Anemia

Patients with congestive heart failure (CHF) may have an associated problem of anemia, a decrease in the number of red blood cells (RBC) - the component of blood that carries oxygen. Even by itself, anemia can cause symptoms of shortness of breath and fatigue, similar to the symptoms of heart failure. A low RBC count (hematocrit) limits the amount of oxygen being carried to the body, which makes the heart work harder. In fact, as the severity of CHF progresses, the findings of anemia increase; and severe anemia due to any cause can worsen CHF. Because of this relationship, anemia treatment may be an important part of CHF.
Two medications erythropoietin and darbepoetin alfa, stimulate RBC growth and production in the bone marrow. These medicines require being given by a shot (like insulin) usually every 1-4 weeks. This can help people with heart failure correct their anemia, when it is due to inadequate bone marrow production.
In general, severe anemia may also be treated with vitamins or blood transfusions.

Reducing side effects of heart treatment

Take medications exactly as your doctor orders.

• Do not stop taking them unless prescribed by your doctor.
• Do not alter the dosage without checking with your doctor.
• Take your medications at the same time each day.
• Check with your doctor before taking any over-the-counter medications.
• Do not take outdated/expired medications. Check with your pharmacist if you have questions about the age of your medications.
• Inform your doctor of other medications you are taking to ensure there are no unfavorable drug interactions with your new prescription.

Diet for health care

Sodium is a critical issue for patients with heart failure. A high sodium intake can cause fluid retention and therefore contribute to edema. Fluid accumulation puts more strain on the heart and can lead to shortness of breath. Salty foods cause the body to hold on to fluids contributing to congestion. Most people consume much more salt than they need. Salt (sodium) is required by the body, but only in small amounts. Try to keep your sodium intake to no more than two grams per day.
Cholesterol
High blood cholesterol levels have been linked to coronary artery disease, the leading cause of heart failure. A diet high in saturated fats leads to a high level of LDL or "bad" cholesterol. If you are at risk for coronary artery disease, reduce your intake of saturated fats such as those found in red meats and whole milk products and reduce cholesterol levels by limiting egg yolks and animal products.
Fluids
In advanced cases of heart failure, your doctor may wish to restrict your fluid intake to reduce the stress on your heart. Check with your doctor to see how much fluid he or she recommends each day.

Symptoms of heart failure

Shortness of Breath
Shortness of breath can be caused by congestion in the lungs. This congestion is known as pulmonary edema. One sign to watch out for is whether your shortness of breath is worse when you lay flat. Orthopnea is the shortness of breath which occurs when blood kept in the legs by gravity returns to the chest when you lay down.

Shortness of breath can also occur at night. Shortness of breath that comes on suddenly at night is known as paroxysmal (par-ox-iz-mal) nocturnal dyspnea.

Fatigue
Fatigue is often attributed to getting old or being out of shape. However, if this condition persists for long periods of time, it may be the result of heart failure. Sluggishness may be the result of your organs not getting enough oxygen. You may feel as tired after getting up in the morning as you did when you went to bed. Let your doctor know if this happens on a regular basis.

Loss of Appetite
Fluid accumulation in the digestive organs can cause you to feel full. You may also feel bloated. You may want to try eating smaller more frequent meals instead of the traditional three large meals a day.


Weight Gain or Loss
Excess fluid in the body may cause an increase in weight. Similarly, when excess fluid is excreted, your weight may fall. Weight increases by about two pounds for each extra quart of fluid. You may notice that your weight has risen before you notice swelling of the ankles or extremities. Inform your doctor of changes of more than five pounds.

Conditions for Heart Failure

Hypertension
This is more commonly known as high blood pressure. It is a condition that is treatable and simple to diagnose with a blood pressure cuff. Although most individuals will not have symptoms, hypertension is detected by a simple measurement with a blood pressure cuff and stethoscope. It is also a risk factor for CAD, stroke, peripheral vascular disease, or kidney impairment.
Cardiomyopathy
A disease of the heart muscle. This can be one of many varieties. It can arise because of genetic causes, a viral infection, or consumption of toxins (lead, alcohol, etc.). In peripartum cardiomyopathy, women who have recently given birth can develop heart muscle impairment. In many cases, the condition is called "idiopathic", which means it has occurred of uncertain origin or cause.

Heart Failure Causes

For heart failure to occur, there must be an unresolved impairment of the heart that compromises its ability to work as a pump. The source of this can be a cutoff of blood supply, an increase in workload due to high blood pressure caused by non-functioning valves or a genetic predisposition. Heart failure can be worsened by a poor diet and lifestyle. Its development follows the scheme below:

Heart Failure

Once the heart has been injured, the body will attempt to compensate for reduced blood flow. Unfortunately, many of the countermeasures actually increase strain on the heart and further the development of heart failure.
The heart, after suffering damage or being placed under physical stress by high blood pressure, will begin to change its own shape. This deforming of the ventricles' shape is known as remodeling or hypertrophy.
For comparative terms, the normal heart essentially looks like a football. When the wall thickens in concentric circles (lower left), The heart works less effectively and takes on the shape of a large fist. This may be caused by hypertension, a blocked aortic valve, or underlying genetics. Dilation of the ventricle walls (lower right) gives the weakened heart a beach-ball shape and an inefficient contraction. This prohibits blood from leaving the heart as it normally would. This remodeling pattern follows damage from a heart attack, sustained hypertension, viral infection, or genetic causes.

working of neuroendocrine system

This system works as a complex series of checks and balances on the heart and circulatory system in a way similar to the action of a thermostat. A thermostat detects transient changes in temperature and has a maximum and minimum temperature range allowed. When the room temperature falls below the minimum, the thermostat signals to the furnace to turn on and raise the temperature in the room. When the addition of heat causes the maximum temperature to be reached, the thermostat signals to the furnace to turn off. Much the same way, the neuroendocrine system monitors certain variables in the body and makes adjustments when variables aren't in the needed range.
Unfortunately, the changes made by the system are not necessarily beneficial in the long run. Imagine that the thermostat in the above example is reset to a higher than desirable level. Once the furnace turns on, it will not receive any input that the room is too hot and will continue to pump heat into the room until the new threshold temperature is reached. In a similar sense, if the brain doesn't receive a proper "off" signal, it will continue to raise blood pressure unnecessarily. Going one step further, impaired heart function will lead to ineffective, sustained signalling activity by the nervous system, which will further create conditions that strain the heart, driving it towards failure.

neuroendocrine system

The heart utilizes electrochemical signals to control the rate at which it contracts. It accomplishes this using bundles of "pacemaker cells" whose signals maintain an internal rhythm independent of the body. However, at rest the rhythm it maintains is slightly faster than what is ordinarily required. The neuroendocrine system usually dampens this rate, but it can elevate it as well using electrical or chemical signals (during exercise or stress).
The neuroendocrine ( neuro-nerve; endocrine-hormone) system is a compilation of inputs from the nervous system as well as glands throughout the body that secrete chemicals. Both usually work together to account for transient or even chronic changes in the body. Using nerve signals or hormones, the neuroendocrine system changes cell activities that alter the diameter of blood vessels, the heart's rate and strength of contraction, and even the amount of fluid the body retains.

working of lungs

WE BREATHE BECAUSE OUR TISSUES BREATHE! The lungs basically work as a pair of bellows - as the chest expands they draw in air (of which oxygen is a component). Upon exhaling the chest uses its elastic properties to passively "snap back" to its original size.
Oxygen and carbon dioxide can travel between the lungs and bloodstream because the capillaries that surround the air sacs are permeable to gases. In essence, this means that oxygen and carbon dioxide molecules are small enough to passively diffuse through the tissues that compose both the blood vessels and alveoli. This same principal applies to gas exchange between the blood in the capillaries and tissues in the body. In heart failure conditions, however, if the blood is leaving the lung against a high pressure downstream in the left atrium, fluid can actually diffuse into the lungs. This condition, known as pulmonary edema, can inhibit gas exchange and make it very difficult and uncomfortable to breathe.

How does the circulatory system work?

Contractions from the heart eject blood into the lungs and body. The vascular network must be vast in complexity and length to cover all of this volume. The combined length of all of the tubing would cover nearly 60,000 miles (100,000 kilometers) - more than TWICE around the earth - if plumbed in a straight line! The vascular system, with the help of neuroendocrine input, can contract and relax different arteries and veins to guide both the speed and destination of blood flow, depending on the needs of the body. This facilitates circulation in performing more specialized tasks.
During physical exertion, the vessels going to muscles can dilate to deliver more oxygen to those tissues. Furthermore, blood also serves as a method to distribute our body heat. By dilating blood vessels at our skin surface, the body allows conductive heat loss during exercise, while contracting their diameter conserves body heat when the environment becomes colder.
As mentioned before, the circulatory system is a closed loop. If there are any serious blockages or changes in vessel resistance along the line, it is like putting a bend or kink in a garden hose - flow through the bend is slowed and pressure to push through the reduced opening may increase. This resistance to flow is of concern in heart failure, not only because of the workload it imposes on the heart, but because it hampers delivery of blood's precious cargoes (food, oxygen, etc.). Placing the heart under such stressful conditions (i.e. increased heart rate and contraction force with a curtailed oxygen supply) will reduce its ability to compensate for the needs of the body.

circulatory system

Our circulatory system can be thought of as a network of living pipes that allows our body to transport oxygen as well as nutrients to the tissues. Chemical wastes produced by our cells enter the blood to be filtered and eliminated by our body (largely by the kidney and liver). Our body circulates about 5 liters (5.3 quarts) of blood; at rest, the heart moves it at a rate of 5 liters per minute. In summary, even without activity, blood can run the entire circuit of the body in one minute. During heavy exercise, the whole loop can be completed in ten seconds.
The main components of the circulation are pictured on the left:

1. Arteries - the red vessels represent arteries. Hemoglobin, the oxygen carrying chemical in red blood cells, takes on blood's distinctive red color when it is combined with oxygen. Arteries carry blood away from the heart and branch into smaller vessels (first arterioles, then capillaries) in order to facilitate delivery of its cargo to the organs and other tissues.
2. Veins - the blue vessels represent veins. This bluish tint is also due to hemoglobin. After releasing oxygen to living cells, hemoglobin undergoes a chemical change that gives it a distinctive reddish-blue tone. Veins also have a series of one-way valves built into their structure. This is crucial for proper circulation, as gravity could cause blood to pool below the heart otherwise!

Latex allergies

Allergic reactions to exposure to natural rubber latex (NRL) have increased significantly over the last ten years, particularly within healthcare occupations.
The proteins naturally present in NRL cause the allergies either through direct contact with the skin or by inhalation of powder from powdered latex gloves.
This website will tell you more about NRL allergies and how you can protect yourself and others against them. It gives advice on single-use glove selection, taking account of the importance of infection control. It does not cover protection against chemicals. The site applies particularly if you are an employer/work in healthcare occupations or are a patient. The site will be expanded in the future to cover other workers.

Cross-section of normal bronchiole

During an asthma attack the muscle wall contracts and the lining of the airways becomes swollen and inflamed. These changes cause a narrowing of the airways which is further aggravated by an increase in secretions from the mucus membrane, which may actually block the smaller airways. All these give rise to an obstruction to airflow. This leads to a significant increase in the effort needed to move air in and out of the lungs, giving rise to wheezing and breathlessness.

Lungs

An asthma attack occurs when the airways of the lung become narrowed causing an obstruction to the flow of air. Symptoms include coughing, wheezing, breathlessness and a tightness in the chest.

Lungs

While the larger airways have cartilage in their walls to prevent their collapse, the smaller bronchi and bronchioles do not have this support. These smaller airways are muscular tubes and their lining contains many mucus secreting cells.

Occupational asthma

Occupational asthma is an allergic reaction that can occur in some people when they are exposed to substances, for example flour or wood dust in the workplace.

These substances are called 'respiratory sensitisers' or asthmagens. They can cause a change in people’s airways, known as the 'hypersensitive state'.
Not everyone who becomes sensitised goes on to get asthma. But once the lungs become hypersensitive, further exposure to the substance, even at quite low levels, may trigger an attack.
The main causes of occupational asthma are set out in Section C of HSE's Asthmagen Compendium.
This list of substances is a useful summary. Also look for the risk phrase R42 ‘May cause sensitisation by inhalation’ on product labels or safety data sheets.

Symptoms of asthma

Asthma is a serious health problem. Thousands of people in Britain have to face the challenges of this disease every day.

Symptoms include severe shortness of breath that can stop you from doing the simplest tasks. Imagine not being able to carry your shopping or walk up the stairs or even play with your children. Some sufferers are unable to work again.
Other symptoms include:

• Wheezing
• Coughing
• Chest tightness

The symptoms can develop right after exposure to a workplace substance. But sometimes symptoms appear several hours later, possibly at night. This can make any link with workplace activities unclear.
Other associated conditions are:

• rhinitis (sneezing/runny nose)
• conjunctivitis (itchy and inflamed red eyes).

Asthma

Breathing in certain dusts, gases, fumes and vapours within the workplace can cause asthma. Asthma is a very serious health problem that can ruin lives. Shortness of breath, wheezing and painful coughing are just some of the symptoms that occupational asthma sufferers may have to deal with every day.

Side Effects of Treatment

Common side effects of alpha interferon and peginterferon (occurring in more than 10 percent of patients) include

• fatigue
• muscle aches
• headaches
• nausea and vomiting
• skin irritation at the injection site
• low-grade fever
• weight loss
• irritability
• depression
• mild bone marrow suppression
• hair loss (reversible)

Most of these side effects are mild to moderate in severity and can be managed. They are worse during the first few weeks of treatment, especially with the first injection. Thereafter, side effects diminish. Acetaminophen or a nonsteroidal anti-inflammatory drug (NSAID) such as ibuprofen or naproxen may be helpful for the muscle aches and low-grade fever. Fatigue and depression are occasionally so troublesome that the dose of peginterferon should be decreased or therapy stopped early. Depression and personality changes can occur on peginterferon therapy and be quite subtle and not readily admitted by the patient. These side effects need careful monitoring. Patients with depression may benefit from antidepressant therapy using selective serotonin reuptake inhibitors. Generally, the psychiatric side effects resolve within 2 to 4 weeks of stopping combination therapy.
Ribavirin also causes side effects, and the combination is generally less well tolerated than peginterferon monotherapy. The most common side effects of ribavirin are

• anemia
• fatigue and irritability
• itching
• skin rash
• nasal stuffiness, sinusitis, and cough

Ribavirin causes a dose-related hemolysis of red cells; with combination therapy, hemoglobin usually decreases by 2 to 3 g/dL and the hematocrit by 5 to 10 percent. The amount of decrease in hemoglobin is highly variable. The decrease starts between weeks 1 and 4 of therapy and can be precipitous. Some patients develop symptoms of anemia, including fatigue, shortness of breath, palpitations, and headache.
The sudden drop in hemoglobin can precipitate angina pectoris in susceptible people, and fatalities from acute myocardial infarction and stroke have been reported in patients receiving combination therapy for hepatitis C. For these important reasons, ribavirin should not be used in patients with pre-existing anemia or with significant coronary or cerebral vascular disease. If such patients require therapy for hepatitis C, they should receive peginterferon monotherapy.
Ribavirin has also been found to cause itching and nasal stuffiness. These are histamine-like side effects; they occur in 10 to 20 percent of patients and are usually mild to moderate in severity. In some patients, however, sinusitis, recurrent bronchitis, or asthma-like symptoms become prominent. It is important that these symptoms be recognized as attributable to ribavirin, because dose modification (by 200 mg per day) or early discontinuation of treatment may be necessary.
Uncommon side effects of alpha interferon, peginterferon, and combination therapy (occurring in less than 2 percent of patients) include

• autoimmune disease (especially thyroid disease)
• severe bacterial infections
• marked thrombocytopenia
• marked neutropenia
• seizures
• depression and suicidal ideation or attempts
• retinopathy (microhemorrhages)
• hearing loss and tinnitus

Who should be treated?

Patients with anti-HCV, HCV RNA, elevated serum aminotransferase levels, and evidence of chronic hepatitis on liver biopsy, and with no contraindications, should be offered therapy with the combination of peginterferon and ribavirin. The National Institutes of Health Consensus Development Conference Panel recommended that therapy for hepatitis C be limited to those patients who have histological evidence of progressive disease. Thus, the panel recommended that all patients with fibrosis or moderate to severe degrees of inflammation and necrosis on liver biopsy should be treated and that patients with less severe histological disease be managed on an individual basis. Patient selection should not be based on the presence or absence of symptoms, the mode of acquisition, the genotype of HCV RNA, or serum HCV RNA levels.
Between 30 and 40 percent of patients with chronic hepatitis C have normal serum aminotransferase levels. These patients usually have mild disease that is unlikely to progress. Nevertheless, such patients may wish to be treated and, indeed, response rates to peginterferon and ribavirin appear to be independent of serum aminotransferase levels. Patients who prefer not to be treated at present should be monitored as advances in the field may ultimately lead to more effective and better tolerated therapies. When questions arise regarding treatment, liver biopsy can be helpful in documenting the level of disease activity and liver fibrosis and thus the advisability of waiting for future improvements in therapy.
Patients with cirrhosis can be offered therapy if they do not have signs of decompensation, such as ascites, persistent jaundice, wasting, variceal hemorrhage, or hepatic encephalopathy. However, combination therapy has not been shown to improve survival or the ultimate outcome in patients with pre-existing cirrhosis.
The role of peginterferon and ribavirin therapy in children with hepatitis C remains uncertain. Ribavirin has yet to be evaluated adequately in children, and pediatric doses and safety have not been established. Thus, if children with hepatitis C are treated, monotherapy is recommended, and ribavirin should not be used outside of controlled clinical trials.
People with both HCV and HIV infection should be offered therapy for hepatitis C as long as there are no contraindications. Indeed, hepatitis C tends to be more rapidly progressive in patients with HIV co-infection, and end-stage liver disease has become an increasingly common cause of death in HIV-positive persons. For these reasons, therapy for hepatitis C should be recommended even in HIV-infected patients with early and mild disease. Once HIV infection becomes advanced, complications of therapy are more difficult and response rates are less. The decision to treat people co-infected with HIV must take into consideration the concurrent medications and medical conditions. In particular, ribavirin may have significant interactions with anti-retroviral drugs used to treat HIV infection. In patients with co-infection, control of the HIV infection should be the first priority; in persons who are inadequately treated for HIV or who have low CD4 counts, therapy of concurrent HCV is unlikely to be successful and may have serious complications.
In many of these indefinite situations, the indications for therapy should be reassessed at regular intervals. In view of the rapid developments in hepatitis C today, better therapies may become available within the next few years, at which point expanded indications for therapy would be appropriate.
Patients with chronic hepatitis C should be advised on the likelihood of a beneficial outcome to antiviral therapy. For patients with genotypes 2 and 3, the likelihood of a sustained virological response is 70 to 80 percent. In patients with genotype 1, the likelihood of a sustained virological response is between 40 and 55 percent, but the individual likelihood correlates with several viral and patient factors. The major predictive factor for a response is the level of HCV RNA in serum: response rates being higher if HCV RNA levels are lower—levels less than 800,000 IU/ml generally being considered low. Furthermore, response rates are higher in women than men, in younger than older persons, in persons with normal body weight compared with those who are overweight or obese, and in persons with lesser degrees of fibrosis on liver biopsy. Strikingly, response rates are also higher among Caucasian Americans and Asian Americans than among African American patients. Thus, average overall response rates in persons with HCV genotype 1 infection are 50 to 60 percent among Caucasian Americans, but only 25 to 30 percent among African American patients. The reasons for these racial differences are not known.
Patients with acute hepatitis C are a major challenge to management and therapy. Because such a high proportion of patients with acute infection develop chronic hepatitis C, prevention of chronicity has become a focus of attention. In small studies, 83 to 100 percent of persons treated within 1 to 4 months of onset have had resolution of the infection. What is unclear is when to initiate treatment, at what dose, for what duration, and with which regimen. A practical but rigorous approach is to start peginterferon (in usual doses) and ribavirin (800 mg daily) for 24 weeks if HCV RNA is still detected 3 months after onset of infection. The role of ribavirin and the use of shorter courses of therapy are currently under evaluation.
In patients with clinically significant extrahepatic manifestations, such as cryoglobulinemia and glomerulonephritis, therapy with interferon can result in remission of the clinical symptoms and signs. However, relapse after stopping therapy is common. In some patients, long-term or maintenance peginterferon therapy can be used despite persistence of HCV RNA in serum if clinical symptoms and signs resolve on therapy.

Treatment

Alpha Interferon

The therapy for chronic hepatitis C has evolved steadily since alpha interferon was first approved for use in this disease more than 10 years ago. At the present time, the optimal regimen appears to be a 24- or 48-week course of the combination of pegylated alpha interferon and ribavirin.
Alpha interferon is a host protein that is made in response to viral infections and has natural antiviral activity. Recombinant forms of alpha interferon have been produced, and several formulations (alfa-2a, alfa-2b, consensus interferon) are available as therapy for hepatitis C. These standard forms of interferon, however, are now being replaced by pegylated interferon (peginterferon).
Peginterferon is alpha interferon that has been modified chemically by the addition of a large inert molecule of polyethylene glycol. Pegylation changes the uptake, distribution, and excretion of interferon, prolonging its half-life. Peginterferon can be given once weekly and provides a constant level of interferon in the blood, whereas standard interferon must be given several times weekly and provides intermittent and fluctuating levels. In addition, peginterferon is more active than standard interferon in inhibiting HCV and yields higher sustained response rates with similar side effects. Because of its ease of administration and better efficacy, peginterferon has replaced standard interferon both as monotherapy and as combination therapy for hepatitis C.

Ribavirin

Ribavirin is an oral antiviral agent that has activity against a broad range of viruses. By itself, ribavirin has little effect on HCV, but adding it to interferon increases the sustained response rate by two- to three-fold. For these reasons, combination therapy is now recommended for hepatitis C, and interferon monotherapy is applied only when there are specific reasons not to use ribavirin.

Combination Therapy

Combination therapy leads to rapid improvements in serum ALT levels and disappearance of detectable HCV RNA in up to 70 percent of patients. However, long-term improvement in hepatitis C occurs only if HCV RNA disappears during therapy and stays undetectable once therapy is stopped. Among patients who become HCV RNA negative during treatment, some will relapse when therapy is stopped. The relapse rate is lower in patients treated with combination therapy compared with monotherapy. Thus, a 48-week course of combination therapy using peginterferon and ribavirin yields a sustained response rate of about 55 percent. A similar course of peginterferon monotherapy yields a sustained response rate of only 35 percent. A response is considered “sustained” if HCV RNA remains undetectable for 6 months or more after stopping therapy.

Dosing

Two forms of peginterferon have been developed and studied in large clinical trials: peginterferon alfa-2a (Pegasys: Hoffman La Roche, Nutley, NJ) and peginterferon alfa-2b (Pegintron: Schering-Plough Corporation, Kenilworth, NJ). These two products are roughly equivalent in efficacy and safety, but have different dosing regimens.

• Peginterferon alfa-2a is given subcutaneously in a fixed dose of 180 micrograms (mcg) per week.
• Peginterferon alfa-2b is given subcutaneously weekly in a weight-based dose of 1.5 mcg per kilogram (kg) per week (thus in the range of 75 to 150 mcg per week).

Ribavirin is an oral medication, given twice a day in 200-mg capsules for a total daily dose based upon body weight. The standard dose of ribavirin is 1,000 mg for patients who weigh less than 75 kg (165 pounds) and 1,200 mg for those who weigh more than 75 kg. In certain situations, an 800-mg dose (400 mg twice daily) is recommended (see Duration).

Duration

The optimal duration of treatment varies depending on whether interferon monotherapy or combination therapy is used, as well as by HCV genotype. For patients treated with peginterferon monotherapy, a 48-week course is recommended, regardless of genotype. For patients treated with combination therapy, the optimal duration of treatment depends on viral genotype. Patients with genotypes 2 and 3 have a high rate of response to combination treatment (70 to 80 percent), and a 24-week course of combination therapy yields results equivalent to those of a 48-week course. In contrast, patients with genotype 1 have a lower rate of response to combination therapy (40 to 45 percent), and a 48-week course yields a significantly better sustained response rate. Again, because of the variable responses to treatment, testing for HCV genotype is clinically useful when considering starting combination therapy.
In addition, the optimal dose of ribavirin appears to vary depending on genotype. For patients with genotypes 2 or 3, a dose of 800 mg daily appears adequate. For patients with genotype 1, the full dose of ribavirin (1,000 or 1,200 mg daily depending on body weight) appears to be needed for an optimal response.
There is little information on the optimal regimen of peginterferon and ribavirin for patients with the rare genotypes 4, 5, and 6. These patients should probably receive the regimen of peginterferon and ribavirin that is recommended for genotype 1.
Many attempts have been made to identify patients who have a rapid response to treatment and who might be able to stop peginterferon and ribavirin early and be spared the further expense and side effects of prolonged therapy. Patients who test HCV RNA negative within 4 weeks of starting therapy are considered “rapid responders.” In several studies, rapid responders with genotypes 2 and 3 have been found to be able to stop therapy after 12 to 16 weeks (12 to 8 weeks early) and still achieve a high rate of response. Similarly, rapid responders with genotype 1 may be able to stop therapy at 24 weeks (24 weeks early) and achieve an excellent response rate. The consequence of early stopping, however, is a higher relapse rate and this approach of abbreviating therapy in rapid responders must be individualized based upon tolerance.

Diagnosis

Hepatitis C is most readily diagnosed when serum aminotransferases are elevated and anti-HCV is present in serum. The diagnosis is confirmed by the finding of HCV RNA in serum.

Acute Hepatitis C

Acute hepatitis C is diagnosed in persons who have symptoms such as jaundice, fatigue, and nausea, together with marked increases in serum ALT (usually greater than 10-fold elevation), and the presence of anti-HCV or de novo development of anti-HCV.
Diagnosis of acute disease can be problematic because anti-HCV is not always present when the patient develops symptoms and sees the physician. In 30 to 40 percent of patients, anti-HCV is not detected until 2 to 8 weeks after onset of symptoms. In this situation, testing for HCV RNA is helpful, as this marker is present even before the onset of symptoms and lasts through the acute illness. Another approach to diagnosis of acute hepatitis C is to repeat the anti-HCV testing a month after onset of illness. Of course, a history of an acute exposure is also helpful in suggesting the diagnosis.

Chronic Hepatitis C

Chronic hepatitis C is diagnosed when anti-HCV is present and serum aminotransferase levels remain elevated for more than 6 months. Testing for HCV RNA (by PCR) confirms the diagnosis and documents that viremia is present; almost all patients with chronic infection will have the viral genome detectable in serum by PCR.
Diagnosis is problematic in patients who cannot produce anti-HCV because they are immunosuppressed or immunoincompetent. Thus, HCV RNA testing may be required for patients who have a solid-organ transplant, are on dialysis, are taking corticosteroids, or have agammaglobulinemia. Diagnosis is also difficult in patients with anti-HCV who have another form of liver disease that might be responsible for the liver injury, such as alcoholism, iron overload, or autoimmunity. In these situations, the anti-HCV may represent a false-positive reaction, previous HCV infection, or mild hepatitis C occurring on top of another liver condition. HCV RNA testing in these situations helps confirm that hepatitis C is contributing to the liver problem.

Noninvasive Tests

While liver biopsy is considered the “gold standard” for assessing the severity of liver disease, it is not always accurate and has several shortcomings. Liver biopsy can under- or over-estimate the severity of hepatitis C, particularly if the biopsy is small and if it is not read by a knowledgeable expert. In addition, liver biopsy is an invasive procedure that is expensive and not without complications. At least 20 percent of patients have pain requiring medications after liver biopsy. Rare complications include puncture of another organ, infection, and bleeding. Significant bleeding after liver biopsy occurs in one out of 100 to one out of 1,000 cases, and deaths are reported in one out of 5,000 to one out of 10,000 cases. Obviously, noninvasive means of grading and staging liver disease would be very helpful.
ALT levels, particularly if tested over an extended period, are reasonably accurate reflections of disease activity. Thus, patients with repeatedly normal ALT levels usually have mild inflammation and liver cell injury on liver biopsy. Furthermore, patients who maintain ALT levels above five times the upper limit of normal usually have marked inflammatory activity. But for the majority of patients with mild to moderate ALT elevations, the actual level is not very predictive of liver biopsy findings.
More important is a means to stage liver disease and measure fibrosis short of liver biopsy. Unfortunately, serum tests are not reliable in predicting fibrosis, particularly earlier stages (0, 1, and 2). When patients develop bridging (stage 3) fibrosis and cirrhosis (stage 4), serum tests may be helpful. The “danger signals” that suggest the presence of advanced fibrosis include an aspartate aminotransferase (AST) that is higher than ALT (reversal of the ALT/AST ratio), a high gamma glutamyl transpeptidase or alkaline phosphatase, a decrease in platelet count (which is perhaps the earliest change), elevations in serum globulins, and, of course, abnormal bilirubin, albumin, or prothrombin time. Physical findings of a firm liver, or enlarged spleen or prominent spider angionata or palmar erythema, are also danger signals. While none of these findings are completely reliable, their presence should raise the suspicion of significant fibrosis and lead to evaluation for treatment sooner rather than later.
Recently, x-ray and imaging studies have been developed that may be able to separate different degrees of fibrosis in the liver. At present, these techniques are experimental and of unproven accuracy, particularly in detecting early stages of fibrosis. The most promising technique is “elastrography,” in which sound or magnetic waves are passed through the liver and the speed with which they return is measured, which provides an index of the elasticity and stiffness of the liver. Liver stiffness is used as an indirect measure of liver fibrosis. Most importantly, measuring the relative stiffness of the liver over time may provide a noninvasive way to monitor the development of fibrosis and help guide recommendations for when therapy should be recommended. Ultrasound elastrography is currently under evaluation for its reliability in measuring the degree of fibrosis in the liver in patients with hepatitis C. Ultimately, elastrography may be able to replace liver biopsy as a way of monitoring the progression of disease in chronic hepatitis C.

Liver Biopsy

Liver biopsy is not necessary for diagnosis but is helpful for grading the severity of disease and staging the degree of fibrosis and permanent architectural damage. Hematoxylin and eosin stains and Masson’s trichrome stain are used to grade the amount of necrosis and inflammation and to stage the degree of fibrosis. Specific immunohistochemical stains for HCV have not been developed for routine use. Liver biopsy is also helpful in ruling out other causes of liver disease, such as alcoholic liver injury, nonalcoholic fatty liver disease, or iron overload.
HCV causes the following changes in liver tissue:

• Necrosis and inflammation at the edge of the portal areas, so-called “piecemeal necrosis” or “interface hepatitis”
• Necrosis of hepatocytes and focal inflammation in the liver parenchyma
• Inflammatory cells in the portal areas (“portal inflammation”)
• Fibrosis may exist in an early stage, being confined to the portal tracts, an intermediate stage consisting of expansion of the portal tracts and bridging between portal areas or to the central area, or a late stage of frank cirrhosis characterized by architectural disruption of the liver with fibrosis and regeneration. Several scales are used to stage fibrosis. One common classification is a scale from 0 to 4 where stage 0 indicates no fibrosis; stage 1 indicates enlargement of the portal areas by fibrosis; stage 2 indicates fibrosis extending out from the portal areas with rare bridges between portal areas; stage 3 indicates many bridges of fibrosis that link up portal and central areas of the liver; and stage 4 indicates cirrhosis.

By assigning scores for severity, grading and staging of hepatitis are helpful in managing patients with chronic hepatitis. The degree of inflammation and necrosis can be assessed as none, minimal, mild, moderate, or severe. The degree of fibrosis can be similarly assessed. Scoring systems are particularly helpful in clinical studies on chronic hepatitis.

Normal Serum ALT Levels

Up to 40 percent of patients with chronic hepatitis C have normal serum alanine aminotransferase (ALT) levels, even when tested on multiple occasions. In this and other situations in which the diagnosis of chronic hepatitis C may be questioned, the diagnosis should be confirmed by testing for HCV RNA. The presence of HCV RNA indicates that the patient has ongoing viral infection despite normal ALT levels.

Genotyping and Serotyping of HCV

There are six known genotypes and more than 50 subtypes of hepatitis C. The genotype is helpful in defining the epidemiology of hepatitis C. More important, knowing the genotype or serotype (genotype-specific antibodies) of HCV is helpful in making recommendations and counseling regarding therapy. Patients with genotypes 2 and 3 are two to three times more likely to respond to interferon-based therapy than patients with genotype 1. Furthermore, when using combination therapy, the recommended dose and duration of treatment depend on the genotype. For patients with genotypes 2 and 3, a 24-week course of combination treatment using peginterferon and 800 milligrams (mg) of ribavirin daily is adequate, whereas for patients with genotype 1, a 48-week course and full dose of ribavirin (1,000 to 1,200 mg daily) is recommended. For these reasons, testing for HCV genotype is clinically important. Once the genotype is identified, it need not be tested again; genotypes do not change during the course of infection.

Quantification of HCV RNA in Serum

Several methods are available for measuring the concentration or level of virus in serum, which is an indirect assessment of viral load. These methods include a quantitative PCR and a branched DNA (bDNA) test. Unfortunately, these assays are not well standardized, and different methods from different laboratories can provide different results on the same specimen. In addition, serum levels of HCV RNA can vary spontaneously by 3- to 10-fold over time. Nevertheless, when performed carefully, quantitative assays provide important insights into the nature of hepatitis C. Most patients with chronic hepatitis C have levels of HCV RNA (viral load) between 100,000 (10⁵) and 10,000,000 (10⁷) copies per mL. Expressed as IU, these averages are 50,000 to 5 million IU.
Viral levels as measured by HCV RNA do not correlate with the severity of the hepatitis or with a poor prognosis (as in HIV infection); but viral load does correlate with the likelihood of a response to antiviral therapy. Rates of response to a course of peginterferon and ribavirin are higher in patients with low levels of HCV RNA. There are several definitions of a “low level” of HCV RNA, but the usual definition is below 800,000 IU (~ 2 million copies) per mL.
In addition, monitoring HCV RNA levels during the early phases of treatment may provide early information on the likelihood of a response. Yet because of the shortcomings of the current assays for HCV RNA level, these tests are not always reliable guides to therapy.

Biochemical Indicators of Hepatitis C Virus Infection

• In chronic hepatitis C, increases in the alanine and aspartate aminotransferases range from zero to 20 times (but usually less than five times) the upper limit of normal.
• Alanine aminotransferase (ALT) levels are usually higher than aspartate aminotransferase (AST) levels, but that finding may be reversed in patients who have cirrhosis.
• Alkaline phosphatase and gamma glutamyl transpeptidase are usually normal. If elevated, they may indicate cirrhosis.
• Low platelet and white blood cell counts and raised levels of serum globulins (including immunoglobulins and rheumatoid factor) are frequent in patients with severe fibrosis or cirrhosis, providing clues to the presence of advanced disease.
• The enzymes lactate dehydrogenase and creatine kinase are usually normal.
• Albumin levels, bilirubin, and prothrombin time are normal until late-stage disease.
• Iron and ferritin levels may be slightly elevated.

Serologic Tests

Enzyme Immunoassay

Persons suspected to have hepatitis C should be tested for anti-HCV as an initial screening test. Anti-HCV is detected by enzyme immunoassay (EIA). The third-generation test (EIA-3) used today is more sensitive and specific than previous ones. As with all enzyme immunoassays, however, false-positive results are occasionally a problem with the EIA-3. Additional or confirmatory testing is often helpful.
The best approach to confirm the diagnosis of hepatitis C is to test for HCV RNA using a sensitive assay such as polymerase chain reaction (PCR) or transcription-mediated amplification (TMA). The presence of HCV RNA in serum indicates an active infection.
Testing for HCV RNA is also helpful in patients in whom EIA tests for anti-HCV are unreliable. For instance, immunocompromised patients may test negative for anti-HCV despite having HCV infection because they may not produce enough antibodies for detection with EIA. Likewise, patients with acute hepatitis may test negative for anti-HCV when first tested. Antibody is present in almost all patients by 1 month after onset of acute illness; thus, patients with acute hepatitis who initially test negative may need follow-up testing. In these situations, HCV RNA is usually present and confirms the diagnosis.

Recombinant Immunoblot Assay

Immunoblot assays can be used to confirm anti-HCV reactivity. These tests are also called “Western blots”; serum is incubated on nitrocellulose strips on which four recombinant viral proteins are blotted. Color changes indicate that antibodies are adhering to the proteins. An immunoblot is considered positive if two or more proteins react and is considered indeterminate if only one positive band is detected. In some clinical situations, confirmatory testing by immunoblotting is helpful, such as for the person with anti-HCV detected by EIA who tests negative for HCV RNA. The EIA anti-HCV reactivity could represent a false-positive reaction, recovery from hepatitis C, or continued virus infection with levels of virus too low to be detected (the last occurs only rarely when sensitive PCR or TMA assays are used). If the immunoblot test for anti-HCV is positive, the patient has most likely recovered from hepatitis C and has persistent antibody. If the immunoblot test is negative, the EIA result was probably a false positive.
Immunoblot tests are routine in blood banks when an anti-HCV-positive sample is found by EIA. Immunoblot assays are highly specific and valuable in verifying anti-HCV reactivity. Indeterminate tests require further follow-up testing, including attempts to confirm the specificity by repeat testing for HCV RNA.

Extrahepatic Manifestations

Complications that do not involve the liver develop in 1 to 2 percent of people with hepatitis C; the most common is cryoglobulinemia, which is marked by

• skin rashes, such as purpura, vasculitis, or urticaria
• joint and muscle aches
• kidney disease
• neuropathy
• cryoglobulins, rheumatoid factor, and low-complement levels in serum

Other complications of chronic hepatitis C are

• glomerulonephritis
• porphyria cutanea tarda

Diseases that are less well documented to be related to hepatitis C are

• seronegative arthritis
• keratoconjunctivitis sicca (Sjögren's syndrome)
• non-Hodgkin's type, B-cell lymphomas
• fibromyalgia
• lichen planus

Clinical Features of Cirrhosis

Once a patient develops cirrhosis or if the patient has severe disease, symptoms and signs are more prominent. In addition to fatigue, the patient may complain of muscle weakness, poor appetite, nausea, weight loss, itching, dark urine, fluid retention, and abdominal swelling.
Physical findings of cirrhosis may include

• enlarged liver
• enlarged spleen
• jaundice
• muscle wasting
• excoriations (scratches or abrasions on the skin)
• ascites (fluid-filled belly)
• ankle swelling

Clinical Symptoms and Signs

Many people with chronic hepatitis C have no symptoms of liver disease. If symptoms are present, they are usually mild, nonspecific, and intermittent. They may include

• fatigue
• mild right-upper-quadrant discomfort or tenderness (“liver pain”)
• nausea
• poor appetite
• muscle and joint pains

Similarly, the physical exam is likely to be normal or show only mild enlargement of the liver or tenderness. Some patients have vascular spiders or palmar erythema.

Unsafe Injection Practices

In many areas of the world, unsafe injection practices in the delivery of health care are an important and common cause of hepatitis C (and hepatitis B as well). Use of inadequately sterilized equipment, reuse of needles and syringes, and inadvertent contamination of medical infusions are unfortunately well-documented causes of transmission of hepatitis C. Careful attention to universal precautions and injection techniques should prevent this type of spread. In the United States, multiple-use vials are a frequent culprit in leading to medical-care linked spread of hepatitis C.

The Hepatitis C Virus

HCV is a small (40 to 60 nanometers in diameter), enveloped, single-stranded RNA virus of the family Flaviviridae and genus hepacivirus. Because the virus mutates rapidly, changes in the envelope proteins may help it evade the immune system. There are at least six major genotypes and more than 50 subtypes of HCV. The different genotypes have different geographic distributions. Genotypes 1a and 1b are the most common in the United States (about 75 percent of cases). Genotypes 2 and 3 are present in only 10 to 20 percent of patients. There is little difference in the severity of disease or outcome of patients infected with different genotypes. However, patients with genotypes 2 and 3 are more likely to respond to interferon treatment.

Sporadic Transmission

Sporadic transmission, when the source of infection is unknown, is the basis for about 10 percent of acute hepatitis C cases and for 30 percent of chronic hepatitis C cases. These cases are usually referred to as sporadic or community-acquired infections. These infections may have come from exposure to the virus from cuts, wounds, or medical injections or procedures.

Sexual Transmission

Sexual transmission of hepatitis C between monogamous partners appears to be uncommon. Surveys of spouses and monogamous sexual partners of patients with hepatitis C show that fewer than 5 percent are infected with HCV, and many of these have other risk factors for this infection. Spread of hepatitis C to a spouse or partner in stable, monogamous relationships occurs in less than 1 percent of partners per year. For these reasons, changes in sexual practices are not recommended for monogamous patients. Testing sexual partners for anti-HCV can help with patient counseling. People with multiple sex partners should be advised to follow safe sex practices, which should protect against hepatitis C as well as hepatitis B, HIV, and other sexually transmitted diseases.

Maternal-Infant Transmission

Maternal-infant transmission is not common. In most studies, less than 5 percent of infants born to HCV-infected mothers become infected. The disease in newborns is usually mild and free of symptoms. The risk of maternal-infant spread rises with the amount of virus in the mother’s blood, if the mother also has human immunodeficiency virus (HIV) infection, or if there are complications of delivery such as early rupture of membranes and fetal monitoring. Breast-feeding has not been linked to the spread of HCV.

Risk Factors and Transmission

HCV is spread primarily by contact with infected blood and blood products. Blood transfusions and the use of shared, unsterilized, or poorly sterilized needles, syringes and injection equipment or paraphernalia have been the main routes of the spread of HCV in the United States. With the introduction in 1991 of routine blood screening for HCV antibody and improvements in the test in mid-1992, transfusion-related hepatitis C has virtually disappeared. At present, injection drug use is the most common risk factor for contracting the infection. However, some patients who acquire hepatitis C do not have a recognized risk factor or known exposure to infected blood or to drug use.
The most common risk factors for acquiring hepatitis C are

• injecting drugs, including having used injection drugs only once many years ago
• having a blood transfusion before June 1992, when sensitive tests for anti-HCV were introduced for blood screening
• receiving clotting factor concentrates (such as anti-hemophilic factor) before 1987, when effective means to inactive HCV were introduced
• hemodialysis for kidney failure
• birth to an HCV-infected mother
• suffering a needle-stick accident from a person with hepatitis C

Other risk factors that have a slightly increased risk for hepatitis C are

• having sex with someone with hepatitis C or having multiple sex partners
• intranasal use of cocaine using shared equipment or paraphernalia

Chronic Hepatitis C

The hepatitis C virus (HCV) is one of the most important causes of chronic liver disease in the United States. It accounts for about 15 percent of acute viral hepatitis, 60 to 70 percent of chronic hepatitis, and up to 50 percent of cirrhosis, end-stage liver disease, and liver cancer. Of the U.S. population, 1.6 percent, or an estimated 4.1 million Americans, have antibody to HCV (anti-HCV), indicating ongoing or previous infection with the virus. Hepatitis C causes an estimated 10,000 to 12,000 deaths annually in the United States.
A distinct and major characteristic of hepatitis C is its tendency to cause chronic liver disease in which the liver injury persists for a prolonged period if not for life. About 75 percent of patients with acute hepatitis C ultimately develop chronic infection.
Chronic hepatitis C varies greatly in its course and outcome. At one end of the spectrum are infected persons who have no signs or symptoms of liver disease and have completely normal levels of serum enzymes, the usual blood test results that indicate liver disease. Liver biopsy usually shows some degree of injury to the liver, but the extent is usually mild, and the overall prognosis may be good. At the other end of the spectrum are patients with severe hepatitis C who have symptoms, high levels of the virus (HCV RNA) in serum, and elevated serum enzymes, and who ultimately develop cirrhosis and end-stage liver disease. In the middle of the spectrum are many patients who have few or no symptoms, mild to moderate elevations in liver enzymes, and an uncertain prognosis.
Chronic hepatitis C can cause cirrhosis, liver failure, and liver cancer. Researchers estimate that at least 20 percent of patients with chronic hepatitis C develop cirrhosis, a process that takes at least 10 to 20 years. Liver failure from chronic hepatitis C is one of the most common reasons for liver transplants in the United States. After 20 to 40 years, a small percentage of patients develop liver cancer. Hepatitis C is the cause of about half of cases of primary liver cancer in the developed world. Men, alcoholics, patients with cirrhosis, people over age 40, and those infected for 20 to 40 years are at higher risk of developing HCV-related liver cancer.

Hepatitis D

Hepatitis D is caused by the virus HDV. You can only get hepatitis D if you are already infected with hepatitis B. It is spread through contact with infected blood, dirty needles that have HDV on them, and unprotected sex (not using a condom) with a person infected with HDV. Hepatitis D causes swelling of the liver.

Hepatitis C

Hepatitis C is caused by the virus HCV. It is spread the same way as hepatitis B, through contact with an infected person's blood, semen, or body fluid (see above). Like hepatitis B, hepatitis C causes swelling of the liver and can cause liver damage that can lead to cancer. Most people who have hepatitis C develop a chronic infection. This may lead to a scarring of the liver, called cirrhosis. Blood banks test all donated blood for hepatitis C, greatly reducing the risk for getting the virus from blood transfusions or blood products.

Hepatitis B

Hepatitis B is caused by the virus HBV. It is spread by contact with an infected person's blood, semen, or other body fluid. And, it is a sexually transmitted disease (STD). You can get hepatitis B by:
• Having unprotected sex (not using a condom) with an infected person.
• Sharing drug needles (for illegal drugs like heroin and cocaine or legal drugs like vitamins and steroids).
• Getting a tattoo or body piercing with dirty (unsterile) needles and tools that were used on someone else.
• Getting pricked with a needle that has infected blood on it (health care workers can get hepatitis B this way).
• Sharing a toothbrush, razor, or other personal items with an infected person.
• An infected woman can give hepatitis B to her baby at birth or through her breast milk.
• Through a bite from another person.
With hepatitis B, the liver also swells. Hepatitis B can be a serious infection that can cause liver damage, which may result in cancer. Some people are not able to get rid of the virus, which makes the infection chronic, or life long. Blood banks test all donated blood for hepatitis B, greatly reducing the risk for getting the virus from blood transfusions or blood products.

Hepatitis A

Hepatitis A:
is caused by eating food and drinking water infected with a virus called HAV. It can also be caused by anal-oral contact during sex. While it can cause swelling and inflammation in the liver, it doesn't lead to chronic, or life long, disease. Almost everyone who gets hepatitis A has a full recovery.

Viral hepatitis

Viral hepatitis is liver inflammation due to a viral infection. It may present in acute (recent infection, relatively rapid onset) or chronic forms. The most common causes of viral hepatitis are the five unrelated hepatotropic viruses Hepatitis A, Hepatitis B, Hepatitis C, Hepatitis D, and Hepatitis E. In addition to the hepatitis viruses, other viruses that can also cause hepatitis include Herpes simplex, Cytomegalovirus, Epstein-Barr virus, or Yellow fever.
A virus previously called Hepatitis G virus is now classified as GB virus C because it does not appear to cause hepatitis.

Hepatitis

Hepatitis (plural hepatitides) is an inflammation of the liver characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar (ἧπαρ), the root being hepat- (ἡπατ-), meaning liver, and suffix -itis, meaning "inflammation". The condition can be self-limiting (healing on its own) or can progress to fibrosis (scarring) and cirrhosis.
Hepatitis may occur with limited or no symptoms, but often leads to jaundice, anorexia (poor appetite) and malaise. Hepatitis is acute when it lasts less than six months and chronic when it persists longer. A group of viruses known as the hepatitis viruses cause most cases of hepatitis worldwide, but it can also be due to toxins (notably alcohol, certain medications and plants), other infections and autoimmune diseases.

Acute

Initial features are of nonspecific flu-like symptoms, common to almost all acute viral infections and may include malaise, muscle and joint aches, fever, nausea or vomiting, diarrhea, and headache. More specific symptoms, which can be present in acute hepatitis from any cause, are: profound loss of appetite, aversion to smoking among smokers, dark urine, yellowing of the eyes and skin (i.e., jaundice) and abdominal discomfort. Physical findings are usually minimal, apart from jaundice in a third and tender hepatomegaly (swelling of the liver) in about 10%. Some exhibit lymphadenopathy (enlarged lymph nodes, in 5%) or splenomegaly (enlargement of the spleen, in 5%).
Acute viral hepatitis is more likely to be asymptomatic in younger people. Symptomatic individuals may present after convalescent stage of 7 to 10 days, with the total illness lasting 2 to 6 weeks.
A small proportion of people with acute hepatitis progress to acute liver failure, in which the liver is unable to clear harmful substances from the circulation (leading to confusion and coma due to hepatic encephalopathy) and produce blood proteins (leading to peripheral edema and bleeding). This may become life-threatening and occasionally requires a liver transplant.

Chronic

Chronic hepatitis often leads nonspecific symptoms such as malaise, tiredness and weakness, and often leads to no symptoms at all. It is commonly identified on blood tests performed either for screening or to evaluate nonspecific symptoms. The occurrence of jaundice indicates advanced liver damage. On physical examination there may be enlargement of the liver.
Extensive damage and scarring of liver (i.e. cirrhosis) leads to weight loss, easy bruising and bleeding tendencies, peripheral edema (swelling of the legs) and accumulation of ascites (fluid in the abdominal cavity). Eventually, cirrhosis may lead to various complications: esophageal varices (enlarged veins in the wall of the esophagus that can cause life-threatening bleeding) hepatic encephalopathy (confusion and coma) and hepatorenal syndrome (kidney dysfunction).