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.

• 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]

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

  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]

• Fatigue

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

  When symptoms are present, they are most commonly fatigue, joint pain, numbness or weakness, and a particular rash called purpura that looks like red spots or purple bruises, usually over the lower legs. [my.clevelandclinic.org]

• Anemia

  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]

  The distinctive features of these cases were anemia, epistaxis, slight lymphadenopathy, lymphocytoid cells in the bone marrow, generalized osteoporosis, and the presence of macroglobulins in the serum. [annals.org]

  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]

• 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]

  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]

  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]

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

• Cold Intolerance

  […] microvasculature upon exposure to cold. [medical-dictionary.thefreedictionary.com]

  Skin manifestations are usually the first signs and are usually moderate; in addition, cold intolerance, Raynaud phenomenon, purpura, or livedo reticularis often occurs. Skin necrosis, acral ulcers, and gangrene can lead to surgery and amputation. [doi.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]

  Some other less frequent manifestations of the syndrome include abdominal pain, acrocyanosis, and arterial thrombosis. Serum precipitation is most common test used to evaluate serum globulins. [symptoma.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]

  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]

  […] 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]

• Cotton Wool Spots

  Ophthalmic examination indicated peripapillary cotton wool spots and superficial retinal whitening in the macula. Cryoglobulinemia complicating hepatitis C was discovered in this patient. [ncbi.nlm.nih.gov]

• 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]

  We report the difficult management of 59 year old female HCV patient presenting cutaneous lesions and arthralgia due to mixed cryoglobulinemia. [ncbi.nlm.nih.gov]

  […] tool=bestpractice.com The clinical presentation includes a triad of purpura, weakness, and arthralgia. Multisystemic involvement may occur, particularly affecting the kidneys, liver, and nervous system. [us.bestpractice.bmj.com]

• Purpura

  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]

  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]

  (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]

  Urine Examination Urinalysis- Hematuria and proteinuria is observed if patient is suffering with Cryoglobulinemia induced glomerulonephritis. Angiogram Test is performed to evaluate tissue perfusion. [epainassist.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]

  Hyperviscous blood is especially dangerous for the kidneys, where vessels are tiny. The presence of blood and protein in the urine can alert your doctor to kidney damage, which can lead to kidney failure. [hepatitisc.net]

  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]

  Complications include: Bleeding in the digestive tract (rare) Heart disease (rare) Infections of ulcers Kidney failure Liver failure Skin death Death Call your provider if: You develop symptoms of cryoglobulinemia. [nlm.nih.gov]

• Peripheral Neuropathy

  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]

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

  We have experienced four cases with mixed cryoglobulinemia showing severe and progressive clinical manifestations, including skin purpura, nephrotic syndrome, acute kidney injury, and peripheral neuropathy. [ncbi.nlm.nih.gov]

• 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]

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.

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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.
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