Percepciones sobre el nivel colectivo

Kindreds can be distinguished by a series of diagnostic features, including the

severity of the cation leak, the temperature dependence of the leak, the presence

or absence of stomatin, the phospholipid content of the membrane and the degree

of hydration of the cell. At present by these means eight variants in the UK can be

distinguished (Table 2.2). The variants to which we have access, and which will

be the main focus of the work in this thesis are: overhydrated HSt (OHSt),

dehydrated HSt (DHSt), cryohydrocytosis (CHC), familial pseudohyperkalaemia

Edinburgh type 1 (FPl) and familial pseudohyperkalaemia Falkirk/ Chiswick

type 2 (FP2), HSt Woking (Jarvis et al., 2001) and HSt Blackburn (Stewart and

Turner, 1999).

2.1.1 Overhydrated hereditary stomatocytosis (OHSt)

This is the most severe condition and will form the main focus of this thesis.

These patients have an extraordinarily high passive leak to Na^ and K^, with a

flux rate 20-40 times normal (Zarkowsky et al., 1968). The influx of Na^ exceeds

the efflux of K^. The NaK pump is stimulated by the high intracellular [Na^] but

cannot compensate for it (Morlé et al., 1989). This leads to grossly abnormal

swollen cells are osmotically fragile (Lux and Palek, 1995). Patients are

chronically jaundiced. Fortunately the condition is rare.

The integral membrane protein ‘stomatin’ is deficient from their cells

(Lande et al., 1982; Eber et al., 1989; Hiebl-Dirschmied et al., 1991; Stewart et

al., 1992). However, the protein was purified from a normal control and the gene

sequenced and was found to be normal in the patients (Wang et al., 1992).

During this work, the OHSt patients have been referred to as Brighton,

Manchester and Harrow. Unless it is stated otherwise, the patient Manchester

always refers to B-III-1 (see table 2.1 or figure 2.1).

2.1.2 Dehydrated hereditary stomatocytosis (DHSt)

This is the most common of the conditions. It is a haematologically milder

condition than OHSt. The fluxes to Na"^ and are only 2-3 times normal

(Stewart and Turner, 1999). The dehydration is probably due to the fact that the

increase in permeability to exceeds the augmentation in Na"^. Monovalent

cation pump activity is stimulated by the increased intracellular [Na^j but is

unable to compensate for loss. Cation and water depletion occur leading to

dehydration of the cells (Joiner et al., 1986).

The stomatin protein is not absent from the erythrocyte membranes from

excess of phosphatidylcholine (PC) and the condition is identical to that described

previously as a high phosphatidylcholine haemolytic anaemia (HPCHA) (Clark et

al., 1993).

Some European cases of DHSt have been associated with a transient, self

limiting, perinatal oedema (Entazami et al., 1996) (Grootenboer et al., 1998). All

DHSt cases tested so far map to a locus on chromosome 16q23-qter (Carella et

al., 1998).

2.1.3 Cryohydrocytosis (CHC)

This is the next most prevalent condition in the UK. It is characterised by a mild

anaemia, a reticulocytosis of about 5% and normal or close to normal levels of

haemoglobin (Miller et al., 1965). When fresh, the red cells display mild

dehydration with a high mean cell haemoglobin concentration (MCHC). If they

are left to stand at room temperature, they begin to lose and gain Na^ and

become overhydrated with a low MCHC. If they are left to stand in the cold,

these changes become very marked, with Na^ entry predominating over loss

(Coles et al., 1999a), leading to marked lysis if left overnight in EDTA or

heparin. Storage at low temperatures leads to an increase in intracellular [Na^], an

increase in cell hydration (Coles et al., 1999a) and a subsequent rise in the mean

Autohaemolysis on cold storage is particularly high and some of the

patients present with artefactually high plasma [K^ readings due to the loss of

into the plasma from red cells during storage. Because the storage falsely

suggests that the patients are hyperkalaemic, this phenomenon is termed

'pseudohyperkalaemia'. Patients are recalled to hospitals by anxious physicians

after routine plasma electrolyte estimations and are retested and found to be

normal when a repeat urgent analysis is performed. These effects can all be

attributed to the bizarre temperature dependence (section 2.4 and Figure 2.2) of

the NaV K'" leak (Stewart and Turner, 1999).

2.1.4 Familial pseudohyperkalaemia (a heterogeneous group)

Familial pseudohyperkalaemia (FPl and FP2) is characterised by erythrocyte

loss which is exaggerated in the cold. It is very mild with the haematology and

the leak at 37°C being virtually normal. Therefore, patients have only mildly

abnormal cells and little or no haemolysis or anaemia (Stewart et al., 1979;

Stewart and Ellory, 1985). The Edinburgh family (FPl) has a mildly dehydrated

condition (Stewart et al., 1979; Stewart, 1993) and maps to chromosome 16 along

with DHSt (lolascon et al., 1999). The Chiswick and Falkirk pedigrees (FP2)

(Haines et al., 2001a) show a similar combination of virtually normal

from the Edinburgh pedigree (FPl) by virtue of a shoulder-shaped temperature

dependence in the ‘passive leak’ to K.

2.1.5 HSt Woking

This is a unique pedigree and is the second most severe after OHSt (Jarvis et al.,

2001). The intracellular [Na^] and [K^] and the 'leak' influxes are more

abnormal than DHSt, while the temperature dependence of the flux is different

from Blackburn (see below) and cryohydrocytosis.

2.1.6 HSt Blackburn

This is another unique kindred, with an almost normal level of haemoglobin, 5-

8 % reticulocytosis, an identical flux to cryohydrocytosis (5-6 times normal)

showing a shallow slope temperature abnormality and frank anaemia (Coles et al.,

1999b). This condition can be differentiated from HSt Woking and

cryohydrocytosis by virtue of the temperature dependence of the cation leak,

which shows a 'shallow slope' abnormality.