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The clinical and immunochemical classification of 376 patients with cryoglobulinemia is presented. In 141 cases (37.5%) the syndrome was considered idiopathic. Among the secondary forms, chronic liver diseases and connective tissue diseases shared most frequently mixed cryoglobulins (18.8 and 15.4% of cases, respectively). Another common association was that with Waldenström's macroglobulinemia: cryoglobulins were found in 20% of these patients. In 5 patients (2 with the essential form and 3 with cryoglobulinemia secondary to Waldenström's disease) a Cl-inhibitor deficiency was discovered; the complement profile was characteristic of the acquired type and episodes of angioedema occurred. Studying the clinical course of 71 cases of essential mixed cryoglobulinemia followed-up for 4-20 years we concluded that the evolution of type II and type III cryoglobulinemias is different because that of type II seems to have a more severe course and may differentiate in a lymphoproliferative disorder; the immunochemical type of cryoglobulins seems therefore to have a prognostic significance. Because of the considerable overlap in the distribution of immunochemical types among the clinical subsets, a mixed classification (both biochemical and clinical) is proposed.

During the last 3 years we have observed 7 cases (4.1%) of cryoglobulinemia-associated polyneuropathy out of 167 patients with demonstrated cryoglobulinemia. Nerve involvement in the course of cryoglobulinemia is usually symmetrical, affecting the distal portions of the limbs and has a chronic or chronic-relapsing evolution. In our experience, the combined treatment by plasmapheresis and glucocorticoids and/or cytostatic drugs has proved to be quite effective, particularly when instituted during the symptomatic exacerbations. Therefore, we suggest to perform a systematic investigation of the cryoglobulinemic phenomenon in every patient presenting with symptoms and/or signs of an apparently idiopathic polyneuropathy.

Ninety-three patients with essential mixed cryoglobulinemia have been followed for more than 5 years in 75% of cases; 21 patients died during this period and the mean age at death was 54 years. The most common cause of death was renal failure. The percentages of patients who survived after 5 and 10 years from the diagnosis were 87 and 74%, respectively. The cryoglobulin type seems to be an important prognostic factor: in our population the type II/III ratio is 6/7 at diagnosis, while it becomes 2/1 when the patients who died are considered.

T lymphocyte subpopulations defined by monoclonal antibodies were determined in patients with essential mixed cryoglobulinemia (EMC) and secondary cryoglobulinemias (SC). A decrease of circulating lymphocytes and a reduction in the absolute number of T3+, T4+ and T8+ (p less than 0.01) as well as in the percentage of T4+ lymphocytes (p less than 0.05) were found in EMC. A significant decrease of T8+ cells, both in percentage (p less than 0.01) and absolute number (p less than 0.001), was evidenced in SC, while T3+ and T4+ cell counts were not significantly different from those of healthy controls.

Liver involvement during essential mixed cryoglobulinemia (EMC) and cryoglobulins secondary to acute and chronic liver diseases has often been reported. Cryoglobulins in the serum seem to depend on an abnormal balance between their production and clearance. In this paper, 58 cases of mixed, mainly polyclonal cryoglobulinemia secondary to chronic liver diseases, and 23 cases of EMC, mainly monoclonal, are described. Amongst the EMC, 15 cases have been histologically followed-up and we have shown different types of related pathological liver involvement: from ‘pathosis torbida’ and chronic persistent hepatitis to chronic active hepatitis and liver cirrhosis. Only a few hepatic lymphoid infiltrates were nodular. According to our data and to those in the literature, we can suggest the following correlations between mixed cryoglobulinemic states and liver diseases: 1. transient polyclonal cryoglobulins are secondary to acute viral liver diseases; 2. polyclonal cryoglobulins are related to chronic liver diseases, initially produced by a polyclonal stimulation; 3. mainly monoclonal, but also polyclonal cryoglobulins in which there is not always liver damage, but nodular infiltrates can be seen at the hepatic site; 4. monoclonal, but also polyclonal cryoglobulins, in which there are nodular lymphoid infiltrates and vasculitis, as in immune complex diseases.