CHILDREN WITH HYPERTENSION HAVE TROUBLE WITH THINKING, MEMORY
The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by University of Rochester Medical Center.
Children with high blood pressure are not as good at complicated, goal-directed tasks, have more working memory problems and are not as adept at planning as their peers without hypertension, according to recent research. If they are both hypertensive and obese, they are also more likely to have anxiety and depression.
Considering the demands on a child's brain - both in continued development and in education - and the fact that up to 10 percent of the increasing population of obese children have hypertension, these novel findings could give physicians and parents more impetus to diagnose and treat high blood pressure in children.
"These results were very surprising to me, despite similar findings in adults," said Marc Lande, M.D., a pediatric nephrologist at the University of Rochester Medical Center and author of the paper published in the Journal of Pediatrics this month. "Adults with hypertension often have other problems that might affect cognition such as chronic disease, smoking or alcohol use. However, children with hypertension usually do not have these comorbidities."
In adults, high blood pressure can lead to stroke, heart disease, heart attack, heart failure and kidney failure. Lande postulates that the cognitive changes demonstrated in this study may represent very early manifestations of hypertensive damage to the brain, which may long precede more overt damage such as stroke.
In addition, more than half the children with both hypertension and obesity demonstrated clinically significant anxiety and depression. Lande said he was initially looking at anxiety and depression only to rule out its interplay with executive function, which is a collection of cognitive abilities that help plan for and respond to complex situations; he did not expect to tease out this new finding.
"Children with only obesity or only hypertension did not have the anxiety and depression that children with both obesity and hypertension did," Lande said. "With further study, screening for anxiety and depression could end up being routine when an obese child is diagnosed with hypertension."
Lande said preliminary results suggest that treatment of hypertension in children may improve their cognitive executive functions, indicating that the changes in cognition associated with hypertension may be reversible with treatment to normalize the blood pressure.
Lande was inspired to conduct the study after finding a correlation between high blood pressure and lower scores on neurocognitive tests in a nationally representative dataset, NHANES III, the National Health and Nutrition Examination Survey conducted from 1988 to 1994. To dig deeper, Lande enrolled 32 newly diagnosed hypertensive children and adolescents (10 to 18 years old) from the Pediatric Hypertension Clinic at the University's Golisano Children's Hospital. Children who didn't have sustained hypertension or had previous medical issues that affected learning or sleeping were excluded. Thirty-two children with normal blood pressure were recruited from the hospital's pediatric practice and other area pediatric practices and were matched with the hypertensive children by age, weight, sex, race IQ and socioeconomic level.
The parents of both sets of 32 children answered a series of surveys to determine their children's executive function. (Testing the children through parental assessments can be a more valid test because these assessments evaluate the child's abilities in real-life situations better than directly testing a child, one-on-one in a lab setting) Although the hypertensive group did not perform poorly enough to require clinical intervention, the results were significantly different than the group without hypertension.
"We don't know the long-term implications of these subtle changes, but the potential for these differences in cognitive function to affect children is certainly concerning enough to warrant further study," Lande said.
CLINICAL RESEARCH IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE NEEDS AND OPPORTUNITIES
Thomas L. Croxton, Gail G. Weinmann, Robert M. Senior,Robert A. Wise, James D. Crapo and A. Sonia Buist
Abstract
Chronic obstructive pulmonary disease (COPD) is a common condition, and one difficult to manage. Available treatments, other than smoking cessation, are only minimally effective, and the knowledge basis for clinical decision making is limited. To identify areas in which further clinical research may lead to significant improvements in the care of patients with COPD, the National Heart, Lung, and Blood Institute convened a Working Group, entitled "Clinical Research in COPD: Needs and Opportunities," on March 21–22, 2002. This group of experts identified important questions in the field and made the following recommendations: (1) establish a multicenter Clinical Research Network to perform multiple, short-term clinical trials of treatments in patients with moderate-to-severe COPD; (2) create a system for the standardized collection, processing, and distribution of lung tissue specimens and associated clinical and laboratory data; (3) develop standards for the classification and staging of COPD; (4) characterize the development and progression of COPD using measures and biomarkers that relate to current concepts of pathogenesis; and (5) evaluate indications for long-term oxygen therapy for patients with COPD.
Much remains to be learned about the disease process in COPD, and other novel approaches to COPD treatment may be forthcoming in the next few years. Vigorous evaluation of all possibilities is important, because experts in COPD do not expect any single agent or approach to be sufficient in itself for the prevention or treatment of COPD. Rather, it is thought that a combination of drugs will be required for adequate control of this complex disease.
IMPORTANT CLINICAL QUESTIONS IN COPD
While considering what is currently known, the Working Group identified a number of specific deficits in knowledge that limit improvements in the clinical management of COPD. These deficits range from basic understanding of the disease process to uncertainties in the use and evaluation of existing treatments to questions of how to better develop and test new therapies. This section describes 14 questions raised by the Working Group, which convey these important deficits of knowledge and which underlie the recommendations developed by the group.
1. What Changes Occur in the Lung Early in the Development of COPD?
Little is known about early changes, before the onset of significant airflow limitation, that occur in the lungs of smokers who will develop COPD. Research is needed to identify molecular, cellular, structural, and functional changes in the lungs of smokers, with and without COPD, across a wide range of ages. A companion need is for the identification and validation of biomarkers that correlate with disease activity and can be related to specific biochemical pathways.
2. Is Early Diagnosis of Value?
Spirometry offers a sensitive and inexpensive means of detecting COPD long before the stage at which most patients seek medical attention. However, few primary care physicians perform routine spirometry, even in those smokers over age 45 for whom it has been recommended. Hence, COPD is greatly underdiagnosed. Because no therapy other than smoking cessation is known to alter the course of mild or moderate COPD, the strongest rationale for early detection is the possibility that a patient's knowledge of disease (i.e., low FEV1) might enhance smoking cessation efforts. Existing studies of the influence of spirometric testing on quit rate are inconsistent. Additional clinical trials, which take into account the covariance of FEV1 and nicotine dependence, are needed to determine if spirometric testing can augment smoking cessation interventions.
3. Can the Heterogeneous COPD Population Be Divided into More Homogenous Subgroups on the Basis of Clinical Features and Laboratory Measures?
COPD is a protean condition whose diverse presentations include centriacinar emphysema, panacinar emphysema, and chronic bronchitis without appreciable emphysema. Furthermore, a host of clinical and laboratory measurements are often abnormal in COPD, and some of these show both great variability among patients and weak correlation with other measures. Various biomarkers have been identified, and certain genotypes have been associated with the disease. Although a rich array of parameters is available for stratification of patients with COPD, few of these (e.g., FEV1, methacholine responsiveness, radiographic indices of emphysema) are commonly used to predict outcome. Guidelines for the selection of therapies are generally based on unidimensional scales of severity. An important challenge in COPD is the development of more powerful, multivariate methods for predicting individual outcome and individual responsiveness to particular therapies on the basis of clinical and laboratory characteristics.
4. What Is the Natural History of COPD during its Later Stages?
Much of our knowledge of the natural history of COPD comes from cross-sectional studies of symptoms and spirometry in occupational cohorts performed more than a quarter century ago. Those studies provided little information about the late stages of COPD. Furthermore, they were performed outside the context of current medical management (e.g., long-term oxygen therapy), without modern measures of the disease (e.g., CT assessment of emphysema), and with littleemphasis on exercise limitation as an important, quantifiable manifestation of severe disease. Improvements in clinical carefor those with severe COPD would be aided by longitudinal studies of late stage disease that correlate advanced measures of the disease with outcome.
5. What Is the Pathogenetic Relationship between COPD and Lung Cancer?
Epidemiologic studies have demonstrated comorbidity of COPD and lung cancer in excess of that attributable to smoking, suggesting that these conditions may share genetic risk factors or involve common pathogenetic mechanisms. For example, inflammatory mediators, including oxidants and NO, that may be important in COPD can also induce DNA damage, inhibit DNA repair, and chemically activate carcinogens. Identification of common molecular processes in COPD and lung cancer could have important implications for the prevention and management of both diseases. Human, animal, and in vitro studies are needed to investigate cellular and molecular mechanisms common to COPD and lung cancer. There is also rationale for unified clinical studies of COPD and lung cancer in the areas of genetic susceptibility and chemoprevention.
6. What Measures of Disease Status Are Useful Indices of Therapeutic Benefit?
Demonstration of airflow limitation (e.g., decreased FEV1) is essential for diagnosis and is the best known predictor of outcome in COPD. Hence, decline in postbronchodilator FEV1 over time has been used as the "gold standard" measure of disease progression in premorbid COPD. However, emerging evidence indicates that alternative measures, such as inspiratory capacity, may better reflect the ventilatory dysfunction in COPD. Furthermore, reliance on FEV1 may cause studies to miss beneficial effects of therapies such as increased exercise capacity, quality of life, or cognitive function, or lessened dyspnea, cough, sputum production, depression, or frequency or severity of exacerbations. Alternative measures are needed that better reflect the clinical status of patients with COPD and allow detection ofclinically important responses to therapies. It is noteworthy that, in a trial of 1-antitrypsin augmentation in patients deficient in this protein, progression of emphysema could apparently be detected in less time by measurement of lung density using computed tomography than by pulmonary function testing.
7. How Can Exacerbations Be Better Managed?
Acute exacerbations of COPD are the major battlefront of the physician's war on this disease, and the arsenal is ineffective. Current treatment consists primarily of supportive measures in combination with drugs appropriated from the pharmacopoeias of asthma and pneumonia, which have limited effectiveness in COPD. Although such treatments are of some benefit, nearly half of patients with COPD hospitalized for severe exacerbations are dead within a year. Controlled studies are needed to rigorously evaluate the efficacy of current management approaches and to refine the indications for existing drugs. Methods of mechanical ventilation can likely be improved with better understanding of how patients with severe exacerbations of COPD respond physiologically to critical care interventions. New pharmacologic agents are needed, especially drugs that are capable of controlling the excess production and/or retention of mucus within the airways. In addition, greater emphasis is needed on the prevention of exacerbations, because this approach may do much to extend life and reduce the costs of care for patients with COPD.
8. Who Should Get Long-Term Oxygen Therapy and When?
Although oxygen supplementation relieves hypoxemia, it may increase oxidative stress, an insult thought to be involved in the pathogenesis of COPD. Hence, the value of oxygen treatment in COPD should be determined by clinical trials of sufficient duration to detect effects on mortality. Although there is clear value for long-term oxygen in those with resting PaO2 ≤55 mm Hg, there have not been adequate trials to assess the benefit of this treatment in other groups . Studies are needed in those with moderate hypoxemia, those with nocturnal oxyhemoglobin desaturation, and those who desaturate with ambulation. Possible effects of oxygen therapy on cognitive function and quality of life need to be assessed.
9. How Can Exercise Capacity Be Increased?
Exercise limitation is prevalent in COPD and is predictive of mortality among those with severe disease. The physiologic basis of this limitation is multifactorial. Ventilatory impairment, sensation of dyspnea, cardiopulmonary interactions, skeletal and respiratory muscle dysfunction, and general systemic illness may all contribute in certain patients. A better understanding of the proximate causes of diminished exercise capacity is important for improvements in pulmonary rehabilitation programs and for the development of new therapeutic strategies that may enhance physical performance in those with COPD. Of particular interest are the origin and treatment of skeletal muscle dysfunction, a well-documented systemic manifestation of COPD that may be amenable to pharmacologic interventions.
10. How Can Nutritional Status Be Improved?
Weight loss is often observed in severe COPD, and low body mass index is an independent predictor of respiratory mortality among those with COPD. There is no satisfactory explanation for why some, but not all, individuals with severe COPD lose weight, and there is no accurate method for predicting who will or will not become cachectic. Understanding the mechanisms of COPD-associated cachexia would be helpful for the design of a rational therapy for this condition. Although it is thought that weight loss in COPD is mainly due to diminished food intake rather than increased metabolism, trials of caloric supplementation have generally been disappointing. A meta-analysis of selected studiesdemonstrated increases in weight, but no significant improvement in other measures of disease severity. Nutritional supplementation in combination with exercise and/or anabolic drugs has not been adequately tested.
11. Is Control of Sleep Disorders an Important Aspect of COPD Management?
Sleep disturbance is common in COPD, and may contribute to depression, cognitive dysfunction, and lessened quality of life in this disease. Effective treatments of sleep disturbance in individuals with COPD are needed that minimize the respiratory depressant effects of many hypnotic drugs. In addition, COPD can coexist with obstructive sleep apnea, compounding the ventilatory defect of each condition. Studies are needed to evaluate the use of oxygen or noninvasive ventilatory support in patients with this "overlap syndrome."
12. How Should Comorbid Conditions Be Managed?
Patients with COPD are at enhanced risk of associated comorbidities such as cardiovascular disease, lung cancer, and sleep-disordered breathing. Despite this, little research has been done to determine the optimal means of managing COPD in combination with other conditions. For example, there is uncertainty as to whether COPD should be a relative contraindication for the use of ß-adrenergic blockers in patients with heart disease; and denials of lung cancer resection because of low FEV1 may unnecessarily discriminate against those with COPD. Studies are needed to improve management strategies for those with coexisting diseases.
13. What Can Be Done to Promote the Development and Testing of Novel Agents for the Treatment of COPD?
Several factors impede the development and testing of novel treatments for COPD. First, because the key pathogenetic pathways are not established, financial incentives for pharmaceutical companies favor trials of drugs already used for other diseases, rather than de novo development of targeted agents for COPD. Second, the unavailability of validated surrogate markers of COPD makes studies to establish proof of principle or appropriate dosage both complex and expensive. Third, the slow progression of COPD requires that efficacy trials be of long duration. Fourth, the heterogeneity of COPD requires large numbers of subjects for clinical trials of therapeutics. Efforts that may reduce these barriers to the development of novel agents include basic research on COPD pathogenesis; investigations of surrogate endpoints and indices for therapeutic stratification; exploration of alternative outcome measures; and greater cooperation among research institutions, funding agencies, health care providers, regulatory agencies, pharmaceutical companies, and health care payors in the conduct of clinical studies. For some drugs, there may be advantages to initial testing in patients with 1-antitrypsin deficiency because of the more rapid decline of FEV1 in this group than in usual COPD. The Alpha-1 Research Registry, now maintained by the Alpha One Foundation and the Medical University of South Carolina (Charleston, SC), contains demographic and clinical data on individuals with severe 1-antitrypsin deficiency, and can assist in the recruitment of this subpopulation of patients with emphysema for research studies.
14. What Is the Cost-Effectiveness of Strategies for COPD Prevention and Treatment?
Despite substantial expenditures on medical care for those with COPD, few studies have examined the cost-effectiveness of different treatment modalities. It is likely that reductions in the frequency and severity of acute exacerbations of COPD would be especially cost-effective, because hospitalizations, primarily for exacerbations, account for approximately two thirds of the direct costs of COPD care. Because those with advanced disease are more likely to be hospitalized, therapeutic advances that produce even modest improvements in the health of those with severe COPD may have a substantial economic impact. Greater emphasis should be placed on studies of the cost-effectiveness of COPD management approaches.
PREVENTIVE CARE IN CHRONIC LIVER DISEASES
Thomas R. Riley
Milton S. Hershey Medical Center
Hershey, PA
Introduction:
Chronic liver disease is the tenth leading cause of death in the United States (US) with over 25,000 deaths annually, according to federal statistics. There are an estimated 4 million known cases of hepatitis C in the US, some of which present with cirrhosis or will eventually become cirrhotic (1). Our current ability to treat hepatitis C and eliminate the infection has been improving with the advent of long acting interferons. After treatment, however, there will continue to be about 40-50% with continued evidence of chronic infection. The natural history of HCV is a progression from hepatitis to cirrhosis over many years, often twenty to fifty years. With an inability to cure the primary disease process in this non-responder group, it becomes important to prevent further insults thus optimizing the length of time between hepatitis to cirrhosis. Once cirrhosis occurs nothing currently can be done to reverse the process. Those with early cirrhosis (Child’s A) may live on average 10 to 15 years before death or liver transplantation (2). Preventive strategies can be used to maximize this time. This review will discuss preventive care methods that have been shown to be effective or have scientific rationale in the setting of chronic liver diseases both in the hepatitis and cirrhotic stages.
Avoidance of alcohol consumption:
Alcohol consumption is associated with an increased risk of cirrhosis, liver cancer and premature death when consumption is greater than four drinks daily (48 grams) (3). The types of injury that can occur to the liver directly related to alcohol include acute alcoholic hepatitis, fatty infiltration, and cirrhosis (4). There is little data available to determine what level of alcohol consumption might be safe in those with a chronic liver condition. In a recent report Corrao et al. examined the combined effect of hepatitis C and alcohol on the development of symptomatic cirrhosis. They found that alcohol had a synergistic (multiplies), not merely an additive role, in the development of cirrhosis in the patients infected with hepatitis C. The moderate alcohol consumption group carried an increased risk for the development of cirrhosis (5). Because the safe level of alcohol consumption is not known, it seems prudent to advise abstinence in the face of chronic liver diseases with the information we now have available. When moderate to heavy alcohol use is present in the face of chronic liver disease, abstinence is likely to be the most important intervention made in prolonging the course and delaying the progression towards cirrhosis. Alcohol has a strong addiction potential and abstinence can be difficult. Support in the process of abstinence should be suggested in many of the cases where heavy use is present. Examples of effective support include Alcoholics Anonymous, in- and out-patient rehabilitation programs and individual counselors (6).
Immunizations:
Case reports have raised the concern about the risks of super-infection with the hepatitis viruses in those with chronic liver diseases. Both hepatitis A and B are reported to cause more virulent (aggressive) acute infections when a chronic liver condition exists (7-10). A recent series by Vento et al. highlighted the risks of super-infection with hepatitis A. They followed prospectively (on an ongoing, current basis) 163 patients with chronic hepatitis B and 432 patients with hepatitis C. The study showed a substantial risk of fulminant hepatic failure and death with hepatitis A super-infection, in particular in those with chronic hepatitis C. Less than 1:1000 cases of hepatitis A are fatal. In this series, when chronic hepatitis C was present, 35% of cases were fatal (a 350 fold risk of death above normal) (11). In another large series of 115,551 cases of acute hepatitis A, there were 381 deaths. Of the deaths, 107 (28%) were in those with chronic liver disease (9). Based on this data, it is important to first test for exposure to the hepatitis viruses. If no immunity (natural protection) is found, then the hepatitis A vaccine (2 part series) and the hepatitis B vaccine (3 part series) should be administered. Both vaccines can be safely given in opposite deltoids (shoulders) at the same time, then the hepatitis B vaccine at one month for the second in the series, and finally both again for completion 6 months later (12-13). A study by Keeffe et al. recently described the safety and efficacy of vaccination in chronic liver disease (14). No vaccination currently is available for clinical use to protect against the acquisition of the hepatitis C virus. Pneumovax is also recommended as a one time vaccination in all patients with cirrhosis. The rationale includes the prevention of pneumococcal spontaneous bacterial peritonitis (infection of fluid in belly) episodes and to prevent pneumococcal pneumonia (lung infection) in a group where infection would be poorly tolerated (15). Finally, all patients with cirrhosis should receive yearly influenza vaccine, given the higher risk of mortality (death) should they contract influenza (16).
Avoidance of potentially liver toxic medications / vitamins / herbs / and minerals :
Most medications and ingested substances are altered chemically as they pass through the liver, which functions as a mechanism for clearance, detoxification, and excretion. Because of this central role of the liver in metabolic processing, the liver is vulnerable to toxicity from drugs and vitamins (17). In the setting of chronic liver diseases, the liver functions may variably become affected. The altered functions may enhance or predispose to toxicity from medications. In addition to a predisposition to medication toxicity, someone with a chronic liver condition may not tolerate a reaction. When these unpredictable reactions occur, patients with only a small amount of reserve function remaining may have a de-compensation in their condition.
To avoid medication toxicity in those with chronic liver disease, one needs to take an extremely cautious approach. Medications should be started only when absolutely indicated and no other option exists. Each medication that is required should be evaluated for possible liver toxicity. If liver toxicity has been reported, an alternative with less or no hepatic adverse effects should be sought. If no options or safer alternatives exist, then the medication can be started under close observation. The chronic liver disease patient should be aware of liver related symptoms, for example, jaundice (yellowing of the skin), pruritis (itching), anorexia (loss of appetite), fatigue (tiredness) and right upper quadrant (under right rib cage) abdominal (belly) pain. Liver injury tests can be followed, at baseline, every two weeks for a month, monthly for three months, then every three months indefinitely while requiring the potentially toxic medication. If an increase in liver injury test occurs that is more than two to three times the baseline or liver-related symptoms develop the medication should be discontinued (18). When a question arises about the safety of a medication in an individual with chronic liver disease, a liver specialist’s input may be helpful.
Pain medications are one of the most widely used medications, with both prescription and over-the counter medications available. The class of non-steroidal anti-inflammatory drugs (NSAIDs) encompasses the largest class of medications used for common maladies such as arthralgias or headache. NSAIDs can cause idiosyncratic (unpredictable) liver toxicity (19). A recent report by Riley et al. (20) described three cases of over-the-counter ibuprofen use in patients with hepatitis C which resulted in a greater than 10 fold rise in the transaminases (liver enzymes). In one of the cases a rechallenge occurred leading to a repeated equal rise in the transaminases. By nature of these unpredictable reactions (idiosyncratic), a risk is taken with each use of NSAIDs in the setting of chronic liver disease. NSAIDs are known to increase the tendency for bleeding by inhibiting platelet function in the setting of cirrhosis where there already is impaired coagulation (ability to clot). NSAIDs also decrease renal prostaglandins (hormones) in cirrhotic patients decreasing kidney blood flow, and thus filtration rates which can lead to renal failure (21). Acetaminophen use leads to an intrinsic, dose dependent, and predictable toxicity to the liver. There are no cases of toxicity reported even in advanced liver disease when less than 2 grams of acetaminophen are ingested (22). For these reasons NSAIDs should be avoided in chronic liver diseases. When pain medications are required preference should be given to acetaminophen at a dose of up to 2 grams per day.
Vitamins and “alternative” natural remedies are commonly consumed in the US with annual sales over 1.6 billion dollars. In informal polls taken in hepatology clinics up to 31% of patients were taking “alternative” therapies (23). These non-traditional medications should be inquired about and reviewed for safety. Vitamin A (betacarotene, retinol) is a known hepatotoxin but is widely available over-the-counter. There are multiple reports of massive doses leading to liver injury, usually in doses greater than 100,000 IU / day (24). There are rare reports of vitamin A doses of as low as 25,000 IU / day leading to liver injury including steatosis (fatty liver), chronic hepatitis (inflammation to liver through time), and fibrosis/cirrhosis (scar tissue). Alcohol use is reported to potentiate the toxicity of vitamin A . Vitamin A has a dose dependent toxicity and is safe to ingest in the usual diet. Patients with chronic liver diseases should be warned about the risks of mega-dose vitamin A consumption. Other possible liver toxins available without prescription include niacin, Chinese herbal tea, Jin Bu Huan, germander, Kalms tablets, gentian, asafetida, valerian, mistletoe, senna fruit extracts, chaparral leaf, comfrey, bush herbal teas, and pennyroyal oil (24). Iron supplementation, usually in the form of a multivitamin preparation is not uncommon. In the usual state of health, excess dietary iron is not absorbed and is excreted in the stool. In the setting of many chronic liver diseases there is a propensity for excessive iron to accumulate in the liver. Hepatitis C and alcoholic liver diseases seem to have a particular tendency for secondary hemosiderosis (iron loading) with up to 30% showing evidence of serum accumulation by iron studies and 10% with liver tissue excesses (25,26). The data has been accumulating along several lines of evidence that iron overload is detrimental to those with chronic liver diseases. Hepatic iron concentration, when high, has been shown by several investigators to be a predictor of non-response to interferon alfa therapy in chronic hepatitis C (27,28). In further support, when phlebotomy was used as the sole treatment in chronic hepatitis C in those with confirmed iron overload histologically, there was a significant improvement in serum transaminases (29). A study from India showed that when combining a low iron diet with traditional treatment of hepatitis C there was an increased response to treatment (30). Animal studies have demonstrated enhanced hepatotoxicity to alcohol in rat models when iron was co-administered (31). Given these findings, patients with chronic liver diseases should avoid excessive iron intake. If a patient with chronic liver disease takes a multivitamin, it should not have iron as a component unless iron deficiency anemia is demonstrated. No evidence exists to suggest that normal dietary iron is harmful.
Heart / Liver Smart Diet:
Fatty infiltration of the liver is a basic response to a variety of injuries. The list of conditions that will produce fatty infiltration is extensive and includes alcoholic liver disease, non-alcoholic steatohepatitis (NASH), hepatitis C, drug reactions, Wilson’s disease and other genetic diseases (32). Predisposing medical risk factors include diabetes mellitus, obesity, and elevated serum triglycerides (33). Fatty infiltration is often well tolerated with minimal to no inflammatory reaction. In some cases, however, an inflammatory reaction to the presence of fat can be intense leading to elevation of liver injury tests and histologic changes of necro-inflammation (death of liver cells from inflammation), fibrosis and cirrhosis (34). A study by Ueno et al. demonstrated in a controlled trial that a weight reduction diet and exercise program can improve liver injury blood tests, and liver biopsy appearance in patients with NASH (35). Liver tests often return towards normal with relatively minor weight reduction of 10 to 15 pounds. Deems et al. reported on a relationship between liver injury tests and dietary intake. A study of dietary intake on 42 chronic liver disease patients showed a correlation between high fat and oil food consumption and elevated liver injury tests (36). Recent studies have highlighted the detrimental effects of obesity and HCV infection, with a higher risk of advanced fibrosis as degree of obesity increases (37). These observations suggest that a low fat diet and exercise program (supervised by a physician for appropriateness) would minimize hepatic steatosis. In those with chronic liver disease and obesity gradual weight reduction should be recommended.
Preventive measures in cirrhosis:
Once cirrhosis is established, the disease is considered irreversible. Survival in early cirrhosis may be up to 15-20 years. Potential risks during this time interval include bleeding from esophageal varices (dilated veins in feeding tube) and the development of hepatocellular carcinoma. Preventive or early detection strategies have been evaluated for both of these conditions.
Beta-Blockade in prevention of first variceal bleed. Portal hypertension (increased blood pressure before the liver) is a frequent complication of cirrhosis. When the portal pressures are consistently high, portal-systemic collaterals (new channels form). The once small veins become enlarged and under pressure and form esophagogastric varices (dilated veins). Varices can be visualized in approximately 60 % of patients with cirrhosis undergoing upper endoscopy (scopes). Patients with large varices will have bleeding episodes at a rate of ~ 40 % per year. The first bleeding episode from varices may be associated with mortality rates as high as 50% (38). Endoscopic criteria have been defined which predict those patients who are at risk of variceal bleeding. These criteria include larger varices, red markings on variceal surface, and the patient’s Child’s score (an ABC system used to rank severity of cirrhosis) (39). The ability to predict high risk patients aids in targeting preventive strategies, and allows those at low risk to avoid unnecessary medications. Several randomized controlled studies have shown that non-selective beta-blockers reduce the risk of the initial variceal bleed in high risk patients by about 50% (45% to 22% risk of bleeding over 2 years) (40). The pulse is indicative of adequate dosing, and beta-blockers are titrated (dose adjusted) to achieve a 25% reduction from baseline pulse. Usual starting doses are propranolol 10 mg three times per day. If either no varices or small varices are found on the initial endoscopy, medication prophylaxis may be withheld. These patients should subsequently undergo surveillance endoscopy every one to two years to determine subsequent risk of bleeding.
Screening for Hepatocellular Cancer: Cirrhosis, irrespective of the cause with few exceptions, carries a high risk for the development of hepatocellular carcinoma (HCC) (tumor of liver origin). HCC is the leading cause of death in a population of cirrhotic patients (41). Advanced HCC carries a poor prognosis, having a three year survival of 17% (42). If HCC lesions are discovered early, and are less than 2 cm at the time of resection, survival of up to 85% at 5 years has been reported (43). In those with decompensated liver disease where a small HCC is found, successful liver transplantation with minimal recurrence has been reported (44). Two tests have been suggested for screening, the serum measurement of alpha-fetoprotein (AFP) and liver ultrasonography. Although imperfect when either is used alone, multiple studies have confirmed the efficacy of combined use of AFP and ultrasound in early detection. Some controversy still exists in the frequency of testing required and achievement of cost effectiveness (45). There is a lack of data to assure that early detection translates into better outcome, because randomized trials in this patient group are difficult to perform (46). Overall, the existing data suggests the need for at least yearly ultrasounds and every 6 month measurements of AFP in all patients with cirrhosis of the liver.
Conclusions:
Many liver diseases have long natural histories with few treatments that directly alter the course. To maximize the time to cirrhosis, need for liver transplantation, or death it becomes important to avoid other injury to the liver. A handout for patients to remind them of good liver health is provided (Table 1).
WHY BRAIN HAS LIMITED CAPACITY FOR REPAIR AFTER STROKE
New Drug Target Identified
ScienceDaily (Nov. 3, 2010) - Stroke is the leading cause of adult disability, due to the brain's limited capacity for recovery. Physical rehabilitation is the only current treatment following a stroke, and there are no medications available to help promote neurological recovery.
Now, a new UCLA study published in the Nov. 11 issue of the journal Nature offers insights into a major limitation in the brain's ability to recover function after a stroke and identifies a promising medical therapy to help overcome this limitation.
Researchers interested in how the brain repairs itself already know that when the brain suffers a stroke, it becomes excitable, firing off an excessive amount of brain cells, which die off. The UCLA researchers found that a rise in a chemical system known as "tonic inhibition" immediately after a stroke causes a reduction in this level of excitability.
But while this "damping down" initially helps limit the spread of stroke damage, the increased tonic inhibition level and reduced brain excitability persists for weeks, eventually becoming detrimental to the brain's recovery.
Based on this finding, the researchers identified a new way to "turn off" this inhibitory response in order to promote stroke recovery and determined the window of time in which this and other brain-repair therapies after stroke should be administered. These findings offer new targets for drug development to promote stroke recovery.
"It was surprising to find that the level of tonic inhibition was increased for so long after stroke and that there was an inflection point where the increased level eventually hindered the brain from recovering," said Dr. Tom Carmichael, associate professor of neurology at the David Geffen School of Medicine at UCLA and a member of the UCLA Stroke Center. "It was also surprising that we could easily manipulate tonic inhibition in the brain after stroke to restore it back to a normal, 'non-stroke' level and, in doing this, enhance behavioral recovery."
Other studies have looked in general terms at excitatory signaling or at a type of inhibitory signaling after stroke known as "phasic inhibition." However, this previous work focused on the direct connections between brain cells.
The UCLA research is the first to examine tonic inhibition in stroke, focusing on the chemical system, which does not directly link brain cells together but instead senses the overall activity level in the brain and sets the thresholds for when brain cells will fire off new signals.
By studying stroke and stroke recovery in mice, the researchers found that since stroke causes a reduction in the normal clearance of an inhibitory brain chemical, it causes neurons in the tissue that borders the stroke to be less excitable. They found that by applying specific blockers of this inhibitory brain chemical, they could then "turn off the switch."
The resulting enhanced brain excitability immediately improved behavioral recovery after stroke. As a result, these findings identified the potential for a new target in the brain for effective stroke recovery treatments.
"An important element in stroke treatment is the timing of drug delivery," added Carmichael. "We found that blocking tonic inhibition too early could produce cell death, but by delaying treatment to three days after stroke, it promoted functional recovery without altering the stroke size."
The next stage of research will be to validate the findings in other pre-clinical models of stroke, and then to design clinical trials for humans. Pharmaceutical companies have been active in this region of neuroscience and there are some promising candidate drugs for human use that exist.
Additional authors were Andrew N. Clarkson, Ben S. Huang, Sarah E. MacIsaac and Istvan Mody.
This research was funded by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, the Larry L. Hillblom Foundation, the Coelho Endowment, a grant from the National Institutes of Health/National Institute of Neurological Disorders and Stroke, and the American Heart Association.