Didn't play the corresponding interactive case or want to try it again? Click here to do so.

Diagnosis and reasoning

This middle-aged lady has presented with an erythematous rash of both legs for several months, along with diffuse arthralgia and myalgia during the same period, without joint swelling. Examination of the rash shows it to be limited to both legs, and that it is purpuric, palpable, and non-tender. No other general or systemic signs are present. Purpura occurs when there is extravasation of blood into the skin. This could be due to an insult to vascular integrity (e.g. infection, vasculitis, or connective tissue diseases), or abnormal hemostasis (e.g. thrombocytopenia, or coagulation disorders). However, the fact that the lesions are palpable provides a potent clue. Palpable purpura is almost always due to a cutaneous vasculitis. In turn, cutaneous vasculitis can be caused by a wide variety of etiologies, including drugs, infections, malignancies, autoimmune diseases, and even idiopathic causes (such as Henoch-Schonlein purpura). Several factors from the history are helping in narrowing down the field of differentials. In particular, this patient is not on any medications, excluding drug-induced vasculitis. Note also the presence of rheumatologic findings and the significant history of IV drug abuse. These should elicit consideration of autoimmune disease, and chronic infections such as Hepatitis C and HIV, respectively. An undiagnosed malignancy cannot be excluded either, although, on the flipside, there is very little evidence to favor this possibility. Given the above considerations, initial investigations should include an autoimmune panel, screening for chronic infections, as well as basic hematological and biochemical investigations. The autoimmune panel shows rheumatoid factor positivity and low levels of C4. Unfortunately, these two findings are common in many conditions. Screening for chronic infections is more fruitful, revealing Hepatitis C positivity. Hepatitis C is known to give rise to a cutaneous vasculitis via the production of cryoglobulins, mandating a cryoglobulin screen. In turn, the cryoglobulin screen shows a markedly elevated cryocrit, with electrophoresis showing a pattern suggestive of type II (i.e. mixed) cryoglobulinemia. The cryoglobulins found in this form of the disease show rheumatoid factor activity, explaining the results of the autoimmune screen. The low C4 levels can also be explained as being due to increased complement activation. Note that in retrospect, this patient has manifested the obscure “Metzler triad”, a combination of myalgias, arthralgias, and palpable purpura that is seen in patients with cryoglobulinemic vasculitis. This patient's hepatitis C infection should be treated as soon as possible. Most likely, this in itself will result in resolution of the cryoglobulinemia. Given the presence of clinical manifestations of the cryoglobulins, treatment with corticosteroids is also justifiable until then. Both cyclophosphamide and plasmapheresis are options in severe disease (e.g. glomerulonephritis). They are not indicated right now.


Cryoglobulinemia refers to the presence of one or more serum immunoglobulins ("cryoglobulins") that precipitate at temperatures below 37 °C, and dissolve upon rewarming. Depending on whether the immunoglobulins are monoclonal, polyclonal with a monoclonal component, or polyclonal alone, cryoglobulinemias are further classified as type I, type II, or type III respectively. Note also that the latter two types are collectively termed mixed cryoglobulinemias. The cryoglobulins found in them typically show rheumatoid factor activity. Cryoglobulinemia is often associated with underlying disease (i.e. hematological, autoimmune, infectious, or neoplastic conditions). It may also occur in the absence of such, with this being termed "essential cryoglobulinemia". In affected patients, high immunoglobulin concentrations can lead to hyperviscosity, while precipitation in the peripheral arteries and capillaries may result in infarction and necrosis of end-organs. Activation of the complement system may also occur, resulting in a systemic vasculitis. The presentation of cryoglobulinemia is variable and may include features of the underlying disorder. Signs and symptoms specific to the disease include: - Skin involvement: palpable purpura or ulcers - Neurological involvement: mononeuritis multiplex or sensory/sensory-motor polyneuropathy - Renal involvement: membranoproliferative glomerulonephritis - Pulmonary involvement: interstitial lung disease - Endocrine involvement: autoimmune thyroiditis The diagnosis can be established by chilling serum to 4 °C for 72 hours, and then centrifuging it to determine the proportion forming a cryoprecipitate (the "cryocrit"). A value >2% is considered diagnostic of cryoglobulinemia. Subsequently, the type of cryoglobulinemia can be established via protein electrophoresis and immunofixation. Testing for an underlying cause should also take place, guided by the clinical presentation and types of cryoglobulins. In most cases, treatment of the underlying cause should be the primary aim of management. This alone will usually result in the resolution of the cryoglobulinemia. Immunosuppressive drugs such as corticosteroids, azathioprine, or cyclophosphamide are indicated if there is organ involvement. Where there is hyperviscosity or severe cryoprecipitation, plasmapheresis may prove to be helpful.

Take home messages

  1. Cryoglobulinemia refers to the presence of serum immunoglobulins that precipitate at below-body temperatures, and dissolve upon rewarming.
  2. Cryoglobulinemia is usually a manifestation of an underlying condition, although uncommonly, it may also occur in the absence of such.
  3. The clinical manifestations of cryoglobulinemia are due to hyperviscosity, precipitation, and inappropriate complement activation.
  4. Treatment of the underlying cause will result in resolution of the cryoglobulinemia in most instances. In severe cases, immunosuppression and plasmapheresis may be required.

Insightful, fun cases to improve your diagnostic skills

Use your detective skills, strengthen fundamentals faster, and access a wealth of knowledge.

  1. CACOUB PATRICE, COMARMOND CLOE, DOMONT FANNY, SAVEY LéA, SAADOUN DAVID. Cryoglobulinemia Vasculitis. The American Journal of Medicine [online] 2015 September, 128(9):950-955 [viewed 10 September 2017] Available from: doi:10.1016/j.amjmed.2015.02.017
  2. FERRI C. Mixed cryoglobulinemia Orphanet J Rare Dis [online] 2008 Sep 16:25 [viewed 10 September 2017] Available from: doi:10.1186/1750-1172-3-25
  3. RAMOS-CASALS MANUEL, STONE JOHN H, CID MARIA C, BOSCH XAVIER. The cryoglobulinaemias. The Lancet [online] 2012 January, 379(9813):348-360 [viewed 10 September 2017] Available from: doi:10.1016/S0140-6736(11)60242-0
  4. TERRIER B, KARRAS A, KAHN JE, GUENNO GL, MARIE I, BENAROUS L, LACRAZ A, DIOT E, HERMINE O, DE SAINT-MARTIN L, CATHéBRAS P, LEBLOND V, MODIANO P, LéGER JM, MARIETTE X, SENET P, PLAISIER E, SAADOUN D, CACOUB P. The Spectrum of Type I Cryoglobulinemia Vasculitis: New Insights Based on 64 Cases Medicine (Baltimore) [online] 2013 Mar 14, 92(2):61-68 [viewed 10 September 2017] Available from: doi:10.1097/MD.0b013e318288925c