Extrahepatic manifestations (Medscape article)

[pooh55811]

Frontline Gastroenterology
Extrahepatic Manifestations of Hepatitis C Virus (HCV)

David G Samuel, Ian W Rees

Abstract

Hepatitis C virus (HCV) is an infectious disease that often remains asymptotic and unrecognised until complications of the virus arise. These often include extrahepatic manifestations of the virus, which first bring patients into contact with the medical profession. First recognised in the 1990s several syndromes and conditions have now been linked to hepatitis C, while others are still emerging. In some patients, extrahepatic manifestations can be the dominant feature, while hepatic disease is mild. Some conditions have an established association with the virus with a proven pathophysiological and epidemiology, such as cryoglobulinaemia. Others have consistently been found to be seen in patients with HCV, but the underlying cause of these conditions is not clearly understood. These include porphyria cutanea tarda. Many other autoimmune conditions are commonly seen in the patients with HCV as well as nephropathies, but the exact interplay between virus and resulting clinical condition is not clear. Clinicians have to have a high index of suspicion and a knowledge of the extrahepatic manifestations of HCV in order to not only treat the manifestation but also in initiated timely therapies for the underlying HCV.
Introduction

Hepatitis C virus (HCV) is an infectious disease that often remains asymptotic and unrecognised until complications of the virus arise. These often include extrahepatic manifestations (EHM) of the virus, which first bring patients into contact with the medical profession.[1] Up to 75% of patients will develop an EHM during their illness. First recognised in the 1990s several syndromes and conditions have now been linked to hepatitis C, while others are still emerging. In some patients, EHM can be the dominant feature, while hepatic disease is mild.[2]

Some conditions have an established association with the virus with a proven pathophysiological and epidemiology such as cryoglobulinaemia.

Others have consistently been found to be seen in patients with HCV, but the underlying cause of these conditions is not clearly understood. These include porphyria cutanea tarda. Many other autoimmune conditions are commonly seen in patients with HCV as well as nephropathies, but the exact interplay between virus and resulting clinical condition is not clear. Among these, glomerulonephritis is an important condition to consider (Table 1).

This review aims to provide an overview of the conditions with the greatest level of evidence supporting a direct link with HCV, as well as looking at the potentially most life-threatening manifestations, with a focus on investigations and management. I have selected conditions, which have the greatest amount of pathophysiological evidence for a causal effect by the HCV, as looking at multiple conditions would be beyond the scope of a single paper, but the principles of investigations and management apply to many of the other conditions listed above. The paper provides a helpful overview for the hepatology clinic as well as encounters on general medical takes.

Before looking at the individual conditions focused on in this article, I will provide a brief overview of the current evidence suggesting the pathophysiology of extrahepatic tissue invasion and pathogenesis of the HCV.

The Pathophysiology of EHM of HCV

It is thought that extrahepatic tissues serve as a reservoir for the hepatitis virus, but especially tropism for the lymphoid tissues.[2] Like other viruses, the HCV has developed an ability to evade detection by the immune system, which in turn leads to chronic inflammation, tissue damage and immune-complex aggregation, activating autoimmune phenomena.[2, 3] In cryoglubulinaemia, which will be discussed in detail below, B-cell lymphoproliferation is the initial immune-cascade trigger. The HCV tropism allows the lymphocytes to serve as host and reservoir, with the virus thought to bind to the CD81 ligand of the B lymphocyte using an E2 protein.[4] Flint was the first to show that this engagement with the HCV envelope activates lymphocytes and subsequently leads to immunoglobulin production.

Cryoglobulinaemia

Cryoglobulinaemia is among the most common and closely linked extrahepatic HCV manifestations and is most often a mixed cryoglobulinaemia of type 2 or 3.[2, 5] Considered a lymphoproliferative disorder, it is thought to result from chronic stimulation and over production of B cells[6] producing immunoglobulin. The disorder is characterised by these abnormal blood-borne protein, which precipitate and aggregate into gel-like substances at reduced temperatures, normally aggregate below 37°C.[2, 4] When the cryoglobulins aggregate and form gel-like substances cause clinical signs and complications through occluding vessels and inflicting target organ damage.[7] Symptoms relate to the organ affected and can range from joint pain, muscle pain, acute kidney injury and glomerulonephritis, or more commonly manifesting as a vasculitic syndrome. Critical ischaemia can result with loss of limbs, particularly digits.[1, 7] Other non-specific symptoms including lethargy are common, with the most common symptoms including arthralgia and pruritus in up to 18% of patients. Up to 50% of patients remain relatively asymptomatic until a critical assault on an organ occurs[1, 6] (Table 2).

At first presentation of cryoglobulinaemia investigating for the cause would include a hepatitis screen. Other investigations include urinalysis, which sometimes shows haematuria, a complement assay, which is low, cryoglobulin levels if available within local hospitals and a full blood count. Rheumatoid factor is often positive in types 2 and 3 and can sometimes point to coexisting disease[4, 6] (Table 3).

Biopsies typically show a leukoclastic vasculitis, which usually involves the medium-sized vessels.[7, 8]

Another important manifestation of cryoglobulinaemia is a peripheral neuropathy, which has been reported in up to 90% of patents depending on the case series.[9] Most cases involve a sensory impairment similar to the diabetic neuropathy, and also in a similar glove stocking distribution, but not exclusively.[9] The condition can be made worse by interferon therapy, which is an important issue to consider in managing the underling HCV.[10] A biopsy typically shows axonal damage and an epineural vasculitic infiltrate.[7, 10]

Therapy is targeted at

   A  treating the underlying HCV and reducing or eradicating viral load

   B  immune-targeted therapy.

The most widely studied and used regimes include cyclophosphamide along with steroid therapy with the aim of suppressing antibody production and cryoglobulin production, but with mixed results.[2, 8, 11] A major concern and drawback of this therapy is the risk of allowing HCV viral replication and the most recent review of therapy does not endorse cyclophosphamide therapy.[12] More targeted therapies such as rituximab have shown greater promise and has been shown to rapidly reduce antibody and cryoglobulin levels.[13, 14] Severe cases, or those involving major organs, warrant early corticosteroid therapy and immunosuppression therapy.[12] Patients are often treated with plasmapheresis[14] (see next section). Treating the underlying HCV remains the cornerstone of preventing both hepatic and extrahepatic complications (figure 1).

Continued next post.

[Dee1956]

Pooh, thanks for posting this, very interesting, I had the cyroglobulinemia for 3 years before being diagnosed.  Like you I treated within a couple of months of being dx.  I too wish I had not gotten the falst negatives back in the 90's. I always think it would have been better to tx back then before I got to cirrhosis.

Ceanthus, thank you for sharing your information. It helps me quite a bit.  I do think that the fatigue is caused by the cirrhosis but I hope as time goes on and the liver has the capability to improve that the fatigue will also.

Really good information, thanks again, Dee

[LN55]

Good information Pooh. Thanks for posting. My PCT dx led to HCV testing and dx. This condition goes misdiagnosed often and HCV is associated with up to 80% of cases of sporadic PCT. It is routine to check for HCV, HBV, and HIV once PCT is confirmed. It was a no brainer for me to treat once both were confirmed. As suggested by the last part of PCT "tarda", this usually hits "later" in life (mid life or older usually) but unfortunately the condition itself is the indicator to test for HCV. PCT is a chronic condition and has no cure but eliminating or controlling the factors that trigger the skin manifestations can keep it in check. Hopefully tx has eliminated the main cause of mine, HCV. Thanks again.

[pooh55811]

"I just have to remind all that even if you had been diagnosed more quickly, the odds of getting rid of the virus were much lower back then. "
-----------------------------------------------------
I wholeheartedly agree with you on that point. I know treatments were not very successful until the Riba was added and then the Interferon was improved and finally now the Protease Inhibitors. I think my wording was not exactly correct.

I should have said, "I only wish that I had been diagnosed sooner and had been able to treat years ago WITH AN EFFECTIVE TREATMENT, before Hepatitis C was able to cause so many extrahepatic manifestations."

My point is, we do have effective treatments now and I truly wish more people realized how important it is to treat ASAP, not only to avoid Cirrhosis and HCC, but also to treat and get rid of the Hep C before they develop autoimmune disorders and/or other life altering or life threatening diseases which are caused by the Hep C virus.

As far as your fatigue, if it was me, I would see a competent Rheumatologist and get evaluated and tested for everything.

[ceanothus]

Thanks for posting this Pooh (and wow, you are a master at dealing with space limitations)! I just have to remind all that even if you had been diagnosed more quickly, the odds of getting rid of the virus were much lower back then. I acquired the virus (presumably) in a 1984 transfusion, and in 1986 I was already having full-blown extra-hepatic manifestations of autoimmune arthritis. Extensive testing over the first year revealed hepatitis (labelled non-A/non-B at that time) but nothing could be done for it. After it was identified as HCV I was in an early study with interferon and later had a very long treatment with interferon and ribavirin. Nothing worked until the triple tx came out so all I could do is try different rheumatology drugs for the autoimmune problems (which were always far more symptomatic than the liver problems). The earlier drugs almost certainly contributed to my rapid progression to cirrhosis by 2004. Now I've had the autoimmune problems for 27 years, and although my HCV is gone, I have no idea whether the autoimmune problems will ever resolve. Since eliminating the virus, I haven't yet shed very much of the fatigue that I developed during the last 10 years of HCV, and my hepatologist tells me that with the virus gone and my cirrhotic liver being very well compensated, I need to look elsewhere for the cause of my fatigue – he is convinced it is not my cirrhosis. I'm starting to think maybe I shouldn't have dismissed the long-ago rheumatologist who tried to diagnose me with fibromyalgia (back in 1990), especially since more current literature shows a high rate of fibromyalgia in people infected with HCV. After 27 years I'm STILL trying to find a way to get this stuff under control so I can function more normally!

[jules2551]

I think the main question is which came first...the chicken or the egg?  I don't think we will ever know.

[pooh55811]

I am hoping that by posting this article people will see that there are far more consequences of not treating Hep C than advancing liver fibrosis (which is bad enough).

I, too, have had my share of extrahepatic manifestations of Hep C. I only wish that I had been diagnosed sooner and had been able to treat years ago, before Hepatitis C was able to cause so many extrahepatic manifestations. I did treat within two months of being diagnosed but, alas, Hep C had about 37 years to reek havoc before I was diagnosed. Hopefully others will be diagnosed sooner than I was and will treat ASAP so that they will not develop as many extrahepatic manifesattions.

The above article lists only a handful of the extrahepatic manifestation that Hep C can cause. However, the extrahepatic manifestations listed in this article are serious and can be life threatening.

A longer list of extrahepatic manifestations, some of them very serious,  can be found here:

http://www.hcvadvocate.org/hepatitis/factsheets_pdf/Extrahepatic.pdf

[jules2551]

Very interesting post Pooh!  And Candyman I agree about the snowball effect.  I was first dx with HCV then a couple months later I was dx with PCT and hemochromatosis.  Even though I relapsed on tx I hope it gave my liver a break and that I didn't cross over into Cirrhosis land.  And I hope I don't add anymore EHM's to my resume.

Thanks Pooh

[pooh55811]

Medscape article continued:

Porphyria Cutanea Tarda

Porphyria cutanea tarda (commonly referred to as PCT) is recognised as the most prevalent subtype of porphyritic diseases. The disease is characterised by onycholysis and blistering of the skin in areas that receive higher levels of exposure to sunlight.[19, 20] The primary cause of this disorder is a deficiency of uroporphyrinogen decarboxylase (UROD), a cytosolic enzyme that is a step in the enzymatic pathway that leads to the synthesis of haem.[19] The disorder results from low levels of the enzyme responsible for the fifth step in haem production.[20] Haem is a vital molecule for all of the body's organs. It is a component of haemoglobin, the molecule that carries oxygen in the blood. Excess circulating iron has been shown to enhance toxic metabolite formation, which include oxidation products which inhibit UROD.[19]

Typically, patients who are ultimately diagnosed with PCT first seek treatment following the development photosensitivities in the form of blisters and erosions on commonly exposed areas of the skin.[19, 21] This is usually observed in the face, hands, forearms and lower legs. It heals slowly and with scarring.[20] Though blisters are the most common skin manifestations of PCT, other skin manifestations like hyperpigmentation (as if they are getting a tan) and hypertrichosis (mainly on top of the cheeks) also occur.[19] PCT is a chronic condition, with external symptoms often subsiding and recurring as a result of a number of factors. In addition to the symptomatic manifestation of the disease in the skin, chronic liver problems are extremely common in patients with the sporadic form of PCT.[20

Diagnosis

While the most common symptom of PCT is the appearance of skin lesions and blistering, their appearance in isolation cannot lead to a conclusive diagnosis.[19, 22] Laboratory testing will commonly reveal high levels of uroporphyrinogen in the urine, clinically referred to as uroporphyrinogenuria.[19, 21]

Treatment options include avoidance of sunlight, which precipitates the typical rash associated with PCT. In addition, smoking cessation and avoidance from alcohol is advised, especially in patients with hepatitis C,[19] although evidence to strongly support these measures specifically to PCT is limited.[23] More targeted treatments include regular venosection, with the aim of reducing iron stores to the lower limit of normal.[20] This in turn improves haem synthesis disturbed by ferro-mediated inhibition of UROD.[23] Clinicians must be careful not to cause anaemia in patients; therefore, interval phlebotomy must be tailored to the individual. Reducing the iron stores, and therefore, the potential detrimental effect on hepatocytes has been shown to improve the efficacy of HCV therapy.[21] A unit of blood is normally removed between twice weekly and once 3 weekly intervals with regular blood counts taken to avoid inducing anaemia, particularly pertinent if being treated with ribavirin.[20, 23] This is also the preferred therapy of choice in patients with a significant iron load.

If phlebotomy is not convenient or is contraindicated or for patients with relatively mild iron overload, oral chloroquine phosphate (125–250 mg per oral (PO) twice weekly) or hydroxychloroquine sulfate (100–200 mg PO 2–3 times/week), doses much lower than those used for antimalarial or photoprotective indications, can be effective, although significant caution has to be applied in patients with hepatitis C, where hepatoxicity can occur even at low doses of these medications.[22, 23] In obese patients, doses should be adjusted to ideal weight in order to avoid toxicity. Remission is often seen within 6–12 months.[23] All patients should receive regular ocular examination both before and during therapy, as recommended by the Royal College of Ophthalmologists. The following steps should be taken when initiating and monitoring hydroxychloroquine therapy (Table 5).

Summary and Conclusions

While hepatitis C is typically associated with liver dysfunction and progression to cirrhosis, its clinical presentation remains diverse and sometimes unexpected. Clinicians have to have a high index of suspicion and a knowledge of the EHM of HCV in order to not only treat the manifestation, but in initiated timely therapies for the underlying HCV.


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[pooh55811]

Medscape article continued:

Glomerulonephritis

Glomerulonephritis is defined as an inflammatory process which, in the case of hepatitis C, is due to immune dysregulation and an ineffective response by the body to deal with the HCV.[5, 15] The most common glomerulonephritis associated with HCV-related cryoglobulinaemia is membranoproliferative glomerulonephritis.[11] The pathophysiology of HCV-related glomerulonephritis is believed to involve deposition of immune complexes, anti-HCV immunoglobulin and an IgM subtype rheumatoid factor.[13]

Presentation ranges from hypertension, which is present in 80% of patients with an associated moderate renal insufficiency.[13] 20%–35% of patients may present as a nephrotic syndrome and up to a quarter of patients will be nephritic.[4, 15] However, 10% of patients will present with rapidly deteriorating renal function and warrant urgent referral to specialist nephrology services (Table 4).

Treatment is underpinned by aggressive hypertensive therapy with associated renin-angiotensin system blockade.[15] This is achieved using ACE inhibitors, angiotensin receptor blockers and diuretics. Patients tend to have high lipid and triglyceride levels and managing coronary risk factors have been proven to be beneficial.[15, 16] Treating the underlying HCV infection has not only been shown to clear the virus successfully but also in preventing or limiting renal damage.[15] Dual therapy with interferon and ribavirin has been shown to reduce viral load, as well as reduce proteinuria but has mixed success in improving glomerular filtration and creatinine levels, but studies have consistently shown that commencing antiviral therapy stabilises renal function.[17] Data also support prolonged therapy for at least 48–52 weeks, irrespective of early reductions in HCV loads at 12 weeks, but therapy can be considered for as long as 72 weeks in patients with non-responding viral load, but with biochemical and clinical improvements.[14] Caution has to be taken in using ribavirin at full dose as clearance is related to renal function.[14, 17]

In patients who present with rapidly progressive glomerulonephritis and nephritic syndrome, early aggressive therapy is crucial.[12] Plasma exchange is used in order to remove circulating cryoglobulins and hence reducing the insult on organs and tissues.[13] This is normally carried out by exchanging 3 litres, three times a week over 2–3 weeks. Pulsed steroid therapy in conjunction with plasma exchange has also been shown to be beneficial in correcting glomerular filtration dysfunction.[7, 16] Cyclophosphamide has been used to suppress B cell function during the acute phase of the illness by reducing cryoglobulin production.[10, 18] However, as discussed previously, more recent studies have not provided evidence to support its recommendation and is not currently recommended as first-line therapy.[14] More recent studies have looked at the potential role of rituximab in treating nephritic syndrome and glomerulonephritis. The rationale behind this research is the impact that the CD20 targeted antibody has on selectively targeting B cells, the driving force in cryoglobulinaemias.[18] Small studies have shown mixed benefits in reducing proteinuria and stabilising renal function, but no large randomised control studies have yet shown clear benefit and concerns remain over the potential to predispose patients to overwhelming sepsis.[13, 17, 18] There also remains concern that suppressing immune function leads, while improving renal disease, paradoxically increases circulating viral load, which has been shown in cyclophosphamide,[14] but not yet shown in rituximab.

Unlike the HCV, prognosis with glomerulonephritis is relatively poor and up to 50% of patients will progress to end stage renal disease[15] (figure 2).