Nonhepatic Manifestations of HCV

The patient was a 55-year-old, young grandmother who said, I’ve tried them all, as I reviewed her HCV treatment history, which included interferon (IFN), pegylated IFN, consensus IFN and now maintenance IFN. She pulled up her pant legs and said, My real problem is here. Her lower legs had hyperpigmentation on them but no obvious purpura or ulcers. Her previous hepatologist had provided her doses of prednisone for her leg flares and now that she was transferring her care to me, she asked for a new prescription for her maintenance PEG and prednisone. This case still rings clear in my mind many years later because of the uncertainty it provoked in me regarding the management of her nonhepatic manifestations of HCV.

Nonhepatic manifestations, which are also referred to as extrahepatic manifestations of HCV, have been widely reported in the literature. However, their frequency in HCV patients and verification of a direct pathophysiologic association with HCV has been less clear. Mixed cryoglobulinemia is a classic nonhepatic manifestation of HCV and is the paradigm for the wide spectrum of disease in nonhepatic manifestations varying from mild palpable purpura to glomerulonephritis or life-threatening vasculitis. Non-Hodgkin’s lymphoma remains another diagnosis strongly associated with chronic HCV. My patient presumably had mixed cryoglobulinemia, which manifested on days when she worked longer hours as a florist or when she flew out of state to visit her grandchildren. But she also had diabetes, nonspecific muscle pain and a growing fatigue that belied her cheerful disposition. This all made it difficult for her to finish shifts on her feet, and at that time I could offer little beyond encouragement. However, there is now increasing awareness that HCV is not just a problem of the liver, but a systemic disease, which impacts the whole patient. Among other things, it increases the risk of insulin resistance, cardiovascular disease and neuropsychiatric disease.

The problem recently, in the age of interferon, has been that nonhepatic manifestations of HCV have been underdiagnosed, and understudied due to limitations in the understanding of its pathogenesis, along with practical challenges posed by the toxicity of available therapies. Treatment options were further constrained because IFN was acknowledged as a possible risk for life-threatening exacerbation of nonhepatic manifestations. In addition, patients with the above-mentioned possible nonhepatic manifestations of HCV, such as psychiatric disease, severe fatigue or cardiovascular disease, were considered to be poor candidates for IFN. Even if patients started on IFN, the rates of sustained virological response (SVR) were suboptimal, and some of those patients who were lucky enough to reach SVR found they still retained symptoms.

With the advent of directly acting antivirals (DAA), which have been shown to have significantly higher rates of SVR, easier tolerability and improvements in quality of life, the growing recognition of HCV as a systemic disease that diminishes the patient’s overall health and quality of life poses new challenges to providers and payors in prioritizing the care of these patients. Those patients previously labeled as poor candidates for IFN may have ironically been those with the greatest need for treatment, even independent of their hepatic disease status. A practical acknowledgment already appears to have occurred as many payors consider nonhepatic manifestations of HCV, even in the absence of significant fibrosis, as an indication for initiating DAA treatment. This is expected to increase diagnostic testing for manifestations outside the liver, such as mixed cryoglobulinemia, and provide greatly needed outcomes data regarding IFN-free DAA treatment of nonhepatic manifestations of HCV. With the expected availability of next generation DAAs and a trend towards shorter duration of treatment, we must be cautious about assuming that SVR with DAA treatment will lead to complete eradication of nonhepatic manifestations of HCV. Further studies are needed on the pathophysiology of these manifestations and optimal management strategies, including the possibility of treatment to improve quality of life and even perhaps, to prevent development of nonhepatic manifestations.


In 2016, the ultimate nonhepatic manifestation of HCV may indeed be the headaches and frustrations that arise from the challenges facing providers, staff and patients.


In 2016, the ultimate nonhepatic manifestation of HCV may indeed be the headaches and frustrations that arise from the challenges facing providers, staff and patients as they struggle with the reality that given the costs of DAA treatment, the diagnosis of HCV does not equal access to treatment. As I ponder these headaches, I sometimes wonder how my patient is doing. She decided to move closer to her grandchildren after taking an early retirement. I hope she’s cured of her HCV and healed of her mixed cryoglobulinemia; because, at that time, all I could do was refill her medications and give her a prescription for hope, with the promise that things would get better in the future. I just pray that this prescription will soon be filled for all patients with HCV.

Dr. Ahn has no conflicts to disclose

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