High levels of immunocomplexes in the serum result in hyperviscosity and thrombosis in blood vessels, leading to specific clinical manifestations. Most common clinical features of the syndrome include retinal hemorrhage, Raynaud phenomenon, purpura, thrombosis, livedo reticularis. Type II and III are associated with arthralgia, fatigue, myalgia, renal disease, cutaneous vasculitis, and peripheral neuropathy. About 25-30% of the patients with mixed cryoglobulinemia have the characteristic triad of symptoms – purpura, arthralgia and weakness. Some of the common clinical manifestations include:

• Cutaneous – Erythematous or purpuric papules, particularly in lower extremities [10]. In type I, papules may develop in head and mucosa. Cutaneous manifestations also include capillary abnormalities in nail fold. 
• Musculoskeletal – More than 70% of the patients with cryoglobulinemia present with musculoskeletal symptoms. Arthralgia and myalgia are the common manifestations in type II and III syndrome. Arthralgia often affect joints of hands, knees and ankles. 
• Renal – This develops secondary to thrombosis or deposition of immunocomplexes in blood vessels. This is one of the most serious complications of cryoglobulinemia. This manifestation is often seen within 3-5 years of diagnosis of syndrome. If left untreated, it may result in renal failure [11]. 
• Pulmonary – Dyspnea, cough, and pleuritic pain and the pulmonary manifestations of the syndrome. Clinical features remain mild.
• Neuropathy affects more than half of the patients with cryoglobulinemia. 

Some other less frequent manifestations of the syndrome include abdominal pain, acrocyanosis, and arterial thrombosis.

• Splenomegaly

  Clinical Examination Hepatomegaly- Liver enlargement Hypertension- Increased blood pressure Splenomegaly- Enlarged spleen Numbness- Peripheral neuropathy and numbness Lab Studies for Cryoglobulinemia Blood Examination CBC- Results are often normal ESR [epainassist.com]

  Total body CT showed a mild splenomegaly with no evidence of malignancy. Electrodiagnostic studies were consistent with a severe sensory-motor peripheral polyneuropathy of the lower limb. [indianjrheumatol.com]

  Independent risk factors for death or dialysis were age >50 yr, purpura, splenomegaly, cryocrit=10%, plasma C3 level <54 mg/dl and serum creatinine >140 μmol/l. [academic.oup.com]

• Gangrene

  We describe a case of an unusual presentation of gangrene after elective digital surgery and highlight the need for a rheumatologic evaluation in cases in which vasculitis is suspected. [ncbi.nlm.nih.gov]

  Abnormal liver biochemical tests, abdominal pain, digital gangrene, and pulmonary disease may also occur. The diagnosis is based on a compatible clinical picture and a positive serum test for cryoglobulins. [accessmedicine.mhmedical.com]

  We report a 45 year old lady with multiple myeloma whose initial presentation was cryoglobulinema with vasculitic ulcers in legs and gangrene of toes. She had monoclonal gammopathy of IgG kappa. [austinpublishinggroup.com]

  To our knowledge this is the first instance in which gangrene has been associated with cryoglobulinemia. FULL TEXT [annals.org]

• Fatigue

  Symptomatic treatment includes: Nonsteroidal anti-inflammatory drugs for arthralgia and fatigue. [dermnetnz.org]

  We ask about general symptoms (anxious mood, depressed mood, fatigue, pain, and stress) regardless of condition. Last updated: January 31, 2019 [patientslikeme.com]

  […] immunoglobulins, one a monoclonal antibody against polyclonal IgG; usually IgG-IgM, in which IgM is monoclonal and has rheumatoid factor activity Type III : both immunoglobulin components are usually polyclonal IgG and IgM Clinical features Symptoms of fatigue [pathologyoutlines.com]

  When symptoms are present, they typically include a skin rash with red spots, or a purplish discoloration from bleeding under the skin (purpura); joint or muscle pain; numbness; weakness; fatigue; and breathing difficulties, among others. [vasculitisfoundation.org]

• Anemia

  […] recurrent DAH Diffuse or patchy focal alveolar infiltrates: seen in cases with DAH Serology ANA/RF: variable Anti-DNA/ANCA/Anti-GBM: negative C3/C4/CH50: decreased-normal Cryocrit (need to deliver warm to lab): positive HBsAg: ESR : usually elevated CBC : anemia [mdnxs.com]

  A 76-year-old woman was diagnosed with chronic active Epstein-Barr virus (EBV) infection (CAEBV) with sustained fever, anemia, numbness of the lower limbs, and liver dysfunction. [ncbi.nlm.nih.gov]

  Complications of untreated chronic gastritis include: Anemia: Erosive gastritis can cause chronic bleeding which, in turn, can lead to anemia Atrophic gastritis: Chronic inflammation in the stomach can cause the loss of both the stomach lining and glands [medicalnewstoday.com]

• Weight Loss

  Weight loss High blood pressure Swelling of ankles and legs Skin ulcers and gangrene Enlarged liver or spleen Numbness, tingling or weakness of hands or feet Kidney damage Cleveland Clinic News & More Cleveland Clinic News & More [my.clevelandclinic.org]

  loss skin ulcers and gangrene numbness or tingling high blood pressure Just as symptoms will vary among individuals, so will the number of flares a person experiences throughout the year. [medicalnewstoday.com]

• Rapidly Progressive Glomerulonephritis

  A proliferative glomerulonephritis can develop and can manifest as rapidly progressive glomerulonephritis. Abnormal liver biochemical tests, abdominal pain, digital gangrene, and pulmonary disease may also occur. [accessmedicine.mhmedical.com]

  Rapidly progressive glomerulonephritis is associated with a poorer prognosis. All patients should be monitored for transformation to neoplastic disease. BIBLIOGRAPHY Abel G, Zhang QX, Agnello V. [rheumaknowledgy.com]

  The need for immunologic criteria in rapidly Progressive glomerulonephritis and hemorragic pneumonitis. Ann Int Med, 75 (1971), pp. 67-76 [3.] Case Records of the Massaachusetts General Hospital (Case 11-1989). [archbronconeumol.org]

  CNS, central nervous system; CTX, cyclophosphamide; GN, glomerulonephritis; NSAIDS, nonsteroidal anti-inflammatory drugs; RPGN, rapidly progressive glomerulonephritis. [ashpublications.org]

• Abdominal Pain

  She consulted the emergency department for diffuse abdominal pain, associated with vomiting. [ncbi.nlm.nih.gov]

  However, when symptoms do occur, they typically include abdominal pain. People with gastritis typically report that their abdominal pain occurs in the upper center of the abdomen. [medicalnewstoday.com]

  Abnormal liver biochemical tests, abdominal pain, digital gangrene, and pulmonary disease may also occur. The diagnosis is based on a compatible clinical picture and a positive serum test for cryoglobulins. [accessmedicine.mhmedical.com]

• Hepatomegaly

  Clinical Examination Hepatomegaly- Liver enlargement Hypertension- Increased blood pressure Splenomegaly- Enlarged spleen Numbness- Peripheral neuropathy and numbness Lab Studies for Cryoglobulinemia Blood Examination CBC- Results are often normal ESR [epainassist.com]

  Neurologic symptoms may occur in a small percentage of patients and typically consists of peripheral sensory and motor polyneuropathy, which may present as paresthesia or foot drop. [5] Hepatic signs consist of hepatomegaly with the elevation of alkaline [e-ijd.org]

  Abdominal ultrasonography showed abundant ascites, mild hepatomegaly, and increased echogenicity of kidneys. [karger.com]

• Acrocyanosis

  A 71-year-old man comes to our observation because of the onset of persistence of paresthesia and painful acrocyanosis in the fingers and toes. [ncbi.nlm.nih.gov]

  Cutaneous lesions may include palpable purpura, urticaria-like lesions, livedo reticularis, Raynaud's phenomenon, acrocyanosis, gangrene and ulceration. [dermpedia.org]

  Type I cryoglobulinemia is frequently asymptomatic per se but patients may develop acrocyanosis, retinal hemorrhage, Raynaud's phenomenon, and arterial thrombosis. [orpha.net]

  Acrocyanosis. Haemorrhage. Arterial thrombosis. Facial swelling. [patient.info]

• Hypertension

  Patients with SSc-CV overlapping syndrome had limited cutaneous SSc with serum anticentromere antibodies, pulmonary hypertension, clinico-serological features of HCV-related CV, and non-healing skin ulcers of the lower limbs. [ncbi.nlm.nih.gov]

  […] immunoglobulin components are usually polyclonal IgG and IgM Clinical features Symptoms of fatigue, purpura over lower extremities, arthralgias, hepatosplenomegaly, lymphadenopathy, Raynaud phenomenon, glomerulonephritis in 50% with proteinuria and hypertension [pathologyoutlines.com]

  Clinical Examination Hepatomegaly- Liver enlargement Hypertension- Increased blood pressure Splenomegaly- Enlarged spleen Numbness- Peripheral neuropathy and numbness Lab Studies for Cryoglobulinemia Blood Examination CBC- Results are often normal ESR [epainassist.com]

• Arthritis

  (see Arthritis, [[Arthritis]]) Dermal Hypersensitivity (Leukocytoclastic) Vasculitis (see Vasculitis, [[Vasculitis]]) Diagnosis Pathology: dermal leukocytoclastic vasculitis -> perivascular polymorphonuclear infiltration with tissue extravasation and [mdnxs.com]

  Arthritis Care & Research. [slideshare.net]

  Arthritis Rheum. 2006; 54: 3696-3706 Terrier B. Saadoun D. Sène D. et al. [amjmed.com]

  Arthritis Rheum 1993;36:1341–1349. PMID: 8216392 Anaya JM, Talal N. Sjogren’s syndrome and connective tissue diseases associated with other immunologic disorders. In: Koopman WJ, ed. [rheumaknowledgy.com]

• Arthralgia

  Arthralgia and myalgia are the common manifestations in type II and III syndrome. Arthralgia often affect joints of hands, knees and ankles. Renal – This develops secondary to thrombosis or deposition of immunocomplexes in blood vessels. [symptoma.com]

  Hepatic – hepatitis Otorhinolaryngological – xerostomia, xerophthalmia Essential mixed cryoglobulinemia – vasculitis Triad of purpura, weakness, and arthralgias Often associated with lymphadenopathy, hepatosplenomegaly, and renal failure [arupconsult.com]

  […] cryoglobulinemia [ kri″o-glob″u-lin-e´me-ah ] the presence of cryoglobulin in the blood, associated with a variety of clinical manifestations including Raynaud's phenomenon, vascular purpura, cold urticaria, necrosis of extremities, bleeding disorders, vasculitis, arthralgia [medical-dictionary.thefreedictionary.com]

  There is a common clinical syndrome in types II and III essential mixed cryoglobulinemia (EMC) characterized by purpura, weakness, and arthralgia. [ncbi.nlm.nih.gov]

• Myalgia

  Type II and III are associated with arthralgia, fatigue, myalgia, renal disease, cutaneous vasculitis, and peripheral neuropathy. [symptoma.com]

  Baseline manifestations were purpura (78%), glomerulonephritis (28%), arthralgia (28%), peripheral neuropathy (22%), skin necrosis (22%), cutaneous ulcers (17%), and myalgia (11%). Cryoglobulinemia was type II in 2/3 of cases. [ncbi.nlm.nih.gov]

  Lower extremity manifestations of cryoglobulinemia include cutaneous vasculitis and resultant skin changes; arthralgias and myalgias; peripheral neuropathy; and acrocyanosis. [podiatrytoday.com]

  […] of the hands and feet from the cold Blue toe syndrome Retinal haemorrhage (bleeding) Severe Raynaud phenomenon Arterial thrombosis Gangrene Arthralgia and arthritis in the PIP and MCP joints (fingers, hands and toe joints), knees and ankles Fatigue Myalgias [dermnetnz.org]

• Purpura

  (see Purpura, [[Purpura]]) Interstitial Pulmonary Fibrosis (see Interstitial Lung Disease-Etiology, [[Interstitial Lung Disease-Etiology]]) Epidemiology: most common pulmonary manifestation Physiology: likely due to immune complex-mediated systemic vasculitis [mdnxs.com]

  Purpura (rash due to blood vessel damage) and the discoloration caused by chronic inflammation is clearly visible. Gangrene infection is visible on the second toe. [bio.davidson.edu]

  Differential Diagnosis: Conditions that may mimic cryoglobulinemia include vasculitis (e.g., polyarteritis nodosa, Henoch-Schönlein purpura), SLE, and lymphoma. Henoch-Schönlein purpura is more likely to be seen in young adults or children. [rheumaknowledgy.com]

  D69.2 ICD-10-CM Diagnosis Code D69.2 Other nonthrombocytopenic purpura 2016 2017 2018 2019 Billable/Specific Code Applicable To Purpura NOS Purpura simplex Senile purpura cryoglobulinemic D89.1 Pyelonephritis - see also Nephritis, tubulo-interstitial [icd10data.com]

• Skin Ulcer

  The treatment with rituximab was useful on skin ulcers of lower limb in 2/3 patients; however, the overall clinical outcome of the four SSc-CV patients was unusually severe: one with very severe skin ulcers complicated by gangrene required bilateral through-the [ncbi.nlm.nih.gov]

  glomeruli, and peripheral nerves most often involved – more common and frequent in type I Skin Vascular purpura Cold-induced urticaria Digital pain/cyanosis Raynaud phenomenon Skin ulcers Renal Glomerulonephritis – hematuria, proteinuria, casts Peripheral [arupconsult.com]

• Palpable Purpura

  Cardinal Findings: Palpable purpura may be present on the lower extremities and rarely extends above the waist. Proteinuria may be present and in some cases can be accompanied by significant edema. [rheumaknowledgy.com]

  Cutaneous lesions may include palpable purpura, urticaria-like lesions, livedo reticularis, Raynaud's phenomenon, acrocyanosis, gangrene and ulceration. [dermpedia.org]

  Cryoglobulinemic vasculitis typically manifests as recurrent palpable purpura (predominantly on the lower extremities) and peripheral neuropathy. [accessmedicine.mhmedical.com]

  (palpable purpura) Skin, glomeruli, and peripheral nerves most often involved – more common and frequent in type I Skin Vascular purpura Cold-induced urticaria Digital pain/cyanosis Raynaud phenomenon Skin ulcers Renal Glomerulonephritis – hematuria, [arupconsult.com]

• Foot Ulcer

  @inproceedings{Krasowska2011ExtensiveLA, title={Extensive leg and foot ulcers as a manifestation of cryoglobulinaemia with accompanying monoclonal gammopathy of undetermined significance}, author={Dorota Krasowska and Katarzyna Kozłowicz and Wojciech [semanticscholar.org]

  (A) Three skin ulcers at the anterolateral dorsum of the left foot in a patient with newly diagnosed WM-associated mixed cryoglobulinemia. [ashpublications.org]

• Hematuria

  She had renal function decline, microscopic hematuria, and proteinuria. A renal biopsy specimen revealed the presence of glomerular macrophages and duplication of the capillary walls with cellular interposition. [ncbi.nlm.nih.gov]

  Vascular purpura (palpable purpura) Skin, glomeruli, and peripheral nerves most often involved – more common and frequent in type I Skin Vascular purpura Cold-induced urticaria Digital pain/cyanosis Raynaud phenomenon Skin ulcers Renal Glomerulonephritis – hematuria [arupconsult.com]

• Kidney Failure

  Am J Kidney Dis. 2009 May;53(5):866-70. doi: 10.1053/j.ajkd.2009.01.015. Epub 2009 Mar 20. Abstract Cryoglobulinemia is rarely reported in children, and kidney failure secondary to cryoglobulinemia is even more uncommon. [ncbi.nlm.nih.gov]

  Possible Complications Complications include: Bleeding in the digestive tract (rare) Heart disease (rare) Infections of ulcers Kidney failure Liver failure Skin death Death Prevention There is no known prevention for the condition. [account.allinahealth.org]

  Possible Complications Complications include: Bleeding in the digestive tract (rare) Heart disease (rare) Infections of ulcers Kidney failure Liver failure Skin death Death When to Contact a Medical Professional Call your provider if: You develop symptoms [pennstatehershey.adam.com]

  The vasculitis may damage the liver and kidneys. In some people, the damage may progress to liver failure and kidney failure and can be fatal. [merckmanuals.com]

• Peripheral Neuropathy

  (see Peripheral Neuropathy, [[Peripheral Neuropathy]]) Hepatitis Treatment Treatment of Type I Cryoglobulinemia-Related Hyperviscosity Plasmapheresis Chemotherapy (if associated with an underlying malignancy) Treatment of Type II/III (Mixed) Cryoglobulinemia-Related [mdnxs.com]

  Peripheral neuropathy usually occurs in types II and III, rather than in type I, EMC. [scielo.br]

  Peripheral neuropathy with symptoms of pain, dysesthesia, or motor abnormalities may be the predominant finding in some patients. [rheumaknowledgy.com]

  RESULTS: Complete remission of pretreatment active manifestations was observed in all cases of purpuric lesions and non-healing vasculitic ulcers, and in 80% of the peripheral neuropathies. [ncbi.nlm.nih.gov]

  Nonsteroidal anti-inflammatory drugs (NSAIDs) Interferon Immunosuppressive drugs (Cytoxan®) Plasmapheresis Corticosteroids For peripheral neuropathy: Discontinue drugs that cause peripheral neuropathy Institute non-drug treatments to reduce pain, such [foundationforpn.org]

• Asthenia

  The clinical manifestations were asthenia, renal involvement, and purpura, which were found in more than 50% of patients with non–HCV-related MC vasculitis. [jamanetwork.com]

  In 1966, Meltzer et al[7] described a clinical triad characterized by palpable purpura, arthralgia and asthenia associated with nephropathy and neuropathy. It is widely accepted that presentation of the complete triad is rare in clinical practice. [wjgnet.com]

  Among patients with MC, 60%-90% are infected with HCV. 2 ⇓ ⇓ – 5 Cryoglobulinemia may be responsible for a systemic vasculitis (CryoVas), with manifestations that range from MC syndrome (purpura, arthralgia, and asthenia) to more serious lesions with [bloodjournal.org]

  […] an IgG RF has been discovered and since then, growing evidence has suggested that IgG subclasses could be involved in the development of cryoglobulinemia.[30] The search for CGs should only be performed in subjects with suggestive clinical symptoms (asthenia [mjhid.org]

  Asthenia, weight loss and/or fever were observed in 18 patients (36.7%). Mild depression was noted in six patients (12.2%), two during the first 3 months of IFNα therapy, while the other four did not receive IFNα. Two men had orchitis (11.1%). [academic.oup.com]

• Numbness of the Hand

  […] turn white, then blue, and then red from constriction and subsequent dilation of the blood vessels), or numbness in the hands and feet. [hepatitiscnewdrugs.blogspot.com]

Serum precipitation is most common test used to evaluate serum globulins. In type I, cryoglobulins precipitate within a day while in type II and III, the proteins may take more than a week to precipitate. Cryoglobulin levels are estimated using spectrophotometric analysis. Components of cryoglobulins are identified using immunologic assays. Urinalysis, complete blood count, serum chemistry, liver function tests, rheumatoid factor analysis, antinuclear antibody, ESR, and complement evaluation are also used in the diagnosis of this syndrome. Antinuclear antibody test is usually recommended if there is a risk of connective tissue disease. Rheumatoid factor tests will be positive for both type II and III. Liver function tests are used to check for hepatitis. Serum chemistry helps to identify abnormalities in levels of electrolytes and serum creatinine, both of which indicate involvement of kidney. For other concomitant diseases further diagnostic tests may be recommended.
Pleural effusions and involvement of lungs are revealed through radiography. CT imaging is suggested in case of suspected malignancy. Other imaging techniques are suggested for bacterial endocarditis and vasculitis. Biopsy is also recommended occasionally for vasculitis and renal disease. Neuropathy can be confirmed using electromyography.

• Hyperglobulinemia

  […] virus [HIV] disease ( B20 ) Certain disorders involving the immune mechanism D89 ICD-10-CM Diagnosis Code D89 Other disorders involving the immune mechanism, not elsewhere classified 2016 2017 2018 2019 Non-Billable/Non-Specific Code Type 1 Excludes hyperglobulinemia [icd10data.com]

• Treponema Pallidum

  HBV, HCV, HIV), bacterial (i.e. subacute bacterial endocarditis, Treponema pallidum) and parasitic (i.e. [slideshare.net]

• Colitis

  Overall, manifestations range from neurologic impairments (ie, due to retinal vasculitis), renal failure, arthritis/arthralgia, to bowel symptoms of ischemic colitis. [dermatologyadvisor.com]

  […] factors associated with noninfectious mixed CryoVas were connective tissue disease in 73 patients (primary Sjögren syndrome in 61 patients, systemic lupus erythematosus in 5, mixed connective tissue disease in 2, systemic sclerosis in 2, ulcerative colitis [bloodjournal.org]

  Small ischemic abnormalities of the brain were observed by magnetic resonance; colonoscopy revealed mucosal hyperemia with small hemorragic areas throughout the left colon, non-specific chronic colitis was found by biopsy. [karger.com]

Treatment strategy focuses on controlling levels of cryoglobulins, reducing inflammation and also to treat the underlying condition, if present [12]. Mild forms of the disease may not require any specific treatment. Treating the underlying condition is the best method to control the symptoms in case of secondary cryoglobulinemia. Nonsteroidal anti-inflammatory drugs are suggested for arthralgia and fatigue. Symptoms of vasculitis, renal disease, neuropathy, and skin manifestations are controlled by immunosuppressive medications like corticosteroids and/or cyclophosphamide. Corticosteroids and cytotoxic agents are also useful in reducing levels of immunoglobulins. Serum hyperviscosity is controlled through plasmapheresis. If the syndrome is related to hepatitis infection, combination of pegylated interferon alfa (INF-alpha) and ribavirin is effective. Entecavir is recommended for remission of vasculitis related to hepatitis B. Anti-CD20 therapy or cytotoxic therapy are found to be effective in type I cryoglobulinemia.
For life threatening conditions like vasculitis and severe nephritis, corticosteroids are used to reduce the inflammation due to lesions. Cyclophosphamide helps to prevent the formation of new antibodies. Serious complications can be controlled by plasma exchange and plasmapheresis.

Prognosis of cryoglobulinemia depends on the presence and severity of underlying disease. Presence of associated renal disease is a poor prognostic factor. Concomitant diseases affect the mortality and morbidity in individuals with cryoglobulinemia. The risk is greater in patients with associated hepatitis [8]. Patients with hepatitis have a good prognosis if they respond to treatment. Those with lymphoproliferative disease and plasma cell disorders also have a poor prognosis. Mean survival of patients with cryoglobulinemia is about 50% after 10 years of diagnosis of these concomitant diseases. Age was found to be a predictor of survival or mortality in patients with cryoglobulinemia and associated renal disease [9].

Cryoglobulinemia is categorized into Type I and II based on the composition of cryoglobulins in the serum.

• Type I is also known as simple cryoglobulinemia. This type is caused by monoclonal immunoglobulins, IgM, IgG or IgA. They do not have any rheumatoid factor activity. This type is often associated with lymphoma, and multiple myeloma. 
• Type II is also referred to as mixed cryoglobulinemia, and the serum is composed of IgM, IgG and IgA rheumatoid factors. The factors are monoclonal. 
• Type III is also known as mixed cryoglobulinemia. This type, instead, is caused by polyclonal rheumatoid factors of IgM, IgG and IgA. 

Mixed cryoglobulinemia is associated with rheumatic diseases, chronic infections, and connective tissue diseases. Cryoglobulinemia is associated with variety of viral, bacterial, parasitic and fungal infections. Some of the disorders associated with cryoglobulinemia includes:

• Autoimmune diseases like rheumatoid arthritis, systemic lupus erythematosus, and Sjogren's syndrome
• Vasculitis
• Lymphoproliferative disorders like multiple myeloma, lymphoma, and leukemia 
• Proliferative glomerulonephritis
• Liver disease like liver cirrhosis and hepatitis

Cryoglobulinemia is a clinically heterogeneous syndrome and the prevalence may be underestimated. Prevalence also varies in different countries. Mixed cryoglobulinemia is more prevalent in Southern Europe when compared to Northern Europe and Northern America. Prevalence of this syndrome ranges from 1-7 in 100,000 people [2].The average age of disease onset is 54 years. This syndrome is found to be more common among female when compared to males. The female to male ratio of occurrence is around 3:1. Relative frequencies of the different types of this syndrome also varies in different reports [3]. Frequency of type I and II was around 25%, while that of type III was 50%. In rheumatologic surveys, frequency of type was found to be more than that of type II mixed cryoglobulins. But when renal involvement is considered, type II cryoglobulins was found to be more prevalent.

Pathophysiology of cryoglobulinemia is not yet clearly defined. A number of factors are presumed to be involved in cryoprecipitation. The structure of heavy and light chains of immunoglobulins affects the solubility of cryoglobulins [4]. Solubility is also affected by temperature-related changes in the conformation of the proteins [5]. Serum levels of cryoglobulins are affected by the ratio of antibody to antigen in the cryoglobulin immunocomplexes. Reduced solubility of cryoglobulins leads to vasculitic damage while rate of clearance of the proteins influences the rate at which it is deposited [6].

Intravascular deposits of this protein along with reduced levels of complement in the serum triggers inflammation. The actual process in which it mediates inflammation is not clear. Cryoprecipitation results in plugging and thrombosis of blood vessels. Increased levels of large monoclonal cryoglobulins in the serum lead to hyperviscosity syndrome. These proteins may obstruct the vessels or result in immunocomplex deposition leading to inflammatory vasculitis. This is most commonly seen in type I cryoglobulinemia.

Type II and III cryoglobulinemia are associated with disorders like HCV infection, systemic lupus erythematosus and Sjogren's syndrome. The proteins are often polyclonal with rheumatoid factor activity presumably caused by B-cell clonal expansion of RF-secreting cells. Abnormal production and clearance of IgM-rheumatoid factor lead to the formation immune complex. The protein aggregates and immunocomplex deposition lead to tissue damage followed by activation of complement. In HCV-associated cryoglobulinemia, viral proteins play a very important role in the development of clinical manifestations of the syndrome [7].

Since cold temperature is a major precipitating factor, avoiding exposure to cold is a very important method to prevent this syndrome. Avoiding late complications with early diagnosis and treatment also goes a long way in controlling the symptoms.

Cryoglobulinemia refers to the clinical systemic inflammation syndrome caused by the presence of cryoglobulins in the serum. Cryoglobulin-containing immune complexes result in small-to-medium blood vessel vasculitis. The disease is categorized into two depending on the presence of associated diseases. Essential or idiopathic cryoglobulinemia is not associated with any particular disease, while cryoglobulinemia associated with a particular disease is categorized as secondary cryoglobulinemia [1]. It may be associated with lymphoproliferative disorder or an autoimmune disease.

It is also categorized on the basis of types of cryoglobulins present. Identifying the type of cryoglobulin helps in predicting the clinical manifestations while alternatively, understanding the clinical features helps to identify the type of cryoglobulin present. Treatment of syndrome depends on the type of cryoglobulin, severity of symptoms and the underlying disease.

Cryoglobulinemia is a condition caused by the presence of certain proteins, called cryoglobulins, in the serum. These proteins are characterized by an unusual property in which they precipitate when chilled and dissolves upon increasing the temperature. Cryoglobulinemia may be present as an isolated condition or in association with other conditions like myeloma or lymphoma. It is also seen in association with viral infections, particularly hepatitis. Cryoglobulinemia present without an associated disease is known as essential or idiopathic cryoglobulinemia. When present along with associated conditions, it is referred to as secondary cryoglobulinemia. These proteins form complexes and get deposited in the walls of small and medium-sized arteries resulting in vasculitis.

This condition is more prevalent among females and the mean age of onset of disease is 42 to 52 years. Type and severity of symptoms of cryoglobulinemia depend on the underlying disease. The most common symptom is a triad – weakness, muscle pain and purple spots on skin. Other symptoms depend on the organ affected. Occasionally dyspnea, cough, numbness, abdominal pain, and bluish color in hands and feet due to poor circulation are also seen. Thrombosis may result in renal disease, one of the most serious complication of the syndrome. History, physical examination, laboratory tests, and imaging studies are recommended based on the clinical features of the syndrome. Laboratory tests include serum chemistry, serum cryoglobulins, rheumatoid factor test, liver function test, complete blood test, urinalysis, and electrolytes. Chest radiography is used to check for involvement of lungs. If malignancy is suspected as the underlying cause, CT scan is suggested.

Mild forms of cryoglobulinemia may not require any specific therapy. The mainstay of treatment for cryoglobulinemia is immunosuppressants. Corticosteroids are often recommended in the treatment. Interferon alpha is recommended in case of disease associated with hepatitis. Treatment of secondary cryoglobulinemia depends on containing the underlying disease. For general weakness and myalgia, non- steroidal anti-inflammatory drugs are recommended. Prognosis is good with early diagnosis and treatment. Presence of renal disease is a worse prognostic factor. Treating the underlying disease helps to improve the symptoms. As the disease is precipitated in cold temperatures, avoiding exposure to cold is very important in preventing cryoglobulinemia.

1. Trendelenburg M, Schifferli JA. Cryoglobulins are not essential. Ann Rheum Dis. 1998;57(1):3-5.
2. Roccattello D, Fornasieri A, Giachino O, et al. Multicenter study on HCV-related cryoglobulinemic glomerulonephritis. Am J Kidney Dis. 2007;49:69-82.
3. Brouet JC, Clauvel JP, Danon F, Klein M, Seligmann M. Biologic and clinical significance of cryoglobulins. A report of 86 cases. Am J Med. 1974;57(5):775-88.
4. Wang AC, Wells JV, Fudenberg HH. Chemical analyses of cryoglobulins. Immunochemistry. 1974;11(7):341-5.
5. Saulk PH, Clem W. Studies on the cryoprecipitation of a human IGG3 cryoglobulin: the effects of temperature-induced comformational changes on the primary interaction. Immunochemistry. 1975;12(1):29-37.
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7. Sansonno D, Dammacco F. Hepatitis C virus, cryoglobulinaemia, and vasculitis: immune complex relations. Lancet Infect Dis. 2005;5(4):227-36.
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9. Bryce AH, Kyle RA, Dispenzieri A, Gertz MA. Natural history and therapy of 66 patients with mixed cryoglobulinemia. Am J Hematol. 2006;81(7):511-8.
10. Monti G, Galli M, Invernizzi F, Pioltelli P, Saccardo F, Monteverde A, et al. Cryoglobulinaemias: a multi-centre study of the early clinical and laboratory manifestations of primary and secondary disease. GISC. Italian Group for the Study of Cryoglobulinaemias. QJM. 1995;88(2):115-26.
11. Tarantino A, Campise M, Banfi G, Confalonieri R, Bucci A, Montoli A, et al. Long-term predictors of survival in essential mixed cryoglobulinemic glomerulonephritis. Kidney Int. 1995;47(2):618-23.
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