Cryoglobulinemia is a medical condition that is caused by abnormal immunoglobulins (blood proteins), called cryoglobulins. Cryoglobulin literally means "cold antibody in the blood." Cryoglobulins are either single or mixed immunoglobulins that clump together at temperatures lower than 37 degrees Celsius. This process is reversed when they are warmed.
Cryoglobulins are often associated with diseases such as, hepatitis, multiple myeloma (type of bone marrow disease), dermatomyositis and lymphoma.
Since cryoglobulinemia makes the blood thicker, symptoms can arise throughout the body. Cryoglobulinemia primarily causes blood clots, stroke and vasculitis (inflamed blood vessels). Vasculitis of the arteries can result in blocked arteries, which often leads to damage in the organs that receive blood from the affected blood vessels (like the skin or kidneys).
The prognosis of cryoglobulinemic patients depends on the presence or absence of underlying diseases. Lymphoproliferative disorders, hepatitis B or C and connective tissue diseases are often associated with cryoglobulinemia, and these diseases increase the risk of complications (like kidney damage) or fatality. Death is usually the result of a serious heart disease, infection or brain hemorrhage (bleeding in the brain).
Treatment depends on the type of cryoglobulin, presence of an underlying disease and severity of symptoms. Cryoglobulinemia is generally treated with a combination of medications that reduce inflammation and suppress the immune system. Patients are encouraged to avoid cold temperatures, which trigger symptoms.
Type I: Type I cryoglobulinemia, or simple cryoglobulinemia, is the result of a monoclonal (single) immunoglobulin, usually immunoglobulin M (IgM). This form is usually associated with lymphoproliferative diseases such as, Waldenstr©m macroglobulinemia, multiple myeloma or chronic lymphocytic leukemia.
Type I cryoglobulinemia may result in hyperviscosity (extremely thick blood) due to high levels of circulating monoclonal cryoglobulin. This can lead to physical obstruction of blood vessels.
and III: Types II and III, also known as the mixed cryoglobulinemias, involve cryoglobulin proteins which are a mixture of various antibody types that form for unknown reasons. The cryoglobulins contain rheumatoid factors (RFs). The RFs form complexes with the fragment, crystallizable portion of polyclonal (derived from multiple cells) immunoglobulin G (IgG). If the RF is monoclonal (derived from a single ancestral cell) it is considered Type II, and if the RF is polyclonal (derived from multiple cells), it is considered Type III.
Mixed cryoglobulinemias, including essential mixed cryoglobulinemia, make up about 80% of all cryoglobulinemia cases. They are associated with chronic inflammatory conditions like systemic lupus erythematosus (SLE), Sj©gren syndrome (autoimmune disorder in which immune cells attack and destroy the glands that produce tears and saliva) and viral infections (particularly Hepatitis C virus). In fact, more than 90% of cryoglobulinemic patients develop the condition as an immune response to chronic hepatitis C infection.
The cause of cryoglobulinemia is unknown. However, it is considered to be an autoimmune disorder. This disorder appears to be triggered by cold temperatures.
Cryoglobulinemia has been associated with many different diseases. Type I cryoglobulinemia is observed in lymphoproliferative disorders (like multiple myeloma or Waldenstr©m macroglobulinemia).
Types II and III cryoglobulinemias are commonly associated with chronic inflammatory diseases like chronic liver disease, infections (chronic hepatitis C virus) and coexistent connective-tissue diseases (like SLE, Sj©gren syndrome). Mixed cryoglobulinemia is rarely associated with lymphoproliferative disorders.
The prognosis of cryoglobulinemia depends on the presence or absence of underlying diseases. Kidney damage resulting from vasculitis can be serious, and recent reports show that permanent kidney failure occurs in about 10% of patients. Death may result from serious heart disease, infection or brain hemorrhage (bleeding in the brain).
Cryoglobulinemia primarily causes blood clots, stroke and vasculitis (inflamed blood vessels). Vasculitis of arteries can result in blocked arteries, which often leads to damage in the organs that receive blood from the affected blood vessels (like the skin or kidneys).
Since cryoglobulinemia makes the blood thicker, symptoms can arise throughout the body. Common symptoms include weakness, arthralgia (joint pain) purpura (bleeding under the skin that causes purple/red spots), Raynaud's phenomenon, fever, weight loss, hypertension (high blood pressure), numbness or tingling in the hands or feet, skin ulcers, gangrene and abdominal pain.
Mixed cryoglobulinemia involves more than one type of cryoglobulin. It is characterized by arthritis, splenomegaly (enlarged spleen), skin vasculitis, purpura (bleeding under the skin), as well as nerve and kidney disease. This can lead to recurrent pain in the abdomen, heart attack and bleeding in the lungs. Weight loss and decreased appetite may also occur. Mixed cryoglobulinemia is often associated with Hepatitis C virus.
After checking the patient's history and performing a physical exam, a blood or urine test may be conducted if cryoglobulinemia is suspected. During these procedures a sample of either blood or urine is analyzed under a microscope to detect the presence of abnormal immunoglobulins.
A blood test may be conducted to determine whether cold sensitivity antibodies are present. During the procedure a sample of blood that is between 15-20mL is taken. The serum (the liquid portion of the blood, where cryoglobulins are found) is then removed and placed in a cooler that is 1 degree Celsius for one to seven days. If clumping occurs, cryoglobulins are present. The amount of cryoglobulins is determined by the amount of clumping that occurs.
A skin biopsy may also be performed. During the procedure a small amount of skin is removed and analyzed in a laboratory to determine whether cryoglobulin deposits are present.
General: Treatment depends on the type of cryoglobulin, presence of an underlying disease and severity of symptoms. Cryoglobulinemia is generally treated with a combination of medications that reduce inflammation and suppress the immune system.
Antiviral therapy: If cryoglobulinemia is associated with Hepatitis C virus, the patient will be treated with antiviral medications like ribavirin (Virazole©).
: Corticosteroids like prednisone have been used to treat inflamed blood vessels associated with the various types of cryoglobulinemia.
: Some evidence suggests that interferon-alpha may help treat patients who have hepatitis C virus, especially if the disease is mild. Peginterferon alfa-2a (Pegasys©) has been used in combination with ribavirin to treat patients with chronic hepatitis C and have not received interferon-alpha before.
Immunosupressants: Immunosupressants like cyclophosphamide (Cytoxan© or Neosar©) or azathioprine (Imuran©) have been used to treat the various types of cryoglobulinemia.
Nonsteroidal anti-inflammatory drugs (NSAIDs): Nonsteroidal anti-inflammatory drugs (NSAIDs) like ibuprofen (Motrin© or Advil©) have been used to reduce inflammation in the blood vessels associated with the various types of cryoglobulinemia.
Plasmapheresis: Plasmapheresis has been used relieve symptoms associated with the various types of cryoglobulinemia. During the procedure, whole blood is removed from the body, and the plasma (which contains antibodies) is separated from the cells. The cells are then suspended in saline, a plasma substitute or donated plasma. The reconstituted solution is then returned to the patient.
: Currently, there is insufficient evidence on the use of integrative therapies for cryoglobulinemia.
The integrative therapies listed below have been investigated for use in autoimmune disorders, immune suppression, hepatitis, and viral infections in general, should be used only under the supervision of a qualified healthcare provider, and should not be used in replacement of other proven therapies or preventive measures.
Unclear or conflicting scientific evidence
: Limited available evidence suggests that alizarin may be of benefit in the treatment of viral infections. Additional research is needed in this area.
Avoid if allergic or hypersensitive to alizarin or any plants in the Rubiaceae family. Alizarin may be toxic and should not be handled for long periods of time, rubbed in the eyes, or eaten. Avoid if pregnant or breastfeeding.
: Ayurveda is an integrated system of specific theories and techniques employing diet, herbs, exercise, meditation, yoga and massage or bodywork. Clinical evidence suggests that the traditional herbal preparation Kamalahar may reduce clinical signs as well as indicators of liver damage in acute viral hepatitis. Kamalahar contains Tecoma undulate, Phyllanthus urinaria, Embelia ribes, Taraxacum officinale, Nyctanthes arbortistis, and Terminalia arjuna.
The root powder from the herb Picrorhiza kurroa has also been shown to improve levels of bilirubin, SGOT (serum glutamic-oxaloacetic transaminase) and serum glutamic pyruvic transaminase (SGPT) in viral hepatitis. Further research is needed before a firm conclusion can be made.
Ayurvedic herbs should be used cautiously because they are potent and some constituents can be potentially toxic if taken in large amounts or for a long time. Some herbs imported from India have been reported to contain high levels of toxic metals. Ayurvedic herbs can interact with other herbs, foods and drugs. A qualified healthcare professional should be consulted before taking.
: Beta-sitosterol and beta-sitosterol glucoside have been studied for immune suppression. Larger populations of patients should be evaluated in high quality clinical studies for conclusions to be made.
Avoid if allergic or hypersensitive to beta-sitosterol, beta-sitosterol glucoside or pine. Use cautiously with asthma or breathing disorders, diabetes, primary biliary cirrhosis (destruction of the small bile duct in the liver), ileostomy, neurodegenerative disorders (like Parkinsonism or Alzheimer's disease), diverticular disease (bulging of the colon), short bowel syndrome, celiac disease, and sitosterolemia. Use cautiously with a history of gallstones. Avoid if pregnant or breastfeeding.
: Biotin is an essential water-soluble B vitamin. Antioxidant therapy with biotin, vitamins A-E, selenium, zinc, manganese, copper, magnesium, folic acid, and coenzyme Q10 was not shown to improve survival rates for hepatitis. More research with biotin alone is needed. Avoid if hypersensitive to constituents of biotin supplements.
: Human research of blessed thistle as a treatment for viral infections is currently lacking. Further evidence is necessary in this area before a firm conclusion can be drawn.
Blessed thistle is generally considered to be safe when taken by mouth in recommended doses for short periods of time, with few reported side effects such as birth defects, bleeding, breathing problems, bruising, cancer of the nose or throat, increased production of stomach acid, itching, kidney disease, liver toxicity, skin rash, stomach discomfort, stomach ulcers, and vomiting. Allergic reactions to blessed thistle including rash may occur, as well as cross-sensitivity to mugwort and Echinacea. Cross-reactivity may also occur with bitter weed, blanket flower, Chrysanthemum, coltsfoot, daisy, dandelion, dwarf sunflower, goldenrod, marigold, prairie sage, ragweed or other plants in the Asteraceae/Compositae family. Avoid if pregnant or breastfeeding.
: For more than 2,000 years bupleurum has been used in Asia to treat hepatitis, cirrhosis and other conditions associated with inflammation. A high-quality clinical trial and several small recent clinical reports suggest that bupleurum and/or an herbal combination formula containing bupleurum may be helpful in the treatment of chronic hepatitis. However, studies to date are small and not all well controlled. Further research is warranted to determine whether bupleurum can effectively treat hepatitis.
Avoid if allergic or hypersensitive to bupleurum, Apiaceae or Umbelliferae (carrot) families, snakeroot, cow parsnip, or poison hemlock. Use cautiously if operating motor vehicles or hazardous machinery. Use cautiously with low blood pressure, diabetes, or edema. Use cautiously with a history of bleeding, hemostatic disorders, or drug-related hemostatic disorders. Use cautiously if taking blood thinners. Avoid if pregnant or breastfeeding.
: Studies have assessed the use of choline for acute viral hepatitis, many of which have been poorly designed. There is currently insufficient evidence available to determine whether choline can effectively treat hepatitis.
Avoid if allergic/hypersensitive to choline, lecithin, or phosphatidylcholine. Use cautiously with kidney or liver disorders or trimethylaminuria. Use cautiously with a history of depression. If pregnant or breastfeeding it seems generally safe to consume choline within the recommended adequate intake (AI) parameters; supplementation outside of dietary intake is usually not necessary if a healthy diet is consumed.
: Chromium, in combination with copper, may have potential suppressive effects on immune function. Further research is needed to better understand the role of chromium in immune suppression.
Trivalent chromium appears to be safe because side effects are rare or uncommon. However, hexavalent chromium may be poisonous (toxic). Avoid if allergic to chromium, chromate, or leather. Use cautiously with diabetes, liver problems, weakened immune systems (such as HIV/AIDS patients or organ transplant recipients), depression, Parkinson's disease, heart disease, and stroke and in patients who are taking medications for these conditions. Use cautiously if driving or operating machinery. Use cautiously if pregnant or breastfeeding.
: Studies using combination herbal treatments that included cordyceps indicate that these combinations suppressed the immune system in kidney transplant and lupus nephritis patients. However, as these treatments used combination products, the effect of cordyceps cannot be defined. More studies are needed to better determine the safety and effectiveness of cordyceps for immune suppression.
Avoid if allergic or hypersensitive to cordyceps, mold, or fungi. Use cautiously with diabetes, bleeding disorders, if taking anticoagulant medications, with prostate conditions, if taking immunosuppressive medications, or if on hormonal replacement therapy or oral contraceptives. Avoid with myelogenous-type cancers. Avoid if pregnant or breastfeeding.
: Limited laboratory research has examined the antiviral activity of cranberry. Further research is warranted in this area.
Avoid if allergic to cranberries, blueberries, or other plants of the Vaccinium species. Sweetened cranberry juice may affect blood sugar levels. Use cautiously with a history of kidney stones. Pregnant and breastfeeding women should avoid cranberry in higher amounts than what is typically found in foods.
: The licorice extracts DGL and carbenoxolone have been proposed as possible therapies for viral hepatitis. Further research is needed before a firm conclusion can be made.
Avoid with a known allergy to licorice, any component of licorice, or any member of the Fabaceae (Leguminosae) plant family. Avoid with congestive heart failure, coronary heart disease, kidney or liver disease, fluid retention, high blood pressure, hormonal abnormalities or if taking diuretics. Licorice can cause abnormally low testosterone levels in men or high prolactin or estrogen levels in women. This may make it difficult to become pregnant and may cause menstrual abnormalities.
: Milk thistle (Silybum marianum) has been used medicinally for over 2,000 years, most commonly for the treatment of liver and gallbladder disorders. Research on milk thistle for acute viral hepatitis has not provided clear results, and milk thistle cannot be recommended for this potentially life-threatening condition at this time.
Caution is advised when taking milk thistle supplements, as numerous adverse effects including an increased risk of bleeding and drug interactions are possible. Milk thistle should not be used during pregnancy or breastfeeding unless otherwise directed by a doctor.
: In preliminary research, some patients achieved complete elimination of the hepatitis virus after treatment with Viscum album, although these studies were not well designed. A small exploratory trial investigated effects of mistletoe on liver function, reduction of viral load and inflammation, and maintaining quality of life by the immunomodulatory and/or cytotoxic actions of mistletoe extracts, but little effect was seen. Larger, well-designed clinical trials are needed to resolve this conflicting data.
Avoid if allergic to plants in the aster family (Compositea, Asteraceae), daisies, artichoke, common thistle, or kiwi. Use cautiously with diabetes. Avoid if pregnant or breastfeeding.
: Early studies have been conducted on rhubarb and its effects on hepatitis. Additional, high-quality clinical studies are needed to establish rhubarb's effects.
Avoid if allergic/hypersensitive to rhubarb, its constituents, or related plants from the Polygonaceae family. Avoid using rhubarb for more than two weeks because it may induce tolerance in the colon, melanosis coli, laxative dependence, pathological alterations to the colonic smooth muscles, and substantial loss of electrolytes. Avoid with atony, colitis, Crohn's disease, dehydration with electrolyte depletion, diarrhea, hemorrhoids, insufficient liver function, intestinal obstruction or ileus, irritable bowel syndrome, menstruation, pre-eclampsia, renal disorders, ulcerative colitis, and urinary problems. Avoid handling rhubarb leaves, as they may cause contact dermatitis. Avoid rhubarb in children under age 12 due to water depletion. Use cautiously with bleeding disorders, cardiac conditions, coagulation therapy, constipation, history of kidney stones, or thin or brittle bones. Use cautiously if taking anti-psychotic drugs or oral drugs, herbs or supplements (including calcium, iron, and zinc). Avoid if pregnant or breastfeeding.
: There is currently not enough evidence on the proposed antiviral effects of sorrel. More research is needed.
Avoid large doses of sorrel because there have been reports of toxicity and death. This may be because of the oxalate found in sorrel. Many sorrel tinctures contain high levels of alcohol and should be avoided when driving or operating heavy machinery. These sorrel formulations may cause nausea or vomiting when taken with the prescription drugs metronidazole (Flagyl©) or disulfiram (Antabuse©). Avoid if pregnant or breastfeeding.
: Turmeric is a perennial plant native to India and Indonesia, and it is often used as a spice in cooking. Based on early research, turmeric may help treat various viral infections. However, reliable human studies are lacking in this area.
Well-designed trials are needed.
Avoid if allergic or hypersensitive to turmeric (curcumin), yellow food colorings, or plants belonging to the Curcuma or Zingiberaceae (ginger) families. Use cautiously with a history of bleeding disorders, immune system deficiencies, liver disease, or gallstones. Use cautiously with blood thinners (e.g. warfarin). Use cautiously if pregnant or breastfeeding.
: In patients with hepatitis on antiviral therapy, vitamin E has been proposed to prevent inflammation. More studies are needed. Avoid if allergic or hypersensitive to vitamin E. Avoid with retinitis pigmentosa (loss of peripheral vision). Use cautiously with bleeding disorders or if taking blood thinners. Avoid above the recommended daily level in pregnant and breastfeeding women.
: Studies have shown that zinc, in combination with interferon or interferon and ribavirin for chronic hepatitis C viral infection, did not show significant benefits except for lower incidence of gastrointestinal side effects. Further study may be warranted.
Zinc is generally considered safe when taken at the recommended dosages. Avoid zinc chloride since studies have not been done on its safety or effectiveness. While zinc appears safe during pregnancy in amounts lower than the established upper intake level, caution should be used since studies cannot rule out the possibility of harm to the fetus.
Fair negative scientific evidence
: Despite findings indicating potential hepatoprotective properties of spirulina, preliminary human study of spirulina for chronic viral hepatitis shows negative results. Additional high quality study is needed to confirm these findings.
Avoid if allergic or hypersensitive to spirulina or blue-green algae. Use cautiously with phenylketonuria (a genetic disorder of a liver enzyme that disrupts normal body functions), autoimmune diseases, bleeding disorders, diabetes, and osteoporosis. Use cautiously with products containing the blue-green algae species Anabaena spp., Aphanizomenon spp., and Microcystis spp.; in underweight patients or in those taking antiobesity agents or appetite suppressants; and if consuming a high-protein diet. Avoid in children and if pregnant or breastfeeding.
Traditional or theoretical uses lacking sufficient evidence
: Adrenal extracts come from the adrenal glands of cows, pigs, or sheep. The adrenal glands are above the kidneys. Until human studies are performed, it remains unknown if adrenal extract is beneficial for autoimmune disorders.
Avoid if allergic to adrenal extract. Since adrenal extracts come from cow, pig, or sheep adrenal glands, there is concern about contamination with diseased animal parts. Avoid with immune deficiencies (such as HIV/AIDS) because adrenal extracts may increase the risk of infection. Avoid in countries where mad cow disease has been found. Avoid if pregnant or breastfeeding.
: Astaxanthin is classified as a xanthophyll, which is a carotenoid pigment that can be found in microalgae, yeast, salmon, trout, krill, shrimp, crayfish, crustaceans, and the feathers of some birds. Astaxanthin has been suggested as a possible treatment for autoimmune diseases, but human studies are currently lacking.
Avoid if allergic to astaxanthin or related carotenoids, including canthaxanthin. Use cautiously if taking 5-alpha-reductase inhibitors, drugs that affect blood pressure, asthma medications, drugs that are broken down by the liver's cytochrome P450 system, menopausal agents, birth control pills, or Helicobacter pylori agents. Use cautiously with high blood pressure, parathyroid disorders, or osteoporosis. Avoid with hormone-sensitive conditions, immune disorders or if taking immunosuppressive therapies. Avoid if low esosinophil levels or if visual changes have occurred while taking astaxanthin. Avoid if pregnant or breastfeeding.
: The root extract of coleus is known as forskolin. Although coleus has been suggested as a possible treatment for autoimmune diseases, research is lacking in this area.
Coleus is generally considered safe, as very few side effects have been reported. However, only a few short-term trials have assessed its safety in a small sample size of patients. Avoid if allergic to Coleus forskohlii or related species. Avoid with active bleeding. Use cautiously with a history of bleeding, blood disorders, drug-related hemostatic problems, asthma, diabetes, thyroid disorders, or heart disease. Use cautiously if taking anticoagulant, anti-thrombotic, and/or antiplatelet medications. Stop taking coleus at least two weeks before and immediately after surgical, dental, or diagnostic procedures that have bleeding risks. Avoid if pregnant or breastfeeding.
Omega-3 fatty acids
: Fish oil appears to play a potential role in the treatment of inflammatory disorders by inhibiting arachidonic acid metabolism. Fish oil has been studied for its role in immune suppression, however research is preliminary.
Early clinical study evaluated the therapeutic efficacy of fish oil on mixed cryoglobulinemia. Researchers noted some improvement in the serological parameters potentially involved in the pathogenesis of the disorder. Further research is necessary before a firm conclusion can be made.
Avoid if allergic or hypersensitive to fish, omega-3 fatty acid products that come from fish, nuts, linolenic acid, or omega-3 fatty acid products that come from nuts. Avoid during active bleeding. Use cautiously with bleeding disorders, diabetes, low blood pressure, or with drugs, herbs, or supplements that treat any such conditions. Use cautiously before surgery. Pregnant and breastfeeding women should not consume doses that exceed the recommended dietary allowance (RDA).
: Thymus extracts for nutritional supplements are usually derived from young calves (bovine). Preclinical research suggests that thymus extract may be beneficial for patients with autoimmune disorders. Conclusions cannot be made until human studies are performed.
Avoid if allergic to thymus extracts. Use bovine thymus extract supplements cautiously due to potential for exposure to the virus that causes "mad cow disease." Avoid use with an organ transplant or other forms of allografts or xenografts. Avoid with thymic tumors, myasthenia gravis (neuromuscular disorder), or untreated hypothyroidism. Avoid if taking immunosuppressants or hormonal therapy. Avoid if pregnant or breastfeeding; thymic extract increases human sperm motility and progression.
Since the exact cause of cryoglobulinemia is remains unknown there currently is no known method of prevention. Cryoglobulinemia is associated with many diseases, especially hepatitis C. Therefore, treating conditions that are associated with cryoglobulinemia quickly may help prevent the disorder.
Avoid cold temperatures to prevent the precipitation of cryoglobulins.
This information has been edited and peer-reviewed by contributors to the Natural Standard Research Collaboration (www.naturalstandard.com).
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- Roane D; Griger D. An Approach to Diagnosis and Initial Management of Systemic Vasculitis. American Academy of Family Physicians. 1999. www.aafp.org. Accessed May 12, 2009.
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