Extrahepatic manifestations: Impacts of hepatitis C beyond the liver

Hepatitis C (HCV) is a viral infection primarily known for its impact on the liver but it also has far-reaching consequences that extend to other parts of the body. These conditions, caused by hepatitis C infection outside the liver, are known as extrahepatic manifestations (EHMs). This post delves into the intricate web of connections between hepatitis C and extrahepatic manifestations by providing brief descriptions of common EHMs. It also shares lived experiences to emphasize that recognizing and addressing these manifestations is an important part of comprehensive care and can improve the quality of life of those affected by HCV.

The hidden dimensions of hepatitis C          

Most people are asymptomatic during the initial stages of chronic HCV infection and the first clinical signs of infection are often symptoms manifested outside the liver. These are diverse conditions affecting various organs and systems, highlighting the systemic nature of the infection. During the course of chronic HCV infection, many patients report having one or more extrahepatic manifestations.

People with chronic hepatitis C infection sometimes report the following:

• neurological conditions,
• heart and blood vessel conditions,
• type 2 diabetes,
• kidney complications,
• fatigue and depression,
• immune related disorders,
• conditions affecting the joints, muscles, and bones.

Our understanding of the complex and multifaceted mechanisms underlying these conditions is currently incomplete, but we know they have a profound impact on the health and quality of life of people living with HCV. Fortunately, many extrahepatic manifestations can be prevented or improved with direct-acting antivirals (DAAs), which are highly effective pills that cure HCV in eight or 12 weeks.

“Hep C left me with a searing case of polyneuropathy. I have what feels like a bad sunburn down my back, torso, arms, legs, shoulders and even neck. The severity ranges from mild to severe.” 

– person with lived/living experience of HCV and EHMs 

Nervous system

Many extrahepatic manifestations can involve the nervous system and have been linked to neurological conditions such as strokes, brain dysfunction, inflammation of the spinal cord and cognitive impairment. Studies also reported that hepatitis C infection was associated with a higher risk of developing Parkinson’s disease. For some, a burning sensation felt in the hands, arms, legs and feet has manifested as a result from damage to the nerves located outside the brain and spinal cord, which a 2021 study showed was improved by HCV treatment with direct-acting antivirals.

Cardiovascular system

Chronic hepatitis C infection has a profound effect on heart and blood vessel health, also known as cardiovascular health. The risk of major cardiovascular events, such as heart attacks, is higher in people with HCV infection compared to those without, regardless of their liver health or other cardiovascular risk factors. Fortunately, current evidence suggests that being cured of HCV reduces the frequency of and mortality from cardiovascular diseases, such as coronary artery disease or heart failure.

Type 2 diabetes and kidney complications

There is evidence that people with chronic hepatitis C infection have a higher risk of type 2 diabetes, and this risk increases when the liver is scarred, also known as cirrhosis. Type 2 diabetes is one of the EHMs most commonly associated with HCV infection, however, many studies show that direct-acting antiviral treatment was associated with improved blood sugar regulation, both among people with and without diabetes. This evidence suggests that treating HCV can play an important role in preventing diabetes among people with this infection.

Hepatitis C also has implications for kidney health, with conditions such as chronic and end-stage kidney diseases, most likely as a result of systemic inflammation and damage to blood vessels. As with diabetes, several studies have shown the benefit of HCV treatment on kidney function.

“Fibromyalgia and Raynaud’s syndrome are manifestations of lifelong HCV. I have both, which cause overwhelming fatigue and brain fog.” 

-person with lived/living experience of HCV and EHMs 

Fatigue, depression and cognitive dysfunction

Current evidence shows links between hepatitis C infection and chronic fatigue, depression and cognitive dysfunction. Mild cognitive dysfunction, particularly in relation to attention and memory, or so-called “brain fog”, is commonly reported by people with chronic HCV infection. All of these conditions have profound impacts on the social and physical functioning of individuals and greatly affect their quality of life. Emerging studies have suggested that being cured of HCV with direct-acting antivirals could have a role in improving some of these conditions, especially in conserving cognitive function and improving mood-related disorders.

Immune system disorders

Cryoglobulinemia (MC) is a condition caused by dysfunction of the immune system that is frequently associated with chronic hepatitis C infection. Type 2 and 3 cryoglobulinemia are known as mixed cryoglobulinemia and are defined by the presence of cryoglobulins, which are abnormal immune proteins that can attack the cells of body tissue. Chronic HCV infection is the most common cause of MC. Clinical features of MC include fatigue, palpable purpura (red or purple rashes on the skin), arthralgia (joint pain), arthritis and damage to the kidneys and nerves outside the brain and spinal cord. In rare but severe cases, inflammation of the arteries and veins in the brain or spinal cord can cause strokes, epilepsy or cognitive impairment.

Other EHMs

Skin disorders have also been associated with hepatitis C infection. However, treatment with DAAs seems to resolve or improve these conditions.

Extrahepatic manifestations can also affect the lungs. Although rare, it has been suggested that HCV infection can scar the lungs, known as pulmonary fibrosis, and lead to decreased lung function in some people with asthma or chronic obstructive pulmonary disease (COPD).

“I have chronic inflammatory demyelinating polyneuropathy. I went undiagnosed for so long and I have bad nerve damage from it. I also have many other neurological issues and autoimmune disorders. I’m sorry for all of us. Jeez, I had hepatitis C for over 40 years, but I was finally cured. Thank God!” 
 
-person with lived/living experience of HCV and EHMs 

Lived experiences and diagnostic challenges

Daryl Luster is an expert in community engagement and peer mentoring, as well as a long-time advocate for raising awareness of extrahepatic manifestations, and a person with lived experience of hepatitis C. He affirms that many people who have had chronic HCV infection, including himself, have experienced various extrahepatic manifestations. Other peers have shared that their quality of life is affected by EHMs, yet many have found it difficult to get a diagnosis.

Although diagnosing EHMs can be challenging, there have been efforts to propose diagnostic guidelines, such as those proposed by Ferri and other leading experts. In their report, the International Study Group of Extrahepatic Manifestations Related to Hepatitis C Virus Infection (ISG-EHCV) advised applying diagnostic guidelines during referral and follow-up of patients undergoing treatment for HCV.

In Canada, there are no such guidelines for diagnosing EHMs, specifically in relation to HCV infection. However, patients who are diagnosed with HCV should have access to further assessments and follow-up for potential extrahepatic manifestations, including those who have been cured. Most importantly, patients should be informed about the risk of EHMs.

Impact of treatment on extrahepatic manifestations

Several studies have shown a reduced risk of various extrahepatic manifestations after hepatitis C is cured with DAAs. In British Columbia, we found that treatment with DAAs greatly reduced mortality risk related to EHMs, with reductions ranging from 78% to 84% in a cohort of over 25,000 people diagnosed with HCV.

These studies highlight the significant benefits of HCV treatment in reducing health conditions and mortality related to extrahepatic manifestations. As previously discussed, DAAs can also help to improve quality of life. Beyond the clinical benefits, DAA treatment had a positive impact on people’s overall well-being, as well as other healthcare system benefits, such as improved linkage to care and health information.

However, in some instances, extrahepatic damage can persist even after HCV is cured, especially in patients with other chronic diseases like cirrhosis or diabetes. Though more research on the risk of EHMs after successful HCV treatment is needed, it appears that the longer a person lives with chronic HCV infection, the more prone they are to being affected by extrahepatic manifestations, resulting in reduced quality of life, chronic pain and poorer long-term health outcomes.

This emerging evidence underscores the importance of treating and eliminating HCV before extensive extrahepatic damage occurs, especially before this damage becomes irreversible. Even post-treatment, it is critical for patients and healthcare providers to be aware of EHMs so they can monitor for existing conditions.

A comprehensive and collaborative approach

Recognizing the effect of extrahepatic manifestations is indispensable for both patients and healthcare providers. As we strive to manage this viral infection as a community, a holistic approach that acknowledges the impact of hepatitis C on various organs and systems is paramount. By understanding and addressing extrahepatic manifestations, we not only enhance the quality of patient care, but also pave the way for a comprehensive and collaborative approach to managing HCV and its associated complexities.

 

Dahn Jeong is a PhD candidate at the School of Population and Public Health at the University of British Columbia. Her doctoral research examines the benefits of direct-acting antiviral treatment for HCV infection, specifically in relation to extrahepatic manifestations. Dahn is a PhD trainee with the Canadian Network on Hepatitis C (CanHepC) and is also supported by the Canadian Institutes of Health Research.  

Daryl Luster uses his experience as a person who lived with HCV to work as an advocate and educator with patients, caregivers, legislators, drug companies and healthcare professionals. He is an advocate for a greater commitment on the part of payers, whether public or private, and speaks with patients regularly. He also has experience as a presenter, peer navigator and blogger, and brings a broad understanding of issues faced by people living with chronic disease. Supporting improved quality of life for all patients is at the center of his work. He is part of multiple organizations such as the CIHR HIV/AIDS and STBBI Research Advisory Committee (CHASRAC), CIHR Institute of Infection and Immunity Community Advisory Committee and Canadian Network on Hepatitis C (CanHepC).