Cardiomyopathy

Any disease that affects the heart. Often
associated with autoimmune disease and a
weakening of the heart muscle. A general
diagnostic term designating primary myocardial disease.
Often of obscure or unknown cause.

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

Chronic Fatigue

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

Cirrhosis

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.

Cognitive Dysfuntion

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:

Hepatitis C - Does Hepatitis C Affect The Brain?
 

Primary author: L. Kramer and colleagues, Department of Medicine IV,
University of Vienna, Austria
Author interviewed: Petra Steindl-Munda, M.D.

In brief: Non-cirrhotic hepatitis C patients were found to have some
subclinical impairment of cerebral function prior to combination therapy
with interferon and ribavirin. After 16 weeks of therapy, one measure of
cognitive function returned to normal range. Measures of health-related quality of
life did not improve.

Besides affecting the liver, hepatitis C is known to affect the central
nervous system more frequently than other liver diseases, causing
depression and fatigue. Similarly, patients with hepatitis C show greater impairment of health-related quality of life measures than do patients with hepatitis B.

Because no correlation has been found between fatigue and ALT level or
histologic severity of hepatitis, people have hypothesized that HCV may
directly affect the brain. To examine this possibility, this study aimed
to determine whether hepatitis C caused measurable but subclinical cognitive
impairment by using a highly sensitive, quantitative measure of brain
function. It also sought to determine whether treatment with combination
therapy improved cognitive function.

The patient population consisted of 83 non-cirrhotic patients with chronic
HCV infection treated at an Austrian hospital. Their mean age was 46 +/-
12 years (same as controls). The clinical diagnosis of HCV was made using
serum HCV antibodies in an enzyme-linked immunoassay and confirmed by PCR of HCV RNA in the absence of other causes of liver disease.

The study protocol involved use of the SF-36 questionnaire to measure
health-related quality of life. Fatigue was quantified by validated
questionnaires. Cognitive processing was measured using P300 event-related
potentials, a highly sensitive and objective test of cognitive function
that measures the brain's response to an acute audio stimulus. (P300 latency is
a measure of processing speed. P300 amplitude reflects the amount of
attention given to the stimulus.)

At baseline, patients with HCV showed a slower reaction time and a lower
amplitude than a control group of {number?} matched, healthy subjects. The
results showed a marked prolongation in the P300 latency in hepatitis C
patients of 359 milliseconds compared to 338 milliseconds for the control
group. Additionally, the amplitude of response was lower in hepatitis C
patients compared to the control group, as shown in the chart below.

P300 EVENT-RELATED POTENTIALS
HCV PatientsControls
Latency (milliseconds)359 +/- 37338 +/-16
Amplitude (microvolts)13 +/- 818 +/- 6

For purposes of comparison, measures of P300 potentials of HCV patients
are listed in the table below with the potentials of patients with other
diseases (as measured in other experiments). The effect of HCV infection was
similar to several other diseases, and latency was worse than in patients with
insulin dependent diabetes.

CEREBRAL DYSFUNCTION IN HCV INFECTION vs. OTHER MEDICAL CONDITIONS
P300 Latency
(milliseconds) P300 Amplitude
(microvolts) Mean Age
(yrs.)
Insulin Dependent Diabetes3421941
HCV Infection3591346
Uremia3861243
Wilson's disease382936
Carotid artery stenosis3961467
COPD3901362

In the second phase of the experiment, hepatitis patients were given a
standard regimen of interferon plus ribavirin combination therapy. Twenty
patients who started a 38-week course of interferon plus ribavirin
combination treatment had their P300 latencies measured at week 16. In
that group, the P300 latency was 349 milliseconds in that group of patients
returned to normal, to 336 in the majority of patients, according to Petra
Steindl-Munda, M.D., one of the study investigators. Dr. Steindl-Munda is
Professor of Medicine at the University of Vienna in Austria.

The study concluded that patients with chronic hepatitis C infection
exhibit a sub-clinical neurophysiological dysfunction that tended to improve with
antiviral combination treatment. But according to the data analyzed to
date, no clear correlation emerged between measures of hepatitis activity and
neurophysiological dysfunction.

Commentary

"The percentage of people with hepatitis C that complain about fatigue and
quality of life is much higher than in other liver diseases," Dr.Steindl-Munda said. "The idea was to see whether there is a correlation between this fatigue and quality of life and [histologic] activity of hepatitis to an objective measurement such as the P300."

Commenting on the limitations of the study, Dr. Steindl-Munda said results
were still being collected for the remaining 63 patients who are still
under treatment. She noted that the majority of patients who received 16 weeks
of antiviral treatment recorded a "normal." P300 latency of 336
[milliseconds].
"This was a significant difference," she said, comparing the
scores to those of HCV patients prior to treatment.

More data, she noted, were also needed to see if this finding continues
with the larger patient group. Additionally, the researchers will examine
whether the P300 potential scores will correlate any better with quality of life
measurements. "The results that we have already analyzed did not reveal any
correlation between quality of life, prolongation of P300, and activity of
hepatitis" she said. "But we will continue and see if there are any correlations that will come out."

Researchers will take P300 measurements at the end of combination therapy
(week 38) to compare them to week 16 results. Additionally, the study will
look at "whether the non-responder to treatment will return back to
normal, or whether there are any changes after the end of therapy," Dr. Steindl-Munda said.

Disclosure

This study was independently funded without contributions from any drug
company. The authors have no relations with Amgen Inc."

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:
 
Assessment of Fatigue and Psychologic Disturbances in Patients with Hepatitis C Virus Infection
www.natap.org/2001/jul/assessment070901.htm
 
HCV and Brain Dysfunction (report of this study at liver conference 2 years ago)
www.natap.org/2000/ddw/rpt_11.htm
 
HCV and Fatigue
www.natap.org/1999/aug/hcvandfatique82399.html
 
Abstract: Patients with chronic hepatitis C virus (HCV) infection frequently report fatigue, lassitude, depression, and a perceived inability to function effectively. Several studies have shown that patients exhibit low quality-of-l ife scores that are independent of disease severity. We therefore considered whether HCV infection has a direct effect on the central nervous system, resulting in cognitive and cerebral metabolite abnormalities. Twenty-seven viremic patients (HCV+) with biopsy-proven mild hepatitis due to HCV and 16 patients with cleared HCV were tested with a computer-based cognitive assessment battery and also completed depression, fatigue, and quality-of-life questionnaires. The HCV-infected patients were impaired on more cognitive tasks than the HCV-cleared group (mean [SD]: HCV-infected, 2.15 [1.56]; HCV-cleared, 1.06 [1.24]; P = .02). A factor analysis showed impairments in power of concentration and speed of working memory, independent of a history of intravenous drug usage (IVDU), depression, fatigue, or symptom severity. A subgroup of 17 HCV-infected patients also underwent cerebral proton magnetic resonance spectroscopy (1H MRS). The choline/creatine ratio was elevated in the basal ganglia and white matter in this group. Patients who were impaired on 2 or more tasks in the battery had a higher mean choline/creatine ratio compared with the unimpaired patients. In conclusion, these preliminary results demonstrate cognitive impairment that is unaccounted for by depression, fatigue, or a history of IVDU in patients with histologically mild HCV infection. The findings on MRS suggest that a biological cause underlies this abnormality. (HEPATOLOGY 2002;35:433-439.)
 
The HCV-infected group scored significantly worse on the power of concentration (P = .001) and on the speed of memory processes (P = .001) factor scores than the healthy controls.
 
With respect to the affective scores, the HCV-infected group scored worse on the Hospital Anxiety and Depression Scales.
 
There were no statistically significant differences in the subjects' assessment of fatigue in either the physical or mental domains, although there was a trend toward increased fatigue in the HCV-infected group. Similarly, with respect to the SF-36 quality-of-life scale, there were no differences between the 2 groups in the mental summary score. However, there was a significant difference in the physical summary score (P = .006), with lower ratings in the HCV-infected group.
 
Comments By Study Authors
 
These preliminary findings are consistent with cognitive and cerebral 1H MRS metabolite abnormalities in patients with histologically defined mild hepatitis due to HCV infection. The data support the clinical impression and assertions of many HCV-infected patients that they are cognitively impaired ("brain fog"). However, the mechanism underlying these findings remains to be defined.
 
The HCV-infected patients were found to be more depressed than the HCV-cleared group, as has been previously reported. There were no statistically significant correlations between the cognitive factor scores that were abnormal in the HCV-infected group and the depression scores, indicating that impairment on these tasks is unlikely to be secondary to depression. Furthermore, if depression was the sole explanation for cognitive impairment in the HCV-infected patients, it is unlikely that it would cause the selective cognitive impairments that we report.
 
A number of explanations may account for or contribute to the cognitive dysfunction observed in HCV-infected patients, including (1) a biological effect of HCV infection on the central nervous system, (2) the effect of personality or HCV acquisition-associated factors such as a history of IVDU, (3) the effect of affective disorders such as depression, or (4) the effect of subjectively experienced symptoms such as fatigue. It should be noted that these explanations are not necessarily mutually exclusive and might interact.
 
Patients with significant fibrosis or cirrhosis were excluded from the study, thereby excluding minimal hepatic encephalopathy as the cause of the abnormalities.
 
A history of serious drug usage that had stopped at least 2 years before participation in the study (and in most cases much earlier) did not have an impact on cognitive performance, regardless of HCV status.
 
The factor score analysis suggests that concentration and working memory processes may be preferentially impaired. These scores are derived from the summation of the reaction times on various tasks. We considered that the abnormalities might simply be a reflection of pure motor slowing as a result of a peripheral neuromuscular abnormality, but there were no differences in the simple reaction time between the 2 groups indicating impairment of central cognitive processes. Similar findings of slowed processing speed and impaired working memory are the most prominent features of cognitive dysfunction in patients with chronic fatigue syndrome. Such findings have also been reported in the medically asymptomatic stages of HIV infection and are consistent with the involvement of subcortical or frontostriatal brain systems.
 
Although every attempt was made to prevent selection bias in this study, we accept that the study populations may not be wholly representative of the HCV-infected population because they were drawn from a tertiary referral HCV clinic. In particular, it is possible that patients with worse symptoms, both physical and psychological, are more likely to attend the clinic. Conversely, the exclusion of patients who were taking antidepressants, comprising 20% of the initial recruits and possibly those HCV-infected patients who were most likely to have cognitive dysfunction, may have led to an underestimation of the level of cognitive impairment. The purpose of this study was to investigate whether cognitive dysfunction is a feature of HCV infection, whereas larger studies will be required to estimate the prevalence.
 
What may be the cause?
 
Using 1H MRS, the authors reported finding an increase in the basal ganglia and whitematter choline/creatine ratio in patients with chronic HCV infection.
 
Similar metabolite abnormalities in the same spatial distribution as those reported here have been extensively documented in cerebral HIV infection, both in neurosymptomatic and neuroasymptomatic individuals. In the case of HIV, infection of cerebral microglia, possibly via infected monocytes entering the brain, and subsequent microglial activation are believed to underlie the MRS changes. This raises the prospect that the metabolite abnormalities reported in this study are due to direct infection of the brain by HCV. The concept of extrahepatic replication of HCV is not novel, with several lines of evidence suggesting that peripheral blood mononuclear cells are infected. Microglia comprise up to 20% of all glial cells and are developmentally derived from bone marrow precursors of monocytic lineage. It is believed that resident microglia turn over slowly and are replaced by circulating monocytes. It is therefore possible that HCV may be introduced to the central nervous system via infected monocytes, through a "trojan horse" mechanism.
 
An alternative explanation for our findings is a centrally mediated effect of peripherally derived cytokines that may cross the blood-brain barrier. Although cytokines are large peptides, animal studies have demonstrated passage of cytokines including tumor necrosis factor , interferons alfa and gamma, and interleukins (IL) 1 and 1 across the blood-brain and blood-spinal cord barriers. Alternatively, peripherally derived cytokines may bind to the cerebral vascular endothelium, inducing the generation of secondary messengers. Intracerebral cytokines have been associated with immunologic, neurochemical, neuroendocrine, and behavioral activities. Indeed, treatment with interferon alfa is associated with a constellation of symptoms, including depression and reports of memory impairment and cognitive slowing. Whether elevated endogenous cytokines in chronic inflammatory and infective conditions exert a significant cognitive effect is unclear. Several studies have reported elevated levels of circulating cytokines, including IL-1, IL-2, IL-4, IL-6, IL-10, and tumor necrosis factor, in chronic HCV infection; however, a recent study found no correlation between levels of circulating IL-1, IL-6, tumor necrosis factor, and fatigue in chronic HCV infection.

Crohn's Disease/ Irritable Bowel

Inflammatory bowel disease (IBD) is a group of chronic disorders that cause inflammation or ulceration in the small and large intestines. Most often IBD is classified as ulcerative colitis or Crohn's disease but may be referred to as colitis, enteritis, ileitis, and proctitis. Ulcerative colitis causes ulceration and inflammation of the inner lining of the colon and rectum, while Crohn's disease is an inflammation that extends into the deeper layers of the intestinal wall. Crohn's disease also may affect other parts of the digestive tract, including the mouth, esophagus, stomach, and small intestine. Ulcerative colitis and Crohn's disease cause similar symptoms that often resemble other conditions, such as irritable bowel syndrome (spastic colitis). The correct diagnosis may take some time. In ulcerative colitis, the inner lining of the large intestine (colon) and rectum becomes inflamed. The inflammation usually begins in the rectum and lower (sigmoid) intestine and spreads upward to the entire colon. Ulcerative colitis rarely affects the small intestine except for the lower section, the ileum. The inflammation causes the colon to empty frequently, resulting in diarrhea. As cells on the surface of the lining of the colon die and slough off, ulcers (tiny open sores) form, causing pus, mucus, and bleeding. An estimated 250,000 Americans have ulcerative colitis. It occurs most often in young people ages 15 to 40, although children and older people sometimes develop the disease, too. Ulcerative colitis affects males and females equally and appears to run in some families. What Are The Symptoms Of Ulcerative Colitis? The most common symptoms of ulcerative colitis are abdominal pain and bloody diarrhea. Individuals also may suffer fatigue, weight loss, loss of appetite, rectal bleeding, and loss of body fluids and nutrients. Severe bleeding can lead to anemia. Sometimes individuals also have skin lesions, joint pain, inflammation of the eyes, or liver disorders. No one knows for sure why problems outside the bowel are linked with colitis. Scientists think these complications may occur when the immune system triggers inflammation in other parts of the body. These disorders are usually mild and go away when the colitis is treated. What Causes Ulcerative Colitis? The cause of ulcerative colitis is not known, and currently there is no cure, except through surgical removal of the colon. Many theories about what causes ulcerative colitis exist, but none has been proven. The current leading theory suggests that some agent, possibly a virus or an atypical bacterium, interacts with the body's immune system to trigger an inflammatory reaction in the intestinal wall. Although much scientific evidence shows that people with ulcerative colitis have abnormalities of the immune system, doctors do not know whether these abnormalities are a cause or result of the disease. Doctors believe, however, that there is little proof that ulcerative colitis is caused by emotional distress or sensitivity to certain foods or food products or is the result of an unhappy childhood. How Is Ulcerative Colitis Diagnosed? If you have symptoms that suggest ulcerative colitis, the doctor will look inside your rectum and colon through a flexible tube (endoscope) inserted through the anus. During the exam, the doctor may take a sample of tissue (biopsy) from the lining of the colon to view under the microscope. He or she may also recommend that you receive a barium enema x- ray of the colon to determine the nature and extent of disease. This procedure involves putting a chalky solution (barium)into the colon. The barium shows up white on x-ray film, revealing growths and other abnormalities in the colon. The doctor will perform a thorough physical exam, including blood tests to see if you are anemic (as a result of blood loss), or if your white blood cell count is elevated (a sign of inflammation). Examination of a stool sample can tell the doctor if an infection, such as by amoebae or bacteria, is causing the symptoms. If you have ulcerative colitis, you may need medical care for some time. Your doctor may recommend that you have regular check ups to monitor the condition. How Serious Is This Disease? About half of individuals have only mild symptoms. Others suffer frequent fever, bloody diarrhea, nausea, and severe abdominal cramps. Only in rare cases, when complications occur, is the disease fatal. There may be remissions periods when the symptoms go away that last for months or even years. However, most individuals' symptoms eventually return. This changing pattern of the disease can make it hard for the individual and his or her doctor to tell when treatment has helped. What Are The Treatment Options? While no special diet for ulcerative colitis is given, individuals may be able to control mild symptoms simply by avoiding foods that seem to upset their intestine. In some cases, the doctor may advise avoiding highly seasoned foods or milk sugar (lactose) for a while. When treatment is necessary, it must be tailored for each case, since what may help one individual may not help another. The individual also should be given needed emotional and psychological support. Recommended treatment for individuals with either mild or severe colitis is usually with the drug sulfasalazine. This drug can be used for as long as needed, and it can be used along with other drugs. Side effects such as nausea, vomiting, weight loss, heart burn, diarrhea, and headache occur in a small percentage of cases. Individuals who do not do well on sulfasalazine often do very well on related drugs known as 5-ASA agents. In some cases, individuals with severe disease, or those who cannot take sulfasalazine-type drugs, are given adrenal steroids (drugs that help control inflammation and affect the immune system) such as prednisone or hydrocortisone. All of these drugs can be used in oral, enema, or suppository forms. Other drugs may be recommended to relax the individuals or to relieve pain, diarrhea, or infection. In order to make a more informed decision about his or her health and well being, individuals are encouraged to ask his or her physician to explain the benefits, risks and costs of all diagnostic and treatment recommendations, including medications. Individuals with ulcerative colitis occasionally have symptoms severe enough to require hospitalization. In these cases, the doctor will recommend trying to correct malnutrition and to stop diarrhea and loss of blood, fluids, and mineral salts. To accomplish this, the individual may need a special diet, feeding through a vein, medications, or, sometimes, surgery. The risk of colon cancer is greater than normal in patients with widespread ulcerative colitis. The risk may be as high as 32 times the normal rate in individuals whose entire colon is involved, especially if the colitis exists for many years. However, if only the rectum and lower colon are involved, the risk of cancer is not higher than normal. Sometimes precancerous changes occur in the cells lining the colon. These changes in the cells are called "dysplasia." If the doctor finds evidence of dysplasia through endoscopic exam and biopsy, it means the individual is more likely to develop cancer. Individuals with dysplasia, or whose colitis affects the entire colon, should receive regular follow-up exams, which may involve colonoscopy (examination of the entire colon using a flexible endoscope) and biopsies. About 20 percent to 25 percent of ulcerative colitis patients eventually require surgery for removal of the colon because of massive bleeding, chronic debilitating illness, perforation of the colon, or risk of cancer. Sometimes the doctor will recommend removing the colon when medical treatment fails or the side effects of steroids or other drugs threaten the individual's health. Individuals have several surgical options, each of which has advantages and disadvantages. The surgeon and individual must decide on the best individual option. Again, in order to make an informed decision, ask the surgeon to fully explain the benefits, risks and costs of each option. The most common surgery is the proctocolectomy, the removal of the entire colon and rectum, with ileostomy, creation of a small opening in the abdominal wall where the tip of the lower small intestine, the ileum, is brought to the skin's surface to allow drainage of waste. The opening (stoma) is about the size of a quarter and is usually located in the right lower corner of the abdomen in the area of the beltline. A pouch is worn over the opening to collect waste and the individual empties the pouch periodically. The proctocolectomy with continent ileostomy is an alternative to the standard ileostomy. In this operation, the surgeon creates a pouch out of the ileum inside the wall of the lower abdomen. The individual is able to empty the pouch by inserting a tube through a small leak-proof opening in his or her side. Creation of this natural valve eliminates the need for an external appliance. However, the individual must wear an external pouch for the first few months after the operation. Sometimes an operation that avoids the use of a pouch can be performed. In the ileoanal anastomosis (pullthrough operation), the diseased portion of the colon is removed and the outer muscles of the rectum are preserved. The surgeon attaches the ileum inside the rectum, forming a pouch, or reservoir, that holds the waste. This allows the individual to pass stool through the anus in a normal manner, although the bowel movements may be more frequent and watery than usual. The decision about which surgery to have is made according to each individual's needs, expectations, and lifestyle coupled with weighing the benefits, risks and costs of the various options. If you are ever faced with this decision, remember that getting as much information as possible is important. Talk to your doctor, to nurses who work with individuals who have had colon surgery (enterostomal therapists), and to other individuals. In addition, read pamphlets and books, such as those available from the Crohn's & Colitis Foundation of America, before you decide. Most people with ulcerative colitis will never need to have surgery. If surgery ever does become necessary, however, you may find comfort in knowing that after the surgery, the colitis is cured and most people go on to live normal, active life. Source: National Institute of Diabetes & Digestive & Kidney Diseases, National Institutes of Health, U.S. Department of Health and Human Services

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 th