The History of Cystic Fibrosis by Dr James Littlewood OBE

Edited and produced by Daniel Peckham

 

Bicarbonate, composition of secretions & tissues, hypoproteinaemia, immunoglobulins, Pseudo-Bartter's Syndrome,

 

 

 

Cuthbert AW. Bicarbonate secretion in the murine gallbladder - lessons for the treatment of cystic fibrosis. J Pancreas 2002; 2(4 Suppl):257-262. [PubMed]
The epithelium lining the gallbladder of mammalian species has absorptive and secretory functions. An important function is the secretion of a bicarbonate rich fluid that helps neutralise stomach acid and provides an appropriate environment for intestinal enzymes. In cystic fibrosis (CF) this secretory function is lost.
This study concerns the bicarbonate secreting activity of murine gallbladders in vitro using wild type and CF mice and four main questions are considered as follows:
a) Does the murine gallbladder secrete bicarbonate electrogenically and is this prevented in CF?
b) Can the secretory activity in CF gallbladders be restored by gene therapy or pharmacologically?
c) How is the cystic fibrosis transmembrane conductance regulator (CFTR) involved in bicarbonate secretion?
d) Does the data offer prospects for the treatment of CF?. Work from both the author's laboratory and the literature is reviewed.

Consideration of the currently available data indicates that the wild type murine gallbladder does secrete bicarbonate electrogenically and that this is absent in CF mice. Further it has been demonstrated that bicarbonate secretory activity can be restored by both gene therapy and by the use of drugs. The role of CFTR in bicarbonate secretion remains equivocal. Much evidence suggests that CFTR can act as a channel for HCO(3)(-) ions as well as Cl(-) ions, while others propose a parallel arrangement of CFTR with a Cl(-)/HCO(3)(-) exchanger is necessary. The matter is further complicated by the regulatory role of CFTR on other transporting activities. Opportunities for possible application to man are discussed.

There is a steady flow of articles on bicarbonate in relation to CFTR. Here Alan Cuthbert reviews the current knowledge on the subject. Professor Paul Quinton has been a strong advocate of the importance of bicarbonate secretion.

 

2010 Quinton PM. Role of epithelial HCO3- transport in mucin secretion: lessons from cystic fibrosis. [Review] Am J Physiol - Cell Physiology 2010; . 299:C1222-33. [PubMed]
Paul Quinton observed that the invitation to present the 2010 Hans Ussing lecture for the Epithelial Transport Group of the American Physiological Society offered him a unique, special, and very surprising opportunity to join in saluting a man whom he met only once, but whose work was the basis, not only for his career, but also for finding the molecular defect in the inherited disease cystic fibrosis (CF). In this context,he would venture to make the tribute with a new explanation of why a mutation in a single gene that codes for an anion channel can cause devastation of multiple epithelial systems with pathogenic mucus. In so doing, he hoped to raise awareness of a new role for that peculiar anion around which so much physiology revolves, HCO(3)(-). Quinton begins by introducing CF pathology as he questioned the name of the disease as well as the prevalent view of the basis of its pathology by considering: 1) mucus, 2) salt, and 3) HCO(3)(-). He then presents recent data showing that HCO(3)(-) is required for normal mucus discharge, and I will close with conjecture as to how HCO(3)(-) may support mucus discharge and why the failure to transport this electrolyte is pathogenic in CF.

 

Paul Quinton has published a great deal on the importance of the bicarbonate transport in cystic fibrosis. Here he reviews the subject in a lecture to the American Physiological Society the full text of which is available without cost on the website of the journal (Am J Physiol - Cell Physiol 2010; 299:C1222-33).

 

2010 Chen EY, Bang N, Quinton PM, Chin WC. A new role for bicarbonate in mucus formation. Am J Physiol - Lung C 2010; 299:L542-9. [PubMed]
The impact of small anions on the physical properties of gel-forming mucin has been almost overlooked relative to that of cations. Recently, based on the coincident abnormalities in HCO(3)(-) secretion and abnormal mucus formed in the hereditary disease cystic fibrosis (CF), HCO(3)(-) was hypothesized to be critical in the formation of normal mucus by virtue of its ability to sequester Ca(2+) from condensed mucins being discharged from cells. However, direct evidence of the impact of HCO(3)(-) on mucus properties is lacking. Herein, we demonstrate for the first time that mucin diffusivity (~1/viscosity) increases as a function of [HCO(3)(-)]. Direct measurements of exocytosed mucin-swelling kinetics from airway cells showed that mucin diffusivity increases by ~300% with 20 mM extracellular HCO(3)(-) concentration. Supporting data indicate that HCO(3)(-) reduces free Ca(2+) concentration and decreases the amount of Ca(2+) that remains associated with mucins. The results demonstrate that HCO(3)(-) enhances mucin swelling and hydration by reducing Ca(2+) cross-linking in mucins, thereby decreasing its viscosity and likely increasing its transportability. In addition, HCO(3)(-) can function as a Ca(2+) chelator like EGTA to disperse mucin aggregates. This study indicates that poor HCO(3)(-) availability in CF may explain why secreted mucus remains aggregated and more viscous in affected organs. These insights bear on not only the fundamental pathogenesis in CF, but also on the process of gel mucus formation and release in general.

 

For some years Paul Quinton has stressed the important role of bicarbonate in the pathogenesis of CF. This paper gives a clear explanation, for us non-scientists, of the mechanism and role of the bicarbonate, or lack of it, on the mucin kinetics.

 

2010 Muchekehu RW, Quinton PM. A new role for bicarbonate secretion in cervico-uterine mucus release. J Physiol 2010; 588:2329-42. [PubMed]
Cervical mucus thinning and release during the female reproductive cycle is thought to rely mainly on fluid secretion. However, we now find that mucus released from the murine reproductive tract critically depends upon concurrent bicarbonate (HCO(3)(-)) secretion. Prostaglandin E(2) (PGE(2))- and carbachol-stimulated mucus release was severely inhibited in the absence of serosal HCO(3)(-), HCO(3)(-) transport, or functional cystic fibrosis transmembrane conductance regulator (CFTR). In contrast to mucus release, PGE(2)- and carbachol-stimulated fluid secretion was not dependent on bicarbonate or on CFTR, but was completely blocked by niflumic acid. The authors found stimulated mucus release was severely impaired in the cystic fibrosis F508 reproductive tract, even though stimulated fluid secretion was preserved. Thus, CFTR mutations and/or poor bicarbonate secretion may be associated with reduced female fertility associated with abnormal mucus and specifically, may account for the increased viscosity and lack of cyclical changes in cervical mucus long noted in women with cystic fibrosis.

Further evidence on the role of bicarbonate in mucus formation from Paul Quinton.

 


2014 Shamsuddin AK. Quinton PM. Native small airways secrete bicarbonate. J Respir Cell Mol Biol 2014; 50(4):796-804.[PubMed]
Since the discovery of Cl(-) impermeability in cystic fibrosis (CF) and the cloning of the responsible channel, CF pathology has been widely attributed to a defect in epithelial Cl(-) transport. However, loss of bicarbonate (HCO3(-)) transport also plays a major, possibly more critical role in CF pathogenesis. Even though HCO3(-) transport is severely affected in the native pancreas, liver, and intestines in CF, we know very little about HCO3(-) secretion in small airways, the principle site of morbidity in CF.
The authors used a novel, mini-Ussing chamber system to investigate the properties of HCO3(-) transport in native porcine small airways (~ 1 mm ).
They conclude their results indicate that two separate components for HCO3(-) secretion, likely via CFTR- and calcium-activated chloride channel-dependent processes, are physiologically regulated for likely roles in mucus clearance and antimicrobial innate defences of small airways.

 

 

 

1958 di Sant’Agnese PA, Grossman H, Darling RC, Denning CR. Saliva, tears and duodenal contents in cystic fibrosis of the pancreas. Pediatrics 1958; 22:507-514[PubMed]
Higher mean values of sodium and chloride but similar potassium levels were present in saliva of people with CF than in controls, as previous studies had shown. Also electrolytes were increased in the tears of people with CF but there was considerable overlap with normals in both tears and saliva. The concentrations of ions were similar in duodenal contents of CF and controls and not related to variations in proteolytic activity. At this stage di Sant’Agnese noted that three abnormalities in CF need explanation – an abnormality of mucus secretion, high electrolyte concentrations in sweat saliva and tears and an increased rate of secretion in parotid glands (also Lawson 1956 above; Barbero & Chernick, 1958 below).

 

 

1958 Barbero GJ, Chernick W. Function of the salivary gland in cystic fibrosis of the pancreas. Pediatrics 1958; 22: 945-952. [PubMed]
Children with CF had greater unstimulated salivary flow and the concentration of sodium and chloride was elevated compared with controls as had been shown by others. Response to mecholyl injection greater but potassium did not differ between CF and controls. This suggested an increased parasympathomimetic sensitivity in cystic fibrosis.

 

 

1959 Chernick WS, Barbero GJ. Composition of tracheobronchial secretions in cystic fibrosis of the pancreas and bronchiectasis. Pediatrics 1959; 24:739-45. [PubMed]
The first of a number of studies in CF examining the composition of secretions in the airways although airway secretions had been studied in other conditions – the authors reviewed the literature. CF secretions, obtained via a bronchoscope, contained twice the organic material found in non-CF bronchiectasis and this was related to their increased viscosity. The amounts of nitrogen, carbohydrate, hexosamine and lipids were similar but the DNA content was higher. “The fluid component is related to the percentage of sodium and chloride ions in the secretions – the lowest levels being in the CF secretions”.

 

These are very pertinent observations in view of the present “low salt” theory caused by the excessive absorption of sodium and reduced secretion of chloride into the airways as a result of defective or absent CFTR. The depletion of the airway surface liquid is now regarded as being of major importance in the pathogenesis of the lung disease. These authors with a very accurate prediction prophetically observed at the end of their paper “an alteration in the ionic concentration may be responsible for the peculiar characteristics observed in the tracheobronchial secretions of patients with cystic fibrosis”!! Also the increased amount of DNA present in CF sputum was relevant when the effect of enzymes was investigated (Chernick et al, 1961 below) - eventually leading to the development of the most effective mucolytic rhDNase in the Nineties.

 

 

1965 Kopito L, Mahmodian A, Townley RRW, Khaw KT, Shwachman H. Studies in cystic fibrosis: analysis of nail clippings for sodium and potassium. N Engl J Med 1965; 272:504-509. [PubMed]
Abnormal electrolyte content of nails was suggested as a possible diagnostic help but the test never became popular as there was overlap between CF and non-CF and it was difficult to perform. (also Leonard PJ, Morris WP. Arch Dis Child 1972; 47:495-498.[PubMed]).

 

 

1963 Lobeck CC, McSherry NR. Response of sweat electrolyte concentrations to 9 alpha-fluorohydrocortisone in patients with cystic fibrosis and their families. J Pediatr 1963; 62: 393-398. [PubMed]
Patients with CF failed to show a significant decrease in their sweat electrolytes after administration of oral 9-alpha fluorohydrocortisone (3.0 mg per square meter for two days). Parents, siblings of people with CF and controls all had a significant decrease in the concentration of their sweat electrolytes after this challenge – for example the fall in chloride in parents was - 40.8%, in controls - 43.6%, in siblings -35.6%, but people with CF only had -1.1% reduction in their sweat chloride level.

This was a useful paper when there was a problem with diagnosis and there was a marginal sweat test result - particularly pre-1989 before genetic mutations could be determined. We used the test on a number of occasions and found it to be helpful when the diagnosis was in doubt and the sweat test result borderline with chloride values of around 50 – 70 meq/l.                                                 Margaret Hodson also found the fludrocortisone suppression test useful in adults with marginal sweat test results (Hodson ME et al. BMJ 1983; 286:1381-1383. [PubMed]).

 

 

2013 Goncalves AC. Marson FA. Mendonca RM. Ribeiro JD. Ribeiro AF. Paschoal IA. Levy CE. Saliva as a potential tool for cystic fibrosis diagnosis. Diagn Pathol 2013; 46:2014.[PubMed]

Saliva and sweat are modified by cystic fibrosis (CF). In both cases the chloride and sodium ion concentrations for healthy subjects and CF patients differ, this representing a possible alternative tool for CF diagnosis. In this context, the aim of this study was to compare the concentrations of these ions in saliva samples taken from CF patients and healthy subjects. The chloride and sodium concentrations in the saliva samples were higher for CF patients in comparison with healthy subjects.

 

Although the authors considered the use of saliva as a tool for CF diagnosis could be considered a new challenge, and recomended a population study including patients in all age classes be performed in different countries over the world, the subject has been explored on a number of occaisions in the past and the degree of separation between normals and CF individuals considered to preclude the use of saliva for diagnosis. (See Electrolytes in the Topics section: Johnson WH. Salivary electrolytes in fibrocystic disease of the pancreas. Arch Dis Child 1956; 31:477-480; Lawson D. Use of a micro-sodium electrode in the diagnosis of cystic fibrosis. Bibl Paediatr 1967; 86:273-278.)

 

 

 

1960 Green MN, Kulczycki LL, Shwachman H. Serum protein paper electrophoresis in patients with cystic fibrosis. Am J Dis Child 1960; 100:365-72. [PubMed]
Increased levels of gamma globulin, as determined by paper electrophoresis paralled the severity of the pulmonary disease. Subsequent studies confirmed the relationship of high immunoglobulin levels with severe chest involvement. The levels correlated with disease activity (Matthews WJ et al. N Eng J Med 1980; 302:245-249); also a subgroup of children with lower immunoglobulin levels appeared to have a better prognosis when followed over 5 years (Wheeler WB et al. J Pediatr 1984; 104:695-699 below). Also later more specific qualitative immunoglobulin abnormalities were reported as characteristic of the condition such as low IgG2 (Garside et al, 2005; Garside et al, 2007 both below)

 

 

1961 Shahidi NT, Diamond LK, Shwachman H. Anemia associated with protein deficiency. A study of 2 cases with cystic fibrosis. J Pediatr 1961; 59:533-42. [PubMed]
There was a fall in serum albumin from 4.0 to 2.6 g/dl over 30 days in an infant with CF fed a soy formula. The normal half life of 131I-labelled albumin excluded an exudative protein loosing enteropathy. The authors suggested that in CF infants soy protein absorption is more affected than cow’s milk protein.

Usually serum albumin is, rather surprisingly, within the normal range in CF unless there is significant liver involvement. However, it became apparent in a number of subsequent reports that soya based milk preparations were particularly likely to be associated with hypoproteinaemia in infants with cystic fibrosis (Fleisher et al, 1964 below; McClean &Tripp, 1974 below; Lee et al, 1974 below).

 

 

1959 Marie J, Salet J, Debris P, Hebert S, Corbin JL, Bezri A. Edematous form of cystic fibrosis of pancreas with hypoproteinaemia and anaemia (French). Sem Hop Paris 1959; 35:2140-2146. [PubMed]
A report of the oedema and hypoproteinaemia in an infant with CF (also Lee PA et al, 1974; Gunn T et al, 1978 below). Also infants with CF presenting in this manner may have a false negative sweat test (MacClean WC, Tripp RW. J Pediatr 1973; 83:86-88). [PubMed]

 

 

1980 Matthews WJ Jr, Williams M, Oliphint B, Geha R, Colten HR. Hypogammaglobulinemia in patients with cystic fibrosis. N Eng J Med 1980; 302:245-249. [PubMed]
Serum immunoglobulins were measured in 419 people with cystic fibrosis. Twenty-two per cent of the 154 patients less than 10 years old had hypogammaglobulinemia-G, whereas the older patients had normal or elevated serum immunoglobulins. The patients with hypogammaglobulinemia had significantly less severe lung disease than did age-matched patients with normal or elevated IgG levels. The authors suggested that the progression of lung disease may be due in part to a hyper-immune response not present in those with the hypogammaglobulinaemia.

Subsequent studies of immunoglobulins (Garside JP et al. Pediatr Pulmonol 2005; 39:135-140. [PubMed]) also showed a number with low immunoglobulins and more with low subgroups – particularly low IgG2. As in previous studies those few with high IgG levels were in worse clinical condition. A follow up of these patients (Garside et al. 2007; 42:125-130.[PubMed]) showed there was a reduction in the prevalence of low levels of IgG2 from 29% to 10% over the 2-year period. Low levels of IgG2 were not associated with any decline in clinical well-being. Again the children with high levels of IgG2 had worse lung function, worse clinical and chest X-ray scores and higher levels of P. aeruginosa infection. Children with low IgG2 levels were not worse clinically compared to those with normal or high IgG2 levels.

 

 

2004 Balfour-Lynn IM, Mohan U, Bush A, Rosenthal M. Intravenous immunoglobulin for cystic fibrosis lung disease: a case series of 16 children. Arch Dis Child 2004; 89:315-319. [PubMed]

Some children with severe cystic fibrosis (CF) lung disease develop chest tightness, recurrent dry cough, and intractable wheeze, often accompanied by deteriorating lung function and failure to expectorate sputum. In an attempt to reduce the use of regular oral corticosteroids, we treated a group of 16 such children with monthly courses of intravenous immunoglobulin (IVIG). The authors suggest that an n = 1 trial of IVIG in carefully selected patients with severe obstructive CF lung disease is worth considering, as for some it may lead to significant benefit.

 

 

2005 Garside JP, Kerrin DP, Brownlee KG, Gooi HC, Taylor JM, Conway SP. Immunoglobulin and IgG subclass levels in a regional pediatric cystic fibrosis clinic. Pediatr Pulmonol 2005; 39:135-40. [PubMed]
Total immunoglobulin levels were measured in 154 patients and IgG subclass levels were measured in 136 patients and compared to age-related normal population data and to levels reported in previously published studies of children with cystic fibrosis. Eleven patients had hypergammaglobulinemia (7.8% compared with 0-69% in the published literature). Patients with hypergammaglobulinemia had lower FEV1 percent-predicted values, and worse clinical and x-ray scores than controls. Three patients had hypogammaglobulinemia (1.9% compared with 0-10.8% in the published literature). There was no difference in any clinical parameter between controls and those with hypogammaglobulinemia. Nineteen patients (14%) had low levels of IgG1, and 40 patients (29%) had low levels of IgG2.

The low percentage of patients with abnormally high immunoglobulin levels compared with previous studies probably reflects the improved respiratory status of today's children with CF. The low percentage of those with low IgG probably reflects better nutritional status. The finding of worse lung function and clinical scores in patients with hypergammaglobulinemia agrees with the published literature. The high percentage of patients with low IgG2 was unexpected and had not been previously reported. The clinical significance of this in patients with CF is unknown. Also later follow-up of those with low Subclass 2 levels (Garside JP et al. Pediatr Pulmonol 2007; 42:125-130. [PubMed] showed no decline in clinical wellbeing and better condition compared with this with high levels of IgG2.

 

 

2007 Garside JP, Kerrin DP, Brownlee KG, Gooi HC, Taylor JM, Conway SP. Low gammaglobulin subclass 2 levels in paediatric cystic fibrosis patients followed over a 2-year period. Pediatr Pulmonol 2007; 42:125-130. [PubMed]
The aim of this study was to relate serum immunoglobulin G2 subclass levels in a large paediatric population with cystic fibrosis, to clinical status and antibody levels to Haemophilus influenzae type b and Streptococcus pneumoniae and to observe any changes over a 2-year period. IgG subclasses were measured in 131 patients. Results were compared with levels from age-related normal population data. The following clinical data were collected at baseline and 2 years later; genotype: height, weight, and BMI z-scores: FEV1 (as percent predicted): Shwachman-Kulczcyki and Northern chest X-ray scores: Pseudomonas aeruginosa status. Antibody levels to H. influenzae type b and S. pneumoniae measured at baseline were related to IgG2 level. There was a reduction in the prevalence of low levels of IgG2 from 29% to 10% over the 2-year period. Low levels of IgG2 were not associated with any decline in clinical well-being. Low levels of IgG2 alone were associated with low antibody levels to S. pneumoniae. Low levels of IgG2 and low levels of antibody to H. influenzae and S. pneumoniae were not associated with any decline in clinical well-being. Children with high levels of IgG2 had worse lung function, worse Shwachman-Kulczcyki and Northern chest X-ray scores and higher levels of P. aeruginosa infection. Children with low IgG2 levels were not worse clinically compared to those with normal or high IgG2 levels. High IgG2 levels were associated with a worse clinical status.

 

 

1984 Wheeler WB, Williams M, Matthews WJ Jr, Colten HR. Progression of cystic fibrosis lung disease as a function of serum immunoglobulin G levels: a 5-year longitudinal study. J Pediatr 1984; 104:695-699. [PubMed]
The children with persistent hypogammaglobulinemia G showed significantly better lung function, better weight for age, fewer hospitalizations for pulmonary exacerbations, less colonization with Pseudomonas aeruginosa, and slower decline in pulmonary functions than did age-matched patients with normal or high IgG levels. Death occurred in five of eight (63%) patients with hypergammaglobulinemia, three of 30 (10%) with normal levels and one of 32 (3%) with low levels. No deaths occurred in the 15 patients with persistent hypogammaglobulinemia.

These data indicate that children with cystic fibrosis and hypogammaglobulinemia G have milder lung disease and slower deterioration in pulmonary function than do age-matched patients with normal or elevated immunoglobulin G values. The mechanisms accounting for this finding are unclear (also Matthews et al, 1980 above; Garside et al, 2005; Garside et al, 2007 both below).

 

 

2011 Pincikova T, Nilsson K, Moen IE, Karpati F, Fluge G, Hollsing A, Knudsen PK, Lindblad A, Mared L, Pressler T, Hjelte L. Scandinavian Cystic Fibrosis Study Consortium. Inverse relation between vitamin D and serum total immunoglobulin G in the Scandinavian Cystic Fibrosis Nutritional Study. Eur J Clin Nutr 2011; 65:102-109. [PubMed]
The hallmark of cystic fibrosis (CF) is chronic lung inflammation. The severity of lung disease is closely correlated with immunoglobulin G (IgG) levels. Beyond its contribution to the bone health, the importance of vitamin D has not been fully recognized owing to the lack of human studies providing evidence of its benefit. In the context of the recently described immunomodulatory functions of vitamin D, the authors aimed to assess the relationship between vitamin D and IgG levels.

Eight hundred and ninety-six CF patients were included (0.53-65.9 years) from seven centres in Denmark, Norway and Sweden. The authors found that Serum 25OHD was positively associated with FEV1 and concluded that increasing vitamin D intake may positively modulate inflammation in CF. This study supports the proposed role of vitamin D in the immune system during infection and substantiates prospective studies.

This is a relatively recently suggested role for vitamin D and reinforces the importance of adequately supplementing patients with CF to achieve a normal serum vitamin D level.

 

 

 

1951 Kessler WR, Andersen DH. Heat prostration in fibrocystic disease of the pancreas and other condition. Pediatrics 1951; 8:648. [PubMed]
One of the most important papers up to that time from New York. Walter Kessler, the senior resident at the time, and Dorothy Andersen reported 12 children with heat prostration. Ten were admitted during a New York heat wave in 1948 and no less than seven were known to have cystic fibrosis. These were the days before air conditioning was generally available in New York and 1948 was a particularly hot summer. Paul di Sant’Agnese was working with Dorothy Andersen at the time and looking after her patients, and later said that he treated these particular infants as Andersen was away vacationing in Europe when they were admitted! The authors of this present report queried whether the sweat glands, as well as the glands of the pancreas and other organs, were inadequate in function or alternatively whether a low grade infection lowered the margin of tolerance to increased temperatures.


At the time of this report there was no explanation as to why infants with CF were particularly susceptible to heat prostration and salt depletion – fortunately Paul di Sant’Agnese decided to find out! This was the first report that children with CF were particularly susceptible to heat. It was this original incident that eventually led Paul di Sant’Agnese to search for the reason for salt depletion in many of these CF infants and eventually to his recognising the abnormally high sweat sodium and chloride, and to a lesser extent potassium.

This was undoubtedly the first and most important major advance in the understanding of the causation of CF up to that time (see di Sant’Agnese et al, 1953 below).

 

1956 Rendle-Short J. Fibrocystic disease of the pancreas presenting with acute salt depletion. Arch Dis Child 1956; 31:28-30. [PubMed]
Referred to as a case of pseudo-Bartter syndrome by Devlin et al. 1989 below.

 

 

1959 Douglas WAC. Acute salt depletion in fibrocystic disease of the pancreas. Med J Australia 1959; 46:962-963. [PubMed]
The Australian climate provides the requisite conditions for acute salt depletion but up to this time no cases of this complication in people with CF had been reported from there. These are the first two children to be reported from Queensland – a girl aged four years who quickly recovered with intravenous (IV) fluids and a girl aged 10 months admitted in a collapsed state but who also recovered with IV fluids. Climate temperature was over 100°F in both instances. Both were discharged on a 4 g salt supplement daily. “The association of pink lips with peripheral circulatory collapse is most unusual” – a sign also noted by Rendle-Short (1956 above). The normal daily sodium chloride requirement is approximately half a gramme per year of age per day up to a total of 5 grammes (4 grammes= a level teaspoonful). In warm conditions this daily salt supplement is recommended. Also see Coates et al, 2009 below.[PubMed]

 

1971 Gottlieb RP. Metabolic alkalosis in cystic fibrosis. J Pediatr 1971; 79:930-936. [PubMed]
An early example of metabolic alkalosis in an infant with cystic fibrosis. This came to be recognised as a mode of presentation eventually known as Pseudo-Bartter’s syndrome. There were subsequently isolated case reports in children with CF and an estimate of incidence in infants with CF by Beckerman & Taussig (1979 below).

 

1979 Beckerman RC, Taussig LM. Hypoelectrolytemia and metabolic alkalosis in infants with cystic fibrosis. Pediatrics 1979; 63:580-583. [PubMed]
In Tucson Arizona five of 11 infants with CF diagnosed in the first year between 1972 to 1977 were seen with hypokalemia, hypochloremia and metabolic alkalosis unassociated with marked dehydration, hyperpyrexia or major pulmonary or gastrointestinal symptoms. Chronic loss of sweat electrolytes together with mild gastrointestinal or respiratory disturbance may predispose. The lack of shock and hyperpyrexia differentiates the clinical state from the heat prostration syndrome described by Kessler & Andersen in 1951 (above).

This complication came to be known as Pseudo-Bartter’s syndrome. Of course occasionally infants with this clinical picture may not have CF but actually do have true Bartter’s syndrome as did an affected infant we reported in the previous year (Littlewood J M, Lee M R, Meadow S R. Treatment of Bartter's syndrome in early childhood with prostaglandin synthetase inhibitors. Arch Dis Child 1978; 53:43-48.[PubMed]). Both these situations will be diagnosed if the precaution is taken to perform serum electrolytes on any infant, CF or non-CF, who has a significant degree of “failure to thrive”.

 

 

1981 Laughlin JJ, Brady MS, Eigen H. Changing feeding trends as a cause of electrolyte depletion in infants with cystic fibrosis. Pediatrics 1981; 68:203-207. [PubMed]
Five infants with CF had eight episodes of hypoelectrolytemia - six of these were not associated with high environmental temperature and were considered possibly related to the current trends in reducing the salt in infant formula feeds.

The salt content of infant formula feeds had been reduced in view of the reports of hypernatraemic dehydration which occurred in some infants on formula milk. But just as the incidence of hypernatraemic dehydration in non-CF infants diminished when the salt content of infant feeds was reduced, so some infants with CF were adversely affected by the reduction in their dietary salt.

 

1989 Devlin J, Beckett NS, David TJ. Elevated sweat potassium, hyperaldosteronism and pseudo-Bartter’s syndrome: a spectrum of disorders associated with cystic fibrosis. J R Soc Med 1989; 82 (Suppl 16):38-43. [PubMed]
Three infants with “pseudo-Bartter’s syndrome” (the term first used by these authors) and two further with related electrolyte disturbances with low potassium and sodium and alkalosis. They emphasise the importance of measuring the serum electrolytes at diagnosis and when unwell. They mention the first report in CF was by Rendle Short J (Arch Dis Child 1956; 31:28-30.[PubMed])

Bartter’s syndrome was described by Fred Bartter in 1962 (Bartter FC et al. Hyperplasia of the juxtamedullary complex with hyperaldosteronism and hypokalemia alkalosis. Am J Med 1962; 33:811-128). In 1978 we described successful treatment of a non-CF infant with Bartter’s syndrome using indomethacin (Littlewood JM, et al. Treatment of Bartter’s syndrome in early childhood with prostaglandin synthetase inhibitors. Arch Dis Child 1978; 53:43-48.[PubMed]). Of course, children with CF who have pseudo-Bartter's syndrome require only adequate salt replacement and an adequate sodium intake to remain well.

 

1990 Kennedy JD, Dinwiddie R, Daman-Willems C, Dillon MJ, Matthews DJ. Pseudo-Bartter's syndrome in cystic fibrosis. Arch Dis Child 1990; 65:786-787. [PubMed]
A further seven cases of pseudo-Bartter's syndrome are described from Great Ormond Street, London. Chronic salt depletion was associated with severe failure to thrive which was soon reversed when the salt deficit was corrected.

Dr Bob Dinwiddie, the senior author, was consultant Respiratory Paediatrician at the Hospital for Sick Children, Great Ormond Street in London where he succeeded Dr Archie Norman as Director of the CF Unit. He was heavily involved in CF care and respiratory paediatrics both nationally and internationally until his retirement.

1994 Ozçelik U, Göçmen A, Kiper N, Coşkun T, Yilmaz E, Ozgüç M .Sodium chloride deficiency in cystic fibrosis patients. Eur J Pediatr. 1994;153(11):829-31. [PubMed]

Sodium chloride deficiency (SCD) was observed within the 1st year of life in 12 of 46 cystic fibrosis (CF) patients between July 1989 and September 1992. All patients showed sweating, loss of appetite, fever, vomiting, irritation, dehydration, weakness, and cyanosis during an attack. Mean plasma sodium, potassium and chloride levels were 122.9 (range 106-135), 2.5 (range 1.6-3.5), and 73.3 (range 60-90) mEq/l respectively. Alkalosis and elevated plasma renin activity were detected in all patients. (Interesting full details in the abstract).

 

Another example of "pseudo-Bartter's syndrome" which is undoubtedly a more common occurence in hot climates such as Turkey.

Professor Ayhan Göçmen (figure 27a in main text) of Ankara has been involved in CF care and research in Turkey for many years since the mid-Seventies. In 2007 he was President of the ECFS Conference in Belek, Turkey.

 

2009  Coates AJ, Crofton PM, Marshall T. Evaluation of salt supplementation in CF infants. J Cyst Fibros 2009; 8:382-385. [PubMed]
CF infants may be at increased risk of sodium depletion which may lead to impaired growth. The objective of this study was to evaluate their sodium supplementation requirements. Ten CF infants had serial measurements of weight and plasma/urine sodium and creatinine. Sodium supplementation was adjusted with the aim of maintaining fractional excretion (FENa) between 0.5% and 1.5% and urinary sodium > 10 mmol/L. The urine sodium:creatinine (UNa:Cr) ratio strongly correlated with FENa [UNa:Cr (mmol/mmol)=35.0 x FENa (r=0.99)]. The FENa target range corresponded to UNa:Cr 17-52 mmol/mmol. All infants required sodium supplementation to achieve UNa:Cr > 17 mmol/mmol. Sodium supplement requirements (mean+/-SD) at ages 0-3, 3-6, 6-9 and 9-12 months were 1.9+/-0.5, 1.8+/-0.8, 1.9+/-0.9 and 0.8+/-0.4 mmol/kg/d. No infant required calorie supplementation to achieve expected weight gain.

The authors concluded that using current UK CF Trust and European CFS guidelines many cases of sodium depletion may be overlooked. Some infants require more than the recommended 1-2 mmol/kg/d. The UNa:Cr ratio is a useful non-invasive measure to monitor sodium supplementation.

This is a particularly useful paper as most infants are diagnosed after neonatal screening and the advice in the UK and European CF Society consensus documents suggested that routine sodium supplementation is unnecessary. 

2013 Dahabreh MM, Najada AS. Pseudo-Bartter syndrome, pattern and correlation with other cystic fibrosis feature. Saudi J Kidney Dis Transpl 2013; 24:292-29. [PubMed]

All patients with CF who attended the respiratory clinic at Queen Rania Al-Abdallah Hospital from January 2000 to April 2010 were included in this retrospective case-control study. Eighteen of 110 (16.3%) patients had one or more episodes of Pseudo-Bartter syndrome (PBS). The median follow-up period was 6.2 years. All the episodes occurred during summer and in infancy. Median age of the initial episode of PBS was three months. One-third of them were initially followed at the nephrology clinic. Three patterns of PBS were identified: single episode in three (16.6%) patients, recurrent in 12 (66.6%) patients and chronic in three (16.6%) patients. Early colonization of Pseudomonas spp before 1st birthday was seen in 44% patients with PBS compared with 12% in other CF patients (P-value = 0.0075) and their mean clinical score lower in those with recurrent PBS. Gene mutation was identified in only 30% of the entire cohort.

The authors concluded that PBS is common in patients with CF, and it should be kept in mind in any patient with hypotonic dehydration and metabolic alkalosis.

As we have mentioned previously this syndrome will be identifeid if the precaution is taken to perform serum electrolytes on any infant, CF or non-CF, who has a significant degree of “failure to thrive” (see Topics - Electrolytes for more on PBS)

 

 

2013 Karanth L. Barua A. Kanagasabai S. Nair NS. Desmopressin acetate (DDAVP) for preventing and treating acute bleeds during pregnancy in women with congenital bleeding disorders. Cochrane Database of Systematic Reviews. 4:CD009824, 2013.

[PubMed]

The authors reviewed randomised and quasi-randomised controlled trials investigating the efficacy of desmopressin acetate versus tranexamic acid or factor VIII or rFactor VII or fresh frozen plasma in preventing and treating congenital bleeding disorders during pregnancy were eligible. The review did not identify any randomised controlled trials investigating the relative effectiveness of desmopressin acetate for bleeding during pregnancy in women with congenital bleeding disorders. In the absence of high quality evidence, clinicians need to use their clinical judgement and lower level evidence (e.g. from observational trials) to decide whether or not to treat women with congenital bleeding disorders with desmopressin acetate.

Our experience in Leeds suggests that desmopressin should be used with extreme caution in people with cystic fibrosis. (Simmonds EJ, Mahony MJ, Littlewood JM. Convulsion and coma after intranasal desmopressin in cystic fibrosis. BMJ 1988; 297:1614.[PubMed]).

A 13 yr old girl with CF was given 10ug, 20ug, 20 ug, and 10ug on cocequtive mornings for nocturnal enuresis. On the morning after her fourth dose of desmopressin the patient developed headache, nausea, andvomiting. She had remained dry for the first time theprevious night. Review of her weight chart showed asharp weight gain since treatment started: 41.35 kg to 43.15 kg. On the third day of treatment serum sodium concentration had been 125 mmol/l and on the fourth
day this had fallen to 114 mmol/l. Later that day she had a convulsion lasting about five minutes and
subsequently remained comatose. Her desmopressin was discontinued and she was managed with fluid
restriction alone to prevent possible pontine myelinolysis. Twenty eight hours after her last dose of
desmopressin she passed urine again and continued topass good quantities of dilute urine. Forty hours after fluid restriction was started intravenous fluids with her normal daily sodium requirements were started. Her serum sodium concentration rose and five days later was normal (135 mmol/l). Forty eight hours after her convulsion she was still deeply comatose, however. Physical examination
showed response only to deep pain, poor corneal reflexes, absent cough reflex, and absent peripheral
reflexes. Computed tomography of her head and lumbar puncture showed nothing abnormal. She
gradually regained consciousness and over two weeks returned to normal with no neurological sequelae.
This patient with cystic fibrosis had a severe adverse reaction to intranasal desmopressin.

 

 

2013 Durmowicz AG. Witzmann KA. Rosebraugh CJ. Chowdhury BA. Change in sweat chloride as a clinical end point in cystic fibrosis clinical trials: the ivacaftor experience. Chest 2013; 143:14-18. [PubMed]

Ivacaftor, a drug recently approved by the US Food and Drug Administration, represents the first mutation-specific therapy for CF. It is a CFTR channel modulator and improves CFTR function in patients with CF who have a G551D mutation. A clinical trial performed to support ivacaftor dose selection demonstrated a dose-response relationship between improvement in FEV(1) and decrease in sweat chloride, a measure of CFTR function. Validation of such a relationship between FEV(1) and sweat chloride would facilitate development of new drugs that target the defective CFTR.

Subsequently, in phase 3 studies, ivacaftor 150 mg bid resulted in significant improvements in FEV(1) (10%-12%) and reduction in sweat chloride (approximately 50 mmol/L). However, a decrease in sweat chloride did not correlate with improvement in FEV(1), nor did there appear to be a threshold level for change in sweat chloride above which an improvement in FEV(1) was apparent.

The lack of correlation of sweat chloride with improvement in FEV(1) speaks to the multiplicity of factors, physiologic, environmental, and genetic, that likely modulate CF disease severity. Future clinical trials of drugs that are directed to the defective CFTR will need take into account the uncertainty of using even established measurements, such as sweat chloride, as clinical end points.

Ivacaftor is the first drug to alter the abnormal sweat electrolytes in people with CF.

 

 

2014 Palermo J. Szabo F. 50 Years ago in The Journal of Pediatrics: hypoproteinemia and edema in infants with cystic fibrosis of the pancreas. Pediatr 2014; 164(3):638.[PubMed]
(Article in question - Fleisher DS, DiGeorge AM, Barnes LA, Cornfeld D. J. Pediatr 1964;64:341-8. No abstract)
When cystic fibrosis (CF) was first described in the 1500s, these children were thought to be bewitched. By the 1800s, the disease and its prognosis were depicted in a German children's song: “The child will soon die whose forehead tastes salty when kissed.” Life expectancy was 1 year.
In the 1900s, malnutrition and diarrhea were the hallmarks of the disease described as a “celiac syndrome.” In 1964, Fleisher et al reported their findings that breast milk or soy formula fed infants were significantly more malnourished with edema and hypoproteinemia and fared worse than those fed cow milk-based formula. Treatment for “cystic fibrosis of the pancreas” emphasized the importance of high fat diet and the use of pancreatic enzymes. Life expectancy was still limited, with 80% death rate by age 5 years.
In the following decades, significant strides were made in disease management without full understanding of its etiology, and life expectancy increased to almost 20 years by the 1980s. The landmark discovery of disease-causing mutations in the cystic fibrosis transmembrane regulator gene (CFTR) in 1989 provided a new focus in CF research.
State screens now help diagnose CF in infancy, resulting in earlier intervention and better outcomes. From 2000-2011, diagnoses through state screen increased from 10% to 60%. Life expectancy has risen significantly from 20 years to 37 years in just 2 decades. However, with improved survival, other complications of CF arise, including CF-related diabetes and liver disease with portal hypertension.
We are now entering a revolutionary era in CF with the development of breakthrough disease-modifying drugs targeting the CFTR protein defect. CFTR modulators are small molecules classified as potentiators, correctors, or premature stop codon suppressors. The first approved small molecule, Kalyedco (ivacaftor) is specific to less common CFTR mutations and increases CFTR channel opening. Other promising small molecules in clinical trials (http://www.cff.org/treatments/Pipeline) may be beneficial to those with classic delta F508 mutations.
Although previous advances in CF therapy mitigated the effects of CFTR dysfunction, the combination of early detection and initiation of personalized medicine targeting CFTR mutations may soon keep foreheads from tasting salty and truly alter the course of this devastating disease.