Cryoglobulins

Neuropathies can result from mutations that alter the structure or level of expression of PNS myelin proteins (e.g. overexpression of PMP22 in Charcot-Marie-Tooth syndrome (CMT) type 1A), the metabolism of myelin lipids (e.g. metachromatic leukodystrophy), or the capacity of PNS neurons to support their axons in patients with CMT caused by mutations of KIF1B [4] or NF-L [5, 6]. Both acquired and inherited amyloid neuropathies can result from the deposition of poorly soluble proteins, for example cryoglobulins or mutant transthyretins, in and around endoneurial bloodvessels [7-9]. 

From the results of the variety of studies undertaken, it now appears certain that no one single immunological factor is responsible for the various forms of heart diseases which are seen in populations in subtropical and tropical countries. Thus, in patients with endomyocardial fibrosis (EMF), rheumatic heart disease, or idiopathic cardiomegaly, heart antibodies were present in 42% and thyroid antibodies in 15% serum cryoglobulins were present in 74% of the patients but was more frequent in those patients who had EMF than in any of the other groups (VI). The suggestion was therefore made that patients with EMF were... 

Flo. 8. Immunoelectrophoretic pattern of serum from a patient with IgG myelomatosis. Note the area next to the top well, where there is a spontaneous precipitation of cryoglobulins in the agar gel, which remained in the gel even after extensive washing with saline. The massive increase of the abnormal precipitin line of the patient s serum in the top well is distinctly different from that of the normal precipitin line below antiserum as in Fig. 7. 

IgM, an immunoglobulin in milk, forms a complex with lipoproteins. This complex, known as cryoglobulin, precipitates onto the fat globules and causes flocculation. The process is known as cold agglutination. As fat globules cluster, the speed of rising increases and sweeps up the smaller globules with them. The cream layer forms very rapidly, within 20 to 30 min, in cold milk. 

This syndrome is characterized by proteinuria >3.5 g/day, hypoalbuminuria <3 g/dl, hyperlip-idaemia with an elevation of serum cholesterol, edema and oval fat bodies and fatty casts in the urinary sediment. A variety of disorders may produce nephrotic syndrome but, in the majority of cases, no cause is found. It is appropriate to define the selection of studies from the history and physical examination. Tests to order are antinuclear antibody, rheumatoid factor, cryoglobulins, serum complement, HBsAg VDRL serology (syphilis), protein electrophoresis of the serum and urine and HIV. If the cause is unclear a renal biopsy is done to define the glomerular lesion as treatment may on the underlying glomerular lesion. 

Figure 9.1 The time needed (t ) at various temperatures (T) to inactivate some enzymes and cryoglobulins to kill some bacteria and spores to cause a certain degree of browning to convert 1 % of lactose to lactulose to cause heat coagulation to reduce available lysine by 1 % and to make 10% and 75% of the whey proteins insoluble at pH 4.6 (from Walstra and Jenness,...

When milk is heated to a moderate temperature (e.g. 70°C x 15 min), the cryoglobulins are irreversibly denatured and hence the creaming of milk is impaired or prevented HTST pasteurization (72°C x 15 s) has little or no effect on creaming potential but slightly more severe conditions have an adverse effect (Figure 9.2). 

In addition to the general decrease in viscosity with increasing temperature, heating milk can also influence its rheology by heat-induced denatura-tion of cryoglobulins and/or other whey proteins. Concentration of milk, e.g. by ultrafiltration, prior to heating results in a greater increase in f/app than in milk heated before concentration. 

Guidelines for clinical and laboratory evaluation of patients with monoclonal gammopathies have been proposed (K7). These proposals address in addition electrophoretic, immunofixation, and quantitative techniques for measurement of M protein, and also provide guidelines for serum viscosity and cryoglobulin measurements. 

Examination of cryoglobulins especially in patients with monoclonal IgM requires collection of at least 10 ml of blood into a prewarmed (to 37°C) tube or syringe, allowing the blood to clot at that temperature for 30-60 min prior to centrifugation to obtain serum. The serum sample should be stored at 4°C for up to 7 days. The presence of cryoglobulins in a formed precipitate should be confirmed by its solubility at 37°C, and further quantitated and characterized immunochem-ically (Kl). 

As to cryoglobulins, both type I (single component or 1 isotype or subclass of immunoglobulin, or, rarely, a monoclonal light chain) and type II (mixed cryoglobulins with monoclonal IgM as antibody and IgG as antigen) may be present. Nearly 10% of all WM molecules are cryoprecipitable (Kl). Infiltration of bone marrow by tumor cells can result in severe anemia. 

A review of plasma purification using secondary filtration has been presented by Siami et al. [19] and Table 18.4 lists the diseases treated with this technique. Diseases treated include immune-mediated disorders and familial type IIA hypercholesterolemia. These authors concluded that cryoglobulins filters were safe and effective for removing cryoproteins, did not induce complement activation and constituted one of the most promising techniques of secondary membrane application. 

Type II Cryoglobulinemia Mono IgM and poly IgG Cryoglobulin filter... 

M15. Meltzer, M., and Franklin, E. C., Cryoglobulins, rheumatoid factors, and connective tissue disorders. Arthritis Rheum. 10, 489-492 (1967). 

Payens, T.A.J., Both, P. 1970. Cryoglobulins from milk and a mechanism for cold agglutination of milk fat globules. Immunochemistry. 7, 869. 

Cryoglobulins Rheumatoid arthritis, systemic lupus erythematosus... 

Trendelenburg, M., Schifferli, J.A. Cryoglobulins in chronic hepatitis C virus infection. Clin. Exper. Immunol. 2003 133 153-155... 

A 59-year-old man, who had taken amiodarone 200 mg/day for 2 years, developed fever, pleuritic chest pain, dyspnea at rest, a non-productive cough, malaise, and joint pains (211). He had a verrucous endocarditis and a pleuropericardial effusion. He had raised titers of antinuclear antibodies (1 320) with anti-Ro specificity. Serum complement was normal and there were no circulating immune complexes, no cryoglobulins, and no anti-dsDNA, anti-La, anti-Ul ribonucleoprotein, anti-Sm, anti-Scl, 70, anti-Jo 1, antihistone, antiphosphohpid, anticentromere, anticardioli-pin, or anticytoplasmic antibodies. Within 7 days of withdrawal of amiodarone the signs and symptoms started to resolve, and he recovered fuUy with the addition of prednisolone. 

However, cryoglobulin-associated vasculitis is a recognized manifestation of hepatitis C infection. Reports of vasculitis in interferon alfa-treated patients should therefore be interpreted with caution (SED-13,1095) (371). In addition, several isolated reports suggested that exacerbation of cryoglobulinemia might also be the result of interferon alfa treatment (SEDA-19, 337). 

Antibodies to the Ro(SSA) cellular antigen (244,397) and circulating cryoglobulins (244) are risk factors for adverse reactions to penicillamine. AntiRo (SSA) antibodies characterize a distinct group of patients with rheumatoid arthritis who are almost exclusively female, express more activated B cell function, have a high prevalence of Sjogren s features, and commonly develop adverse reactions to penicillamine. Rashes and febrile reactions were especially associated with anti-Ro(SSA) antibodies, and renal pathology was more frequent in men (244). 

Steinmuller DR, Bolton WK, Stillman MM, Couser WG. Chronic interstitial nephritis and mixed cryoglobulin associated with drug abuse. Arch Pathol Lab Med 1979 103 63-66. 

The majority of patients also had an elevated leukocyte count with modestly elevated levels of aldolase, a marker of muscle injury however, creatine phosphokinase, another indicator of muscle injury, was normal in most patients. This inconsistency between the levels of these two muscle-associated enzymes, previously described in some patients with systemic sclerosis and the toxic oil syndrome (TOS) (see below), is helpful in differentiating EMS from other myopathies (muscle diseases) and from eosinophilic fasciitis (EE) (see below). Approximately one-half of patients had abnormal liver function tests, although the changes were mild. The erythrocyte sedimentation rate, rheumatoid factor, and levels of IgE, complement, and cryoglobulin (all markers of immune dysfunction) were normal in most patients tested. 

All specimens listed, except those to be assayed for cryoglobulins, should be transported at temperatures below 15°C, except as noted. 

---