E-Case # 6:  February 5-9, 2001

Tim Crimmins, M.D.

• CC: Rash

• HPI: Mrs. M is a 53-year-old woman with 3-month history of right lower extremity rash.  She has had the painful, pruritic rash off and on since 1992 and was treated with multiple courses of antibiotics in 1998 for cellulitis in the same area.  Review of symptoms is significant for fatigue, subjective fevers and dry cough, but no arthralgias, chest pain, dyspnea, night sweats or weight loss.

• PMH:

  • Primary hyperparathyroidism s/p parathyroidectomy 4/98

  • Uterine fibroids with menorrhagia

  • Iron deficiency anemia

  • History of TB exposure

  • History of elevated ESR related to cellulitis in 1998, ANA negative

  • History of elevated LFT's, resolved spontaneously.

• No PSH, Meds or KDA.

• SH: Single, employed in customer service. Former smoker, rare alcohol use.  No IVDU. Lived for 6 years with a boyfriend who used IV heroin.

• PE: Afebrile, VS unremarkable.

• SKIN: There are diffuse, scattered erythematous round and oval mostly flat lesions.  A few are somewhat palpable.  They extend from the feet to the thighs bilaterally. There are more pink confluent areas around the medial ankles bilaterally.  They are non-blanching.Exam otherwise unremarkable.

Assessment:  Recurrent palpable purpura of the lower extremities, rule out vasculitis.  Consider your own approach to this workup before reading the discussion.

Tim Crimmins

January 29, 2001

E-Case #6 Discussion

In this case the primary provider was concerned about vasculitis because of the classic physical finding of palpable purpura.  On chart review red flags such as the elevated ESR and abnormal LFT's raised the level of suspicion even more.  Initial lab tests were sent and a skin biopsy was considered.  Results are as follows: ESR 125, RF 306, ANA neg, ANCA, neg.  A rheumatology consultation suspected mixed cryoglobulinemic vasculitis from hepatitis C and confirmed the diagnosis with HCV Ab, HCV RNA by PCR and a "cryocrit" of 2%. Skin biopsy was not obtained.  Other organ systems were screened, but no vasculitic involvement was found.  UA neg, CrCl 116, 300mg proteinuria in 24 hours, CXR neg, neuro exam excluded peripheral neuropathy.  CBC and iron studies confirmed iron deficiency anemia.  Gastroenterology consult found ALT mildly elevated with a normal bilirubin and INR.  There were no stigmata of chronic liver disease.  Because extrahepatic manifestations of hepatitis C are an indication to treat, interferon and ribavarin combination therapy was recommended.

Do internists need to know about mixed cryoglobulinemia (MC)?

Probably.  Hepatitis C is a common chronic infectious condition and its manifestations are legion.  Only since 1990 has hepatitis C been recognized as the cause of almost all cases of "essential" mixed cryoglobulinemia. Given that MC is a late manifestation of HCV infection, it should be on our radar screens when vasculitic lesions are suspected.

What is cryoglobulinemia, and why does hepatitis C cause it?

Cryoglobulins are globulins that precipitate in the serum at cold temperatures and then become soluble again when warmed up. Hepatitis C is both a hepatotrophic and lymphotrophic virus.  During the normal course of fighting infection, the body produces IgG targeted against hepatitis C proteins. In addition, HCV infects B cells in blood, bone marrow and liver and induces IgM production with rheumatoid factor activity.  Recall that rheumatoid factor activity means these IgM molecules bind to human IgG.  Cryoprecipitate consists mostly of these IgM molecules bound to antiHCV IgG plus a mixture of HCV antigens and HCV RNA.  The presence of IgM with rheumatoid activity explains Mrs. M's high RF.

What are the symptoms and complications of MC?

Cryoglobulins precipitate in small blood vessels and activate complement leading to inflammation and vasculitis.  Common organ systems affected are listed.

What other systemic diseases are associated with vasculitis?

Vasculitis has many causes.  If it is suspected or confirmed by biopsy, keeping a list at hand (or in mind) can help direct your investigation based on other clues in history, physical and existing lab data.

How are the symptoms of MC treated?

Symptomatic extrahepatic manifestations of hepatitis C are an indication for treatment.  However, treatment is not very effective.  In the initial studies with interferon alone, cryoglobulinemic symptoms resolved during treatment while viral load was eliminated. However, a sustained response was only achieved in about 10% of patients.  With the combination of interferon and ribavarin and the new interferon delivery systems, more sustained responses may be possible.  For severe disease such as chronic ulcers, nerve involvement or MPGN, rheumatologists can use immunosuppressive therapy with prednisone and cyclophosphamide or they may try plasmapheresis.

References (available in clinic - see Dr. Heller or Smith)

1. Ramos-Casals M. Mixed cryoglobulinemia: New Concepts. Lupus 2000; 9:83-91.

2. Jennett JC. Small Vessel Vasculitis. New Engl J Med 1997; 33721):1512-.