Liver disease caused by disorders of bile acid synthesis

Bile acid synthetic defects are uncommon disorders that cause progressive cholestatic liver disease that is often lethal in infancy or early childhood. Five specific primary defects have been described. Diagnosis is based on mass spectrometry of urine and serum. Pathogenesis of liver injury is related to persistent reduction in levels of normal bile acids and accumulation of abnormal, potentially hepatotoxic, intermediaries. Sites of injury are the liver cell, the bile canaliculus, and the smallest bile ductules. The interlobular bile ducts are normal. The liver lesion is progressive chronic hepatitis with an especially high incidence of GCT in patients who present in infancy. Bile acid replacement therapy is usually effective in arresting the liver injury. Regression of liver damage has been documented during treatment of patients who were diagnosed early in life. Because bile acid synthetic disorders are the only cholestatic diseases of infancy in which GCT of hepatocytes is consistently present, the author suggest that the injury responsible for GCT may be specific for toxic bile acids. Accordingly, immaturity of the bile acid synthetic pathway may render many otherwise normal infants vulnerable to transient "neonatal hepatitis" with GCT in a broad range of cholestatic disorders.     

Liver disease caused by propylthiouracil.

This report presents the clinical, laboratory, and light and electron microscopic observations on a patient with chronic active (aggressive) hepatitis caused by the administration of propylthiouracil. This is an addition to the list of drugs that must be considered in the evaluation of chronic liver disease.     

Heart failure caused by a novel amyloidogenic mutation of the transthyretin gene: ATTR Ala45Ser.

Cardiac failure in transthyretin (TTR) amyloidosis patients has been shown to be caused by different mutations in the TTR gene. In the present case, a 73-year-old man from Northern Sweden was evaluated for heart failure. Amyloid deposits were found in subcutaneous fat and in intestinal biopsies. The presence of a variant form of TTR was detected in the plasma by electrospray ionisation mass spectrometry (ESI-MS). The mutation was located by single-strand conformation polymorphism (SSCP) analysis of the TTR gene where a band shift was seen in exon 2. Direct sequencing of exon 2 revealed a single base-pair substitution (G1724T). This transversion results in an amino acid substitution at codon 45, alanine to serine (ATTR Ala45Ser). Mass spectrometry analysis excluded that the variant is a polymorphism, since no similar shift in molecular weight has been present in more than 200 control samples. Congo red and immunostaining of duodenum biopsy specimens confirmed the presence of systemic ATTR amyloidosis, and clinical examination, including echocardiography, found evidence of a restrictive cardiomyopathy. He had 10 years previously been operated for a bilateral carpal tunnel syndrome, but otherwise no symptoms were present that could be attributed to his systemic amyloidosis. No axonal polyneuropathy was noted at nerve conduction studies. This novel mutation is the second amyloidogenic TTR mutation found in the Swedish population.     

肝衰竭:定义、诊断与治疗

肝衰竭是临床上常见的严重肝病证候群,在我国尤其多见于重型肝炎,病死率极高.尽管国内外学者在对肝衰竭发病机制和诊治长期不懈的探索中取得了较大进步,但在肝衰竭的定义、分类及诊断方面尚未取得一致意见,尤其是此类患者的救治尚无突破性进展[1].     

Liver failure caused by prolonged state of malnutrition following bariatric surgery

Bariatric surgery is an effective tool in the treatment of patients with morbid obesity. In these case reports we describe 2 patients who developed liver failure after currently-practiced types of bariatric surgery, caused by a prolonged state of malnutrition provoked by psychiatric problems. Despite intensive guidance of a psychologist and dieticians after surgery, our patients deteriorated psychologically, resulting in a prolonged state of severe malnutrition and anorexia. Finally, a state of starvation was reached, passing a critical level of the liver capacity. Patients who present with signs of severe protein malnutrition after bariatric surgery should be closely monitored and checked for nutritional status. Specific attention should be given to patients who develop psychiatric problems post-bariatric surgery. If refeeding does not result in clinical improvement, reversal surgery should be considered in a timely manner.     

Herbert Falk: a vital force in the renaissance of bile acid research and bile acid therapy

Herbert Falk died on August 8, 2008, after a long illness. It was his vision that initiated the Bile Acid Meetings and brought to market chenodeoxycholic acid and ursodeoxycholic acid for the dissolution of cholesterol gallstones as well as the successful treatment of cholestatic liver disease. The 1st Bile Acid Meeting was a small workshop held at the University Hospital of Freiburg in 1970. Great interest in the topic was evident at that small meeting and led to a larger meeting in 1972, whose scope included both the basic and clinical aspects of bile acids. These meetings have continued at biennial intervals, the 2010 meeting being the 21st. The program has always included discussions of the most fundamental aspects of bile acid biosynthesis and metabolism as well as clinical applications of bile acid therapy. The meetings featured brief presentations, ample time for discussion, and imaginative social programs. They have always been flawlessly organized. Social programs usually included a hike through the beautiful countryside of the Black Forest followed by dinner in a rustic restaurant. Herbert Falk took part in these programs, personally welcoming every participant. In the warm glow of the 'Badische' hospitality, friendships developed, and scientific collaborations were often arranged. From a scientific standpoint, there has been enormous progress in understanding the chemistry and biology of bile acids. Herbert Falk established the Windaus Prize in 1978, and the prize has been given to individuals whose contributions moved the field forward. These bile acid meetings have been marvelous, rewarding experiences. We must all be grateful to Herbert Falk's vision in establishing the Falk Foundation that has so generously sponsored these meetings. We also express our gratitude to his widow, Ursula Falk, who continues this worthy tradition.     

LEMD3基因突变导致骨斑点症1例报告及文献复习

分析1例骨斑点症患者的临床特点并检测LAP2-emerin-MAN1 domain-containing protein 3(LEMD3)基因突变,结合文献探讨骨斑点症的发病机制、临床表现、病理特征及影像学特点。患者,女性,37岁,汉族,因体检X线胸片发现肩关节异常就诊。父母非近亲结婚,家族中无类似病史。体格检查示四肢关节活动自如,无压痛。X线片检查发现肱骨、锁骨、肩胛骨及部分肋骨、骨盆、双膝关节和双踝关节骨内多发边缘清晰、密度均匀的圆形或卵圆形钙化点。实验室生化检查未见异常。基因组DNA进行LEMD3基因突变检测,结果显示在12号外显子上存在1个杂合错义突变,即c. 2569G>A,导致p. Gly858Arg。骨斑点症是一种罕见的良性骨质硬化性疾病,临床症状常不明显。临床上对骨斑点症应常规检测LEMD3基因突变。     

Serum bile acids as related to bile acid secretion in liver disease

The level of serum bile acids and their rate of secretion into the duodenum were measured in normal subjects and patients with cholesterol gallstones and hepatobiliary disease. These studies were undertaken to determine if changes in serum bile acids reflected alterations in bile acid secretion within the enterohepatic circulation, especially in association with disordered bile acid metabolism and liver dysfunction. To quantitate bile acid secretion, an intestinal marker-perfusion technique was used which measured duodenal output under stimulated but steady-state conditions. During these perfusion studies, serum bile acids were determined at hourly intervals. In normal subjects, serum bile acids during fasting were low (6.6±0.7 μM) with only a modest rise occurring after a fat meal (7.6±0.7 μM). The average bile acid secretion rate in these subjects was 1321 μmol/hr, and little fluctuation was noted in the serum levels (7.5±0.8 μM) during the perfusion studies. Patients with cholesterol galistones demonstrated a decreased rate of bile acid secretion at 714 μmol/hr but had normal serum values. After cholecystectomy, their bile acid secretion rate increased without any corresponding change in serum levels. In patients with liver disease, however, serum bile acids were elevated while bile acid secretion was reduced. Thus, in normal subjects the liver is quite capable of handling an increased endogenous bile acid return with only a small rise in serum levels. In liver disease, bile acid secretion is reduced while serum concentrations are increased, implying a defect in bile acid handling by the liver. In cholesterol gallstone disease, serum levels do not reflect the abnormality in bile acid metabolism. The relation between bile acid concentration in the serum and secretion rate into the enterohepatic circulation is therefore complex, depending on whether or not hepatic dysfunction is present or if bile acid metabolism is abnormal.     

Analysis of the clinical characteristics of arthritis with renal disease caused by a NPHS2 gene mutation

Clinical Rheumatology - The co-existence of juvenile idiopathic arthritis (JIA)/rheumatoid arthritis (RA) and focal segmental glomerulosclerosis (FSGS) is rare, and the existence of co-pathogenesis...     

TCIRG1基因突变致恶性型骨硬化症一例报告

报告1例恶性型骨硬化症患儿,影像学检查显示全身骨骼密度增高硬化、头颅畸形、颅板增厚并脑积水,临床症状为生长发育迟缓、贫血、血小板减少及肝脾肿大。a3亚基的质子泵ATP酶(a3 subunit of the V-ATPase,TCIRG1)基因检测发现患儿为C. 117+1G>A+1213G>A复合杂合变异。TCIRG1相关常染色体隐性遗传恶性骨硬化症(autosomal recessive osteopetrosis,ARO)主要临床症状包括贫血、血小板减少、肝脾肿大,生长发育迟缓、听力受损等。恶性骨硬化症的诊断主要通过临床和基因检测,TCIRG1基因突变是该患儿恶性骨硬化症的致病原因。TCIRG1基因突变是导致恶性骨硬化症最常见原因,尤其在我国多见。骨髓移植是根治恶性ARO的唯一方法。     

Chylomicronemia caused by lipoprotein lipase gene mutation related to a hyper-response of insulin secretion to glucose

A 39-year-old man with lipoprotein lipase (LPL) deficiency (height 177.7 cm, body weight 67 kg, and body mass index 21.2 kg/m2) showed severe hypertriglyceridemia (2,032 mg/dl). LPL activity and concentration were markedly low in postheparin plasma. LPL gene analysis revealed a homozygous mutation, Asp204 --> Glu in exon 5. Fasting plasma glucose (81 mg/dl) and insulin (2.7 microU/ml) levels were normal. Plasma glucose pattern during oral glucose (75 g) tolerance test was normal, however 30 minutes after glucose-loading the insulin secretion unexpectedly increased to 89.4 microU/ml. These data suggested that chylomicronemia might be related to a hyper-response of insulin secretion to glucose without obesity.     

Thrombosis of sinus sagitalis during puerperium caused by thrombophilic gene mutation

Cerebral veno-sinus thrombosis (CVT) during puerperium may have fatal consequences. A nonspecific clinical picture must be complete with computed tomography of the brain and digital substract angiography of the brain blood vessels, and, once the clinical diagnosis is confirmed, coagulation tests and genetic analysis of the coagulation factor are to be made as well. Genetic polymorphisms associated with thrombophilia such as factor V Leiden, prothrombin G20210A, MTHFR C677T, ACE and PIA1/A2 may be the cause of the hypercoagulability that results in CVT.