Open Wide - By: Tamra B. Orr
Summary:
If you have hepatitis C or any number of liver diseases, your dental health may be more important than you think

Story:
If you have hepatitis C or any number of liver diseases, your dental health may be more important than you think. In many instances, poor dental health can result in a patient’s being rejected for transplant. Even in less dire circumstances, problems with your teeth and gums are no laughing matter, and the risk of infection is greatly increased. In other words, you may not need that perfect smile to remain healthy or ensure your eligibility for transplant, but you should at least be concerned about maintaining good dental health. If not, you should probably take heed the next time a doctor tells you to ... Open Wide When you combine the conditions of hepatitis and dental problems, three issues tend to surface: the special dental concerns of the hepatitis patient, the risk of transmission to the dentist – now considered very low – and the strict dental requirements for the patient who needs a transplant. All three can cause stress and concern. To worry or not to worry For the most part, hepatitis patients do not have to worry about dental problems any more than the average person. “A hepatitis patient has the same responsibility to his or her teeth as every other citizen out there,” says Richard Darling, D.D.S. “They simply need to keep their teeth clean and free of plaque.” One study, published in the Australian Dental Journal in 2000, said there is some evidence that shows hepatitis patients are slightly more prone to tooth decay, but it is nothing serious. One problem that may show up in patients, especially those on antidepressants, is a chronic condition of xerostomia, or dry mouth. Saliva is much more than just spit. It cleans, lubricates and protects the teeth. If the amount of saliva in your mouth decreases, it can adversely affect those very same teeth. “If a patient has a dry mouth, the chance of dental caries (cavities) climbs,” says Dr. Martin Greenberg, chairman of the department of the at the . “Saliva protects the teeth from bacteria. Under management, we sometimes give extra fluoride treatments.” Besides having a mouth that feels like it is stuffed with cotton, xerostomia patients may have a sore tongue, gums or cheeks; frothy or foamy saliva; difficulty talking, eating and swallowing; bad breath; or sensitive teeth. If the condition persists, decay can accelerate. Simple help can be found in chewing gum or eating sugar-free candies, as well as in increasing your fluid intake. Another dental complication can come quite indirectly. “One-third of hepatitis patients on medication suffer depression and, thus, impaired perception of self-care,” says Darling. “They may take less care of their teeth, and problems will occur.” For the hepatitis patient who is searching for a dentist, it is considered respectful to let him or her know that you have the condition because it can potentially affect how he cares for you, what prescriptions he recommends and so on. “I care for a bunch of heppers and advise them that it is simply proper courtesy to notify the dental technicians and dentists about their diagnosis, as it has blood-borne risks. If a dentist runs away screaming into the wilderness when you tell him you have hepatitis, he is the wrong doctor for you anyway,” says Dr. Patricia Raymond, a physician in gastroenterology and general internal medicine, as well as author of the humorous “Don’t Jettison Medicine” and “Colonoscopy: It’ll Crack u Up” and host of the popular National Public Radio show “Housecalls.” “As a physician, I assume you have every possible infectious disease when you come into my office, and I take universal precautions.” This doesn’t mean you have to announce the fact over the phone to the entire front desk, however. “You don’t necessarily want to have this information stamped across all of your records,” says Dr. Raymond. “Ask to speak one-on-one with the dentist instead.” Simply share the information with those who need to know because they will be exposed. Letting the dentist know about your condition is just playing fair. Often he will ask to see your most current numbers and medical records as well. He has good reason to be cautious. Although some dentists might be worried about the risk of contracting the disease from an accidental needle stick, most of them just need to know the information before they can safely place you in the chair. For example, if you have a significant amount of cirrhosis, it can affect how your blood clots – or doesn’t. After a dental procedure like an extraction, a root canal or other work, your dentist needs to know if you’re going to have prolonged bleeding thanks to a lack of coagulation. Knowing what kind of medications you are on is also essential. If you have severe liver disease, for example, and are taking antibiotics, your ability to metabolize medications may be altered. Interferon can also occasionally cause mouth sores, which your dentist also needs to know. If you have already had a transplant, you will be more susceptible to several health problems (such as cold sores, herpes and yeast infections) due to the immunosuppressants you are taking so your body does not reject the new liver. Before the dentist uses any kind of anesthesia or analgesic on you for any procedure, he has to know what you are already taking so he can be aware of any problems or contraindications. That is simple medical common sense, and it not only protects him, but certainly protects you as well. But what about me? It isn’t unusual for a dentist to be concerned about treating a hepatitis patient. After all, this is a blood-borne disease, and they work pretty up close and personal with blood and saliva. In this day and age of barrier protection, however, that fear should be declining fast. “Dentists now use universal precautions,” says Dr. Greenberg. “That has really cut back on the problem. Basically, all patients are treated as if they have a contagious disease now. Because of that, transmission is almost unheard of.” “I feel that the biggest problem with dental care and hepatitis today is the lack of education,” says Dr. Bernstein, chief of the combined Divisions of Gastroenterology, Hepatology and Nutrition at and Long Island Jewish Medical Center in . “I have many dentists calling me every week about treating the hepatitis patient. This is a disease that is misunderstood, and they need this education.” Dr. Bernstein lectures to dental professionals in his area of about the epidemiology and stages of hepatitis so that dentists have a better concept of the condition. “It would be so nice to find a way to educate dentists so they do not have to keep calling and asking questions,” he says, “but that is a very big task.” On the list If you are on the transplant list, you already know that you have to be completely free of any dental disease before an operation will occur. “At the Department of Oral Medicine here at the , we have a service where all transplant patients get a full dental evaluation,” says Dr. Greenberg. “We must eliminate any possible oral influences on infection. While dental problems are not as serious with a liver transplant as they might be with a bone marrow transplant, for instance, it is still an important issue.” All transplant centers offer some kind of dental care for their patients, from the smallest sign of infection to having every tooth removed. Hepatitis is a condition that already has enough questions and concerns not to need any more. When it comes to dental health, the keys are simply remembering basic hygiene, reporting any anomalies to your dentist, being honest with him about your condition and treatment and, if possible, making sure he has the knowledge he needs so he will not be worried that his health is at risk with you as his patient. A Personal Perspective In the pamphlet “Dental Health and Hepatitis C” from the Australian Society for HIV Medicine Inc. ( www.ashm.org.au ), one patient recalls his experience with having the disease and his concerns about going to the dentist. “I’ve never disclosed that I have hep C to a private dentist, primarily because I’d be worried about their level of knowledge and their attitude. Will they make assumptions and value judgments? Will they be less attentive and less careful? Will they be less likely to repair or restore my teeth and more likely to just pull a tooth out? When you’re a patient, you don’t always know what a treatment decision is based on. I also worry about confidentiality. Will dental assistants and receptionists, as well as the dentist, respect my right to privacy? Do they have enough knowledge of the disease not to behave in a discriminatory manner?” A Story of Hope and Help Making sure you are free of dental disease can be an expensive part of treatment. Between the expense of that care, plus the astronomical cost of a liver transplant, it can be daunting, or even impossible. Just ask Julie Smith. She is in desperate need of a transplant, but first came the dental care. At age 32, she had such severe periodontal disease that she had to have all of her teeth removed. It was the more economical choice. Once her teeth were out, Julie struggled to eat – no easy chore. That is when dentist Richard Darling of the FAIR Foundation ( www.fairfoundation.org ) heard about her. (The foundation defines itself as “a national movement to reverse inequities in research funding distributions by the National Institutes of Health.”) Thanks to his help and the assistance of another health care provider, Dr. George Hardy, Julie got a complimentary full set of dentures. “She got them yesterday,” Darling says. “She was exceptionally happy and said that she felt she had a normal face again.” As the mother of three young children, this was especially important to her. Now that Julie has found hope, she needs help. Medicaid covers only half of the $450,000 fee for the transplant, medications and care. Darling is helping raise the rest of the money for Julie and urges all fellow physicians, dentists and other caring people to consider contributing also. You can check out the web site at www.geocities.com/save_julie /. Darling has reason to hope that the money will be found. Recently, the foundation raised $1 million to help another patient get a life-saving heart and liver transplant. Darling also knows the desperate need for a liver transplant on a personal level. He has had three of them due to hepatitis that he contracted from a blood transfusion years ago. He wrote of his experience with the transplants, as well as liver cancer, diabetes and a heart attack, in a book called “Coma Life” (www.comalife.org ). “The whole point of this is giving Julie hope,” Darling says.

http://www.hepatitismag.com/storydetail.asp?storyid=143

Hepatitis C and Dental Care

Alan Franciscus,
Editor-in-Chief, HCV Advocate

Poor dental health is a rising problem among people living with hepatitis C. Hepatitis C is associated with a wide range of dental problems ranging from dry mouth, tooth decay, gum infections, tooth sensitivity and mouth infections which can dramatically affect one’s quality of life.

The majority of patients with hepatitis C experience periods of having a dry mouth. The degree of dry mouth can also be made worse with medications that many patients with hepatitis C are taking including, but not limited to, anti-depressants and interferon. Saliva plays a key role in lubricating the mouth and is important in speaking, tasting and chewing the food that we eat. Saliva can also prevent viruses, fungus and bacteria from causing infections in our mouths that can lead to tooth decay and gum disease. A dry mouth in of itself can be frustrating and can be improved by frequently sipping water, chewing sugarless gum that will stimulate the salivary glands in your mouth to release saliva or by using a saliva substitute which can be purchased in your local pharmacy.

As a result of dry mouth and lack of saliva for protection, patients with hepatitis C need to be concerned about tooth decay. Tooth decay in the early stages is reversible so regular dental check-ups are important especially while on HCV medications. Other things that you can do to prevent tooth decay is to include good oral hygiene, using a soft toothbrush and fluoride toothpaste. Also reduce your carbohydrate (sugar) consumption, cut back on your intake of sweetened foods and beverages high in sugar. Again, chewing sugarless gum is good as it helps with saliva production and can also neutralize the acid that causes the tooth decay.

The first sign of a gum infection is most likely to be bleeding from the gum margin usually as a result of brushing your teeth, which can increase the risk for transmission. Other signs which would indicate more advanced gum infection include swelling and redness of the gums, receding gums, loose teeth, a bad taste or halitosis (bad breath). The main cause of gum infection is plaque which is a colorless sticky film of bacteria that forms on the teeth, produces toxins and causes inflammation. Patients with hepatitis C who are taking interferon therapy or those with cirrhosis have a much lower resistance to gum infection than others. In addition, hepatitis C patients who smoke worsen this gum condition. Gum infection can be reduced with appropriate thorough tooth brushing with a soft toothbrush angled at 45 degrees to the gum margin, as well as dental floss use. Dental floss should be passed gently between the teeth and rubbed up and down to the gum margin.

People with hepatitis C will sometimes complain of having sensitive teeth. If enamel is lost from the surface of the tooth or if the root surface is exposed this can cause sharp pain when exposed to hot or cold extremes. Causes of sensitive teeth include poor brushing, erosive foods (including lemons, grapefruit, vinegar and soda) frequent vomiting or gastric reflux and grinding of teeth most commonly during sleep. There are desensitizing toothpastes on the market as well as gum guards for people who are prone to grinding their teeth.

As discussed earlier, patients with hepatitis C often experience dry mouth due to lack of saliva production. This lack of saliva production can also cause mouth infections as bacteria, viruses and fungus can flourish, resulting in patients with hepatitis C being more prone to mouth ulcers and thrush. Thrush is an overgrowth of a yeast (fungus) called "candida." The medical name for thrush is candidiasis. In the mouth, thrush looks like creamy white patches or small red spots on the tongue, roof of the mouth (also called the hard palate), gums or throat. Crusting on the corners of the mouth is also a symptom of thrush. Thrush can make it difficult or painful to swallow and can cause chest pain. It can cause nausea and make your food taste different. This is further exacerbated when on interferon therapy. Daily intake of natural yogurt may help with thrush but, if that is not effective, thrush can be resolved by using a medicine called nystatin.

October 2002

Depression

Why Depression is Likely With Hepatitis C

January 19, 2009

Physicians are finding an increasing correlation with HCV infection and clinical depression. Learn about the four possible mechanisms linking depression with Hepatitis C, as well as the role standard combination therapy may play in this relationship.

by Nicole Cutler, L.Ac.

As the most common blood borne viral infection today, the Hepatitis C virus (HCV) is a major cause of chronic liver disease and affects an estimated 180 million people worldwide. For many living with HCV, the standard therapy of peginterferon-alfa and ribavirin is either not an option or it was unsuccessful. Whether an HCV-infected person has not attempted standard therapy or is a non-responder, physicians are finding an increasing correlation with HCV infection and clinical depression. Being aware of depression’s prevalence among this population and its potential mechanisms will encourage both patients and their physicians to take depression seriously.

Defining Depression
According to the Diagnostic and Statistical Manual for Mental Disorders (DSM-IV), major depressive disorder is characterized by a period of depressed mood or anhedonia (inability to experience pleasure from normally pleasurable life events such as eating, exercise, social or sexual interaction) occurring for at least two consecutive weeks. Depressed mood or anhedonia must also be accompanied by at least four of the following:

· Overwhelming sadness or emptiness
· Lack of interest or pleasure in daily activities
· Appetite or weight changes
· Disturbed sleep patterns
· Changes in psychomotor activity
· Fatigue or loss of energy
· Feelings of guilt or worthlessness
· Difficulty focusing, concentrating or making decisions
· Recurrent thoughts of death or suicidal ideation

A result of inconsistent measures of depression, calculating the actual prevalence of depression among patients with chronic HCV infection is challenging. Nevertheless, most researchers and physicians agree that the prevalence of depressive disorders is significantly higher among HCV-infected patients compared with the general population. According to the DSM-IV criteria, reported prevalence rates for major depressive disorder are higher in those with HCV:

· Ranging from 24 to 70 percent with chronic Hepatitis C infection
· Ranging from 6 to 10 percent in the general population

HCV Treatment
Hepatitis C’s current standard of treatment consists of combination therapy with peginterferon-alfa and ribavirin for 24 or 48 weeks depending on viral genotype. Although the treatment response rates are favorable for those able to complete this therapy, many must abandon the treatment protocol due to combination therapy’s severe side effects. Some studies indicate that chemically-induced depression occurs in approximately 20 to 40 percent of treated patients. Administering physicians have observed that depression associated with HCV therapy reduces the likelihood of eliminating the virus with peginterferon-alfa and ribavirin, due to patient non-compliance or even premature discontinuation.

Possible Mechanisms
The various factors contributing to major depressive disorder makes it difficult to establish a causative relationship between HCV infection and depression. The origins of depression with Hepatitis C are most likely a combination of physiological characteristics of the virus, emotional and physical health of the individual, the extent of a person’s social support network, personal beliefs and available treatment options. Following are four potential mechanisms connecting chronic HCV infection and depression:

1. Pre-Existing Condition – This theory suggests that having a psychiatric disorder, such as depression or posttraumatic stress disorder, can lead to high-risk behaviors increasing the probability for HCV infection, such as intravenous drug use or unprotected sexual practices. According to this premise, HCV itself is not the causative agent for depression, but there is a high prevalence of depression in individuals who engage in risky behaviors. Several studies have found higher incidences of drug use and unsafe sexual practices among patients with major depressive disorder or other depressive symptoms.

2. Psychological Impact of HCV – This theory suggests that depression related to HCV infection is due to the psychological burden and distress associated with this chronic disease. Foster and colleagues demonstrated that in a sample of HCV-infected patients without cirrhosis, quality of life scores were reduced, particularly regarding mental health and physical function, when compared with a control group. Many health experts are recognizing that chronic Hepatitis C virus infection alone leads to physical symptoms capable of reducing a person’s quality of life, the springboard for depression.

3. Biological Result of HCV – This theory describes the potential for the Hepatitis C virus to negatively affect the central nervous system bringing about depression. Although not directly proven, this hypothesis is supported by studies demonstrating that HCV directly causes fatigue and other neuro-cognitive symptoms. Adair and colleagues used gene expression analysis to evaluate gene expression in HCV-infected patients and a control group. The researchers found a difference in the expression of 29 genes, including those involved in brain oxidative and energy metabolism. These findings support a biological basis for the link between HCV infection and depression. Additionally, Hepatitis C viral particles noted to cause chemical changes that could initiate depressive symptoms have been found in the central nervous system.

4. Psycho-Spiritual Perception – Best-selling author and motivational speaker, Esther Hicks, describes depression as a location on one extreme edge of an emotional scale. On one end of this scale, good feelings are likened to the perception of freedom; on the other end bad feelings are likened to the perception of bondage. Bondage, otherwise felt as lack of freedom or control, embodies the empty sensation of depression. According to this psycho-spiritual theory, Hepatitis C is often associated with depression, because many affected feel that their ability to recover from this illness is beyond their control. Such feelings of hopelessness in those with Hepatitis C may occur when those affected:

· Are informed their disease is incurable
· Feel doubtful about ridding themselves of Hepatitis C
· Experience severe side effects from standard therapy, causing the perception that their condition is worsening – further confirming a loss of control over their health

By accumulating hopefulness about a Hepatitis C diagnosis, a person will naturally progress on the emotional scale away from fear, and thus away from depression.

Patients and their physicians must be aware of the simultaneous presentation of HCV and depression, the role combination therapy may play in this relationship and the four possible mechanisms linking depression with Hepatitis C. Armed with this knowledge, we can be proactive in addressing major depressive disorder as affiliated with chronic Hepatitis C infection.

References:

http://clinicaloptions.com, Risks and Mechanisms of Depression in HCV, Michael R. Krauss, MD, PhD, Depression Associated With HCV Infection and Its Therapy: Impact on Patient Management, Clinical Care Options, LLC, March 2007.

http://jac.oxfordjournals.org, Interferon-induced depression in chronic hepatitis C, Y. Horsmans, Journal of Antimicrobial Chemotherapy, September 2006.

www.abraham-hicks.com, It’s All About Vibrational Relativity, Abraham-Hicks Publications, 2007.

www.natap.org, Chronic Hepatitis C, Depression and Interferon, Journal of Hepatology, June 2005.

www.psychiatrictimes.com, Depression as Co-Pilot: Clinical Implications of Hepatitis C and Interferon/Ribavirin Treatment, James A. Bourgeois, MD, OD, Lorenzo Rossaro, MD, and Robert D. Canning, PhD, Psychiatric Times, April 2005.

Posted by Editors at January 19, 2009 10:59 AM

http://www.hepatitis-central.com/mt/archives/2009/01/why_depression.html

Coping with Depression and Hepatitis C

Managing Depression

HCV and Mental Health: Overview of Depression

PSYCHOLOGIC STRESS, DEPRESSION AND QUALITY OF LIFE IN PATIENTS WITH LIVER DISEASE DUE TO HEPATITIS C VIRUS. N. Singh^{*}, T. Gayowski, M.M. Wagener, I.R. Marino.

Veterans Affairs Medical Center, Pittsburgh, PA. Background: Quality of life is frequently compromised by chronic illnesses. While numerous studies have assessed the clinical impact of hepatitis C virus (HCV) hepatitis, the psychosocial sequelae and quality of life impairment in patients with liver disease due to HCV is not known. Methods: Depression, psychologic stress and quality of life was prospectively assessed in 82 liver transplant candidates. Comparisons were made between patients with HCV hepatitis (n=42) versus patients with other liver diseases (n=40). Depression was assessed by Beck Depression Inventory, emotional stress by Profile of Mood States scale (POMS), coping by Ways of Coping scale, and stressful life events by Recent Events Inventory. Quality of life measure included a self-assessed rating of perceived quality of life. Results: Patients with HCV were significantly younger than all other patients (p=.002). Emotional stress, i.e., total mood disturbance score (p=.038), tension and anxiety (p = .047) and confusion and bewilderment (p=.035) were significantly higher in patients with HCV. Patients with HCV were significantly more depressed as assessed by Beck Depression Inventory scores (p = .014) and had significantly greater impairment in Beck inventory items pertaining to somatic manifestations of depression (perceptions of body images, work inhibition, sleep disturbance, fatigue, appetite and weight loss, somatic preoccupation) than all other patients (p = .018). A significantly higher number of patients with HCV reported experiencing pain (p=.001). There was no difference in coping, social support, religious support, education, employment, income, Karnofsky score, Child-Pugh score, or liver function tests between patients with HCV versus all other patients. Conclusion: Patients with HCV hepatitis are uniquely vulnerable to depression and psychological stress in the pretransplant period than all other patients. Symptoms of depression should be sought in these patients since depression is a treatable and modifiable disorder.

Hepatitis C virus infection and incident type 2 diabetes

	Hepatology July 2003, Vol 38, Numb 1 Shruti H. Mehta et al. Departments of 1Epidemiology and 2Medicine, Johns Hopkins University, Baltimore, MD; and the 3Division of Epidemiology, University of Minnesota School of Public Health, Minneapolis, MN. "...compared with persons without HCV infection at high risk for diabetes, those with HCV infection at high risk were more than 11 times as likely to develop type 2 diabetes (relative hazard, 11.58; 95% confidence interval, 1.39-96.6; P value for test of interaction = 0.04)... a significant increase in the incidence of diabetes was not detected among anti-HCV-positive persons who were at low risk for diabetes (relative hazard, 0.48; 95% confidence interval, 0.05-4.40).." What about the influence of diet, alcohol and other behavior influences (see below for Discussion by authors). Based on these preliminary findings HIV-infected individuals with HCV or perhaps HBV may have even a greater risk for developing diabetes. What is the influence of having HCV or HBV on study findings in HIV of a higher prevalence of diabetes or insulin resistance? I don't think this has been examined in such studies. Considering that the HIV Lipodystrophy Workshop takes place next week in Paris, the publication of this article is good timing. This is an interesting topic. These study findings are based on a small number of 15 cases of HCV infection. Although studies show individuals with HCV are often more likely to have diabetes, does HCV contribute to development of diabetes. My feeling is yes for some individuals. And having predisposition to developing diabetes plus having HCV may both contribute synergistically. It should be noted that the risk for developing diabetes is higher among individuals on HAART (HIV therapy). Two small studies find that HCV/HIV and HBV/HIV co-infected individuals are at greater risk for developing insulin resistance and diabetes, as well as having lipid abnormalities and body changes.. This study did not examine the stage of liver disease as a factor in developing diabetes. Perhaps having cirrhosis or more advanced liver disease predisposes individuals to developing diabetes, as well as lipid abnormalities and HIV-related body changes. The relationship between HIV, HCV and HBV, the stage of liver disease, and body changes in HIV+ individuals has received little research attention. For individuals with diabetes or a predisposition for glucose abnormalities, the difficulty in tolerating HCV therapy may make it more difficult to monitor diet and glucose levels. After initiating therapy for HCV co-infected individuals should be particularly careful in monitoring their diet and glucose levels. For HCV or HBV mono- or co-infected individuals it appears reasonable that an impaired liver might play a role in contributing to changes in metabolism related to fats and sugar. In order to better understand this question more in-depth study is important and should be seriously considered by researchers particularly by researchers specializing in HIV-lipodystrophy. The authors of this study said: "...The present findings suggest that the association between HCV infection and type 2 diabetes may be stronger for persons defined as high risk on the basis of their age and BMI. Although this study suggests a temporal relationship between HCV infection and type 2 diabetes, these results should be considered to be of a preliminary nature due to the low prevalence of HCV infection." "...In this investigation, the incidence of type 2 diabetes was increased substantially for persons with recognized diabetes risk factors and HCV infection compared with those with similar diabetes risk factors but not HCV infection...and supports many of the previous investigations... In addition, the present study extends this research by showing that HCV infection antedated the development of type 2 diabetes, providing preliminary epidemiologic evidence supporting the hypothesis that HCV infection causes type 2 diabetes. Further studies are needed to confirm these preliminary findings and to elucidate the underlying biologic mechanism before causality can be firmly established... The conclusions that can be made from this study are limited by the unexpected low prevalence of HCV infection in this population... With only 15 cases of HCV infection, it is possible that some cases were highly influential..... It also was not possible to determine whether the observed effect modification by age and BMI was real or caused by random variation. Likewise, it is possible that no increased risk for diabetes was detected among anti-HCV-positive persons who were otherwise at low risk because of limited power.... It also is possible that HCV infection modified the effect of age and BMI on the risk for diabetes. (see discussion below)... It also is possible that HCV infection was a marker for some other risk factor of type 2 diabetes that was not measured in this population (see discussion below) Nearly 4 million persons in the United States and 170 million persons worldwide have been infected with the hepatitis C virus (HCV). HCV infection primarily causes liver disease, but also has been linked to other conditions including type 2 diabetes mellitus. The association between HCV infection and type 2 diabetes has been clearly shown by cross-sectional studies that included prevalent cases of diabetes, but there is insufficient evidence to conclude that HCV infection causes type 2 diabetes. Although most of the evidence supports that HCV infection antedates type 2 diabetes, it also is possible that persons with diabetes are at increased risk for acquiring HCV infection because of frequent hospital interventions and daily use of syringes. To ascertain if HCV infection causes type 2 diabetes, the temporal relationship needs to be established. In a community-based sample of adults in the United States, we assessed whether persons with HCV antibodies were at increased risk for type 2 diabetes. Because previous studies have suggested that among individuals with HCV infection, those with diabetes are more likely to have traditional risk factors of diabetes, we also examined whether this relationship between HCV infection and type 2 diabetes was modified by known risk factors of diabetes including age and obesity. ABSTRACT-Summary Although hepatitis C virus (HCV) infection is more common among adults with type 2 diabetes, it is uncertain whether HCV precedes the development of diabetes. Thus, we performed a prospective (case-cohort) analysis to examine if persons who acquired type 2 diabetes were more likely to have had antecedent HCV infection when enrolled in a community-based cohort of men and women between the ages of 44 and 65 in the United States (Atherosclerosis Risk in Communities Study [ARIC]). Among 1,084 adults free of diabetes at baseline, 548 developed diabetes over 9 years of follow-up evaluation. Incident cases of diabetes were identified by using fasting glucose and medical history and HCV antibodies were assessed at baseline. A priori, persons were categorized as low-risk or high-risk for diabetes based on their age and body mass index, factors that appeared to modify the type 2 diabetes-HCV infection incidence estimates. The overall prevalence of HCV in this population was 0.8%. Among those at high risk for diabetes, persons with HCV infection were more than 11 times as likely as those without HCV infection to develop diabetes (relative hazard, 11.58; 95% confidence interval, 1.39-96.6). Among those at low risk, no increased incidence of diabetes was detected among HCV-infected persons (relative hazard, 0.48; 95% confidence interval, 0.05-4.40). In conclusion, pre-existing HCV infection may increase the risk for type 2 diabetes in persons with recognized diabetes risk factors. Additional larger prospective evaluations are needed to confirm these preliminary findings. Study population The Atherosclerosis Risk in Communities (ARIC) study is a multicenter cohort designed to study the etiology and natural history of atherosclerosis. The details of the study design have been published elsewhere. Briefly, between 1987 and 1989, 15,792 men and women aged 45 to 64 were recruited from 4 communities in the United States-Forsyth County, NC; Jackson, MI; northwest suburbs of Minneapolis, MN; and Washington County, MD. At baseline and 3 follow-up visits (1990-1992, 1993-1995, 1996-1998), subjects underwent an interview, examination, and blood draw. Written informed consent was obtained from all participants and a repository of plasma and serum aliquots from each visit was stored frozen at -70¡C. A total of 5,517 (35%) individuals were excluded from this analysis because of prevalent or missing diabetes status at baseline (n = 2,018), missing baseline plasma specimens due to use in other substudies (n = 2,506), missing information on essential covariates (n = 14), restricted access to stored specimens (n = 7), race other than African American or white (n = 95), failure to return for any follow-up (n = 851), and insufficient information to characterize diabetes in even one follow-up visit (n = 26), leaving 10,275 (65%) individuals in the sampling frame. Definition of cases (diabetes) Fasting serum glucose measurements were performed at each follow-up visit by using the hexokinase method.16 Incident cases of diabetes were defined as participants meeting one of the following criteria at any of 3 follow-up visits: (1) self-reported use of hypoglycemic medications; (2) fasting (>8 hours) serum glucose level greater than 7.0 mmol/L (126 mg/dL); (3) nonfasting serum glucose level greater than 11.1 mmol/L (200 mg/dL); or (4) self-report of physician diagnosis. For individuals classified by physician diagnosis or medication use, date of diabetes onset was considered to be the midpoint between the last visit when an individual was not diabetic and the first visit when an individual was diabetic. For those diagnosed by fasting or nonfasting glucose level, date of diabetes onset was the estimated date at which blood sugar level crossed a threshold (7.0 mmol/L for fasting and 11.1 mmol/L for nonfasting), assuming a linear increase in glucose level between visits. RESULTS Cases of type 2 diabetes tended to be older, male (43% vs 34%, p=.03), and African American (37% vs 20%, <.0001) when compared with noncases and the cohort sample. Persons with type 2 diabetes also tended to have lower educational attainment, higher BMI (morbidly obese: >35 kg/m2 BMI, 23% vs 6% p=.00004) and were more likely to report a family history of diabetes than those without type 2 diabetes. Obese (30-35 kg/m2 BMI) individuals trended towards having diabetes rather than not having diabetes but it wasn't identified as being significant (27% vs 19%). Individuals categorized as lean/normal BMI (<25 kg/m2) and overweight (25-30 kg/m2) trended towards not having diabetes although this was not significant either. Showing that keeping weight down helps in preventing diabetes. Because the cohort sample was sampled to be representative of the original ARIC cohort, the association between HCV infection and diabetes risk factors was examined in these 628 persons, of whom 8 (0.8%) were anti-HCV positive. The prevalence of HCV infection was higher among men than women (1.5% vs. 0.47%, P = .04) and African Americans than whites (2.47% vs. 0.3%, P = .03). However, there were no differences in HCV prevalence by other correlates of type 2 diabetes (e.g., age, BMI, or family history of diabetes). Overall, persons with HCV infection were nearly twice as likely as those without HCV infection to develop diabetes, but this difference was not statistically significant (relative hazard, 1.9; 95% confidence interval, 0.6-6.2). After stratification for underlying diabetes risk, a significant increase in the incidence of diabetes was not detected among anti-HCV-positive persons who were at low risk for diabetes (relative hazard, 0.48; 95% confidence interval, 0.05-4.40). However, compared with persons without HCV infection at high risk for diabetes, those with HCV infection at high risk were more than 11 times as likely to develop type 2 diabetes (relative hazard, 11.58; 95% confidence interval, 1.39-96.6; P value for test of interaction = 0.04). When the analysis was restricted to include only the 12 persons who had ongoing HCV infection, the relationship between HCV and type 2 diabetes among high-risk persons was attenuated (relative hazard, 7.61; 95% confidence interval, 0.85-68.4, P = .07). At baseline, among the 15 individuals with HCV infection, those who developed diabetes had higher fasting insulin levels (136 pmol/L; interquartile range [IQR], 108-230 pmol/L) and more insulin resistance (4.8 pmol/L; IQR, 4.0-9.8) as measured by the HOMA-IR method (fasting insulin [Uu/mL] ´ fasting glucose [mmol/L]/22.5) compared with those who did not develop diabetes (72 pmol/L; IQR, 50-176 and 2.5; IQR, 1.5-5.9, respectively), but these differences were not statistically significant (P = .18 and .13, respectively). Albumin levels at baseline were significantly lower among HCV-infected persons who developed diabetes (median, 3.6; IQR, 3.5-3.9) compared with HCV-infected persons who did not develop diabetes (median, 4.1; IQR, 4.0-4.2; P = .02), a result driven by differences in the high-risk group. However, median platelet counts did not differ between the 2 groups (225 and 210 for persons who did and did not develop diabetes, respectively, P = .89). Among all high-risk persons, fasting insulin levels and insulin resistance were slightly higher in those who were HCV-infected compared with those who were not, but these differences were not statistically significant. However, among persons with a high BMI (>30 kg/m2), median insulin levels and insulin resistance were significantly higher among HCV-infected persons compared with HCV-uninfected persons. DISCUSSION by authors In this investigation, the incidence of type 2 diabetes was increased substantially for persons with recognized diabetes risk factors and HCV infection compared with those with similar diabetes risk factors but not HCV infection. Detection of an increased risk for type 2 diabetes among those with HCV infection supports many of the previous investigations that have documented an association between HCV infection and type 2 diabetes in other settings, including liver clinics, diabetes clinics, and the general U.S. population. In addition, the present study extends this research by showing that HCV infection antedated the development of type 2 diabetes, providing preliminary epidemiologic evidence supporting the hypothesis that HCV infection causes type 2 diabetes. Further studies are needed to confirm these preliminary findings and to elucidate the underlying biologic mechanism before causality can be firmly established. The conclusions that can be made from this study are limited by the unexpected low prevalence of HCV infection in this population. With only 15 cases of HCV infection, it is possible that some cases were highly influential. However, in a sensitivity analysis, systematic removal of cases did not significantly alter the results. Additionally because the sampling weights varied quite widely, we investigated the sensitivity of the results to the weights. The hazard ratios remained large despite reductions in the weights of up to 50%. When the largest weights were reduced dramatically (40%), some results were no longer statistically significant, but this is probably more because of the small number of cases rather than the weighting scheme itself. The small number of HCV cases also prohibited multivariate analysis. Although we indirectly accounted for age and BMI through the risk group classification, we were not able to account for other known correlates of diabetes including race and socioeconomic status. However, in our previous analysis, adjustment for these factors actually strengthened the association between HCV infection and type 2 diabetes,13 suggesting that the relative hazard observed in this study might even be an underestimate of the relationship between HCV and type 2 diabetes. It also was not possible to determine whether the observed effect modification by age and BMI was real or caused by random variation. Likewise, it is possible that no increased risk for diabetes was detected among anti-HCV-positive persons who were otherwise at low risk because of limited power. Although power calculations performed before the study was conducted suggested greater than 80% power based on an HCV prevalence of 1.8% among persons without diabetes (the average among U.S. adults), post hoc power calculations based on the observed prevalence of 0.8% revealed only 30% power to detect in the low-risk stratum a difference of the same magnitude as was observed in other studies. It also is possible that HCV infection modified the effect of age and BMI on the risk for diabetes. This is supported by the observation that HCV-infected individuals who were obese (BMI > 30 kg/m2) had significantly higher insulin levels and insulin resistance at baseline compared with HCV-negative individuals who also were obese regardless of diabetes status. In previous studies, HCV-infected persons with diabetes also were more likely than HCV-infected persons without diabetes to be older and obese. There are insufficient data to explain these observations. However, it is interesting to note that both obesity and older age were associated with more severe liver disease among HCV-infected patients. The link between advanced liver disease and type 2 diabetes has been suggested by a number of studies. Patients with cirrhosis are predisposed to insulin resistance and, consequently, type 2 diabetes. Some studies have shown that even among HCV-infected persons without type 2 diabetes or cirrhosis, insulin resistance and glucose intolerance are present. In these individuals, the degrees of insulin resistance and glucose intolerance still were related closely to the severity of liver damage. Steatosis is also a feature of chronic HCV infection. A recent study suggested that greater than 60% of persons chronically infected with HCV had steatosis. In this and other studies, steatosis also was associated with high BMI and fibrosis. Because steatosis also has been associated with type 2 diabetes, it may not be surprising that HCV infection, age, and obesity combined dramatically increase a person's risk for type 2 diabetes. Unfortunately, we were not able to address adequately the role of liver disease because neither liver biopsy specimens nor markers of severe liver disease including total bilirubin and prothrombin time were available. Baseline albumin levels were available and were observed to be significantly lower among HCV-infected persons who developed diabetes compared with those who did not develop diabetes. On the other hand, there were no differences in platelet counts and none of the 15 HCV-infected persons reported a history of liver disease or cirrhosis (asked at the third visit, data not shown). Further support for the hypothesis that diabetes occurs more frequently among HCV-infected persons because of advanced liver disease would come from showing that the hazard of developing diabetes would be greatest in those with ongoing HCV infection, which was only observed (positive HCV antigen and/or RNA) in 12 individuals in this study. The relative hazard among the high-risk group with ongoing HCV infection remained elevated but was reduced in magnitude and statistical significance compared with the relative hazard for all HCV antibody-positive persons. It is difficult to speculate on the reasons for this because the precision of these estimates is very low given that so few people were HCV-RNA positive. Because the overall number of positives was already low, because we found essentially the same estimates in the ongoing infection group, and because we could not test sera from additional visits to ensure there was not a problem with sample handling or storage, we chose to focus our analysis on HCV antibody-positive persons. It also is possible that HCV infection was a marker for some other risk factor of type 2 diabetes that was not measured in this population. HCV infection could be a marker for ongoing inflammation, which has been associated with the development of type 2 diabetes. Although plasma fibrinogen levels were not different among HCV-infected persons who developed diabetes and those who did not (data not shown), we did not have information on other markers of inflammation such as C-reactive protein. It is less likely that HCV infection was a marker for some other behavioral risk factor of type 2 diabetes because we had information on most known risk factors for diabetes including alcohol use and exercise, neither of which were associated with HCV infection or the development of type 2 diabetes. The present findings suggest that the association between HCV infection and type 2 diabetes may be stronger for persons defined as high risk on the basis of their age and BMI. Although this study suggests a temporal relationship between HCV infection and type 2 diabetes, these results should be considered to be of a preliminary nature due to the low prevalence of HCV infection. Larger prospective studies should include persons at high risk for both HCV infection and type 2 diabetes to have enough power to firmly establish a temporal relationship between these 2 conditions.

http://www.natap.org/

Diabetes & Lipids Associated with Liver Disease

Reported by Jules Levin

These studies were reported at the 40th annual EASL liver meeting in Paris (April 2005). The studies support numerous previous studies that insulin resistance and diabetes can contribute to advancing liver disease, particularly in people with viral hepatitis C or B. As well, elevated lipids may contribute.

Impact of Overweight & Diabetes on Liver-Related Death in Patients with Alcoholic & Viral Hepatitis C Cirrhosis

G. N'Kontchou1, M. Tin Tin Htar1, J. Paries2, F. Kazemi1, V. Bourcier1, N. Ganne-Carrie1, P. Nahon1, V. Grando-Lemaire1, J.C. Trinchet1, M. Beaugrand1

1 Liver Unit, Jean Verdier Hospital, Bondy, France 2 Public Health Unit, Jean Verdier Hospital, Bondy, France

Obesity and diabetes have been suggested to be risk factors of liver-related death in recent population-based cohort studies. This study was aimed to assess prospectively the impact of these factors on liver-related death (including liver transplantation).

Overweight & diabetes type II are risk factors of cirrhosis in patients with alcoholic & viral HCV. They are also risk factors for liver cancer (hepatocellular carcinoma). Their influence on liver-related death in patients has not yet been evaluated.

A large cohoht of 963 patients with compensated cirrhosis regularly followed for a screening program for HCC were included. All clinical and biological variables were collected at inclusion. Ultrasonography & alfa-feto protein were used for follow-up evaluation. Outcomes evaluated were: liver-related death, liver-related death including liver transplantation (HCC, liver failure, portal hypertension), & occurrence of HCC was also recorded.

Predictive factors for overall and liver-related death were determined by log-rank test and Cox proportional hazards model. Survival to events was estimated by Kaplan-Meier method.

BASELINE CHARACTERISTICS n=963:
Age: 57
63% male
Etiologies: (alcohol/HCV/mixed): 484/322/157
Diabetes: 298 (31%)
BMI (kg/m2): 25/6 +/-4.7
Prothrombine time: 72+/-17
Platelet counts: 137 +/-64
Bilirubin: 28 mmol/l
Albumin (g/l): 39+/-6
AST (N): 2
ALT (N): 2
AP (N): 1.4
y-GT (N): 3.9

Results
-There were 484 alcoholic cirrhosis, 322 HCV, 157 HCV+alcohol.
-Mean age was 57.2±11 yr and mean BMI was 25.6 kg/m2.
-607 were male patients.
-298 patients were diabetic.
-After a mean follow-up of 66.7±45.2 months, 384 patients died, of which 279 were liver-related deaths (liver failure: 142; hepatocellular carcinoma: 117; portal hypertension: 20).

In univariate analysis, factors associated with liver-related death were:
--BMI ³27.5 [OR 1.9; 1.5-2.4; p < 0.0001]
--age >57 yr [OR 1.6; 1.3-2.0; p < 0.0001]
--male sex [1.7; 1.3-2.1; p < 0.0001]
--platelet count <140,000/mm3 [OR 1.9; 1.5-2.5; <0.0001]
--serum albumin <42 g/l [2.8; 2.0-3.9; p < 0.0001]
--prothrombin activity <82% [2.3; 1.7-3.1; p < 0.0001]
--alkaline phosphatase >1.4 ULN [OR 1.9; 1.5-2.4; p < 0.0001]
--total bilirubin >17 mm/ml [OR 1.9; 1.5-2.4, p < 0.0001].

Diabetes was not significantly related.

In multivariate analysis, independent risk factors for liver-related death were:
--serum albumin <42 g/l [OR 2.00; 1.4-2.9; p = 0.0004]
--BMI ³27.5: [OR 1.8; 1.4-2.4; p < 0.0001]
--age >57 yr [OR 1.7; 1.3-2.3; p = 0.0002]
--male sex [OR 1.5; 1.1-2.1; p = 0.01]
--prothrombin activity <82% [OR 1.6; 1.1-2.2 p = 0.02]
--alkaline phosphatase >1.4 ULN [OR 1.4; 1.0-1.9; p = 0.03].

These results were confirmed in different etiological subgroups.

Conclusion: Overweight was an independent and important predictive factor of liver-related death in patients with compensated HCV and alcohol cirrhosis.

Diabetes is Strongly Associated with Advanced Fibrosis; Elevated Lipids May Be Associated with Fibrosis --Patient Populations with High prevalence of Diabetes, like Hispanics, May Be Particularly At Risk for Advancing Liver Disease

"ASSOCIATION BETWEEN DIABETES, OVERWEIGHT, OBESITY AND DYSLIPIDEMIA WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS C PATIENTS"

A. Loaeza-del Castillo, F. Vargas-Vorackova

1 Department of Gastroenterology, Instituto Nacional de Ciencias MŽdicas y Nutrici—n, Mexico

2 Department of Gastroenterology, Instituto Nacional de Ciencias MŽdicas y Nutrici—n, Mexico

Fibrosis progression in chronic hepatitis C (CHC) patients is variable, factors associated with an accelerated progression have been identified, but they do not account for the heterogeneity seen between individuals.

Aim: To determine the prevalence of diabetes, overweight, obesity and dyslipidemia in CHC patients and the association of these metabolic factors with liver fibrosis progression.

Method: Patients with CHC seen in our institution between 1993 and 2003 were retrospectively studied (n = 1618). Patients with a known duration of infection acquired by transfusion with a liver biopsy performed before any antiviral treatment were included. Patients with overt hepatic insufficiency were excluded. The diagnoses of diabetes, overweight, obesity and dyslipidemia were investigated and liver fibrosis stage (METAVIR). Variables were tested for their association with significant fibrosis (F2, F3, F4).

RESULTS
--108 patients were included, 71 (66%) female and 37 (34%) male,
--mean age was 48.7+12.2 years.
--Age at infection was 24.7±13 years, acquired between 1944-2000.
--78% were HCV-genotype 1.
--Fibrosis stage was: F0 = 15 (14%), F1 = 38 (35%), F2 = 9 (8%), F3 = 8 (8%) and F4 = 38 (35%).
--Mean fibrosis progression rate was 0.106±0.101 (0-0.44).
--26 patients (24%) had diabetes, 10 (9%) glucose intolerance, 24 (22%) obesity [body mass index (BMI) ³30 kg/m2] and 49 (45%) overweight (25 £ BMI < 30 kg/m2). --Dyslipidemia was investigated in 75 patients and confirmed in 25 (33.3%). Association between these variables and fibrosis is depicted in the table.

Conclusions: Diabetes is a factor strongly associated with advanced fibrosis and cirrhosis. In populations with a high prevalence of diabetes, such as Hispanics, this association must be taken into account. Lipid metabolism has a specific role in the pathogenesis of CHC and the possible protector role of dyslipidemia for significant liver fibrosis should be investigated in further studies.

"INSULIN RESISTANCE PROMOTES FIBROSIS PROGRESSION AND PREDICTS NECRO-INFLAMMATORY ACTIVITY IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE"

D. Sanchez-Munoz1, E. Suarez1, M.V. Galan1, L. Grande1, G. Munoz2, M. Romero-G—mez1

1 Hepatology Unit, Hospital Universitario de Valme, Sevilla, Spain 2 Pathology Unit, Hospital Universitario de Valme, Sevilla, Spain

Aims: To assess the presence of metabolic syndrome X (MSx) and insulin resistance (IR), and its relationship with histologic damage, in patients with non-alcoholic fatty liver disease (NAFLD).

Patients and Methods: Thirty-five patients, 25 male and 10 female, with an average age of 45.7±12.7 [24-76] years, diagnosed by NAFLD, were included. Liver biopsy was carried out after persistence for, at least, six months of altered liver enzymes with appropriate diet and physical activity therapies. Histological damage was assessed according to Brunt criteria (Semin Liver Dis 2001; 21: 3-16). Body mass index (BMI) was calculated. MSx was diagnosed according to ATP III criteria. IR was calculated using the HOMA-IR index = [Glucose(mmol/l) _ Insulin(UI/ml)]/22.5.

RESULTS
Only one patient (2.5%) showed normal weight; 17/35 (48.6%) patients showed overweight and 17/35 (48.6%) patients were obese.
--MSx was present in 14/35 (42.5%) patients;
--central obesity in 65.7%,
--high triglyceride levels in 62.9%,
--altered glucose metabolism in 28.6%,
--hypertension in 31.4% and
--low HDL-colesterol levels in 24%.
--IR was present (HOMA-IR >2) in 23/33 (74.3%) patients.
--The histologic diagnosis was simple hepatocyte steatosis (HS) in 8/35 (22.9%) patients and steatohepatitis (NASH) in 27/35 (77.1%) patients: Fibrosis degree was: absent in 13 patients, mild fibrosis (F1-F2) in 6 patients, bridging fibrosis (F3) in 7 patients and cirrhosis (F4) in 1 patient.

Patients with HS showed lower triglyceride levels (99±43 vs 169±85 mg/dl; p = 0.034) and HOMA-IR (2.54±0.9 vs 4.5±2.5; p = 0.002) than patients with NASH.

Triglycerides >180 mg/dl or HOMA IR >4.5 was associated with NASH (Specificity: 100% and Sensitivity: 54.3%.

Fibrosis correlated with age (r = 0.37; p = 0.027), AST (r = 0.5; p = 0.002), and HOMA-IR (r = 0.45; p = 0.007).

In multiple lineal regression, the only factor associated with fibrosis was the HOMA-IR (R = 0.60; p = 0.0001). All of the patients with advanced fibrosis (F3-F4) showed a HOMA-IR index >4.5, but only 8/26 (30%) patients with F0-F2; p < 0.001.

Conclusions: Insulin resistance is present in the majority of the patients with non-alcoholic fatty liver disease. HOMA-IR index >4.5 or triglyceride levels >180 mg/dl are predictors of the presence of NASH. Insulin resistance may play a role in the pathogenesis of fibrosis progression in patients with NAFLD. Drugs able to decrease insulin resistance could be useful in the therapy of this disease.

Total Calories May Contribute to Development of Fatty Liver

"LIVER STEATOSIS (Fatty Liver) IN OPEN POPULATION: PREVALENCE AND RELATIONSHIP TO THE DIET. PRELIMINARY RESULTS OF THE "ARSITA-ONE" PROJECT"

I. Petridis1, E. Lattanzi1, B. Marraccini1, I. Carderi1, E. Claar1, C. Liani1, S. Lobello1, O. Di Andrea2, M. Chiaramonte1

1 Hepato-Gastroenterology and Nutrition Unit - Dept. of Internal Medicine and Public Health - L'Aquila University, L'Aquila, Italy 2 Arsita Family Doctor, Italy

Background and Aim: This study, part of a larger epidemiological study for liver and metabolic diseases carried out on Arsita (Abruzzo) (805 adult registered inhabitants), was designed: 1) to assess the prevalence of liver steatosis; 2) to evaluate the relationship with the diet.

Materials and Methods: All subjects aged over 18 yr were invited to have liver ultrasound (US) and an alimentary questionnaire computer analyzed (Winfood 1.5). Liver steatosis was classified as none, mild, moderate and severe. Diet was classified as: diet 1, a traditional local diet, hypercaloric (3500-4500 kcal), hyperlipidic (55% of calories); diet 2, similar but with less calories (2500-3500 kcal); diet 3, classic Mediterranean (2000-2500 kcal).

RESULTS
--541 subjects (253 M and 288 F), completed the US and diet study.
--Moderate/severe steatosis was found in 89/253 (35%) males and 75/288 (26%) females; in 41/164 (25%) subjects under 40 yr, in 63/119 (33%) subjects aged 40-59 yrs and in 92/196 (47%) subjects over 60 yr.
--143/253 males (57.5%) and 86/288 females (30%) followed diet 1, which was related to obesity (BMI > 30) in 61% of males and 69% of females, while 14% of subjects having diet 2 were obese.

--All subjects with mediterranean diet had normal BMI.
--In diet 1 group, 71.5% of males and 64.5% of females had steatosis, while in diet 2 this was respectively 25.1% and 31.3%.
--In subjects with steatosis, alcohol consumption was present in 82% of males and in 48% of females, while BMI > 30 was present in 61% of males and 78% of females.
--Out of 164 subjects with steatosis 22 (13%) had altered AST and/or ALT (13 anti-HCV+).

Conclusions: Prevalence of steatosis is increasing with age and is more frequent in males. In females severe steatosis is mainly correlated with overweight and in males with alcohol abuse. The amount of total calories instead of the proportion of fat seems to be related to liver steatosis. Elderly people had moderate/severe in 47%, however in most cases steatosis is indolent. Hepato cytolisis, without virus, seems to be very rare. Liver steatosis without "a second hit" seems to be a benign condition.

Association Between Diabetes, Overweight, Obesity, and Dyslipidemia with Fibrosis Progression in Chronic Hepatitis C Patients

Fibrosis progression in chronic hepatitis C (CHC) patients is variable. Factors associated with an accelerated progression have been identified, but they do not account for the heterogeneity seen between individuals. The purpose of the present study was to determine the prevalence of diabetes, overweight, obesity and dyslipidemia in CHC patients and the association of these metabolic factors with liver fibrosis progression.

Patients with CHC seen in a medical center in Spain between 1993 and 2003 were retrospectively studied (n=1618). Patients with a known duration of infection acquired by transfusion with a liver biopsy performed before any antiviral treatment were included. Patients with overt hepatic insufficiency were excluded.

Results

· 108 patients were included, 71 (66%) female and 37 (34%) male, mean age was 48.7 + 12.2 years.

· Age at infection was 24.7 +/- 13 years, acquired between 1944-2000. 78% were HCV-genotype 1.

· Fibrosis stage was: F0=15 (14%), F1=38 (35%), F2=9 (8%), F3=8 (8%) and F4=38 (35%).

· Mean fibrosis progression rate was 0.106 +/- 0.101 (0 – 0.44).

· 26 patients (24%) had diabetes, 10 (9%) glucose intolerance, 24 (22%) obesity (body mass index (BMI) >/= 30 kg/m2) and 49 (45%) overweight (BMI >/= 25 < 30 kg/m2).

· Dyslipidemia was investigated in 75 patients and confirmed in 25 (33.3%).

Association between these variables and fibrosis is depicted in the table below.

Conclusions

In conclusion the authors write, “Diabetes is a factor strongly associated with advanced fibrosis and cirrhosis. In populations with a high prevalence of diabetes, such as Hispanics, this association must be taken into account.”

“Lipid metabolism has a specific role in the pathogenesis of CHC and the possible protector role of dyslipidemia for significant liver fibrosis should be investigated in further studies. “

05/04/05

Reference
A Loaeza-del Castillo and others. ASSOCIATION BETWEEN DIABETES, OVERWEIGHT, OBESITY AND DYSLIPIDEMIA WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS C PATIENTS. Abstract 581. 40th EASL. April 13-17, 2005. Paris, France.

Type II Diabetes

Disease Associations (HCV); Hepatitis C May Be a Cause of Diabetes

Hepatitis Weekly via Individual Inc.

Hepatitis C virus may have a direct role in the development of diabetes, according to a report from Spain. Researcher Rafael Simo and colleagues found a high prevalence of hepatitis C virus (HCV) infection in patients with diabetes, and found that most HCV patients presented with abnormal liver function tests. "Testing for HCV infection of diabetic patients with an abnormal liver function test is mandatory," Simo et al. wrote ("High Prevalence of HCV Infection in Diabetic Patients," Diabetes Care, September 1996;19(9):998- 1001). "The lack of any particular epidemiological factor for HCV infection in our diabetic population suggests that HCV may have a direct role in the development of diabetes." Mild asymptomatic elevations of serum aminotransferases in a diabetic patient do not receive much attention because they are often attributed to fatty infiltration. It has been hypothesized that, during the course of the disease, diabetic patients are more prone to acquire an HCV infection because they are subjected to more frequent medical interventions. While a link between diabetes and HCV has recently been suggested, a controlled study of prevalence and risk factors for HCV infection has not yet been performed.

"The aim of this study was to evaluate the prevalence of HCV infection in diabetic patients attending our outpatient clinic in comparison with blood donors who were matched for the main risk factors associated with anti-HCV seropositivity," Simo et al. wrote. "Furthermore, we investigated the influence of several epidemiological and clinical factors on HCV infection in diabetic patients, including type of diabetes, duration of the disease, mode of therapy, and presence of late complications." A total of 176 consecutive diabetic patients were compared with 6172 blood donors, matched by recognized risk factors to acquire HCV infection. Serologic testing for anti-HCV was done using a second-generation commercial enzyme-linked immunosorbent assay (ELISA), and an immunoblot assay was performed in anti-HCV positive samples to confirm HCV specificity. Diabetic patients were divided into two groups according to their HCV antibody status and analyzed for age, sex, type of diabetes, duration of disease, mode of therapy, late diabetic complications, previous blood transfusion, intravenous drug addiction, hospital admissions, major surgical procedures, and liver function tests.

Anti-HCV was detected in 18 diabetic patients and 156 blood donors (11.5 versus 2.5 percent; P < 0.001). The estimated risk for HCV infection in diabetic patients was 4.39 times higher (95 percent CI 2.61-7.24) than in the control group. In addition, Simo et al. did not observe a significant difference for previous blood transfusion (21.8 versus 16.7 percent) and intravenous drug addiction (10.2 versus 5.5 percent) between blood donors and diabetic patients with HCV infection, respectively. Only age (63.8 +/- 10.2 versus 49.4 +/- 17.8 years) and previous blood transfusion (16.7 versus 1.2 percent; P < 0.05) were statistically related to HCV infection. After excluding the three anti-HCV positive diabetic patients with previous blood transfusion, the global prevalence of anti-HCV seropositivity in the diabetic population (15 of 175, or 8 percent) remained significant in comparison with the control group (P < 0.001; odds ratio 3.59; 95 percent CI 2.04-6.23).

Furthermore, the three anti-HCV positive diabetic patients with previous blood transfusion were transfused for unrelated diseases seven, 15, and 23 years before diagnosis of diabetes. In anti-HCV positive diabetic patients, abnormal liver function tests were seen in 72.3 percent, compared with only 24.7 percent of anti-HCV negative diabetic patients (P < 0.001). "Diabetic patients have a high prevalence of abnormal liver function tests that are often attributed to fatty infiltration without further investigation," Simo et al. wrote. "In this study, we have demonstrated for the first time that diabetic patients present a higher prevalence of HCV infection than control subjects who are matched for the main risk factors, such as age, previous blood transfusion, and intravenous drug addition. In addition, most of anti-HCV positive patients presented with an abnormal liver function test, being a combination pattern of cytolysis and cholestasis as the predominant biochemical alteration. We feel that this is an important point, since none of these patients had been previously diagnosed with liver disease, and diabetes was the only reason for referral to our unit. In consequence, based on our results, testing for HCV infection in diabetic patients with an abnormal liver function test is mandatory."

The authors suggest their results could be interpreted to mean either that diabetic patients have some undiscovered epidemiological factor that increases the risk of acquiring HCV infection or that HCV infection may have some etiopathogenic role in the development of diabetes. In recent studies Allison et al. reported a significantly increased rate of diabetes in patients with HCV related cirrhosis, compared with other causes, and suggested that HCV infection has some etiopathogenic role in the development of diabetes (J Hepatol 1994;21:1135-1139). "Several possible mechanisms can be postulated to link HCV to diabetes," Simo et al. wrote. "It may be possible that HCV, similar to the hepatitis B virus, could infect pancreatic islet cells and thereby induce damage to (alpha)-cells. On the other hand, HCV has been related to diseases in which the autoimmune phenomena play an important role, such as cyroglobulinemia, glomerulonephritis, thyroiditis, and Sjogren disease. Therefore, an autoimmune destruction of endocrine pancreatic tissue related to HCV antigens or immunocomplexes cannot be excluded."

The corresponding author for this study is Rafael Simo,
Department of Endocrinology, Hospital General Universitari Vall d'Hebron,
Pg. Vall d'Hebron 119-129, 08035 Barcelona, Spain.

HCV and Diabetes Although the association is poorly understood, there appears to be a connection between HCV and diabetes. A recent study reported that people with diabetes had four-times the rate of HCV infection than controls, who were comprised of blood donors. In this study, 11.5 percent of 176 patients with diabetes (type I and II) tested positive for HCV antibodies, compared to 2.5 percent of 6,172 blood donors.. Another study reported that of 100 patients with cirrhosis, 34 had HCV infection. Of those, 17 (50 percent) had concurrent diabetes. Of the 66 HCV-free patients, only six (9 percent) had concurrent diabetes. Additional studies substantiate that diabetes is more prevalent in people with HCV infection than in people with other liver diseases – even when a family medical history and other risk factors for diabetes are considered.

Sources: "Methods of Transmission of Hepatitis C," C.J. Tibbs, J Viral Hepat, 1995; 2(3), pp. 113-9.

HealthWise: Hepatitis Seeing
Lucinda Porter, RN

No organ is more important than any other, but try to convince us of that when it comes to our eyes. This point was demonstrated recently when a patient I was working with developed vision problems. Six months earlier he had completed hepatitis C (HCV) treatment. Naturally he wondered if there was a correlation between his eye condition and the treatment.

His liver specialist and other experts in the field did not believe there was a correlation in this particular case. Eye diseases are common, particularly as we age. According to the National Eye Institute (NEI), in the 2000 U.S. census there were more than 119 million adults over age 40 with age-related eye diseases. This number is expected to double in the next three decades.
Some eye conditions are associated with HCV. The most common of these is dry eye syndrome. HCV treatment may cause or worsen some eye problems. Corneal ulcers are associated with HCV and its treatment. Prescription information for peginterferon-alpha with ribavirin warns of ophthalmologic (eye) disorders such as decreased, blurred or loss of vision, retinopathy including macular edema and retinal thrombosis/hemorrhages, optic neuritis and papilledema. Let’s discuss these and other terms.

Diagram of the eye, showing the location of the iris, pupil, cornea, lens, vitreous, macula, sclera, optic nerve, and retina.

Courtesy of the National Eye Institute – www.nei.nih.gov

The outer most layer of the eye is the cornea. Ulcerations on the cornea may be caused by a variety of factors, HCV being one of them. One example, Mooren’s ulcer is discussed in the HCV Advocate’s Medical Writers’ Circle’s Extrahepatic Manifestations of Chronic Hepatitis C, by Remoroza and Bonkovsky.

Retinopathy refers to retina problems. The retina is a nerve-rich area in the back of the eye. It receives light and transmits images to the brain. Many factors cause retinopathy. People with high blood pressure or diabetes have a higher risk for retinal problems. White puffy spots on the retina are called cotton wool spots and may indicate nerve damage. A retinal thrombosis is a blockage in one of the retinal vessels. A retinal hemorrhage is a bleeding vessel. Treatment-related retinopathy usually ceases after medication is stopped.

The macula lies near the center of the retina. It is responsible for clarity of sight. Macular edema means that there is swelling caused by fluid accumulation.

Optic neuritis is swelling of the optic nerve. This nerve transmits information from the retina to the brain. The head of the optic nerve is the optic disc. If the disc swells due to an increase in pressure from the brain or spinal fluid, the result is known as papilledema.

When undergoing HCV treatment, report eye problems immediately. Many of these problems turn out to be minor, often caused by dry eyes or even fatigue. However, since some eye problems can contribute to permanent vision impairment, let your doctor evaluate the situation.

Dry eye syndrome or keratoconjunctivitis sicca is common, more so in people with HCV. It can be caused by insufficient or improper tear production or when tears evaporate too quickly. Inflammation may accompany dry eyes. This condition may be uncomfortable or painful. Ulcers, scars, and even vision loss may occur if dry eye syndrome is not treated.

Certain factors may intensify dryness, such as air travel, dry climates, menopause, and some medications. Antihistamines, decongestants, antidepressants, tranquilizers, estrogen and interferon may cause eye dryness. Some people develop dry eyes after vision surgery, such as the Lasik procedure.

Eye dryness is associated with other diseases, particularly autoimmune disorders. Those with HCV have an increased risk of autoimmune disease, so your medical provider may want to rule out other causes before assuming that dry eyes are related solely to HCV.

Treatment of dry eyes begins with understanding the cause of the problem. Over-the-counter tear replacement drops or ointment may be suggested. Choose preservative-free artificial tears if you use them more than 4 times daily. Avoid sun and glare. Use sunglasses that wrap around your head and block out UVA and UVB rays. Your specialist may suggest a dietary supplement, such as omega-3 fatty acids. Since too much or too little of certain vitamins may contribute to dryness or other problems, do not take a supplement without first discussing it with your medical provider. Your eye specialist may prescribe medication or recommend plugging your eyes’ tear drainage holes.

Your HCV medical provider may know something about eye diseases, but you should see an eye specialist to manage these. Unless you have a severe problem or need surgery, you will likely see a doctor of optometry (O.D.). Optometrists have 4 years of advanced training in their field. Although they are not physicians, optometrists can prescribe medication and handle most eye problems except surgery. If the problem is more complicated, you may be referred to an ophthalmologist (M.D.). This specialist has attended medical school and can perform surgery. If you need glasses, you may see an optician. This professional dispenses glasses and in some states, contact lenses, but does not treat eye diseases.

Patients should have a baseline eye exam prior to beginning HCV treatment. Those with diabetes or hypertension should consult with an ophthalmologist before treatment. Patients with multiple health conditions, such as HIV and diabetes, need close monitoring during HCV treatment.

HCV patients who need a liver transplant are at risk for post-operative eye infections that may occur in all post-transplant situations. Post-transplant patients with vision or eye problems are encouraged to report these immediately.

Eye problems are a concern for those living with HCV, but can occur in anyone. In spite of the numbers, many of us are tempted to blame every ache and pain on hepatitis C. It is a natural response to living with a chronic disease. Others operate in the opposite extreme and deny having any aches or pains of any cause. Learning to live somewhere in between is sensible. It takes knowledge and practice to navigate illness. While you are practicing, keep your eyes wide open.

Vote Health
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Erythema Nodosum

A tender, red, nodular rash on the shins that typically arises in conjunction with another illness; inflammatory bowel disease; occult cancer; or sarcoidosis. Biopsies of the rash reveal inflammation of subcutaneous fat (panniculitis). Because the disease is often associated with other serious illnesses, a diagnostic search for an underlying cause usually is undertaken. In some patients, no cause is identified.

ETIOLOGY: In children, this condition is commonly caused by upper respiratory infection, esp. from streptococcus. In adults, streptococcal infections and sarcoidosis are the most common causes [as well as HCV]. This condition is also caused by certain drugs and food poisoning.

TREATMENT: Therapy is directed at the cause, when it is known. Nonsteroidal anti-inflammatory drugs provide symptomatic relief for many patients.