This Web Site is committed to the memory of Janis Morrow.
| Related Conditions Page Two Crohns Disease (Irritable Bowel) |
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Any disease that affects the
heart. Often Hepatitis C virus infection and cardiomyopathy. The importance of hepatitis C virus (HCV) infection has been recently noted in patients with cardiomyopathies. HCV RNAs were found in the hearts of patients with cardiomyopathies, and negative strands of HCV RNA were also detected in the hearts, suggesting that HCV replicates in myocardial tissues. In a collaborative research project of the Committees for the Study of Idiopathic Cardiomyopathy, HCV antibody was more frequently found in patients with cardiomyopathies than that found in volunteer blood donors in Japan. HCV antibody was detected in 5.4% seeking care in 5 academic hospitals. Various cardiac abnormalities were found, and arrhythmias was the most frequent. These observations suggest that HCV infection is an important cause of a variety of otherwise unexplained heart diseases. It is likely that antiviral agents such as interferons and ribavirin will be valuable in the treatment of cardiomyopathy due to HCV infection. AUTHOR: Matsumori A, Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine. SOURCE: Nippon Rinsho 1999 Feb;57(2):455-63
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The fatigue of chronic hepatitis C virus infection is more severe and difficult to treat, and is associated with greater feelings of anger and hostility than fatigue associated with other chronic non-liver diseases. This was the conclusion of Dr. Jagdeep Obhari, Digestive Diseases section, Baylor College of Medicine, Houston, Texas, United States. Dr Obhari and colleagues studied 149 subjects who were divided into five groups: healthy controls; patients with chronic hepatitis C virus (HCV) infection; HCV infection combined with chronic alcohol abuse; alcoholic liver disease; and chronic non-liver diseases. Total fatigue scores were higher in HCV-infected subjects than in any other group but this was not statistically significant. The fatigue with HCV infection did not improve with rest as effectively as in the other study groups. Said Dr. Obhari, "The current study shows that fatigue and psychologic disturbances occur frequently in chronic diseases. The fatigue experienced by patients with HCV infection is more severe and intransigent and responds poorly to relieving factors." He added that patients with HCV infection are more depressed and have greater feelings of anger and hostility compared with patients with non-liver chronic diseases. Dr. Dobhari suggests that proper management of the psychological symptoms may have a favourable impact on the quality of life of patients with HCV infection. SourceURL:http://www.docguide.com FATIGUE AFFECTING PEOPLE WITH LIVER DISEASE Why do patients with liver disease become fatigued and what can they do about it? One of the most common and debilitating symptoms among individuals with liver disease is fatigue. It is universal to all varieties of liver disease from Primary Biliary Cirrhosis to Chronic Hepatitis C. In some patients, fatigue begins several years after the diagnosis of liver disease is made. In others, it was the primary reason for seeking medical attention. In such individuals multiple visits are made to a variety of physicians in search of a cause of their extreme lassitude. Some patients even seek psychiatric evaluation, as an accompanying symptom is often depression. Fatigue may occur at any time of day but is most common in the morning about an hour after awakening. By 9 a.m. one may already feel the exhaustion of a full workday. Others describe weakness and a lack of energy throughout the entire day. Their usual "pep" is now gone. Even little tasks become more trying and around 4 p.m., they simply must lie down to take a nap. The treatment of fatigue can be challenging. First, a search for all other potential causes should be made, as some are easily treated. Thyroid disease and anemias commonly coexist with liver disease and can worsen any existing lethargy. Nutritional deficiencies as well as disturbances in fluid balance also contribute to exhaustion. Primary depression from causes other than liver disease lead to fatigue and may require pharmacological control. Finally, all medications that the patient is taking must be reviewed and the unnecessary ones eliminated. If all of the above conditions are corrected, and fatigue continues to persist, there are a few simple measures that may be of help. A healthy, low fat, well balanced diet, cessation of smoking, alcohol intake in moderation, and a daily exercise routine are all essential lifestyle adjustments. Any excess weight should be eliminated with a sound weight reducing diet. The demands of a hectic job or home life may need to be modified, as an overworked, overwhelmed person even without liver disease may suffer from fatigue. If possible, a 30-45 minute daytime nap can help to rejuvenate the patient, and may need to be incorporated into a schedule. Finally, one must remember that the treatment for fatigue does not come in a bottle as many medications, whether over-the-counter or prescription,may adversely affect the liver (as well as the wallet). One must always consult with the hepatologist prior to trying any new fad products that promise to cure fatigue. Copyright 1997 by Melissa Palmer, M.D. Fatigue
Fatigue and Hepatitis CBy Ian Campsall and C.D. Mazoff Fatigue is the most widely reported and documented symptom of hepatitis C; so much so that it is most often the sudden onset of fatigue that prompts many people to seek medical advice allowing their condition to be diagnosed. However, despite this fact, the debate over the exact nature of the relationship between fatigue and Hep C is ongoing This is not surprising considering the difficulty inherent in attempting to establish a definition of something that is entirely relative in its affect on an individual patient, while still retaining sufficient scope in that definition so that it can be applied to the majority of Hep C patients. Fatigue is relative in that, as a symptom, it presents itself mainly as an inability to participate in activities that were previously a central part of the patient’s life. This means, therefore, that fatigue is closely linked to the individual patient’s established lifestyle, and the degree to which it is affected. For example, the tri-athlete finds herself unable to compete, and the waiter finds that he can no longer cope with the stress of the job. The difficulty for researchers lies in creating a scale to measure fatigue that can meaningfully compare its impact on a large sample of people with different medical histories, levels of physical fitness, and lifestyles. As the number of people infected with Hep C are identified worldwide, this difficulty becomes increasingly complex. For the person living with Hep C this complexity has a much more immediate effect on his or her life. The person finds himself or herself in a situation in which access to treatment and benefits are dependant upon his or her ability to describe a symptom which may or may not be related to Hep C, and cannot be fully scientifically calculated. Furthermore, the term “fatigue” itself is somewhat misleading, or, at least ambiguous enough to cause confusion. To the non-Hep C community “fatigue” suggests a general tiredness similar to what you could expect at the end of a busy workweek. However, the levels of fatigue that some Hep C patients are facing are so extreme that they are unable to function on a day-to-day basis. The term identifies the general sensation, but does nothing to express the magnitude. Instead, Hep C patients are forced to use a word that denotes the common experience of sleepiness to try to describe a debilitating set of symptoms. Both Hep C patients and persons suffering from Chronic Fatigue Syndrome (CFS) have, to some degree, been stigmatized by the misleading name that their condition or symptom has been given. The word “fatigue” implies exhaustion, but fails to convey the debilitating effects that constant exhaustion has on a patient over time. A recent American study employing one hundred medical students found that if the name given to Chronic Fatigue Syndrome were changed, patients were likely to be considered more disabled and receive better care. CFS sufferers are not the only group to have initially had their illness dismissed as something less than an actual diagnosable disease or condition by institutionalized medicine. Thirty years ago patients with Multiple Sclerosis were often labeled as having “hysterical paralysis” rather than a serious debilitating disease. It was only through a combination of advocacy and scientific research that MS came to be recognized as the debilitating disorder that we now know it to be. Currently, CF and Hep C sufferers are still working to establish sufficient recognition and knowledge about their conditions so that they can have access to affordable treatment, and a level of benefits which allows them to live with dignity. In some cases physicians accept a patient’s description of fatigue without question; in other cases, they are less forthcoming. Some people have had their claims questioned; others have been called lazy, or have been told that they are mentally ill rather than physically ill. If the person is newly diagnosed and still attempting to come to an understanding of what kind of impact hepatitis C will have on his or her life, statements such as these serve only to increase their fear and confusion. The patient turns to the physician as someone who can interpret and explain the symptoms that he or she is experiencing and offer clarification and help. It is these kinds of misinterpretations that fuel the sense of rage and abandonment that many Hep C patients feel. While progress has been made in developing improved cooperation between patients, doctors, and healthcare policy makers, there is certainly more work to be done. Hep C patients have described levels of fatigue that are comparable to “being so thirsty that no amount of water would quench the sensation,” or being unable even to speak or sit up. One of the most tiring aspects of the fatigue is having to deal with symptoms that contradict one another. One person described his need to sleep as really being a need to retreat from low-level muscle and bone pain, as well as other painful bodily sensations, such as skin and limbs feeling as though they were simultaneously scalded and frozen. These changes in sensation, known as parasthesia, may cause a person to feel utterly disconnected from any sort of surrounding pace or rhythm. He or she simply wants to “curl up” and withdraw from the world to protect himself or herself from the overwhelmingly conflicting sensations. It is not necessarily a feeling of sleepiness comparable to what a person might feel at the end of a long day, but an inability to cope with such a massive wave of feelings and sensations all of which are at odds with one another. The combination of fatigue, parasthesia, and sense of being disconnected from the social world can lead to isolation from family and friends as well as to depression. The loss of energy can mean that patients do not feel like cooking or exercising and, consequently, do not eat properly which in turn means an even greater loss in energy, poorer health, and disrupted sleep patterns. Without help this process can develop into a vicious cycle and significantly lower the patient’s quality of life. Extended studies of the relationship between Hep C and fatigue are rare. One study conducted in 1999 at the Department of Hepatology, Mater Misericordiae Hospital and University College in Dublin Ireland used the Fatigue Impact Scale (FIS), a standardized questionnaire designed to assess a patient’s perceptions of the impact of fatigue on his or her ability to function, to try to define a correlation between the amount of liver damage and the level of fatigue. The study employed a cohort of Irish women who were PCR-positive for HCV genotype 1b, and had all been infected in 1977 after being inoculated with contaminated anti-D products. The researchers assessed the damage to the patients’ livers using the Knodell histological activity index (HAI) score on their previous liver biopsies. Both clinical and laboratory evidence of cryoglobulinaemia, Sjogren's syndrome, connective tissue diseases, autoimmune thyroid disease and glomerulonephritis were also recorded. While those who were infected with Hep C did have significantly higher FIS scores than the healthy control group—in other words they were more fatigued—the study did not find any statistical difference between those patients with more or less severe liver damage, nor between persons with autoimmune diseases and those without, or between patients previously treated with interferon and those who had not been treated. The study concluded that fatigue has a much more significant impact on persons infected with Hep C than upon those who are not. However, there was no correlation between the degree of damage to the liver and the level of fatigue, nor could the fatigue be explained only by the presence of other autoimmune disorders. While there is still a great deal of work to be done, both to advance our scientific understanding of the relationship between Hep C and fatigue and to improve the care available to patients who are having to cope with it, progress is being made. Studies on patients who have had a sustained response to treatment have shown a decrease in fatigue. Light exercise has also been helpful in improving energy levels. Of course, a physician should be consulted before beginning any new form of treatment. But, as one person noted, the best way to break out of the cycle of loneliness, isolation, and fatigue is to talk with other persons living Hep C and participate in building a strong community that can offer support and improve quality of life for all. Learn more about fatigue and HCV quality of life issues:
Copyright –2002 --- Hepatitis C Support Project – All Rights Reserved. Permission to reprint is granted and encouraged with credit to the Hepatitis C Support Project. October 2002
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The liver weighs about 3 pounds and is the largest organ in the body. It is located in the upper right side of the abdomen, below the ribs. When chronic diseases cause the liver to become permanently injured and scarred, the condition is called cirrhosis. The scar tissue that forms in cirrhosis harms the structure of the liver, blocking the flow of blood through the organ. The loss of normal liver tissue slows the processing of nutrients, hormones, drugs, and toxins by the liver. Also slowed is production of proteins and other substances made by the liver. What Is the Impact of Cirrhosis? Cirrhosis is the seventh leading cause of death by disease. About 25,000 people die from cirrhosis each year. There also is a great toll in terms of human suffering, hospital costs, and the loss of work by people with cirrhosis. What Are the Major Causes of Cirrhosis? Cirrhosis has many causes. In the United States, chronic alcoholism is the most common cause. Cirrhosis also may result from chronic viral hepatitis (types B, C, and D). Liver injury that results in cirrhosis also may be caused by a number of inherited diseases such as cystic fibrosis, alpha-1 antitrypsin deficiency, hemochromatosis, Wilson's disease, galactosemia, and glycogen storage diseases. Two inherited disorders result in the abnormal storage of metals in the liver leading to tissue damage and cirrhosis. People with Wilson's disease store too much copper in their livers, brains, kidneys, and in the corneas of their eyes. In another disorder, known as hemochromatosis, too much iron is absorbed, and the excess iron is deposited in the liver and in other organs, such as the pancreas, skin, intestinal lining, heart, and endocrine glands. If a person's bile duct becomes blocked, this also may cause cirrhosis. The bile ducts carry bile formed in the liver to the intestines, where the bile helps in the digestion of fat. In babies, the most common cause of cirrhosis due to blocked bile ducts is a disease called biliary atresia. In this case, the bile ducts are absent or injured, causing the bile to back up in the liver. These babies are jaundiced (their skin is yellowed) after their first month in life. Sometimes they can be helped by surgery in which a new duct is formed to allow bile to drain again from the liver. In adults, the bile ducts may become inflamed, blocked, and scarred due to another liver disease, primary biliary cirrhosis. Another type of biliary cirrhosis also may occur after a patient has gallbladder surgery in which the bile ducts are injured or tied off. Other, less common, causes of cirrhosis are severe reactions to prescribed drugs, prolonged exposure to environmental toxins, and repeated bouts of heart failure with liver congestion. What Goes Wrong in Cirrhosis? Cirrhosis results from damage to liver cells from toxins, inflammation, metabolic derangements and other causes. Damaged and dead liver cells are replaced by fibrous tissue which leads to fibrosis (scarring). Liver cells regenerate in an abnormal pattern primarily forming nodules that are surrounded by fibrous tissue. Grossly abnormal liver architecture eventually ensues that can lead to decreased blood flow to and through the liver. Decreased blood flow to the liver and blood back up in the portal vein and portal circulation leads to some of the serious complications of cirrhosis. Blood can back up in the spleen causing it to enlarge and sequester blood cells. Most often, the platelet count falls because of splenic sequestration leading to abnormal bleeding. If the pressure in the portal circulation increases because of cirrhosis and blood back up (note: this can also sometimes occur in severe cases of acute hepatitis and liver damage), blood can flow backwards from the portal circulation to the systemic circulation where they are connected. This can lead to varicose veins in the stomach and esophagus (gastric and esophageal varices) and rectum (hemorrhoids). Gastric and esophageal varices can rupture, bleed massively and even cause death. Hypertension in the portal circulation, along with other hormonal, metabolic and kidney abnormalities in cirrhosis, can also lead to fluid accumulation the abdomen (ascites) and the peripheral tissue (peripheral edema). Decreased bilirubin secretion from hepatocytes in cirrhosis leads to the back up of bilirubin in the blood. This leads to jaundice, the yellow discoloration of the skin and eyes. As the water-soluble form of bilirubin also backs up in the blood, bilirubin can also spill into the urine giving it a bright yellow to dark brown color. Abnormal biochemical function of the liver in cirrhosis can lead to several complications. The serum albumin concentration falls which can lead to aggravation of ascites and edema. The metabolism of drugs can change requiring dose adjustments. In men, breast enlargement (gynecomastia) sometimes occurs because metabolism of estrogen in the liver is decreased. Decreased production of blood clotting factors can lead to bleeding complications. Derangements in the metabolism of triglycerides, cholesterol and sugar can occur. In earlier stages, cirrhosis frequently can cause insulin resistance and diabetes mellitus. In later stages or in severe liver failure, blood glucose may be low because it cannot be synthesized from fats or proteins. Cirrhosis, especially in advanced cases, can cause profound abnormalities in the brain. In cirrhosis, some blood leaving the gut bypasses the liver as blood flow through the liver is decreased. Metabolism of components absorbed in the gut can also be decreased as liver cell function deteriorates. Both of these derangements can lead to hepatic encephalopathy as toxic metabolites, normally removed from the blood by the liver, can reach the brain. In its early stages, subtle mental changes such as poor concentration or the inability to construct simple objects occurs. In severe cases, hepatic encephalopathy can lead to stupor, coma, brain swelling and death. Cirrhosis of the liver can also cause abnormalities in other organ systems. Cirrhosis can lead to immune system dysfunction causing an increased risk of infection. Ascites fluid in the abdomen often becomes infected with bacteria normally present in the gut (spontaneous bacterial peritonitis). Cirrhosis can also lead to kidney dysfunction and failure. In end-stage cirrhosis, a type of kidney dysfunction called hepatorenal syndrome can occur. Hepatorenal syndrome is almost always fatal unless liver transplantation is performed.
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The development of problems
of normal mental status. Problems with memory sequencing, spatial
disorganization, trouble giving and following directions, difficulty
processing problems, slow intellectual speed, difficulty processing visual
and auditory information, forgetfulness, irritability, mental confusion,
inability to concentrate, impairment of speech and/or reasoning, light
headedness, or feeling in a fog, word finding problems, distractibility,
difficulty processing more than one thing at a time, inability to perform
simple math functions, problems with verbal recall, related motor problems,
disturbances in abstract reasoning, sequencing problems, memory
consolidation, short-term memories being easily distorted or perturbed. HCV and Brain Dysfunction We know that HIV enters the brain shortly after a person is infected with HIV. It does appear as though individuals with HIV may experience symptoms related to this such as reduced alertness or a slower thinking capacity due to HIV. At both recent liver conferences--DDW and EASL--two different research groups reported research findings suggesting that HCV in individuals with less advanced disease (non-cirrhotics or mild fibrosis) affects the brain and reduces its functioning capacity. This suggests to me that a person with both HCV and HIV may be affected even more with regards to brain functioning. Over the years people with HIV have complained about experiencing fatigue and/or itching. We now know that many people with HIV also have HCV, and that HCV can cause itching and fatigue. The findings reported at DDW and EASL suggest that HCV related fatigue may be associated with the affect of HCV on the brain. It's known that individuals with advanced cirrhosis can experience hepatic encephalopothy which can cause brain disorder, but it's important to bear in mind that the participants in the studies discussed below did not have such advanced HCV disease so the brain dysfunctioning found was not due to hepatic encephalopoathy. At DDW, Ludwig Kramer and a research group from the University of Austria, reported that "cognitive processing was subclinically impaired in patients as compared to healthy subjects". They studied the impact of HCV infection on sensitive markers of cognitive brain function. Fifty-eight noncirrhotic patients with chronic HCV infection (age, 45±13 years, mean±SD) were studied by P300 event-related potentials (an objective measure of cognitive processing) and by the SF-36 questionnaire for assessment of health-related quality of life. Findings were compared to 58 matched healthy subjects. He found that P300 test results were imparied in patients with HCV compared to healthy volunteers, and conluded that patients with chronic HCV infection in the absence of cirrhosis exhibit a subclinical neurophysiological impairment. Cerebral function, however, seems to normalize with antiviral treatment. Although it was not apparent to me if normalization was tied with significant reductions in HCV viral levels, my feeling is that improvements in cerebral function can improve with HCV treatment despite no HCV viral level reductions. More detailed data and discussion are available below at the end of this report. At EASL, DM Horton presented an oral talk on brain dysfunction in people with HCV for a UK research group from the Imperial College School of Medicine and St Mary's Hospital in London. First he reviewed two studies. He mentioned a UK study (Foster et al 1998) using the SF-36 questionaire, and reported people with HCV compared to normal controls scored worse in physical and social functioning, energy and fatigue, and other measures. These results were independent of intravenous drug use. In a large US (Johnson et al 1998), 309 IVDUs both with or without HCV were tested for depression and those with HCV (57.2%) were found to have significantly more depressive symptomology than those who were negative to hepatitis (48.2%). In an attempt to further define this neuropsychological syndrome, they administered a battery of neuropsychometric tests to 15 patients with histologically mild hepatitis C from liver biopsy. They tested for attention (included: simple reaction time, choice reaction time), working memory (numeric & spatial working memory), and secondary memory (delayed word recall). They found that patients with mild or minimal hepatis C from liver biopsy were slower in tests of working memory. He noted that although they were slow their accuracy on these tasks was preserved, and this has been described in chronic fatigue syndrome. There were no attention or secondary memory abnormalities. In the view of these findings they asked themselves if HCV infects cells in the CNS (central nervous system), does this cause cerebral metabolite abnormalities, and is cerebral HCV infection the cause of the observed neuropsychological symptoms? They carried out a proton cerebral magnetic resonance spectroscopy study to determine if metabolite abnormalities exist in the brain of patients with hitologically mild hepatitis C. They randomly selected 30 patients with biopsy proven mild or minimal hepatitis due to HCV. As well, they studied 29 matched controls, and 12 eAG+ve patients with chronic HBV. No patient in the HBV or HCV groups had significant fibrosis or cirrhosis. The researchers reported seeing metabolic abnormalities in the testing in those with HCV compared to both normals (volunteers) and chronic HBV patients. There were no statistical differences between the normals and those with HBV. These abnormalities were not due to hepatic encephalopathy. They described the abnormalities as being similar to those abnormalities observed in HIV. Again, no patient in this study had significant fibrosis or cirrhosis. None of the study participants had used IV drugs in the 6 months preceding the study. There was no statistical difference in the study results between those with or without prior drug use. Those with prior drug use had the same abnormalities as those who never used IV drugs. The researchers concluded that prior drug use did not affect the outcome of the study. Is there direct infection by HCV of the CNS? He presented a suggested potential model by which this could happen. Microglial cells in the brain turn over slowly and are replenished by circulating monocytes, possibly up to 30% in one year. Circulating monocytes are potentially infectable by HCV, and may carry the virus across the blood brain barrier into the brain and the microglial cells. Once in the cells they become activated and produce chemokines, cytokines, and neurosteroids which may mediate the neuropsychiatric symptoms described in this presentation. The question still remains--does HCV infect the microglial cells in the brain? The only way to answer this question is to conduct direct post mortem viralogic examination of brain tissue which is being currently undertaken at Imperial College School of Medicine in London. He also sugested that of equal or possibly greater importance is the possibility that the brain may act as a sancutary site for HCV allowing immune evasion and protection against antiviral therapy. He suggested that cessation of viral production from the liver may occur during phase 1 of viral decline after starting HCV therapy, but the slower viral decline during phase 2 may be due to a continued release of virus from the brain. He suggested that an alternative explanation for possible brain dysfunction seen with HCV could be that systemic cytokines cross the blood-brain barrier and may exert an effect. But he discounted this theory because in this study patients with HBV had normal spectroscopy. HCV antiviral therapy has been administered to the study patients and results are pending. In the study reported at DDW, and discussed above, the study authors reported therapy improved cerebral function, and they suggest their data may indicate a direct action of HCV infection on the brain. DDW abstract:
Gut Nov 2006;55:1535-1537 D M Forton Department of Gastroenterology and Hepatology, St George's Hospital, University of London, Blackshaw Rd, London SW17 0QT, Fatigue, depression, and complaints of mild cognitive impairment, such as poor concentration and forgetfulness, are the commonest symptoms reported by patients with chronic hepatitis C virus (HCV) infection.1 Yet there remains considerable debate as to whether theses symptoms are caused by the virus itself. Fatigue is a multidimensional symptom with multiple, sometimes coexisting, determinants which may be biological, psychological, or sociological. It is an important cause of impaired health related quality of life (HRQL) in HCV infection.2 Numerous surveys have documented high prevalences of fatigue but consistently show no relationship with the degree of liver fibrosis, markers of inflammation, or viral load.3 This has led to the conclusion that there is no causal relationship between HCV and neuropsychological symptoms.4 Rather, psychological processes associated with diagnostic labelling, social functioning, anxiety about treatment, substance abuse, and depression have been invoked to account for impairments in HRQL.5,6 In contrast, a number of neuroimaging studies, including a single photon emission computerised tomography (SPECT) study published in this issue by Weissenborn and colleagues,7 have suggested that measurable abnormalities exist within the central nervous system (CNS) in a proportion of HCV infected individuals (see page 1624).8,9,10,11 The issue has tended to become polarised between functional and biological arguments, and the likely interaction between physical and psychological factors has been relatively ignored. Attempts have been made to control for relevant confounding factors to determine whether CNS dysfunction relates directly to HCV infection. In a carefully executed study where 300 HCV infected patients were screened for potential risk factors for cognitive impairment such as cirrhosis, psychiatric comorbidity, or previous substance abuse, a highly selected cohort of only 37 patients was identified to have no likely cause for cerebral dysfunction, other than HCV infection itself.11 This small group underwent cognitive testing and patients were found to have significant impairments in learning efficiency, which did not relate to fatigue and depression, which were also reported. These findings followed on from previous studies which had demonstrated deficits in attention, learning ability, and memory in HCV infected individuals without cirrhosis.9,10,12 Cerebral magnetic resonance spectroscopy gives information on cerebral metabolism and has been used to test the hypothesis that a biological mechanism underlies the neuropsychological dysfunction in HCV infection. Four published studies have showed significant alterations in cerebral choline (Cho) and N-acetylaspartate (NAA) in HCV infected patients without cirrhosis.8,9,10,11 The findings of elevated Cho and reduced NAA mirror those reported in human immunodeficiency virus (HIV) infection,13 a virus which is tropic to the CNS. Detection of replicative intermediates of HCV (negative strand RNA) within the CNS14 and different viral variants in the CNS, liver, and serum15 support the concept of low level HCV replication within the brain. Although the mild neurocognitive impairments seen in HCV infection are not progressive as in AIDS dementia, it has been suggested that they may result from cerebral immune activation, possibly as a result of CNS infection by HCV.9 There is some clinical evidence that ondansetron, a serotonin type 3 receptor antagonist, may ameliorate HCV associated fatigue.16 In view of this and the evidence of cognitive and cerebral metabolic abnormalities in HCV infection, Weissenborn and colleagues sought to determine whether altered monoaminergic neurotransmission is associated with cognitive dysfunction in selected patients.7 They studied 20 patients with exposure to HCV, 16 of whom were still viraemic and four who had no detectable virus in serum, as determined by polymerase chain reaction (PCR). Patients had been referred to a tertiary hospital neurology clinic for assessment of fatigue and cognitive decline. In agreement with previous studies, these patients displayed varying degrees of neurocognitive impairment, predominantly in the domain of attention. They also recorded high rates of depression, anxiety, and fatigue. The four PCR negative patients appeared to be equally impaired on all scales. Patients were studied with SPECT to measure serotonin and dopamine transporter binding capacity (SERT and DAT, respectively). Statistically significant reductions in hypothalamus/midbrain SERT and striatal DAT binding were found compared with healthy controls. Pathological SERT and DAT binding were evident in 50-60% of HCV exposed cases, including three of the four PCR negative patients. There were no correlations between the SPECT data and fatigue, mood, or HRQL. However, patients with impaired DAT or DAT and SERT binding did worse as a group on the cognitive tests compared with both healthy controls and HCV infected patients with normal SPECT measurements. These novel findings are interpreted as implicating a role for disturbed monoaminergic neurotransmission in the pathophysiology of HCV-associated cerebral dysfunction. A number of lines of less direct evidence support this conclusion. The therapeutic use of cytokines such as interleukin 2 (IL-2) and interferon (IFN-a) is associated with the induction of depressive symptoms in patients with cancer or viral hepatitis.17 These symptoms respond to treatment with the selective serotonin reuptake inhibitors, which are active at the presynaptic serotonin transporter.18 This has led to research into the immune basis of depression by investigators within the psychoneuroimmunological community.19 Interactions between the immune system and serotonergic neurotransmission have been demonstrated at a number of levels, both peripherally and within the CNS. Cytokine receptors are expressed on glia and neurones within the brain. Peripherally derived cytokines may signal to the CNS through a number of pathways,20 including induction of proinflammatory cytokines by perivascular macrophage-like cells, saturable transport across the blood brain barrier at high concentrations, and an action on afferent nerves to the CNS such as the vagus nerve.21 This mechanism may be particularly relevant in HCV infection where the cytokine milieu in the liver, innervated by the vagus nerve, is deranged. Although the basal level of cytokine production within the brain is likely to be low, a network exists whereby cells, particularly microglia, may produce cytokines in response to peripheral signals. For example, peripheral administration of lipolpolysaccharide to rats results in intracerebral IL-1β production.22 Cerebral immune activation may alter the metabolism of key monoamines (for example, IL-1β increases expression of the serotonin transporter gene in vitro).23 There is also evidence that IFN-a increases serotonin uptake in vitro through increased expression of the serotonin transporter,24 and that intracerebroventricular injections of IFN- in rats reduce frontal cortex and midbrain serotonin concentrations in a dose dependent manner.25 Studies of IFN-a administration in humans have generated data on serotonin metabolism. IFN-a increases serum kynurenine (KYN) concentrations and reduces serum serotonin and tryptophan (TRP) concentrations and these changes have been shown to correlate with depression ratings.17,26 The mechanism whereby this occurs is thought to be related to induction by IFN- of the enzyme indoleamine 2,3-dioxygenase (IDO), expressed on immune cells, including microglia.27 IDO catalyses the conversion of TRP to KYN, reducing the availability of TRP for serotonin synthesis. There is also evidence that endogenous cytokine production in states of chronic immune activation, such as HIV infection or rheumatoid arthritis, may results in TRP depletion and high KYN levels, expressed as an increased KYN/TRP ratio.28 For example, in HIV infection, elevated KYN/TRP correlates with levels of IFN- and neopterin,29 suggesting that in states of chronic Th-1 type immune activation, IDO is induced. Furthermore, an association between TRP depletion and cognitive impairment has been reported in HIV infection.30 To date, there are no data in chronic HCV infection but a similar interaction seems possible. There are therefore a number of possible mechanisms through which peripheral and central immune activation could result in alterations in monoaminergic neurotransmission in HCV infection. These mechanisms remain theoretical and untested in HCV infection. Given the complexity of these systems and the possibility of changes in regulation of monoaminergic transporters and receptors over time in chronic disease, the functional significance of the findings of reduced midbrain SERT and striatal DAT binding in this study remains unclear. Although the role of these brain regions in cognitive processing is not resolved, the findings in this study do implicate a role, or at least an association, between disturbed monoamine function and cognitive function in HCV infection. Indeed, the concept of cerebral immune activation as the basis for these changes may allow a model that incorporates both the biological and psychological theories to date. Animal data suggest that psychogenic stressors and proinflammatory cytokines may result in similar outcomes, in terms of neurotransmitter activity.20 This may go some way to explaining why reduced SERT and DAT binding were observed in three of the four patients who had cleared HCV from serum. As Weissenborn and colleagues7 have postulated, there may be a sustained CNS effect even after the virus has been eradicated from serum, which may result in some form of sensitisation, conferring increased vulnerability to psychogenic stressors. CNS symptoms are only present in a proportion of individual with HCV infection. In others it is a truly asymptomatic condition. It is likely that these symptoms result as a consequence of a complex interplay between viral and host genetic factors and external stressor events. Further investigation of the CNS effects of HCV infection and chronic immune activation may enable, in time, the development of strategies to treat the neuropsychological symptoms in those who do not respond to or tolerate antiviral therapy. REFERENCES 1. Poynard T, Cacoub P, Ratziu V, et al. Fatigue in patients with chronic hepatitis C. J Viral Hepat 2002;9:295-303.[CrossRef][Medline] 2. Kramer L, Hofer H, Bauer E, et al. Relative impact of fatigue and subclinical cognitive brain dysfunction on health-related quality of life in chronic hepatitis C infection. AIDS 2005;19 (suppl 3) :S85-92. 3. Goh J, Coughlan B, Quinn J, et al. Fatigue does not correlate with the degree of hepatitis or the presence of autoimmune disorders in chronic hepatitis C infection. Eur J Gastroenterol Hepatol 1999;11:833-8.[Medline] 4. Wessely S, Pariante C. Fatigue, depression and chronic hepatitis C infection. Psychol Med 2002;32:1-10.[Medline] 5. Barrett S, Goh J, Coughlan B, et al. The natural course of hepatitis C virus infection after 22 years in a unique homogenous cohort: spontaneous viral clearance and chronic HCV infection. Gut 2001;49:423-30.[Abstract/Free Full Text] 6. Rodger AJ, Jolley D, Thompson SC, et al. The impact of diagnosis of hepatitis C virus on quality of life. Hepatology 1999;30:1299-301.[CrossRef][Medline] 7. Weissenborn K, Ennen JC, Bokemeyer M, et al. Monoaminergic neurotransmission is altered in hepatitis C virus infected patients with chronic fatigue and cognitive impairment. Gut 2006;55:1624-30.[Abstract/Free Full Text] 8. Forton DM, Allsop JM, Main J, et al. Evidence for a cerebral effect of the hepatitis C virus. Lancet 2001;358:38-9.[CrossRef][Medline] 9. Forton DM, Thomas HC, Murphy CA, et al. Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease. Hepatology 2002;35:433-9.[CrossRef][Medline] 10. Weissenborn K, Krause J, Bokemeyer M, et al. Hepatitis C virus infection affects the brain\evidence from psychometric studies and magnetic resonance spectroscopy. J Hepatol 2004;41:845-51.[CrossRef][Medline] 11. McAndrews MP, Farcnik K, Carlen P, et al. Prevalence and significance of neurocognitive dysfunction in hepatitis C in the absence of correlated risk factors. Hepatology 2005;41:801-8.[CrossRef][Medline] 12. Hilsabeck RC, Perry W, Hassanein TI. Neuropsychological impairment in patients with chronic hepatitis C. Hepatology 2002;35:440-6.[CrossRef][Medline] 13. Meyerhoff DJ, Bloomer C, Cardenas V, et al. Elevated subcortical choline metabolites in cognitively and clinically asymptomatic HIV+ patients. Neurology 1999;52:995-1003.[Abstract/Free Full Text] 14. Radkowski M, Wilkinson J, Nowicki M, et al. Search for hepatitis C virus negative-strand RNA sequences and analysis of viral sequences in the central nervous system: evidence of replication. J Virol 2002;76:600-8.[Abstract/Free Full Text] 15. Forton DM, Karayiannis P, Mahmud N, et al. Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants. J Virol 2004;78:5170-83.[Abstract/Free Full Text] 16. Piche T, Vanbiervliet G, Cherikh F, et al. Effect of ondansetron, a 5-HT3 receptor antagonist, on fatigue in chronic hepatitis C: a randomised, double blind, placebo controlled study. Gut 2005;54:1169-73.[Abstract/Free Full Text] 17. Capuron L, Neurauter G, Musselman DL, et al. Interferon-alpha-induced changes in tryptophan metabolism. Relationship to depression and paroxetine treatment. Biol Psychiatry 2003;54:906-14.[CrossRef][Medline] 18. Kraus MR, Schafer A, Faller H, et al. Paroxetine for the treatment of interferon-alpha-induced depression in chronic hepatitis C. Aliment Pharmacol Ther 2002;16:1091-9.[CrossRef][Medline] 19. Wichers MC, Maes M. The psychoneuroimmuno-pathophysiology of cytokine-induced depression in humans. Int J Neuropsychopharmacol 2002;5:375-88.[CrossRef][Medline] 20. Hayley S, Merali Z, Anisman H. Stress and cytokine-elicited neuroendocrine and neurotransmitter sensitization: implications for depressive illness. Stress 2003;6:19-32.[Medline] 21. Bluthe RM, Michaud B, Kelley KW, et al. Vagotomy blocks behavioural effects of interleukin-1 injected via the intraperitoneal route but not via other systemic routes. Neuroreport 1996;7:2823-7.[Medline] 22. Nguyen KT, Deak T, Owens SM, et al. Exposure to acute stress induces brain interleukin-1beta protein in the rat. J Neurosci 1998;18:2239-46.[Abstract/Free Full Text] 23. Ramamoorthy S, Ramamoorthy JD, Prasad PD, et al. Regulation of the human serotonin transporter by interleukin-1 beta. Biochem Biophys Res Commun 1995;216:560-7.[CrossRef][Medline] 24. Morikawa O, Sakai N, Obara H, et al. Effects of interferon-[alpha], interferon-[gamma] and cAMP on the transcriptional regulation of the serotonin transporter. Eur J Pharmacol 1998;349:317-24.[CrossRef][Medline] 25. Kamata M, Higuchi H, Yoshimoto M, et al. Effect of single intracerebroventricular injection of [alpha]-interferon on monoamine concentrations in the rat brain. Eur Neuropsychopharmacol 2000;10:129-32.[CrossRef][Medline] 26. Bonaccorso SM, Marino VM, Puzella AM, et al. Increased depressive ratings in patients with hepatitis C receiving interferon-[alpha]-based immunotherapy are related to interferon-[alpha]-induced changes in the serotonergic system. J Clin Psychopharmacol 2002;22:86-90.[CrossRef][Medline] 27. Wichers MC, Maes M. The role of indoleamine 2,3-dioxygenase (IDO) in the pathophysiology of interferon-alpha-induced depression. J Psychiatry Neurosci 2004;29:11-17.[Medline] 28. Schrocksnadel K, Wirleitner B, Winkler C, et al. Monitoring tryptophan metabolism in chronic immune activation. Clin Chim Acta 2006;364:82-90.[CrossRef][Medline] 29. Fuchs D, Moller AA, Reibnegger G, et al. Increased endogenous interferon-gamma and neopterin correlate with increased degradation of tryptophan in human immunodeficiency virus type 1 infection. Immunol Lett 1991;28:207-11.[CrossRef][Medline] 30. Fuchs D, Moller AA, Reibnegger G, et al. Decreased serum tryptophan in patients with HIV-1 infection correlates with increased serum neopterin and with neurologic/psychiatric symptoms. J Acquir Immune Defic Syndr 1990;3:873-6.[Medline]
Hepatitis C and Cognitive Impairment Robin C. Hilsabeck, PhD Cognitive impairment, or difficulty in thinking
abilities, has long been recognized as a consequence of chronic
liver disease. However, until recently, cognitive impairment was
considered a complication of cirrhosis associated with hepatic
encephalopathy (HE). Patients with HE may demonstrate subtle
reversible cognitive difficulties, such as poor attention and
concentration, or they may suffer severe cognitive deficits, such as
disorientation and fluctuating consciousness that can result in coma
and death [1]. HE originally was thought to be a metabolic disorder
caused by the injured liver’s inability to remove toxins effectively
from the blood stream, which then were carried to the brain,
altering its function. Current theories postulate that HE might also
result from a variety of brain abnormalities, including vascular
changes, brain cell (e.g., astrocyte) swelling, hemorrhage, and the
deposition of certain metals in the brain stem [2-3]. New assessment
techniques also have identified particular brain structures and
functions that appear to be differentially affected by HE, resulting
from both acute and chronic liver disease [4-5].
Back to Medical Writers' Circle
Hepatitis C - Does Hepatitis C Affect The Brain?
Primary author: L. Kramer and colleagues, Department of Medicine IV, In brief: Non-cirrhotic hepatitis C patients were found to have some Besides affecting the liver, hepatitis C is known to affect the central
Because no correlation has been found between fatigue and ALT level or
The patient population consisted of 83 non-cirrhotic patients with
chronic The study protocol involved use of the SF-36 questionnaire to measure At baseline, patients with HCV showed a slower reaction time and a lower
P300 EVENT-RELATED POTENTIALS For purposes of comparison, measures of P300 potentials of HCV patients
CEREBRAL DYSFUNCTION IN HCV INFECTION vs. OTHER MEDICAL CONDITIONS In the second phase of the experiment, hepatitis patients were given a
The study concluded that patients with chronic hepatitis C infection Commentary "The percentage of people with hepatitis C that complain about fatigue
and Commenting on the limitations of the study, Dr. Steindl-Munda said
results More data, she noted, were also needed to see if this finding continues
Researchers will take P300 measurements at the end of combination therapy
Disclosure This study was independently funded without contributions from any drug
Ludwig Kramer, Edith Bauer, Harald Hofer, Georg Funk, Petra Munda-Steindl, Christian Madl, Peter Ferenci, Dept of Medicine IV, Univ of Vienna, Vienna, Austria; Univ Hosp of Vienna, Vienna, Austria; Dept of Medicine IV, Vienna, Austria. Fatigue and depression occur more frequently in chronic hepatitis C virus (HCV) infection than in other causes of chronic liver disease. However there is no correlation between severity of hepatitis and cerebral symptoms. It has been hypothesized that HCV exerted a direct effect on the brain. We studied the impact of HCV infection on sensitive markers of cognitive brain function. Fifty-eight noncirrhotic patients with chronic HCV infection (age, 45±13 years, mean±SD) were studied by P300 event-related potentials (an objective measure of cognitive processing) and by the SF-36 questionnaire for assessment of health-related quality of life. P300 latency is related to signal-processing speed; P300 amplitude reflects the amount of conscious attention paid to a stimulus. Findings were compared to 58 matched healthy subjects. We found that cognitive processing was subclinically impaired in patients (P300 latency: 361±38 ms, means±SD) as compared to healthy subjects (344±27 ms, p=0.01). Similarly, P300 amplitude was reduced in patients with HCV infection (12±7 vs. 18±7 µV, p<0.01). Health-related quality of life was significantly reduced in patients with HCV infection but there was no clear correlation between neurophysiological function and health-related quality of life or activity of hepatitis. In 7 out of 9 patients who were followed during antiviral combination treatment, P300 latency was improved after 12 weeks (345±29 ms) as compared to baseline (363±48 ms, p=0.08). In conclusion, patients with chronic HCV infection in the absence of cirrhosis exhibit a subclinical neurophysiological impairment. Cerebral function, however, seems to normalize with antiviral treatment. Our data might indicate a direct action of HCV infection on the brain. A theory that I've heard is that improvement from therapy is due to ribavirin because interferon does not enter the brain. But in HIV it's hypothesized that brain or cognivtive functioning may improve also because of improved immune function and not necessarily due only to direct antiviral drug affect in the brain or CNS. Study Reports Hepatitis C Impairs Cognitive Functioning: memory, concentration, depression This article is published in the current issue
of the journal called Hepatology. The authors report their findings from a
small preliminary study. They recommend further study is needed to confirm
their findings. These authors report patients in their HCV clinic who have
HCV appear to have cognitive impairment and more fatigue, depression, less
concentration ability, and less memory ability. The authors caution this is
a small preliminary study. They also caution that study bias is possible
because these patients were referred to the HCV clinic and so they may not
represent all patients such as those not referred to the clinic. Clinic
referrals may be sicker. The authors suggest two possible explanations for
these symptoms: (1) HCV may directly infect the brain similarly to the way
HIV infects the brain, (2) HCV may stimulate the immune system in a way that
dysregulates cytokine functioning causing these cytokines to be able to
enter the brain and cause dysregulation; this is discussed further near the
end of the article. These study findings are consistent with reports from
some patients with HCV, that they experience fatigue, anger, hostility,
anxiety and depression, and that they feel its associated with having HCV.
But, this association has not been well studied. This study was first
reported at liver meetings two years ago. In addition other studies have
reported similar findings. Here are a few links to these studies, and
related articles: |
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Cryoglobulinemia 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. Sources Mark Schiele, M.D., Gastroenterologist, Health First Medical Group, Portland, OR. Sandra L. Wilborn, M.D., Gastroenterologist, Health First Medical Group, Portland, OR.
Cryoglobulinemia and Hepatitis C
By Liz Highleyman Chronic hepatitis C virus (HCV) infection is associated with many long-term complications. Among these is cryoglobulinemia (also sometimes called cryoglobinemia), a condition in which abnor-mal proteins called cryoglobulins form in the blood. Although many people with hepatitis C have evi-dence of cryoglobulins in their blood, most do not experience symptoms. Cryoglobulins are made up of immunoglobulins (antibodies), substances produced by the body to fight infection. When the blood is cooled, 'the cryoglobulins clump together, or precipitate. This causes the blood to thicken or “gel,” thus restricting blood flow. In the general population, cryoglobuline-mia is rare; it occurs most often in people over age 40, and women are twice as likely as men to develop the condition. The cause of essential cryoglobulinemia is not known, but it is believed to have an autoimmune component. There are three types of cryoglobuline-mia (I, II, and III), classified by the makeup of the cryoglobulins; types II and III are mixed, meaning the cryoglobulins are made up of various antibody types. Secondary cryoglobulinemia is associated with an underlying disease, for example multiple myeloma, lymphoma, rheumatoid arthritis, or systemic lupus erythematosus. Essential mixed cryoglobulinemia types II and III are strongly associated with hepatitis C - so much so that some experts believe the "essential" should be dropped, since the condition is now known to be secondary to HCV. Although estimates vary widely, it appears that about half of people with chronic HCV have evidence of cryoglobulins in their blood. However, only an estimated 20% of these experience symptomatic cryoglobulinemia. Conversely, an estimated 80-90% of people with essential mixed cryoglobulinemia types II and III have HCV. For some people, cryoglobulinemia symptoms are their first indication that they have chronic hepatitis C. Cryoglobulinemia is more likely to develop in people with who have had HCV for longer periods of time and those who have developed cirrhosis (liver scarring). It is not known why hepatitis C is linked with cryoglobulinemia, but researchers increasingly believe that the presence of HCV itself somehow triggers the production of cryoglobulins; this is supported by the fact that cryoglobulin complexes often contain HCV genetic material and anti-HCV antibodies. Cryoglobulinemia is typically diagnosed by testing the blood for the presence of cryoglobulins. Because cryoglobulins precipitate when the blood is cooled and dissolve again when it is rewarmed, the test should be done immediately after the blood sample is drawn. Some people who show evidence of cryoglobulins on a blood test do not experience any symptoms. Others, however, may develop serious organ or tissue damage. Because cryoglobulinemia can affect almost any part of the body, it can lead to a wide variety of symptoms. The most characteristic signs of essential mixed cryoglobulinemia are general-ized weakness, joint pain (arthralgia), and purpura (purplish blotches on the skin). Cryoglobulinemia can lead to blood vessel, skin, and tissue damage - especially in the extremities -including vasculitis (blood vessel inflammation), Raynaud’s phenomenon (blood vessel spasms), livedo (red or purple marks on the skin due to restricted blood flow), hives, skin ulcers, and gan-grene (tissue necrosis or death). Some people experi-ence peripheral neuropathy (nerve damage), signaled by pain, tingling, numbness, or weakness in the hands or feet. Restricted blood flow and/or deposi-tion of cryoglobulins can damage organs such as the eyes, liver, and kidneys (deposition of immune com-plexes in the kidneys is known as glomerulonephritis). Cryoglobulinemia may also lead to spleen enlarge-ment, abdominal pain, weight loss, and cardiovascular problems such as heart attack or stroke. In some people, exposure to the cold makes cryoglobulinemia symptoms worse. In others, however, symptoms are intermittent, flaring up and subsiding for no apparent reason. In part because it is so uncommon, treatment of cryoglobulinemia is not very advanced. In many cases, doctors recommend ongoing monitoring rather than treatment. Most treatment strategies are intended to limit further tissue or organ damage. Treatment specifics will depend on the severity of symptoms and which parts of the body are affected. Medications that reduce inflammation or dampen the immune response seem to help control essential mixed cryoglobulinemia. The conditions is often treated with nonsteroidal anti-inflammatory drugs (e.g., acetominophen, aspirin, ibuprofen, and a variety of prescription medications), corticosteroids (e.g. prednisone), or immunosuppressive drugs (e.g., cyclophosphamide). Unfortunately, drugs that suppress the immune system make a person more susceptible to infections. In severe cases, plasmapheresis may be done, a proce-dure in which cryoglobulin-containing blood plasma is removed and replaced with donated plasma or a replacement fluid such as saline solution. If cryoglo-bulinemia is associated with another disease, treatment of that illness may reduce cryoglobulinemia symptoms. In people with HCV, studies have shown that treatment with interferon-alpha and/or ribavirin can improve cryoglobulinemia. There are steps people can take to minimize cryo-globulinemia symptoms.
http://www.hcvadvocate.org/200110/page5.cfm Skin Rashes and Hepatitis C
Symptoms May Relate to Other Organs While it is well known that chronic hepatitis C can lead to end stage
liver failure, most patients are often surprised to learn that infection may
manifest itself through symptoms related to another organ. This week's
update looks at two skin rashes that are highly associated with hepatitis C
infection. Mixed cryoglobulinemia is a disorder that can lead to the deposition of immune complexes in small and medium sized vessels. It often presents with a characteristic skin finding: palpable, purplish discoloration most common on the thighs. In addition, patients often complain of joint pains and aches. There is a strong association between hepatitis C infection and mixed cryoglobulinemia. Antibodies to, and RNA from hepatitis C are found in a large number of people with mixed cryoglobulinemia Antibodies to the hepatitis C virus can also be detected in biopsies of
the skin lesion. Furthermore, treatment with currently available interferon
therapy can lead to a decrease in viral RNA and, more importantly,
resolution of symptoms including the rash and arthritis.
Hepatitis C virus infection may be the cause of mixed cryoglobulinemia, according to a report from Italy. "Interferon alpha (IFN-(alpha)) seems to be an effective agent, able to induce complete regression of mixed cryoglobulinemia in only a few patients but obtaining symptomatic responses in most individuals," researcher Cesare Mazzaro et al. wrote ("Regression of Monoclonal B-Cell Expansion in Patients Affected by Mixed Cryoglobulinemia Responsive to INF-(alpha) Therapy," Cancer, June 15, 1996;77(12):2604-2613). "As in patients affected by HCV positive chronic liver disease only, the most important predictive factor for the response to antiviral therapy is the HCV genotype." Several previous studies have reported on the effectiveness of IFN- (alpha) in the treatment of patients with mixed cryoglobulinemia. Because of this, Mazzaro et al. sought to investigate the long term effects of this drug on clinical, hematologic, and virologic parameters in a group of 20 patients (13 women and seven men) affected by mixed cryoglobulinemia. In all patients, bone marrow biopsy, phenotyping of marrow cells, and polymerase chain reaction (PCR) immunoglobulin gene rearrangment in peripheral blood lymphocytes were performed before therapy and at the end of the follow-up. A liver biopsy was obtained in patients with biochemical signs of chronic liver disease. The presence of hepatitis C virus (HCV) RNA in serum was assessed by detection of anti-HCV antibodies, and by PCR amplification of the 5' untranslated region of HCV. The HCV genotype was also determined by PCR amplification of the core region of the virus with type-specific primers. The treatment schedule followed by all patients was three million units of recombinant IFN-(alpha) 2b three times weekly for one year. In six patients, the marrow histology before therapy showed a massive (more than 50 percent) monomorphous infiltration by plasmacytoid lymphocytes, indicating the presence of low grade non-Hodgkin's lymphoma. Anti-HCV antibodies were present in 19 (95 percent) subjects, and HCV RNA was detectable in all patients. In addition, all patients affected by Type II mixed cryoglobulinemia showed a monoclonal B-cell expansion in peripheral blood mononuclear cells (PBMC). With therapy, five patients (25 percent) achieved a complete response and 11 patients (55 percent) a partial response, whereas minor responses were observed in the remaining four patients (20 percent). One of the complete responders and all patients showing partial responses relapsed a few months after therapy withdrawal. At the end of the follow-up, four patients had obtained a complete remission. Bone marrow examination showed that B-lymphocytic monoclonal infiltrate disappeared in three patients. Moreover, these three patients had become negative for B-cell expansion in PBMC. Lack of response, or relapse, was associated with the presence of Type II HCV. "At present, there is increasing evidence that many lymphoproliferative disorders are related to infectious agents, such as Epstein-Barr virus infection in Burkitt's lymphoma and Hodgkin's disease, human T-cell leukemia virus-I in T-cell leukemia/lymphoma, and Helicobacter pylori in gastric B-cell lymphomas," Mazzaro et al. wrote. "Therefore, the possibility of preventing the transmission or curing the infection caused by these agents provides new opportunities for strategies against hematologic malignancies. In fact, a recent report showed the regression of gastric B-cell lymphoma after Helicobacter pylori eradication (Witherspoon et al., Lancet 1993;342:575-577) and it is likely that the extensive and systematic identification of this agent, and its elimination, might reduce the prevalence of gastric lymphomas in the near future. "In line with these observations, the possibility to induce regression of mixed cryoglobulinemia-associated B-cell monoclonal proliferation with IFN-(alpha) therapy could reduce the prevalence of hematologic malignancies such as immunocytomas." The corresponding author for this study is Gabriele Pozzato, Istituto di Medicina Clinica, Ospedale di Cattinara, Strada di Fiume 447, 34149 Trieste, Italy.
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