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A Painful Connection: HCV, Cryo, and Neuropathy

By: Roger Smith

People with Hepatitis C who suffer numbness or tingling in their extremities know from experience there is an association between HCV and neuropathy. Increasingly, their claims are finding support: according to medical researchers and clinical physicians, there is a “very strong association” between hepatitis C virus and a blood condition called essential mixed cryoglobulinemia (EMC). Among other symptoms, EMC can cause nervous system abnormalities. Researchers have not yet explained the precise connection between HCV, EMC, and neuropathy, nor have they found significantly effective treatments, but knowledge is sure to increase as more people are diagnosed with HCV and its symptoms increasingly studied.

Neuropathy refers to any disease of the nervous system resulting from localized inflammation of the nerves. If symptoms appear in the body’s extremities, the condition is called “peripheral neuropathy,” and most HCV-related neuropathies are of this sort. Patients complain of numbness, tingling, and muscle weakness. A physical examination may also reveal decreased deep tendon reflexes. Occasionally, arm and back pain occurs. One patient has even blamed the nerve inflammation for lost teeth.

If symptoms derive from brain malfunction, the condition is an encephalopathy, or central nervous system disease, and the symptoms are more sinister than those of peripheral neuropathy. A team led by George W. Petty reported two cases of encephalopathy in HCV-infected patients in the July 1996 issue of the Mayo Clinic Proceedings. In both cases small vessels in the brain became inflamed, impairing blood flow. One patient had numbness in the right lip, hand, and leg, weakness in the right hand and arm, and word-finding difficulty. The other patient had headaches and seizures, although the latter may have come in part from medication for the headaches.

In both peripheral neuropathy and encephalopathy the key physiologic change is the inflammation of blood vessels (vasculitis). The hepatitis C virus probably does not inflame the blood vessels directly. Instead, the vessels are responding to immune system products floating through the blood stream.

When the body senses an invasion by foreign organisms, such as HCV, chemical responses are triggered. Among those responses are various kinds of immunoglobulin, proteins that help kill the foreigners or regulate the immune response. For some reason * biologists are not sure why * these immunoglobulins can “glob” together and lodge on the walls of medium and small blood vessels.

The immunoglobulins that are involved are called cryoglobulins because they turn into a gel at cool temperatures (cryo comes from the Greek word for cold). Since cold temperature readily affects the small and middle-sized vessels in the body’s extremities, the cryoglobulins are most likely to form in them. It appears that this glob-and-lodge action causes the inflammation of blood vessels. Cryoglobulinemia is the condition of having cryoglobulins in the blood.

Cryoglobulinemia and HCV became linked when researchers found bits of HCV and HCV-specific antibodies trapped in globs of cryoglobulin. They speculated that the cryoglobulinemia was HCV-incited, occurring when cryoglobulins specifically attacked the hepatitis virus. Other organisms can cause cryoglobulinemia * cancerous lymph cells, for instance * but the HCV-related version always involves a particular mixture of two types of immunoglobulins. Hence, the “essential mixed” of EMC.

However, the link between HCV and EMC is not entirely straightforward. The chemical tests used to identify specific immunoglobulins and the blood assays used to spot HCV products are complex. Doctors do not order them routinely. As for neuropathies, unless there is an obvious reason to suppose they result from HCV infection, doctors are likely to assume that another, more common system-disturbing disease is responsible. Diabetes mellitus may cause very similar symptoms, for instance.

Medical journals have described only a few cases of the HCV-EMC-neuropathy connection. Reviews of the published literature found that 36 to 54 percent of HCV-infected subjects also had cryoglobulins. According to one study, 21 percent of those with the cryoglobulins showed symptoms, but the authors did not specifically mention neuropathy.

The article by Petty’s research team cited a handful of other reported cases of HCV-associated cerebral ischemia similar to their two but added that no detailed description of the condition is available. All the articles warn that their findings are exploratory, not definitive.

The experience of clinical gastroenterologists agrees with the research estimates. Mark Schiele, M.D., a gastroenterologist for Health First, Inc., in Portland, Oregon, estimates that fewer than one percent of HCV patients develop neuropathy. “In general,” he said, “it’s thought to be quite an uncommon manifestation of HCV infection.” Sandra Wilborn, M.D., also a Health First gastroenterologist, concurs. “It’s not something that has been clinically important to my practice,” she said. In fact, Dr. Wilborn has seen only four cases of cryoglobulinemia altogether, and she encountered them before research uncovered the HCV-EMC link. She typically cares for 25 new HCV-infected patients a year.

Dr. Wilborn emphasizes that the long-term effects of HCV infection are only slowly becoming clear because HCV is so recent a discovery. First identified in 1989 as a distinct viral type, HCV usually takes years to become symptomatic. Most patients are diagnosed with chronic HCV ten to 13 years following infection. Typically, about 20 years pass before the most common serious result, liver cirrhosis, appears. But, Dr. Wilborn points out, the virus causes a “cascade effect” from the immune system, and the symptoms that might come from the cascade, including neuropathy, are just beginning to surface in sufficient numbers to study.

It is a good thing that EMC-related neuropathy is uncommon, according to Dr. Schiele, because “it can be a very disabling consequence of viral infection.”

The standard treatment for HCV with EMC-caused neuropathy is interferon alfa, which is also the standard treatment for uncomplicated chronic HCV. Unfortunately, interferon alfa treatment eases EMC symptoms in only about one half to two-thirds of patients, and the side effects include headaches, cognitive changes, irritability, and depression. Still, current research supports long-term treatment with interferon alfa.

There are several possible new treatments in the pipeline, either used alone or in combination with interferon alfa. Ribavirin combined with interferon alfa apparently can trick the hepatitis C virus into becoming harmless by mimicking part of its RNA structure, although on its own ribavirin treatment has proven only partially effective. The antiviral agent amantadine has shown promise in clinical trials, and researchers are developing several HCV-specific protease inhibitors similar to those used to quell HIV retrovirus.


Mark Schiele, M.D., Gastroenterologist, Health First Medical Group, Portland, OR.

Sandra L. Wilborn, M.D., Gastroenterologist, Health First Medical Group, Portland, OR.

“Immunologic and Extrahepatic Manifestations of HCV Infection,” Linda Scully, Update on Liver Disease and Hepatitis Conference, Florida, June 4-8, 1997 (Webmaster@hepnet.com).

“Cerebral Ischemia in Patients with Hepatitis C Virus Infection and Mixed Cryoglobulinemia,” George W. Petty, et al., Mayo Clinic Proceedings, Vo. 71 (July 1966), pp. 671-678.

“Hepatitis C: A Multifaceted Disease,” by Subhash C.Gumbar and Sanjiv Chopra, Annals of Internal Medicine, Vol. 123, No. 8 (October 15, 1995), pp. 615-620.

“Serum Cryoglobulin and Chronic Hepatitis C Virus Disease Among Japanese Patients,” by Kazuma Tanaka, et al., The American Journal of Gastroenterology, Vol. 90, No. 10 (1995), pp. 1847-52.

“Summary of the NIH Consensus Development Conference

Statement on the Management of Hepatitis C,” Clinical Courier, Vol. 16, No. 4 (June 1997), pp. 1-8.

“Hepatitis C Virus Genotype Analysis In Patients with Type II Mixed Cryoglobulinemia,” Anna Linda Zignego, et al., Annals of Internal Medicine, Vol. 124, No. 1 (January 1, 1996), pp. 31-34.

“HCV Infection May Cause Mixed Cryoglobulinemia,” Salynn Boyles, Cancer Weekly Plus, July 22, 1996, pp. 20-22.

“Mixed Cryoglobulinemia and Hepatitis C Virus,” Vincent Agnello, Hospital Practice, Vol. 30, No.3, pp. 35-43.

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