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Abstract
Background : Wilson's disease is a genetic disorder characterized by accumulation of copper in various tissues. In order to remove copper accumulated in the body, the patients are treated with administration of trientine, penicillamine or zinc. These treatments should be continued throughout their life. Recently, breastfeeding is recommended for babies in the world. When female patients with Wilson's disease have a baby, they want to breastfeed their infants even while continuing their treatment for Wilson's disease. However, no studies have been carried out on the safety of the breast milk feeding of the mother who is under treatment for Wilson's disease. This study deals with the safety of the breast milk feeding of mothers under treatment of Wilson's disease. Materials and Methods : Breast milks were obtained from 4, 4 and 2 patients with Wilson's disease who were under treatment with trientine, penicillamine and zinc, respectively. As control breast milk, Colostrums, transitional and mature milks were obtained from 16, 6 and 11 healthy mothers, respectively. The copper and zinc concentrations in the breast milk were analyzed by an atomic absorption spectrometry. At the same time, the distribution profiles of copper in the breast milk were also analyzed by HPLC-ICP-MS. Copper level bound with trientine or penicillamine in the patients was also analyzed by HPLC-ICP-MS. Results and Discussion : The copper and zinc concentrations were almost normal in the breast milk from mothers with Wilson's disease treated with the medicines described above. A slightly higher concentration of zinc and copper was detected in a few breast milks from the patients, but these levels were within those of infant formula. In HPLC-ICP-MS analysis of the breast milk from these mothers, the highest peak was detected in lactoalbumin-bound copper. No peak of trientine and penicillamine was detected in the milk. Conclusions : These results suggest that mothers with Wilson's disease can give her breast milks to their babies even when they are continuing the treatment for Wilson's disease.
... In addition, control data were retrieved from another study, however, the reason for the low zinc levels in breast milk was not explained. In contrast to this study, we previously published a report in Japanese in our university bulletin 18 describing that copper and zinc concentrations were normal in the Open access breast milk from nine mothers with WD who were treated with trientine, penicillamine or zinc. Isagawa et al 19 also reported that the zinc concentration in breast milk from a mother treated with zinc was normal compared with control breast milk. ...
Objective
To evaluate the concentrations of copper and zinc in the breast milk of mothers undergoing treatment for Wilson’s disease (WD) and clarify whether they can safely breast feed their infants.
Design
This was an observational and prospective study in an individual-based case series.
Setting
Breast milk samples were collected from participants across Japan from 2007 to 2018 at the Department of Pediatrics, Teikyo University in Tokyo. This was a primary-care level study. Clinical data were collected from the participants’ physicians.
Patients
Eighteen Japanese mothers with WD who were treated with trientine, penicillamine or zinc, and 25 healthy mothers as controls, were enrolled.
Main outcome measures
Whey exacted from the milk was used to evaluate the distribution of copper by high-performance liquid chromatography-inductively coupled plasma mass spectrometry. Copper and zinc concentrations in the breast milk samples were analysed by atomic absorption spectrometry.
Results
Copper distribution was normal in the breast milk of mothers with WD treated with trientine, penicillamine or zinc. No peak was detected for trientine-bound or penicillamine-bound copper. The mean copper concentrations in the mature breast milk of patients treated with trientine, penicillamine and zinc were 29.6, 26 and 38 µg/dL, respectively, and were within the normal range compared with the value in healthy controls (33 µg/dL). Likewise, mean zinc concentrations were normal in the mature breast milk of patients treated with trientine and penicillamine (153 and 134 µg/dL, respectively vs 160 µg/dL in healthy controls). Zinc concentrations in the breast milk of mothers treated with zinc were significantly higher than those in control milk. All infants were born normally, breast fed by mothers undergoing treatment and exhibited normal development.
Conclusions
Our results suggest that mothers with WD can safely breast feed their infants, even if they are receiving treatment for WD.
Background and aim
Recommendations on pregnancy, lactation, and contraception in women with Wilson disease are briefly stated in international guidelines but are not entirely homogeneous. Data regarding the management of these special events among patients with Wilson disease in Spain are lacking. We used the Wilson Registry platform of the Spanish Association for the Study of the Liver to question patients on their reproductive and gestational lives.
Methods
This was a multicentre ambispective study including adult women with Wilson disease in the Spanish Wilson Registry interviewed about their contraception, childbearing, pregnancy, and lactation experiences. Clinical and analytical data were extracted from the registry.
Results
The study included 92 women from 17 centres in Spain. Most (63%) reported having a previous pregnancy history. The rate of spontaneous miscarriages was 21.6%, mainly occurring in the first trimester and up to one third among undiagnosed patients. Most pregnant women received chelator therapy during pregnancy, but dose reduction was recommended in less than 10%. After delivery, artificial lactation predominated (60.3%) and its use was mainly based on physician’s recommendations (68%). Up to 40% of the women included reported some concerns about their reproductive lives, mainly related to the potential drug toxicity to their children. Most of the patients considered the information given by specialists to be sufficient.
Conclusion
Gestational management among women with Wilson disease in Spain was found to be highly heterogeneous and frequently different from what is described in international guidelines. Education on rare liver diseases should be a priority for scientific societies in order to homogenize patient follow-up and recommendations.
Neonatal Formulary bridges a gap between a standard formulary (stating doses, indications, etc.) and a standard neonatal textbook by expanding information about the conditions for which each drug is used. Much of drug use during pregnancy, lactation, and in neonates and young infants is ‘off license’ (i.e. using licensed drugs but for an indication that is outside the licensed use—in many cases simply because the studies and the licensing application did not include data about neonatal use). The book offers information to allow practitioners to make informed choices whether to use such a drug or not by presenting data from published studies to support such a use. Part 1 concentrates on drug prescribing and drug administration, presenting general information on drug storage, drug licensing, and drug prescribing. It also explains to the reader why the metabolism of drugs differs in premature and sick infants and why the practice of extrapolating doses from adult studies is wrong. Patient safety, excipients, and therapies that affect drug metabolism (such as therapeutic hypothermia) are also covered. Part 2 consists of drug monographs for over 250 drugs that may find use in the neonatal population but which nonetheless may also find use outside the neonatal unit. Each monograph is divided into sections covering use, pharmacology, treatment, drug interactions, or other administration information, supply, and administration, and references. The monographs also contain links to Cochrane Database of Systematic Reviews and national guidelines supported by bodies such as the National Institute for Health and Care Excellence or the Royal Colleges. Part 3 contains brief notes on a range of additional drugs and groups of drugs that are often taken by mothers during pregnancy, labour, or during breast feeding where effects on either the fetus or infant can be seen. This information will help to provide safe and effective prescribing of drugs to all mothers and their babies.
Chronic liver disease in pregnancy is rare. Historically, many chronic liver diseases were considered contraindications to pregnancy; however, with current monitoring and treatment strategies, pregnancy may be considered in many cases. Preconception and initial antepartum consultation should focus on disease activity, medication safety, risks of pregnancy, as well as the need for additional monitoring during pregnancy. In most cases, a multidisciplinary approach is necessary to ensure optimal maternal and fetal outcomes. Despite improving outcomes, pregnancy in women with the chronic liver disease remains high risk.
In the prior sections, we have provided an introduction to basic copper metabolism and discussed disease diagnosis and treatment of Wilson disease. However, there are special circumstances where there is more expert opinion on management of patients than evidence for how best to practice. In the following section, we consider some special circumstances and provide some guidance while recognizing that these are areas for future study.
Wilson disease (WD) is an autosomal recessive defect of copper transport characterized by massive accumulation of copper in the liver, which can lead to liver failure. Mutations in a copper transporting ATPase (WND or ATP7B) have been shown to cause the disease. The toxic milk mouse mutant (tx) accumulates copper in the liver in a manner similar to that observed in patients with WD. However, some physiological differences between tx mice and human WD patients have cast doubts on whether this mutant mouse is a valid model for WD. In this paper we report the isolation of cDNA clones encoding the murine homologue of WND. The predicted amino acid sequence is 1462 amino acids and contains the same functional domains identified in human and rat WND. As in the rat, the fourth metal binding domain is apparently non-functional. Similar levels of a 7.5 kb WND mRNA were detected in liver and kidney from normal and tx mice, indicating that transcription of this gene was unaffected in the mutant mice. The coding sequence of WND cDNA from the tx mouse liver identified a single nucleotide difference between the normal DL mouse and the tx which is predicted to change methionine 1356 in the eighth transmembrane domain to valine. This methionine is conserved in all copper ATPases including those from bacteria and yeast. The conclusion that this is the causative mutation is supported by the recent mapping of tx and WND to the same region of mouse chromosome 8. Thus the tx mouse is presented as a valid model for studies of the role of WND in copper transport and for investigation of different treatment strategies for WD.
The presence of a complex of the copper-containing protein ceruloplasmin (Cp) with lactoferrin (Lf) in breast milk (BM) is shown for the first time. In SDS-free polyacrylamide gel electrophoresis (PAGE), electrophoretic mobility of Cp in BM is lower than that of plasma Cp, coinciding with the mobility of the complex obtained upon mixing purified Cp and Lf. Affinity chromatography of delipidated BM on Cp-Sepharose resulted in retention of Lf. SDS-PAGE of the 0.3 M NaCl eluate revealed a single band with Mr approximately 78,000 that has the N-terminal amino acid sequence of Lf and reacts with antibodies to that protein. Synthetic peptides R-R-R-R (the N-terminal amino acid stretch 2-5 in Lf) and K-R-Y-K-Q-R-V-K-N-K (the C-terminal stretch 29-38 in PACAP 38) caused efficient elution of Lf from Cp-Sepharose. Cp-Lf complex from delipidated BM is not retained on the resins used for isolation of Cp (AE-agarose) and of Lf (CM-Sephadex). Anionic peptides from Cp--(586-597), (721-734), and (905-914)--provide an efficient elution of Cp from AE-agarose, but do not cause dissociation of Cp-Lf complex. When anti-Lf is added to BM flowed through CM-Sephadex, Cp co-precipitates with Lf. Cp-Lf complex can be isolated from BM by chromatography on CM-Sephadex, ethanol precipitation, and affinity chromatography on AE-agarose, yielding 98% pure complex. The resulting complex Cp-Lf (1 : 1) was separated into components by chromatography on heparin-Sepharose. Limited tryptic hydrolysis of Cp obtained from BM and from blood plasma revealed identical proteolytic fragments.
A role for the copper transporter, ATP7B, in secretion of copper from the human breast into milk has previously not been reported, although it is known that the murine ortholog of ATP7B facilitates copper secretion in the mouse mammary gland. We show here that ATP7B is expressed in luminal epithelial cells in both the resting and lactating human breast, where it has a perinuclear localization in resting epithelial cells and a diffuse location in lactating tissue. ATP7B protein was present in a different subset of vesicles from those containing milk proteins and did not overlap with Menkes ATPase, ATP-7A, except in the perinuclear region of cells. In the cultured human mammary line, PMC42-LA, treatment with lactational hormones induced a redistribution of ATP7B from a perinuclear region to a region adjacent, but not coincident with, the apical plasma membrane. Trafficking of ATP7B was copper dependent, suggesting that the hormone-induced redistribution of ATP7A was mediated through an increase in intracellular copper. Radioactive copper ((64)Cu) studies using polarized PMC42-LA cells that overexpressed mAtp7B protein showed that this transporter facilitates copper efflux from the apical surface of the cells. In summary, our results are consistent with an important function of ATP7B in the secretion of copper from the human mammary gland.
In this review, we discuss genetic disorders involving altered coppermetabolism, particularly in relation to Menkes disease (MD), occipital horn syndrome (OHS), and Wilson’s disease (WD). The responsible genes for MD and WD are ATP7A and ATP7B, respectively. Both proteins encoded by these genes are responsible for transporting copper from the cytosol to the Golgi apparatus. However, the pathology of MD is completely different from that of WD, that is, MD is characterized by a copper deficiency while WD is caused by a toxic excess of copper. The reason for this difference is related to the particular cell types in which the ATP7A and ATP7B proteins are expressed. ATP7A is expressed in almost all cell types except hepatocytes, whereas ATP7B is mainly expressed in hepatocytes. MD and OHS are X-linked recessive disorders characterized by copper deficiency. Typical features of MD, such as neurological disturbances, connective tissue disorders, and hair abnormalities, can be explained by the abnormally low activity of copper-dependent enzymes. The current standard-of-care treatment for MD is parenteral administrations of copper–histidine. When the treatment is initiated in newborn babies prior to two months of age, the neurological degeneration may be prevented, but delayed treatment is considerably less effective. Moreover, copper–histidine treatment does not improve symptoms of the connective tissue disorders. As such, systems for mass screening of neonates for MD should be implemented. At the same time, novel treatments targeting connective tissue disorders need to be developed. OHS is a milder form of MD and is characterized by connective tissue abnormalities. Although formal trials have not been conducted for OHS, OHS patients are typically treated in a similar manner to those with MD. WD is an autosomal recessive disorder characterized by the toxic effects of chronic exposure to high levels of copper. The hepatic and nervous systems are typically most severely affected. Numerous other symptoms can also be observed, however, making an early diagnosis difficult. Chelating agents and zinc are effective for the treatment of WD, but they are ineffective for the patients with fulminant hepatic failure. Some patients with neurological diseases show poor response to chelating agents; here again, early diagnosis and treatment are critical. Screening of newborn babies or infants for WD can help lead to timely diagnosis and treatment. Patients with WD may have a risk of hepatocellular carcinoma despite receiving treatment. An understanding of the relation between WD and hepatocellular carcinoma will provide clues to help prevent hepatocellular carcinoma in patients with WD.
Daily changes in components of breast milk with number of days of lactation after delivery were demonstrated by determining concentrations and distributions of several elements simultaneously. Concentrations of calcium, copper, magnesium, phosphorus, sulfur, and zinc were determined simultaneously by inductively coupled argon plasma-atomic-emission spectrometry (ICP) for whole milk and milk fractions (skimmed milk and whey) collected from 2 to 196 d postpartum from a healthy lactating mother. Calcium and phosphorus concentrations increased in transitional milk. With days postpartum, the other elements decreased from the highest concentrations in colostrum milk, the modes of decrease being characteristic for each element. Distributions of copper, iron, phosphorus, sulfur, and zinc in whey were determined on a gel-filtration column by HPLC with ICP detection (HPLC-ICP method). Distributions of the five elements and absorbance peaks at 254 and 280 nm changed dramatically day by day at the beginning (colostrum milk), resulting in constant distributions after 30 d (mature milk). These results suggest the important roles of daily changing constituents in breast milk, especially in colostrum milk, in the nutrition of the newborn. Several element peaks on a gel-filtration column were identified by comparison with standard samples.
Toxic milk, tx, a new autosomal recessive mutation in mice is described. Litters produced by mutant females display a syndrome including poor growth, hypopigmentation, tremors, and ultimately death at two weeks of age. These features, consistent with copper deficiency, are attributed to failure in gestational hepatic copper accumulation exacerbated by subsistence on milk with greatly reduced copper content. Such infants can be rescued by foster-nursing on normal dams or by administered of supplemental cooper. Mutants themselves amass extraordinarily large concentrations of hepatic copper that ultimately leads to liver disease. Erroneous hepatic copper metabolism is further evidenced by reduced ceruloplasmin activity.
The regulation of milk trace mineral homeostasis requires the temporal integration of three main processes, (A) mineral uptake into the secretory mammary epithelial cell (MEC); followed by (B) mineral secretion from MEC into the alveoli lumen of the mammary gland for sequestration in milk; and then (C) milk release in response to suckling. Trace mineral requirements of term infants are generally met by exclusive breast-feeding through about the first 6 months of life and although milk zinc (Zn), iron (Fe), and copper (Cu) concentrations are relatively refractory to maternal trace mineral status, they normally decline throughout lactation. Recently, Zn-, Fe- and Cu-specific transporters have been identified that regulate trace element uptake and efflux in various cell types; however, there is currently little information available regarding the processes through which the mammary gland regulates milk trace mineral transport. The homology of trace mineral transporters between species permits the utilization of rodent models to examine the regulation of mammary gland mineral transport. Therefore, we have used the lactating rat to determine changes in mammary gland Zn, Fe and Cu transporter expression and localization that occur throughout lactation and in response to maternal trace mineral deficiency in hope of elucidating some of the changes which occur during mammary gland trace element homeostasis and also may be occurring in lactating women.
This research focuses on the role of milk ceruloplasmin (Cp), the main extracellular copper-containing protein of vertebrates, as a source of copper for newborns. In the first part of the study, Cp concentration and Cp-associated copper were measured in human skimmed milk at the 1st and the 5th days postpartum. It was shown that most of the copper was associated with Cp and that the decrease in copper concentration during lactation was related to the drop of Cp levels. The following in vivo experiments demonstrated that milk [(125)I]Cp per os administered to 6-day-old rats (embryonic-type copper metabolism) was transported into their bloodstream. The electrophoretic mobility and relative molecular weight of [(125)I]Cp transferred through the cellular barrier remained unaltered. However, 22-day-old rats (adult-type copper metabolism) digested the administered milk [(125)I]Cp completely. In the final part of the study, newborn rats were fed with baby formula for 8d. It was found that these rats switched their copper metabolism from embryonic type to adult type earlier than their littermates fed by dams. Activation of Cp gene expression in the liver, increased Cp and copper concentrations in the blood, and reduced copper content of the liver were observed in the rats fed with baby formula. In the brain, no copper concentration change was observed, but Cp and copper concentrations were dramatically increased in the cerebrospinal fluid. The role of milk Cp as a source of copper adapted to embryonic-type copper metabolism is discussed.