Clues to Cryoglobulinemia: A Four-Part Quiz


Rheumatologists can play a key role in management of the many subtypes of cryoglobulinemia by recognizing the chief symptoms. Challenge your knowledge in this brief quiz, then read a review by experts.

[[{"type":"media","view_mode":"media_crop","fid":"27786","attributes":{"alt":"","class":"media-image media-image-right","height":"142","id":"media_crop_9250487092030","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"2757","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"margin: 3px; float: right;","title":" ","typeof":"foaf:Image","width":"131"}}]]Despite its "complicated etiologic, clinical, and pathologic scenario," if you can quickly recognize the most common clinical presentations of cryoglobulinemia you can play a key role in successful management, write Harvard rheumatologist John H. Stone MD MPH and his coauthors in their recent review of the condition.

Diagnosis of cryoglobulinemia, which is characterized by the precipitation of immunoglobulins in vitro at temperatures below 37° C, requires detecting these cryoglobulins in serum. Given the crucial involvement of temperature, correct handling of the sample is imperative. But recognizing the clinical red flags is an essential first step.

On the next few pages, you can test yourself on some of the key signs of cryoglublinemic disease, and continue to read the entire review after completing the quiz.

Start the quiz by clicking here.[[{"type":"media","view_mode":"media_crop","fid":"27787","attributes":{"alt":"Type 1 cryoglobulinemia","class":"media-image media-image-right","height":"217","id":"media_crop_1385617146243","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"2747","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"margin: 3px; float: right;","title":" ","typeof":"foaf:Image","width":"189"}}]]Question 1. Type 1 (monoclonal) cryoglobulinemia is caused by a pathogenic expansion of a single B-cell clone, mainly IgG or IgM, that damages tissue by causing occlusion of blood vessels, leading to ischemia. At right, you see the foot of a patient with this type of cryoglobulinemia, showing some of its classic cutaneous signs, which include purpura, skin necrosis and ulcers, and livedo reticularis. (Click on the image to enlarge it.)

Which of the following noncutaneous features are principal characteristics of this type of cryoglobulinemia?

a.  peripheral neuropathy
b.  gastric ulcers  
c.  glomerulonephritis
d.  headache and confusion
e.  dyspnea
f.   multiple myeloma
g.  epistaxis
h.  cardiac hypertrophy

Click here for the answer.

Correct answer:  b and h. Neither gastric ulcers nor cardiac hypertrophy are characteristic of Type 1 cryoglobulinemia. A few case reports mention gastric ulcers. Myocardial involvement is infrequent.

Peripheral neuropathy, headache and confusion, and epistaxis are all characteristic of hyperviscosity syndrome in cryoglobulinemia, as discussed in the next question.

Continue with the quiz.

Question 2.  Hyperviscosity syndrome, particularly common among type 1 cryoglobulinemia patients who have either multiple myeloma or Waldenström macroglobulinemia, typically involves the brain, eyes, and ears. The chief symptoms are headache and confusion, blurred vision or vision loss, and hearing loss or epistaxis.

Which of the following is not true?

a.  For patients with symptomatic hyperviscosity who have very high measures of serum viscosity, corticosteroids are the preferred immediate course of treatment.
b.  Most signs and symptoms are reversible with prompt diagnosis and treatment.
c.  Response to therapy is higher and relapses are less common in patients with hematologic neoplasia than in those with monoclonal gammopathy of unknown significance (MGUS).
d.  The main therapeutic goal is to rid the body of the cancer, rather than merely clearing the crystals that cause the hyperviscosity.

Click here for the answer.

Correct answer:  Choice a. is false.

Plasma exchange and plasmapheresis, which directly remove circulating cryoglobulins from the circulation, are the most useful approaches in these urgent cases.

Go to the next question.

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Question 3. Types II and III (mixed cryoglobulinemia) may be associated with autoimmune disease, cancer, or infections, particularly hepatitis C.

The most common initial presentation of infectious mixed cryogloublinemia is the triad of purpura, arthralgia (affecting the hands, knees, and wrists), and weakness. Vasculitic flares may also be accompanied by myalgia and fever.

Mixed cryoglobulinemia can also cause digital ischemia, manifested dramatically in the image at right. (Click on the image to enlarge it.)

Which of the following internal organs is most commonly affected in this infectious subtype?

a. Lungs
b. Liver
c. Heart
d. Kidneys  
e. Intestines

Click here for the answer.[[{"type":"media","view_mode":"media_crop","fid":"27802","attributes":{"alt":"cryoglobulinemia","class":"media-image media-image-right","height":"116","id":"media_crop_1208224712012","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"2755","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"margin: 3px; float: right;","title":" ","typeof":"foaf:Image","width":"132"}}]]Correct answer:  The internal organs affected most frequently are the kidneys (in about 30% of patients). Kidney biopsy typically shows membranoproliferative glomerulonephritis, which is indolent in about half of cases. Nephrotic and nephritic syndrome are less frequent.

The gastrointestinal system and the lungs are seldom involved in mixed cryoglobulinemia (fewer than 5% of patients).

Ischemic heart disease has been reported, but very rarely. These cases were due to coronary vasculitis in the absence of standard cardiovascular risk factors.

Go to the next question.

Question 4.  Non-infectious mixed cryoglobulinemia is associated mainly with systemic autoimmune and lymphoproliferative diseases, although in nearly half of cases an underlying explanation is never found.

Which of the following systemic autoimmune conditions is (1) most commonly associated with this comorbidity, and which is (2) not commonly associated with mixed cryoglobulinemia?

a.  systemic lupus erythematosus
b.  primary Sjögren syndrome
c.  gout
d.  rheumatoid arthritis

Click here for the answers.

Correct answers:

(1) b. Primary Sjõgren syndrome is the autoimmune disorder most commonly associated with mixed cryoglobulinemia. It also develops in patients with lupus and rheumatoid arthritis.

(2) c. Gout is not commonly reported to be associated with cryoglobulinemia.

This quiz is based on information from Cryoglobulinemic Disease, by Soledad Retamozo MD, Pilar Brito-Zerón MD PhD, Xavier Bosch MD PhD, John H. Stone MD MPH, and Manuel Ramos-Casals MD PhD. Oncology. Nov. 15, 2013

Soledad Retamozo, MD, Pilar Brito-Zerón, MD, PhD, Xavier Bosch, MD, PhD, John H. Stone, MD, MPH, and Manuel Ramos-Casals, MD, PhD - See more at:

Soledad Retamozo, MD, Pilar Brito-Zerón, MD, PhD, Xavier Bosch, MD, PhD, John H. Stone, MD, MPH, and Manuel Ramos-Casals, MD, PhD - See more at:


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