Sunday, May 22, 2011

Cryoglobulinemia in elderly patients with HCV-related chronic hepatitis.

What is essential mixed cryoglobulinemia?

Essential mixed cryoglobulinemia is characterized by joint pains and swelling (arthritis), enlargement of the spleen, skin vasculitis (inflammation of the blood vessels) with purplish patches, and nerve and kidney disease. This can lead to recurrent pain in the abdomen, heart attack, and bleeding in the lungs. Weight loss can occur, as well as poor appetite.On a molecular level, this condition is characterized by cryoglobulins forming in the blood. When these are a mixture of various antibody types, and they are forming for unknown reasons (essential), the condition is referred to as essential mixed cryoglobulinemia. Cryoglobulins are abnormal blood proteins that have the unusual properties of precipitating from the blood when it is chilled in the laboratory and redissolving upon rewarming.
Essential mixed cryoglobulinemia is sometimes associated with hepatitis C virus infection.
Abstract; May 2011

Updated May 5 2011 From Medscape Full Text;  Cutaneous Manifestations of Hepatitis C 

Abstract; April 2011

Related; March 2011
 Hepatitis C-related vasculitis

Abstract; Autoimmun Rev. 2011 Feb 15.
Full Text
World J Gastrointest Pharmacol Ther. 2010 Apr 6;1(2):72-4.

Cryoglobulinemia in elderly patients with HCV-related chronic hepatitis.
Francesco Giuseppe Foschi, Anna Chiara Dall'Aglio, Arianna Lanzi, Giorgio Marano, Sara Savini, Giuseppe Francesco Stefanini, Department of Internal Medicine, Faenza Hospital,Viale Stradone 9, 48018 Faenza (RA), Italy.
Hepatitis C virus (HCV) infection affects about 3% of the world's population and often leads to chronic liver disease. In some industrialized countries, HCV prevalence increases with age, but the optimal management of older patients has not been accurately defined. HCV infection can also lead to lymphoproliferative disorders, the most common being mixed cryoglobulinemia (MC), and also for this condition that frequently affects elderly patients, the optimal therapeutic strategy is still debated. We report the case of a 77-year-old Caucasian woman with HCV-related chronic hepatitis and cutaneous manifestations consisting of urticaria and pruritus related to MC resistant to antihistamines. The patient underwent a treatment with interferon and ribavirin. Such a treatment led to early biochemical and virological response associated with the resolution of cryoglobulinemia and cutaneous symptoms. After the end of treatment, HCV replication relapsed, but cryoglobulinemia and cutaneous symptoms did not recur. In the absence of definite treatment guidelines in this particular context, our experience suggests that the presence of symptoms related to HCV-infection that deeply affect patient quality of life warrants antiviral therapy even beyond the age limits that currently exclude patients from treatment.

Cryoglobulinemia in elderly patients with HCV-related chronic hepatitis.

Francesco Giuseppe Foschi, Anna Chiara Dall’Aglio, Arianna Lanzi, Giorgio Marano, Sara Savini, Pietro
Andreone, Mauro Bernardi, Giuseppe Francesco Stefanini


Hepatitis C virus (HCV) infection affects about 3% of the world’s population and often leads to chronic liver disease. HCV infection can also lead to lymphoproliferative disorders, the most common being mixed cryoglobulinemia (MC)[1].

In some industrialized countries, such as Japan and Italy, the prevalence of HCV infection increases with age[2]. Unfortunately, antiviral therapy with PEG-interferon alpha and ribavirin, which represents the current treatment of choice, often fails in older patients, especially in those
affected by HCV-related MC. Moreover, in this context,neither the optimal therapy strategy nor prognostic criteria have been accurately defined[1].

We report the case of an elderly woman with HCV related chronic hepatitis associated with MC, presenting with severe urticaria and itching resistant to antihistamines,who underwent PEG-interferon and ribavirin treatment.


In January 2007, a 77-year-old Caucasian woman with HCV-related chronic hepatitis, diagnosed in the early 1990s, was referred to our outpatient clinic because of urticaria and itching resistant to antihistamines. The most common causes of urticaria had been previously excluded, such as allergic and haematologic diseases, other gastrointestinal infections, parasitosis, autoimmune diseases (other than MC), and tauopathies. In 1998, she had undergone treatment with interferon 3 times a week with no benefit.

The patient was not able to report either type or dosage of interferon or treatment duration. When we first saw the patient, she was in good physical condition and was not affected by heart, lung, renal or neurological diseases.

Physical examination revealed urticaria and scrabble signs. Laboratory tests are listed in Table 1.(see below)

Liver, renal and thyroid functions were normal, as well as serum immunoglobulins, anti-DNA, anti-mitochondrial,anti-nuclear antibodies and anti-neutrophil cytoplasmic antibody, lactate dehydrogenase and β-2–microglobulin.

The serological markers of HBV and HIV infections were negative. Physical examination and laboratory tests excluded renal or neurologic involvement of MC; purpura was absent. Ultrasound examination showed moderate hepatosplenomegaly,without evidence of cirrhosis and portal hypertension. No focal liver lesions were detected. A reactive lymph node of about 1 cm was present at the hepatic hilus.

After written informed consent, the patient was treated with PEG-interferon a-2a (180 μg/wk) plus ribavirin 800 mg/d. After 3 wk, PEG-interferon α-2a was shifted to human leucocyte interferon-α at the dosage of 6 MU thrice a week, because of progressive reduction of neutrophil
granulocyte count and profound weakness.

Thereafter, the treatment was well tolerated and did not require further dosage adjustment. Overall treatment lasted 6 mo.
The patient’s cutaneous manifestations resolved in 10 d, and HCV-RNA and cryoglobulins were negative 1 mo from the beginning of treatment. After 3 mo from the end of treatment, ALT and AST again increased and HCV-RNA became detectable.

However, the relapse of viral replication was not accompanied by the recurrence of cryoglobulinemia, and serum cryoglobulins were negative after a 2 year follow-up.


Chronic HCV infection is the most common cause of MC. 70% to 80% of patients with MC are infected by HCV[2]. Conversely, cryoglobulinemia is detected in a third of patients with HCV infection, although most are asymptomatic[2]. The close association between HCV and MC is witnessed by the finding of HCV-RNA in both cryoprecipitate and supernatant[3], but the mechanism (s) through which HCV may induce MC remains unclear.

Cryoglobulinemia is defined by the presence of circulating mmunoglobulins, which precipitate with cold temperature and re-solubilise when reheated. The most common symptoms are weakness, arthralgias and purpura (Meltzer and Franklin triad). Raynaud phenomenon, peripheral neuropathy, sicca syndrome, renal involvement, lung disorders, fever and thrombocytopenia can also be observed[1].

In addition to purpura, MC-associated dermatological disorders include the presence of leukocytoclastic vasculitis, leg ulcer, pruritus and urticaria[4]. In a retrospective study on 62 MC patients, pruritus was reported in 8% of cases and urticaria in 6%[5]. Moreover, pruritus was the most frequent (15%)cutaneous manifestation in 2000 consecutive HCV patients, 40% of whom presented with cryoglobulinemia, even though the extent of association between pruritus and MC was not reported[6]. Indeed, even in the absence of MC, it should not be forgotten that several other dermatological manifestations may result from disorders potentially associated with HCV infection, such as porphyria cutanea tarda,linchen planus (LP), psoriasis, polyarteritis nodosa, systemic lupus erythematosus, sarcoidosis, xerosis, pruritus and nonspecific

Although a wide spectrum of dermatological disorders have been described in association with HCV infection, their pathophysiological relationship with HCV is still a matter of debate[4,5]. In any case, HCV particles have been localized within skin lesions in MC, LP, pruritus and psoriasis. Moreover, parallel improvement in HCV viremia and some dermatological symptoms under antiviral treatment suggests a close correlation.

In our case, the absence of other common causes of urticaria claims a relationship between HCV virus and this dermatological manifestation. Skin biopsy has an essential role in the diagnosis of urticaria vasculitis, and the lack of this information does not allow us to know for certain the exact mechanism of urticaria in our case, but the presence of MC suggests an immune mediated pathogenesis.

The treatments that can be offered to patients with MC include corticosteroids, cyclophosphamide, plasmapheresis, cryoapheresis, low-antigen continent diets and anti-CD20 antibodies. However, antiviral treatments are first line therapy in HCV-related MC[1,3], even though the lack of standardized protocols, the high rate of relapses, and general or MC-specific contraindications to antiviral treatments (i.e. old age, severe liver disease, acute nephritis, and widespread vasculitis) render such treatments rather difficult[1].

A main problem with our patient was associated with her age. Whether to treat patients older than 65 years with interferon and ribavirin is highly debated, especially in terms of cost/benefit ratio. In addition, the natural history of chronic hepatitis C in elderly patients is scarcely known, as the presence of comorbidities can affect illness progression and life expectancy.

Data favoring treatment are represented by the reduction in liver-related mortality and risk of developing hepatocellular carcinoma achieved by treatment in HCVrelated chronic hepatitis[7], while resistance to reatment, due to either advanced liver fibrosis or reduced interferon immunomodulatory activity, and frequent comorbidities,which limit indications and reduce tolerance, militate against treatment. In any case, it should be pointed out that the prevalence of HCV infection in elderly patients is increasing in industrialized countries[2], and, therefore, physicians will more often face this condition.

Click Here To Enlarge Table 1


Our 77-year-old patient did not have remarkable liver damage, and laboratory and ultrasound evidence of cirrhosis was lacking. Therefore, the risk to develop frank cirrhosis or hepatocellular carcinoma in the short run was theoretically low.

However, she suffered from severe cutaneous symptoms due to HCV-related MC, which were not responsive to symptomatic therapy and deeply affected her quality of life. This was the reason that prompted us to undertake antiviral therapy. In the lack of precise guidelines for the treatment of elderly patients and, in particular,elderly patients with cutaneous manifestation of HCV related MC, we decided to start with PEG-interferon and ribavirin as indicated for adult patients with a favourable

Treatment led to a rapid resolution of the cutaneous symptoms. However, intolerance to treatment induced us to shift PEG-interferon α-2a to leukocyte interferon- after 3 wk.

The decision to continue with treatment was supported by fast improvement of the cutaneous symptoms, strong patient motivation, and the available and convincing data on the tolerability of this type of interferon[10,11].

The main reason for the rapid resolution of the cutaneous symptoms we achieved in the present case is likely the concomitant virological response. Available data about treatment efficacy on MC-related cutaneous manifestations are conflicting[4], even though the resolution of itching with antiviral treatment has already been reported[3,4].

It is of interest to note that MC and cutaneous symptoms did not reappear for 2 years despite the relapse of viral replication. We do not have a definite explanation for this,but it may be somewhat related to the antiproliferative and immunomodulatory properties of interferon [12] along with low immunoreactivity that characteristic elderly subjects.

In conclusion, we think that undertaking antiviral treatment with interferon and ribavirin in elderly patients in the attempt to resolve particular conditions, such as MC induced pruritus and urticaria, can be taken into account

Treatment should be offered after full disclosure of risks and benefits, and close patient monitoring is warranted to avoid complications. In this context, leukocyte interferon-a seems to be better tolerated than PEG-interferon.

1 Zignego AL, Giannini C, Ferri C. Hepatitis C virus-related
lymphoproliferative disorders: an overview. World J Gastroenterol
2007; 13: 2467-2478
2 Antonucci G, Longo MA, Angeletti C, Vairo F, Oliva A,
Comandini UV, Tocci G, Boumis E, Noto P, Solmone MC,
Capobianchi MR, Girardi E. The effect of age on response to
therapy with peginterferon alpha plus ribavirin in a cohort of
patients with chronic HCV hepatitis including subjects older
than 65 yr. Am J Gastroenterol 2007; 102: 1383-1391
3 Tedeschi A, Baratè C, Minola E, Morra E. Cryoglobulinemia.
Blood Rev 2007; 21: 183-200
4 Berk DR, Mallory SB, Keeffe EB, Ahmed A. Dermatologic
disorders associated with chronic hepatitis C: effect of
interferon therapy. Clin Gastroenterol Hepatol 2007; 5: 142-151
5 Dupin N, Chosidow O, Lunel F, Cacoub P, Musset L, Cresta
P, Frangeul L, Piette JC, Godeau P, Opolon P. Essential mixed
cryoglobulinemia. A comparative study of dermatologic
manifestations in patients infected or noninfected with hepatitis
C virus. Arch Dermatol 1995; 131: 1124-1127
6 Cacoub P, Poynard T, Ghillani P, Charlotte F, Olivi M, Piette
JC, Opolon P. Extrahepatic manifestations of chronic hepatitis C.
MULTIVIRC Group. Multidepartment Virus C. Arthritis Rheum
1999; 42: 2204-2212
7 Honda T, Katano Y, Urano F, Murayama M, Hayashi K,
Ishigami M, Nakano I, Yoshioka K, Toyoda H, Kumada T, Goto
H. Efficacy of ribavirin plus interferon-alpha in patients aged
>or=60 years with chronic hepatitis C. J Gastroenterol Hepatol
2007; 22: 989-995
8 Chevaliez S, Pawlotsky JM. Hepatitis C virus: virology, diagnosis
and management of antiviral therapy. World J Gastroenterol
2007; 13: 2461-2466
9 National Institutes of Health Consensus Development Conference
Statement: Management of hepatitis C 2002 (June 10-12,
2002). Gastroenterology 2002; 123: 2082-2099
10 Cacopardo B, Benanti F, Brancati G, Romano F, Nunnari A.
Leucocyte interferon-alpha retreatment for chronic hepatitis C
patients previously intolerant to other interferons. J Viral Hepat
1998; 5: 333-339
11 Cagnoni C, Pancotti D, Carrara G. Management of patients
with HCV infection poorly tolerant to recombinant interferon
alpha. Hepatogastroenterology 2000; 47: 199-203
12 Saadoun D, Resche-Rigon M, Thibault V, Piette JC, Cacoub P.
Antiviral therapy for hepatitis C virus--associated mixed cryoglobulinemia
vasculitis: a long-term followup study. Arthritis
Rheum 2006; 54: 3696-3706


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