The insulin‐like growth factor binding protein 3 ternary complex is reduced in cirrhosis

Abstract: Background/Aims: In healthy adults, serum insulin‐like growth factor I (IGF‐I), IGF binding protein 3 (IGFBP‐3) and acid labile subunit (ALS) form a 150‐kDa ternary complex under the control of growth hormone (GH). Approximately 80–90% of circulating IGF‐I is bound to the ternary complex. In cirrhosis the GH/IGF axis is severely disturbed and the individual components of the ternary complex are reduced. However, the degree of ternary complex formation in cirrhosis has not previously been described. Methods: Serum IGF‐I, IGFBP‐3, ALS, the 150‐kDa ternary complex and IGFBP‐3 proteolysis were all measured in six compensated and six decompensated cirrhotic patients and compared to six healthy controls. Results: Patients with compensated cirrhosis had decreased levels of IGF‐I (55%), IGFBP‐3 (64%) and ALS (53%), and in the decompensated patients these levels were decreased even further: IGF‐I (32%), IGFBP‐3 (37%) and ALS (27%) compared to healthy controls. The levels of the ternary complex followed this pattern, with low levels seen in the compensated patients (66%) and a further reduction in the decompensated patients (27%). Ternary complex levels correlated negatively with the Child–Pugh score. No increase in IGFBP‐3 proteolysis was found in cirrhotic patients compared to healthy controls. Conclusion: Cirrhosis is associated with reduced levels of the 150‐kDa ternary IGFBP‐3 complex correlating with the degree of liver disease.     

Carbohydrate‐deficient isoforms of transferrin (%CDT) and sialic acid (SA) in iron‐deficiency anemia

This study has investigated the serum levels of carbohydrate‐deficient isoforms of transferrin (CDT) and sialic acid (SA) in iron‐deficiency anemia (IDA). Blood samples were collected from 60 women with IDA and from 20 healthy controls. CDT was estimated by anion‐exchange chromatography on minicolumns followed by photometric detection of transferrin and was expressed as a percentage of total transferrin (%CDT). SA was measured by an enzymatic method. There was no difference in the mean level of %CDT between patients with IDA (2.26%) and control patients (2.05%). SA increased significantly from control level 0.61 to 0.69 g/l in anemic patients. We concluded that elevated concentration of total transferrin in IDA did not change the relative value of low sialylated isoforms (%CDT) and the increase of total SA level in the sera of anemic patients is not related to the increase of total transferrin.     

Rituximab for refractory and or relapsing thrombotic thrombocytopenic purpura related to immune‐mediated severe ADAMTS13‐deficiency: a report of four cases and a systematic review of the literature

Thrombotic thrombocytopenic purpura (TTP) is a potentially life‐threatening disorder that in significant proportion of cases is related to the development of autoantibodies to, and resulting severe deficiency of, the ADAMTS13 protease. However, ADAMTS13 deficiency does not account for all cases. Response to plasma exchange (PE) is seen in TTP with and without ADAMTS13 deficiency and is therefore indicated for all with a clinical diagnosis of TTP, although the pathogenesis of the latter group remains to be defined. Although the majority of cases respond to PE, a significant percent are refractory or experience relapse. Rituximab is being increasingly used off‐label in this setting, but many reports do not define the pathogenesis of TTP so treated. We here report our experience with, and systematically review the published experience to date, of rituximab in management of refractory and or relapsing TTP specifically related to immune‐mediated severe ADAMTS13‐deficiency. In total, 73 patients met defined study inclusion criteria. The majority (～95%) achieved complete remission within weeks of the first application of rituximab. The reported relapse rate was low in this patient subgroup, which carry an anticipated relapse rate of up to 60%. However, caution in interpretation of this data is needed given the relatively short median duration of follow‐up of approximately 10 months. Rituximab was generally well tolerated, with few serious adverse events reported. However, three severe infectious complications were identified, including viral reactivation in keeping with black box warnings for this agent. Furthermore, reflecting the rarity of this disorder, only a relatively small number of patients have been treated and data with regards to long‐term follow‐up are largely based on individual case reports. Prospective studies are urgently needed to define the true efficacy and long‐term safety of rituximab.     

Haematologic data,iron parameters and molecular findings in two new cases of iron‐refractory iron deficiency anaemia

Matriptase‐2 (Tmprss6), a type II transmembrane serine protease, has an essential role in iron homoeostasis as a hepcidin regulator. Recently, patients with TMPRSS6 mutations and suffering from iron‐refractory iron deficiency anaemia (IRIDA) have been reported. We describe two new cases of IRIDA, one patient of Swiss origin and the second of Italian origin. The first case results from a large deletion of 1054 nucleotides corresponding to an in frame deletion of 30 amino acid residues in the low‐density lipoprotein receptor‐1/‐2 (LDLR‐1/‐2) domains and from a missense mutation in CUB1 (S304L). In the second case, a homozygous G→C mutation in the last nucleotide of exon 15 and which modified the consensus sequence of the 5′ splice donor site of intron 15 (AGgt→ACgt) was identified. Both patients had a high hepcidin level and low serum iron and transferrin saturation compared to age‐matched controls. Continuous perfusion of i.v. iron 4 h/d × 5 d in the first case resulted in a significant rise in haemoglobin. These new cases of IRIDA illustrate the importance of LDLR‐1/‐2 and CUB1 domains in matriptase‐2 function as well as the role of matriptase‐2 in hepcidin regulation. Furthermore a deletional form of TMPRSS6 (in LDLR‐1/‐2 domains) resulting in IRIDA is described for the first time. These cases reinforce the belief that patients suffering from IRIDA have no specific geographical or ethnic distribution and are sporadic secondary to different mutations of the matriptase‐2 gene.     

Diagnosis and treatment of lung disease associated with alpha one‐antitrypsin deficiency: A position statement from the Thoracic Society of Australia and New Zealand*

AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD‐associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i.v. infusions of exogenous AAT protein harvested from pooled blood products. Its clinical efficacy has been the subject of some debate and the use of AAT augmentation therapy was recently permitted by regulators in Australia and New Zealand, although treatment is not presently subsidized by the government in either country. The purpose of this position statement is to review the evidence for diagnosis and treatment of AATD‐related lung disease with reference to the Australian and New Zealand population. The clinical efficacy and adverse events of AAT augmentation therapy were evaluated by a systematic review, and the GRADE process was employed to move from evidence to recommendation. Other sections address the wide range of issues to be considered in the care of the individual with AATD‐related lung disease: when and how to test for AATD, changing diagnostic techniques, monitoring of progression, disease in heterozygous AATD and pharmacological and non‐pharmacological therapy including surgical options for severe disease. Consideration is also given to broader issues in AATD that respiratory healthcare staff may encounter: genetic counselling, patient support groups, monitoring for liver disease and the need to establish national registries for people with AATD in Australia and New Zealand.