心电图结果进行分析;另设健康体检者60例为对照组。结果肝移植患者术前组与对照组心电图异常率比较,差异有统计学意义(P<0.01);肝移植术后围手术期组与术后其他组比较,差异有统计学意义(P<0.01);术前组与术后≤6个月组比较差异有统计学意义(P<0.05);术前组与术后>6个月组比较差异有统计学意义(P<0.01);肝功能A级、B级、C级术后组QTc间期分别与对照组比较,差异有统计学意义(P<0.01)。结论肝硬化患者心电图异常率明显升高,主要表现为QTc间期延长,且随肝损害严重程度加重而延长;肝移植术后,心电图异常率下降,QTc间期较术前缩短,心电生理得到改善;围手术期心电图异常率增高,临床医师应密切注意肝移植患者围手术期心电图的变化,及时治疗心脏并发症。     

Characterization of protoporphyrin in red blood cells of patients with erythropoietic protoporphyria.

It was investigated whether the protoporphyrin that can be extracted from red blood cells of erythropoietic protoporphyria (E.P.P.) patients is present in the cells as free molecules or protein-bound. With isoelectric focusing and with starch gel electrophoresis it could be shown that virtually all protoporphyrin in the erythrocytes is protein-bound. It is very likely that the protoporphyrin is bound to hemoglobin at heme-binding sites. This was indicated by several observations: 1. With isoelectric focusing the protoporphyrin-protein complex is focused at a pH only slightly higher than the isoelectric point of hemoglobin. 2. With chromatography on Sephadex columns it appeared that hemoglobin and the protopotphyrin-protein complex have the same molecular weight. 3. A Heme-protoporphyrin exchange occurred when the heme-globin bond was labialized by conversion to hemiglobin. The resulting protoporphyrin-hemoglobin complex had the same electrophoretic mobility with starch gel electrophoresis as the protoporphyrin-protein complex, extracted from red blood cells of E.P.P. patients.     

Decreased haem synthetase activity in blood cells of patients with erythropoietic protoporphyria.

A constant finding in erythropoietic protoporphyria (E.P.P.) is a raised protoporphyrin content of the erythrocytes. It has been shown before that the biosynthesis of this protoporphyrin takes place in the erythroid cell. In circulating blood cells of patients with E.P.P. the haem synthetase activity is significantly decreased. This observation and the increased protoporphyrin concentration in the cells can be explained by assuming a decreased stability of haem synthetase in the red blood cells of E.P.P. patients.     

肝移植病人的围手术期护理管理

目的 探讨加强肝移植围手术期护理管理,积极预防、处理早期并发症.对降低病人病死率的影响.方法 加强肝移植护理管理,包括成立移植护理小组加强人员培训;建立规范化管理的移植病房;肝移植护理表格的应用;充分完善的术前准备、术后护理;及时认真总结经验.结果 通过加强肝移植护理管理,积极预防和及早发现早期并发症,及时采取有效干预措施,提高了肝移植病人的生存率.结论 完善的护理管理,严密的围手术期监护,积极预防和及早发现肝移植术后早期并发症,适时采取有效干预措施,可降低病人的病死率,故应加强肝移植护理管理.     

终末期肝病患者肝移植术前肺功能的改变

目的 探讨终末期肝病患者肝移植术前的肺功能情况.方法 选择在我院等待肝移植的154例终末期肝病患者为研究对象,测定其肺通气功能、小气道功能及弥散功能,并对其术前肺功能损害情况进行分析.结果 154例患者中出现肺功能异常140例(90.9%),140例弥散功能均减低;其次表现为限制性通气功能减低(42.8%,66/154)和小气道功能减低(37.7%,58/154),少数为阻塞性通气功能减低(28.6%,44/154).结论 终末期肝病患者肺功能异常较常见,肝移植术前肺功能检查对评价肺功能受损程度及对术后呼吸道管理具有一定参考价值.

Abstract：

Objective To assess the pulmonary function before liver transplantation in patients with end-stage liver disease. Methods One hundred and fifty-four patients with end-stage liver disease, who were waiting for liver transplantation in our hospital, were enrolled into the study. The pulmonary ventilation function,small airway function and diffusion capacity were measured and analyzed respectively. Results Among 154 subjects,140 (90. 9%, 140/154) patients had abnormal pulmonary function, shown as pulmonary diffusing capacity reduction;followed by restrictive ventilatory function reduction (42. 8% ,66/154) and small airway function reduction (37. 7%, 58/154 ), the least common manifestation was obstructive ventilatory function reduction (28.6 % ,44/154 ). Conclusion Abnormal pulmonary function in patients with end-stage liver disease is common, and the pulmonary function tests before liver transplantation has certain referential value for pulmonary function damage evaluation and postoperatively respiratory tract management.