Hepatitis C virus as a systemic disease: reaching beyond the liver.
K. Gill.
Hepatol Int 2016; 10:415–23.
Chronic hepatitis C (CHC) is associated with multiple extrahepatic manifestations that may impact infected patients. The mechanisms through which these develop include those which are immunological and those which are virological and related to the extrahepatic tropism of the virus to other tissues. It is estimated that 40–74 % of patients with CHC may develop at least one extrahepatic manifestation during the course of the disease. Extrahepatic syndromes may represent the first signal of hepatitis C infection in some patients.
Extrahepatic manifestations :
- Cryoglobulinemia and immune complex disease : CHC is primarily associated with type II cryoglobulinemia (prevalence: 36–54 % of patients). Vasculitis occurs in the skin, joints, kidneys, lungs, heart, digestive tract, and brain. Patients with mixed cryoglobulinemia are also predisposed to malignancies, specifically lymphoma as well as IgM paraproteinemia and low-grade lymphoma, a syndrome known as Waldenstrom macroglobulinemia.
- Renal involvement : this is the most common severe manifestation of mixed cryoglobulinemia, present in 35-60% of cases). It includes Type I membranoproliferative glomerulonephritis, mesangial glomerulonephritis and focal and segmental glomerulonephritis. In 30 % of cases, renal involvement begins with a nephritis syndrome and acute renal failure, while in 55 % there is only mild hematuria, microalbuminuria, proteinuria and renal insufficiency. Some authors recommend annual screening for microalbuminuria, microscopic hematuria, and cryoglobulinemia in patients with CHC.
- Dermatological manifestations : most common are purpura (7 %) and Raynaud's phenomenon (7 %). Others include porphyria cutanea tarda, lichen planus, necrolytic acral erythema (painful or pruritic, erythematous skin lesions involving acral skin surfaces, possibly linked to impairment in the regulation of zinc), erythema multiforme, and pruritus.
- Ocular manifestations : dry eye, Mooren ulcer, scleritis and episcleritis, trichomegaly, and peripheral ulcerative keratopathy, posterior segment involvement (ischemic retinopathy).
- Metabolic manifestations : four-fold increased risk of insulin resistance and type 2 diabetes mellitus.
- Salivary glands : Sjögren syndrome.
- Malignancies : hepatocellular carcinoma. Other malignancies more common in those with CHC compared to the general population : prostate cancer, oral and other digestive tract cancers, lymphoma, specifically diffuse large B-cell non-Hodgkin lymphoma.
- Pulmonary fibrosis.
- Psychiatric manifestations : higher prevalence of both mental illness and substance abuse. Patients with CHC are more likely to have depression and an impaired quality of life
- Thyroid involvement : autoimmune thyroid disease.
- Cardiovascular disease : increased risk of stroke (biological gradient of cerebrovascular mortality correlating with an increasing serum viral load) ; less frequent hypertension, lower mean total cholesterol, low-density lipoprotein cholesterol and triglycerides, but increased risk of coronary arterial disease despite this favorable risk profile ; higher risk of developing peripheral arterial disease.
- Neuropathies : higher prevalence of sensory, motor and autonomic dysregulation, linked to vitamin deficiency (B12), cryoglobulinemia and immune complex deposition, and metabolic conditions such as diabetes, as well as alcoholism and substance abuse
- Neurologic disorders : cognitive impairment, particularly in power of concentration and speed of working memory, executive functions
Although data are limited on the resolution of extrahepatic manifestations with the new direct acting antiviral medications, multiple studies over the course of the past few decades have shown marked improvement of extrahepatic manifestations upon eradication of HCV after treatment with previous therapies, primarily combination therapy with peg-IFN and ribavirin. With standard courses of peg-IFN/ribavirin the following have been seen:
- Reduced insulin resistance, with improved insulin sensitivity seen at 12 weeks and 24 weeks, and at end of therapy (24 or 48 weeks).
- Improved health-related quality of life.
- Improved work productivity.
- Reduced depression.
- Resolution of dermatological manifastations, including porphyria cutanea tarda and lichen planus, although data on the latter are conflicting with both worsening and regression having been reported.
- Reduced stroke risk.
- Clearance of cryoglobulins with reduced risk of end organ damage.
Expert's Commentary
« Chronic HCV infection not only affects the liver but also leads to significant organs involvement outside the liver. Most organs are affected, with various consequences in terms of morbidity and mortality, from the most benign – dermatological, thyroid – to the most severe conditions including cardiovascular events, renal insufficiency associated with cryoglobulinemia, lymphoma. The extrahepatic effects of HCV are likely multifactorial and include HCV replication in extrahepatic cells, auto-immune and immune-mediated effects as well as endocrine effects.
Many studies, with pegylated interferon and ribavirine, have shown that SVR improves liver-related but also non-liver morbidity and mortality. Such improvement is with no doubt a consequence of HCV cure, and is independent of the treatment used to achieve such cure.
With availability of simpler, well tolerated, and more efficacious anti-HCV regimens, the extent of improvements in the extrahepatic manifestations of HCV will likely increase in the near future.
Given the burden and frequency of these extrahepatic manifestations of chronic HCV infection, more systematic treatment of HCV should be offered in patients presenting with pre-existing co-morbidities which could be worsened by chronic HCV infection. Also, extrahepatic manifestations of HCV should be considered as a major indication for treatment even in the absence of liver disease. »
Pr François Raffi, Nantes
