Department Editor: Tania Phillips, MD, FRCPC
Overall Learning Objective: The physician or podiatrist participant will develop a rational approach to the evaluation and treatment of a variety of uncommon wounds and will have an increased awareness of the differential diagnosis of cutaneous wounds and the systemic diseases associated with these wounds.
Submissions: To submit a case for consideration in Diagnostic Dilemmas, e-mail or write to: Executive Editor, WOUNDS, 83 General Warren Blvd., Suite 100, Malvern, PA 19355, email@example.com 
Completion Time: The estimated time to completion for this activity is 1 hour.
Target Audience: This CME/CPME activity is intended for dermatologists, surgeons, podiatrists, internists, and other physicians who treat wounds.
At the conclusion of this activity, the participant should be able to:
1. Describe a presentation of cryoglobulinemia
2. Diagnose cryoglobulinemia
3. Discuss pathogenesis of cryoglobulinemia
4. Describe and discuss management of cryoglobulinemia.
Disclosure: All faculty participating in Continuing Medical Education programs sponsored by HMP Communications, LLC, are expected to disclose to the program audience any real or apparent conflict(s) of interest related to the content of their presentation. Drs. Lin and Phillips disclose no financial conflicts.
Accreditation: HMP Communications, LLC, is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. HMP Communications, LLC, is approved by the Council on Podiatric Medical Education as a sponsor of continuing education in podiatric medicine.
Designation: HMP Communications, LLC, designates this continuing medical education activity for 1 credit hour in Category 1 of the Physician’s Recognition Award of the American Medical Association. Each physician should claim only those hours he/she spent in the educational activity. HMP Communications designates this continuing medical activity for .1 CEUs available to participating podiatrists.
Method of Participation: Read the article, take, submit, and pass post-test by March 1, 2003.
This activity has been planned and produced in accordance with the ACCME Essential Areas and Policies.
Release date: March 1, 2002
Expiration date: March 1, 2003
A 50-year-old Caucasian man with Raynaud’s phenomenon and numbness and tingling in his toes complained of purpuric lesions. The lesions began on his bilateral lower extremities approximately six years previously when he was diagnosed with Hepatitis C. An ulcer developed on his dorso-lateral foot approximately five months prior to presentation, which began as a small erosion. He complained of intermittent joint pain of his shoulders.
His past medical history includes gastroesophageal reflux disease and precirrhotic liver changes. Medications include interferon, prednisone, cyclophosphamide, cisapride, oxycodone hydrochloride/acetaminophen, and levofloxacin.
Physical exam revealed multiple, reddish-brown, 1–3mm macules extending from the thighs down to the toes. There was pitting edema of the left lower extremity, particularly of the left foot (Figure 1). A large, deep ulcer with a necrotic base, measuring 4.5cm x 4.5cm, was present on the lateral aspect of the left foot. Tendons were visible. The ulcer was covered with thick yellow exudate as well as a hemorrhagic crust (Figure 2). There was an erythematous border around the ulcer and it was exquisitively painful, most likely from infection (Figure 3).
Hepatitis C was positive, rheumatoid factor was elevated (148, normal is < 14 IU/mL), and serum cryoglobulin was two percent. His AST was normal and ALT was slightly elevated (ALT = 44, normal value is between 5–40U/L). Erythrocyte sedimentation rate was normal (13, normal 0–20mm/hr). Complements were low (C3 = 62, normal 90–180mg/dL; C4 = 3, normal 10–40mg/dL). His wound culture grew Pseudomonas aeruginosa and coagulase negative staphylococcal species. Plain film was negative for osteomyelitis.
Skin biopsy of the purpuric lesion revealed numerous extravasated red blood cells, subtle nuclear debris, fibrosis, two intravascular thrombi, and no active vasculitis. Biopsy of the ulcer revealed neutrophils at the edge of the ulcer but no frank vasculitis and no hyaline thrombi.
Our patient has a foot ulcer likely secondary to type II cryoglobulinemia. Infectious disease, usually hepatitis C, is the etiologic agent of type II cryoglobulinemia in most cases (80–90%).1
Cryoglobulins are immunoglobulins that precipitate from serum at temperatures below 37?C.2,3 Normally, cryoglobulins are cleared from the body by hepatic receptors. They accumulate when a diseased liver fails to remove them or when they are over produced in disease states. The level of cryoglobulinemia does not always correlate with the level of symptomatology, although some report that palpable purpura is more likely in hepatitis C antibody-positive patients with higher cryocrit levels.4
Three types of cryoglobulins have been identified (Table 1).2,5 We will focus our discussion on type II cryoglobulinemia, the most frequent variant and the type involved in this case.
Type I cryoglobulinemia. Type I cryoglobulinemia is the least common type2 and is composed of a single monoclonal immunoglobulin (IgM, IgG, IgA, or Bence Jones protein) without rheumatoid factor activity. Type I is associated with malignancies of the immune system.
Clinically, infarcted and hemorrhagic crusts and ulcers are more frequent in type I than in types II and III cryoglobulinemia.2 Cutaneous lesions of the head or neck or petechial, purpuric, or ulcerated/infarcted lesions of the lip, buccal mucosa, or palate are also more common in type I than in the other types of cryoglobulinemia.2
Mixed cryoglobulinemias types II and III. The mixed cryoglobulinemias have several immunoglobulins with (type II) or without (type III) a monoclonal component. Both have anti-IgG activity.6 Mixed cryoglobulinemia type II consists of a mix of IgM and IgG proteins that resemble classic rheumatoid factor.7 Therefore, mixed type II is associated with elevated rheumatoid factor.
Mixed cryoglobulinemia is associated with autoimmune diseases and chronic inflammatory, immunoproliferative, and infectious diseases. Renal and neurologic involvement is more frequent in types II and III than in type I.5 If no other disease is present, the cryoglobulin is termed “essential mixed cryoglobulinemia.” Essential mixed cryoglobulinemia frequently has concomitant chronic liver disease.8 Thus far, all cases of type II cryoglobulinemia have been associated with hepatitis C virus9 and there has been increasing evidence suggesting many of the past cases of “essential” cryoglobulinemia associated with chronic liver disease are actually due to the hepatitis C infection.1,3,10 Interestingly, hepatitis B is involved only in a small number of cryoglobulinemia cases.7
Epidemiology. The mean age at diagnosis of cryoglobulinemia is 47 years (range is 34–66 years).2,12 In one study, men were affected 2:1.11
Etiology. Several findings, including hepatitis C virus RNA sequences, have contributed to the belief that hepatitis C is the etiologic agent for mixed cryoglobulinemia and that the virus very likely has a role in the pathogenesis of the vasculitis. In addition, hepatitis C antibodies have been discovered in the sera and cryoprecipitates.10 Also, hepatitis C has been found associated with the IgM or the IgG in the cutaneous vasculitis lesions of some patients.10 Origin of the rheumatoid factor is unclear, but there is speculation that the chronic hepatitis C infection in a subject with a predisposition to an abnormal immune response may induce production of rheumatoid factor and cryoglobulins.8
Pathogenesis. In type I cryoglobulinemia, there is a direct obstruction of vessels, in contrast to types II and type III, which cause a systemic vasculitis secondary to inflammation of the vessel walls induced by the deposition of IgM-IgG complexes and activation of complement. It remains to be elucidated whether the cryoglobulins, other circulatory factors, or local vascular alterations initiate the immunoreactant deposition.2
Histopathology. Type I. Amorphous, precipitated cryoglobulin is deposited subjacent to endothelium and throughout the vessel wall and within the vessel lumen. A thrombus-like appearance results. Precipitates stain pink with hematoxylin and eosin and light red with PAS stain. There is usually no inflammatory component.
Type II and type III. Typically, leukoclastic vasculitis occurs with fibrinoid necrosis and thickening of the vessel wall and inflammatory infiltrate consisting of neutrophils as well as destruction of neutrophils, nuclear dust, and neutrophilic debris. Intramural and intravascular cryoprecipitate (PAS positive) may be found (occurs less frequently than in type I).
Laboratory features. In addition to elevated serum cryocrit and evidence of liver pathology, type II cryoglobulinemia usually shows elevated erythrocyte sedimentation rate, hypergammaglobulinemia, high rheumatoid factor titer, and a decreased serum complement.13
Clinical features. The most common reported manifestations of disease are cutaneous involvement, articular involvement, and peripheral neuropathy.3,11,14 Renal involvement also occurs frequently. Other symptoms include fever, weakness, lymphadenopathy, central nervous system, and pulmonary involvement at the onset. The most frequent cutaneous feature is palpable purpura.3,10,11 Other cutaneous manifestations of disease include Raynaud’s phenomenon,11,15 skin rash, supramalleolar ulcers, distal ischemia, gangrenous changes, livedo reticularis, and acrocyanosis. Type II is more likely to present with lower extremitiy lesions.11 Types I and III are more likely to show truncal and upper extremity lesions (type I > type III > type II).2 Duration of the cutaneous lesions ranges anywhere from days to 15 years.11
Systemic manifestations of the vasculitis of type II cryoglobulinemia may include renal involvement that ranges from proteinuria to renal failure. Peripheral neuropathy can include mixed neuropathy or purely sensory neuropathy. Central nervous system involvement includes cerebral ischemia, spinal cord involvement, and cranial nerve involvement.6 In one study, the appearance of clinical manifestations attributable to cryoglobulins was associated with higher cryocrit levels, concomitant underlying autoimmune disease, and presence of immunologic markers, such as hypocomplementemia, rheumatoid factor, and ANA.6
Management. Management involves treatment of underlying disease and may include immunosuppression (prednisone and/or other cytotoxic agents, such as chemotherapy), interferon alfa (for hepatitis), and plasmapheresis (for progressive systemic involvement of vasculitis). Results of several studies suggest that treating the hepatitis C infection helps to eradicate the hepatitis C-associated cryoglobulinemia. Therefore, high doses of interferon alfa for longer treatment periods and antiviral drugs may be beneficial.1,12,13,16–19 Prognosis is poorer when renal involvement has occurred.12,20
Because of the intense pain, infection of the ulcer was suspected (Figure 4), and the patient was prescribed amoxicillin-clavulanic acid twice a day (BID) in addition to his levofloxacin with improvement of his symptoms. The patient underwent a therapy course of plasmapheresis, which did not reduce the level of the cryocrit. He received pegylated interferon and ribavirin, with continuing enlarging of his ulcers. He also tried cyclophosphamide unsuccessfully. He is currently on cyclosporine, which seems to halt the enlargement of his ulcers. The patient may possibly be a candidate for a skin graft in the future.
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1. Of the three types of cryoglobulinemia, which is the most common?
A) Type I
B) Type II
C) Type III
D) Types I and II
E) Types II and III
2. The most common presentation of cryoglobulinemia is which of the following?:
A) Palpable purpura
D) Macular hyperpigmentation
E) Renal failure
3. Which of the following statements are true?:
A) Cryoglobulins are immunoglobulins that precipitate from serum at temperatures below 37?C.
B) Cryoglobulins accumulate when a diseased liver fails to remove them or when they are over produced in disease states.
C) The level of cryoglobulinemia does not always correlate with the level of symptomatology.
D) Type I consists of monoclonal IgG or IgM reacting against another monoclonal immunoglobulin, usually IgG. Type II cryoglobulins most commonly consist of a monoclonal IgM and a polyclonal IgG, and they are associated with multiple myeloma, CLL, rheumatoid arthritis, and Sjogren’s syndrome. Type III cryoglobulins are polyclonal and are associated with SLE, rheumatoid arthritis, Sjogren’s syndrome, mononucleosis, cytomegalovirus, and biliary cirrhosis.
E) All of the above
4. Type I cryoglobulinemia:
A) Often presents clinically with purpura
B) Pathology reveals a leukocytoclastic vasculitis
C) May occur in association with autoimmune diseases, such as SLE, rheumatoid arthritis, Sjogren’s syndrome, or in association with the hematologic malignancies
D) Cryoglobulins are circulating immune complexes
E) Causes activation of the complement cascade and an occlusive phenomenon in the vasculature
F) Most likely to manifest with head and neck lesions, as well as oral and nasal mucosal lesions
5. Type II cryoglobulinemia:
A) Usually manifests with acral necrotic plaques
B) Histologically shows dense intravascular eosinophilic deposits with a thrombus-like appearance. There is usually no inflammatory component.
C) May be associated with hepatitis B and more commonly with hepatitis C
D) Is seen in patients with multiple myeloma, Waldenstrom’s macroglobulinemia, lymphoma, and lymphocytic leukemia
E) Consists of monoclonal IgG or IgM reacting against another monoclonal immunoglobulin, usually IgG
6. Cryoglobulinemic vasculitis affects:
D) Musculoskeletal system
E) Nervous system
F) All of the above
7. Management includes all of the following except:
A) Treating the underlying disease
C) Immunosuppression (prednisone and/or other cytotoxic agents, such as chemotherapy)
D) Interferon alfa (for hepatitis)
E) Plasmapheresis (for progressive systemic involvement of vasculitis)
F) Local wound care
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1. Describe a presentation of cryoglobulinemia? YES NO
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References 1. Agnello V, Chung RT, Kaplan LM. A role for hepatitis C virus infection in type II cryoglobulinemia. N Engl J Med 1992;327:1490–5. 2. Cohen SJ, Pittelkow MR, Su WPD. Cutaneous manifestations of cryoglobulinemia: Clinical and histopathologic study of seventy-two patients. J Am Acad Dermatol 1991;25:21–7. 3. Trejo O, Ramos-Casals M, Garcia-Carrasco M, et al. Cryoglobulinemia: A study of etiologic factors and clinical and immunologic features in 443 patients from a single center. Medicine 2001;80(4):252–62. 4. Dupin N, Chosidow O, Lunel F, et al. Essential mixed cryoglobulinemia. Arch Dermatol 1995;131:1124–7. 5. Brouet JC, Clauvel JP, Danon F, et al. Biological and clinical significance of cryoglobulins. Am J Med 1974;57:775–88. 6. Karlsberg PL, Lee WM, Casey DL, et al. Cutaneous vasculitis and rheumatoid factor positivity as presenting signs of hepatitis C virus-induced mixed cryoglobulinemia. Arch Dermatol 1995;131:1119–23. 7. Meltzer M, Franklin EC, Elias K, et al. Cryoglobulinemia: A clinical and laboratory study. Am J Med 1966;40:837–56. 8. Marcellin P, Descamps, Martinot-Peignoux M, et al. Cryoglobulinemia with vasculitis associated with hepatitis virus infection. Gastroenterology 1993;104:272–7. 9. Burke E, Humphrey RL, Horn TD. Nonhealing ulcers on the lower extremities. Arch Dermatol 1997;133(7):909–14. 10. Doutre M. Hepatitis C Virus-related skin diseases. Arch Dermatol 1999;135:1401–3. 11. Daoud MS, el-Azhary RA, Gibson LE, et al. Chronic hepatitis C, cryoglobulinemia, and cutaneous necrotizing vasculitis. J Am Acad Dermatol 1996;34:219–23. 12. Gumber SC, Chopra S. Hepatitis C: A multifaceted disease: Review of extrahepatic manifestation. Ann Int Med 1995;123(8):615–20. 13. Rallis TM, Kadunce DP, Gerwels JW. Leg ulcers and purple nail beds. Arch Dermatol 1995;131(3):341–6. 14. Misiani R, Bellavita P, Fenili D, et al. Interferon Alfa-2a therapy in cryoglobulinemia associated with hepatitis C virus. N Engl J Med 1994;330(11):751–6. 15. Cooley JE, Papadimitriou, Kauffman CL. Hepatitis C- associated cryglobulinemia. Cutis 1995;56:324–8. 16. Pawlotsky J-M, Dhumeaux D, Bagot M. Hepatitis C virus in dermatology. Arch Dermatol 1995;131:1185–93. 17. Levey JM, Bjornsson B, Banner B, et al. Mixed cryoglobulinemia in chronic hepatitis C infection. Medicine 1994;73(1):53–67. 18. Davis GL, Balart LA, Schiff ER, et al. Treatment of chronic hepatitis C with recombinant interferon alfa. N Engl J Med 1989;321(22):1502–5. 19. Smith JB, Shenefelt PD, Soto O, Valeriano J. Pyoderma gangrenosum in a patient with cryoglobulinemia and hepatitis C successfully treated with interferon alpha. J Am Acad Dermatol 1996;34(5 Pt 2):901–3. 20. Gorevic PD, Kassab HJ, Levo Y, et al. Mixed cryoglobulinemia: Clinical aspects and long-term follow-up of 40 patients. Am J Med 1980;69:287–303.