MEDICINE

Dangers of high-normal blood pressure

People whose blood pressure readings are at the high end of the normal range (borderline hypertension) may be at increased risk of cardiovascular disease, according to a new study. The findings reinforce the need for people in this category to take steps to control blood pressure and prevent heart problems.

One such study involved 6,859 people without evidence of cardiovascular disease whose blood pressure fell into one of three categories: high-normal, normal or optimal.

Over a 10-year period, both the women and the men in the study with high-normal blood pressure were considerably more likely to develop cardiovascular disease than those in the optimal range. Women were 2 ½ times more likely, while men were over 1 ½ times more likely to develop cardiovascular disease than those in the optimal range. The study is in the Nov. 1, 2002, New England Journal of Medicine.

Cardiologists say for people in the high-normal range, it’s especially important to take steps to lower blood pressure and prevent cardiovascular disease. These include losing weight if necessary, maintaining an exercise program, eating a healthy diet with an emphasis on fruits, vegetables and low-fat dairy foods, controlling your intake of sodium and eliminating tobacco.

If those steps don’t help lower your blood pressure adequately, your doctor may consider prescribing a medication designed to lower blood pressure. I personally feel it’s important to have your blood pressure checked at least once a week beyond the age of 40 years.

Understanding your blood pressure measurement

Systolic Diastolic

Optimal * below 120 and lower than 80
Normal below 130 and lower than 85
High-normal ** 130 to 139 or 85 to 89
High (hypertension) *** 140 or higher or 90 or higher

* Optimal means the preferred range in terms of cardiovascular risk. Unusually low readings should be evaluated.

** High-normal blood pressure may increase your risk of cardiovascular disease.

*** Hypertension diagnosis is based on the average of two or more readings (high systolic or diastolic readings – or both) taken at each of two or more visits after an initial screening. Systolic hypertension is a major risk factor for cardiovascular disease, even without elevated diastolic pressure, especially in older people.

Source : National Institutes of Health, 1997. Numbers are in millimeters of mercury (mmHg).

TREATMENT OF HIGH LDL CHOLESTEROL

By K. Gireesh

Reduction of LDL Cholesterol is just one part of a program to reduce the risk of cardiovascular disease. Other measures - including smoking cessation, hypertension control, and aspirin - are also of central importance. Less well studied but of potential value is raising the HDL cholesterol level. Quitting smoking reduces the effect of other cardiovascular risk factors (Such as a high cholesterol level); it may also increase the HDL cholesterol level. Exercise (and weight loss) may reduce the LDL cholesterol and increase the HDL. Modest alcohol use (1-2 ounces a day) also raises HDL levels and appears to have a salutary effect on coronary heart disease rates. While the clinician may not wish to recommend alcohol use to patients, its use in moderation need not be discouraged.

Diet Therapy

Studies of nonhospitalized adults have reported only modest cholesterol-lowering benefits of dietary therapy, typically in the range of a 5 - 10% decreases in LDL cholesterol, with even less in the long term. The effect of diet therapy, however, varies considerably among individuals, as some patients will have striking reductions in LDL cholesterol - up to 25 - 30% decrease - while others will have clinically important increases. Thus, the results of diet therapy should be assessed about 4 weeks after initiation.

Cholesterol-lowering diets may also have a variable effect on lipid fractions. Diets very low in total fat or in saturated fat may lower HDL cholesterol as much as LDL cholesterol. It is not known how these diet-induced changes affect coronary risk.

Several nutritional approaches to diet therapy are available. Most American currently eat 35-40% of calories as fat, of which 15% is saturated fat. Dietary cholesterol intake averages 400 mg/d. A standard "Step 1" cholesterol-lowering diet recommends reducing total fat to 30% and saturated fat to 10% of calories. Dietary cholesterol should be limited to 300 mg/d. The "Step 2" diet further restricts saturated fat to 7% of
calories and dietary cholesterol to 200 mg/d. These diets replace fat, particularly saturated fat, with carbohydrate. In most instances, this approach will also result in fewer total calories consumed and will facilitate weight loss in overweight patients. Other diet plans, including the Dean Ornish Diet, the Pritikin Diet, and most vegetarian diets, restrict fat even further. Low-fat, high-carbohydrate diets may, however, result in reductions in HDL cholesterol.

Table 1: Macronutrient composition of three lipid-modifying diets.
Recommended Intake

An alternative strategy is the "Mediterranean diet," which maintains total fat at approximately 35 - 40% of total calories but replaces saturated fat with monounsaturated fat such as that found in canola oil and in olives, peanuts, avocados, and their oils. This diet is equally effective at lowering LDL cholesterol but is less likely to lead to reductions in HDL cholesterol. This diet is less likely to lead to weight loss. Thus, a traditional low fat approach is still preferred for patients with lipid disorders who are overweight.

Other dietary changes may also result in beneficial changes in blood lipids. Soluble fiber, such as that found in oat bran or psyllium, may reduce LDL cholesterol by 5 - 10%. Garlic, soy protein, vitamin C, and certain plant sterols may also result in reduction of LDL cholesterol. Because oxidation of LDL cholesterol as a potential initiating event in atherogenesis, diets rich in antioxidant vitamins, found primarily in fruits and vegetables, may be helpful.

Pharmacologic Therapy

All patients whose risk from coronary heart disease is considered high enough to warrant pharmacologic therapy of an elevated LDL cholesterol should be given aspirin prophylaxis at a dose of 81 - 325 mg/d unless there are contraindications such as aspirin sensitivity, bleeding diatheses, or active peptic ulcer disease. The benefit of aspirin in reducing the risk of coronary heart disease is equivalent to that of cholesterol lowering. Other coronary heart disease risk factors, such as hypertension and smoking, should also be controlled.

If the decision to treat a patient with an LDL-lowering drug is made, a goal for treatment is set. The therapeutic goal is approached slowly, watching for side effects and encouraging continued compliance with nonpharmacologic measures. Combinations of drugs may be necessary. Once the goal is reached, the lipid profile should be monitored periodically, with consideration given to periodic reductions in drug dose. With the exception of niacin (available generically for a few dollars per month), lipid-lowering agents are expensive and may need to be given for decades. Thus their cost-effectiveness is generally low, especially in primary prevention.

Table 2: Effects of selected lipid-modifying drugs.

A. NIACIN (NICOTINIC ACID):

Niacin was the first lipid-lowering agent that was associated with a reduction with a reduction in total mortality. Long -term follow-up of a secondary prevention trial of middle aged men with previous myocardial infarction disclosed that about half of those who had been previously treated with niacin had died, compared with nearly 60% of the placebo group. This favorable effect on mortality was not seen during the trial itself, though there was a reduction in the incidence of recurrent coronary events.

Niacin reduces the production of VLDL particles, with secondary reduction in LDL and increases in HDL cholesterol levels. The average effect of full-dose niacin therapy, 3 - 4.5 g/d, is a 15 - 25% reduction in LDL cholesterol and a 25 - 35% increase in HDL cholesterol. Full doses are required to obtain the LDL effect, but the HDL effect is observed at lower doses, e.g., 1 g/d. Niacin will also reduce triglycerides by half and will lower lipoprotein levels. Thus, its effect on blood lipids is nearly optimal. Unfortunately, intolerance to niacin is common; only 50 - 60% of patients tolerate full doses. Niacin causes a prostaglandin-mediated flushing that patients may describe as hot flashes or pruritus. This problem can be decreased by pretreatment with aspirin or other nonsteroidal anti-inflammatory agents. Flushing may also be decreased by initiating niacin therapy with a very small dose, e.g., 50 - 100 mg with the evening meal. The dose can be doubled each week until 1.5 g.d is reached. Only immediate-release niacin is recommended for lipid modification. Sustained release preparations are more expensive and have less effect on raising HDL cholesterol. Both immediate-release and sustained-release niacin are associated with hepatitis, but the most severe cases have been reported with the sustained-release preparations.

It is not known whether routine monitoring of liver enzymes results in early detection and thus reduced severity of this side effect. Niacin can also exacerbate gout and peptic ulcer disease and may worsen hyperglycemia in patient with diabetes mellitus.

Table 3: Selection of lipid-modifying medications.

Primary prevention

Premenopausal women (rare):
Statins, niacin, Resins
Men (35 - 75 years):
Statins, niacin, resins
Postmenopausal women(<75 years):
Statins, niacin
Secondary prevention
Men :
Statins, niacin, combinations
Women :
Statins, niacin, combinations

B. BILE ACID - BINDING RESINS (CHOLESTYRAMINE, COLESTIPOL):

Treatment with these agents reduces the incidence of coronary events in middle-aged men by about 20% with no significant effect on total mortality. The resins work by binding bile acids in the intestine. The resultant reduction in the enterohepatic circulation causes the liver to increase its production of bile acids, using hepatic cholesterol to do so. Thus, hepatic LDL receptor activity increases, with a decline in plasma LDL levels. The triglyceride level tends to increase slightly in some patients treated with bile acid-binding resins; they should be used with caution in those with elevated triglycerides and probably not at all in patients who have triglyceride levels above 500 mg/dL. The clinician can anticipate a reduction of 15 - 25% in the LDL cholesterol level, with insignificant effects on the HDL level.

The usual dose of cholestyramine is 12 - 36 g of resin per day in divided doses with meals, mixed in water or, more palatably, juice. The prepackaged 4-g doses are more expensive than the bulk form; the "candy bars" are even more expensive. Doses of colestipol are 20% (the packets each contain 5 g of resin).

These agents often cause gastrointestinal symptoms, such as constipation and gas. They may interfere with the absorption of fat-soluble vitamins (thereby complicating the management of patients receiving warfarin) and may bind other drugs in the intestine. Concurrent use of psyllium may ameliorate the gastrointestinal side effects.

C. HMG-CoA REDUCTASE INHIBITORS (LOVASTATIN, PRAVASTATIN, SIMVASTATIN,
FLUVASTATIN, ATORVASTATIN, CERIVASTATIN):

These agents work by inhibiting the rate-limiting enzyme in the formation of cholesterol. They reduce myocardial infarctions and total mortality in secondary prevention, as well as in middle-aged men free of coronary heart disease. A meta-analysis has demonstrated significant reduction in risk of stroke. Cholesterol synthesis in the liver is reduced, with a compensatory increase in hepatic LDL receptors (presumably so that the liver can take more of the cholesterol that it needs from the blood), and a reduction in the circulating LDL cholesterol level by up to 35%. There are also modest increases in HDL levels and decreases in triglyceride levels.

Doses are a s follows: lovastatin, 10 - 80 mg/d; pravastatin, 10 - 40 mg/d; simvastatin, 5 - 40 mg/d; fluvastatin, 20 - 40 mg/d; and atorvastatin, 10 - 80 mg/d. These agents are usually given once a day in the evening (most cholesterol synthesis takes place overnight); at the high end of the dose ranges twice-a-day dosing may be used. Side effects include myositis, whose incidence may be higher in patients concurrently taking fibrates or niacin. Manufacturers recommend monitoring liver and muscle enzymes. Several agents (notably erythromycin, cyclosporine, and azole antifungals) reduce the metabolism of these agents.

D. FIBRIC ACID DERIVATIVES (GEMFIBROZIL, CLOFIBRATE, FENOFIBRATE):

In the largest clinical trial that used clofibrate, there were significantly more deaths - especially due to cancer - in the treatment group; it should not be used Gemfibrozil reduced coronary heart disease rates in hypercholesterolemic middle-aged men free of coronary disease in the Helsinki Heart Study. The effect was only observed among those who also had lower HDL cholesterol levels and high triglyceride levels. In a recent VA study, gemfibrozil was also shown to reduce cardiovascular events in men with existing coronary heart disease whose primary lipid abnormality was a low HDL-cholesterol. There was no effect on all-cause mortality.

The fibrates reduce the synthesis and increase the breakdown of VLDL particles, with secondary effects on LDL and HDL levels. They reduce LDL Levels by about 10 - 15% and triglyceride levels by about 40% and raise HDL levels by about 15 - 20%. The usual dose of gemfibrozil is 600 mg once or twice a day. Side effects include choleithiasis, hepatitis, and myositis. The incidence of the latter two conditions may be higher among patients also taking other lipid-lowering agents.

E. PROBUCOL:

The effects of probucol on coronary heart diseases - and its long-term safety - are not known. It does reduce the deposition of LDL into xanthomas in humans (and into atherosclerotic plaques in rabbits). The mechanism of action of probucol is not clear. It apparently reduces the amount of oxidized LDL. Probucol reduces LDL levels by 10 - 15% but has the potentially important adverse effect of lowering HDL levels by up to 10%. Probucol, if used at all, should be reserved for patients with a clear genetic disorder who have failed other therapies.

Initial Selection of Medication

At present there are no absolute guidelines for selection of available lipid-modifying medications in particular patients. Nonetheless, clinical trials provide guidance. For men with known coronary heart disease who require a lipid-modifying medication, an HMG-CoA reductase inhibitor is preferred. Although niacin will also have beneficial effects on lipids in both men and women with coronary heart disease, there is less evidence demonstrating the desired effects on coronary heart disease and all-cause mortality. While estrogen also has beneficial effects on lipids in postmenopausal women, it probably should not be used to treat lipid disorders in women with coronary heart disease.

For patients without known coronary heart disease, the choice of medications is less clear. For men 45 - 64 years of age, and HMG-CoA reductase inhibitor is preferred. For men aged 35 - 44 and for men aged 65 - 75, either an HMG-CoA reductase inhibitor or niacin can be considered. For postmenopausal women up to age 75, an HMG-CoA reductase inhibitor or niacin can also be used. Hormone therapy will improve lipids as well, but the effect on heart disease outcomes is still unknown. Premenopausal women rarely require lipid-modifying therapy. Resins are the only lipid-modifying medication considered safe in pregnancy. If pregnancy is not a concern, an HMG-CoA reductase inhibitor and niacin are reasonable choices.

Combinations lipid-modifying medications may be more cost-effective than high doses of a single medications and may have beneficial effects on lipids. Low-dose niacin, for example, will substantially in crease the HDL cholesterol when added to an HMG-CoA reductase inhibitor. Combinations, however, may increase the risk of severe complications of drug therapy. The combination of gemfibrozil and HMG-CoA reductase inhibitors increases the risk of myopathy more than either drug alone.

Wilson's Disease (WD)
(Hepatolenticular Degeneration)

Definition

A rare autosomal recessive disease caused by a gene defect on chromosome 13 that results in a disorder of hepatobiliray copper excretion that leads to the deposition of free copper in nearly all the body's tissues, particularly the liver, brain, kidneys and cornea.

Epidemiology

· Prevalence : 1:30 000 (30 per million) are affected ; 1 : 100 individuals in the general population carry the Wilson's disease gene (i.e. have one normal and one abnormal gene).
· Age : onset : 8 to > 50 years
Neurologic and psychiatric presentation somewhat later than hepatic.
· Gender : M=F.

Pathology

Varies with rate of progress of the disease.

Macroscopic

Lenticular (putaminal and pallidal) nuclei :
· Frank cavitation (rapidly and advancing fatal form).
· Shrinkage and light-brown discoloration (more chronic form).

Microscopic

· Marked hyperplasia of protoplasmic astrocytes (Alzheimer type II cells) in the cerebral cortex, basal ganglia, brainstem nuclei, and cerebellum.
· Nerve cell loss and some degree of degeneration of myelinated fibers in lenticular nuclei, substantia nigra, and dentate nuclei are usually apparent.

Etiology and Pathophysiology

Genetic

Autosomal recessive inheritance. Therefore, it is not sexlinked, and in order to inherit it, both parents must carry a Wilson's disease gene, which each passes to the affected child. If both parents have the WD gene, then the chance of the child getting WD is 25%. All children of a person with WD will receive a WD gene from the affected person. 50% of children of a carrier will receive a WD gene, since the carrier has one normal and one abnormal gene.

The gene defect, designated ATP7B, spans an 80kb region of chromosome 13q14.3 and encodes a copper transporting ATPase.

More than to unique mutations in ATP7B, a relatively large gene, have been found to cause Wilson's disease to date. Most are spontaneous mutations in the gene and are single base transversions or deletions. A substantial number of other cases are simply transmitted from generation to generation.

Although only one gene is involved in Wilson's disease many different mutations causes various defects in its product, a copper transporting ATPase. The existence of different alleles and combination of two allels explain much of the variability in Wilson's disease among different families. For example, mutations that result in complete absence of the gene product are associated with development of liver disease at a particularly early age.

Because most patients are compound heterozygotes, containing different mutations of the WD gene on each allele, genetic screening for this disease is complicated. However, in a particular family, if the precise mutation is identified, a genetic diagnosis is possible. Individuals heterozygous for the WD gene may manifest mild abnormalities in copper metabolism but do not develop the disease; one normal allele is adequate for disease prevention.

Hepatic copper metabolism and pathogenesis of WD

Disruption of the one of the genes controlling copper metabolism, located on chromosome 13, leads to a reduction in the rate of biliary excretion of copper, and an accumulation of excess copper in the body. The role of ceruloplasmin is unclear.

Clinical features :

· Variable : asymptoms or a range of hepatic, neurologic and psychiatric symptoms.
· No two patients are ever quite the same, even in a sibship.
Neurologic and psychiatric disease
Insidious onset and progressive course.

The four main clinical categories
· Pseudosclerotic, with tremor of the limbs that closely resembles that seen in multiple sclerosis and which can be severe enough to be described as 'wing-beating', titubation of the head, incoordination, limb ataxia, and dysarthria.
· Parkinsonian, with rigidity and bradykinesia of the tongue, lips, pharynx, larynx and jaw, dysarthia, dysphagia, hoarseness and drooling.
· Choreic movements of the limbs.
· Dystonic postures of the limbs, with hypertonia and rigidity; the liver latter two subgroups being more common in children.

Other features

· Kayser - Fleischer (K-F) rings
- A golden brownish coloration on the outer margin of the cornea present in virtually all patients with neurologic and 80% with hepatic WD.
- Almost diagnostic of WD.
- Gonioscopic examination provides earliest detection, and later may be seen through an auroscope or ophthalmoscope or with the uniaded eye.
- Slit lamp examination is necessary to demonstrate definitely copper granules in Descemer's membrane.
· Loss of motor control : bizarre spontaneous movements.]
· Change in personality and behavior
· Depression.
· Cognitive decline
· Seizures (rare)
· Occasional autonomic dysfunction, causing hyperhidrosis and exophthalmos.

Ultimately, the 'classic syndrome' develops : dysarthria, dysphagia and
drooling, rigidity and slowness of movements of the limbs, fixed flexed postures, fixity of facial muscles grinning or a 'vacuous smile'; slow saccide eye movements, a virtual anarthria; and tremor in repose which increases when the limbs are outstretched.

In most neurologic cases, the liver lesion plays a relatively minor role.

Liver disease
May take many forms :
· Asymptomatic
· Chronic active hepatitis.
· Cirrhosis
· Fulminant hepatits with massive necrosis ; there does not appear to be a significant increased risk of hepatocellular carcinoma.
· Pallor of mucous membranes
· Jaundice.
· Sunflower cataracts
· Azure lunulae of the nailbeds.
· Hepatocellular carcinoma is rare, in contrast to hemochromatosis.

Differential Diagnosis

More than half of patients are initially suspected to have a disease other than WD.
· Parkinson's disease : WD mainly affects the bulbar musculature and spreads caudally.
· Psychiatric disease : anxiety ; depression; schizophrenia.
· Encephalitis.
· Myasthenia gravis.
· Thyrotoxicosis.
· Hypothyroidism.
· Hereditary ceruloplasmin deficiency : mutation of the ceruloplasmin gene on chromosome 3q; autosomal recessive phenotype ; dementia, involuntary movements and diabetes; iron deposition in the brain and liver instead of copper.
· Pseudo K-F rings have been described in :
- Primary biliary cirrhosis.
- Chronic active hepatitis
- Progressive intrahepatic cholestasis of childhood
- Intraocular copper foreign body
- Multiple myeloma
- Infestation with Schistosoma japonicum and African trypanosomiasis.
- Copper therapy.

Investigation
Patient
· Slit lamp examination for K-F rings : may be absent early in disease,
· invariably present in patients with neurologic or psychiatric symptoms.
· Full blood count : hemolytic anemia, thrombocytopenia.
· Liver function tests : abnormal
· Serum ceruloplasmin : <200 mg/1; sensitivity 95% ; specificity high but level also decreased in 20% of heterozygote carries.
· Serum copper : low, <15.7 mol/1 ; normally decreased in proportion to serum ceruloplasmin; markedly elevated in fulminant Wilsonian hepatitis.
· DNA analysis : gene defect on chromosome 13.
· 24-hour urinary copper excretion : >1.6 mol in 24 hours; completeness of collection is important.
· 24-hour urinary copper excretion post-penicillamine : high, >25.1 mol; may also be increased in cholestatic disorders.
· Cranial CT scan : normal or may show atrophy of the caudate nuclei and brain stem, with hypodense areas in the basal ganglia, dentate nuclei and thalami.
· MRI brain : normal or increased signal intensity on T2W image in the above areas, atrophy of the caudate nuclei and scattered areas of increased signal in the brain stem, midbrain, red nucleus, periaqueductal gray matter and external capsules. Generalized atrophy may occur.
· Liver biopsy : copper concentration : high >3.9 mol/g dry weight ; can be intermediate in heterozygotes, cholestatic disorders; can be intermediate in heterozygotes, cholestatic disorders; can be elevated in primary biliary cirrhosis, childhood cirrhosis.
- Histology : Steatosis, glycogen nuclei, fibrosis, chronic active
hepatitis, cirrhosis.
- Rhodanine histochemistry : positive, present in some but not all nodules; may be negative early in disease.
- Electron microscopy : stage specific mitochondrial and lysosomal alterations.
· Failure to incorporate Cu into ceruloplasmin
· Aminoaciduria : present and persistent in most but not all cases.

Relatives

Screening by clinical, biochemical and genetic assessment.

Diagnosis

Clinical and laboratory evidence of :
· K-F rings.
· Low serum ceruloplasmin and copper.
· High urine copper excretion over 24 hours.
· High hepatic copper content on liver biopsy.

The abundance of specific mutations of the gene on chromosome 13
and their location at multiple sites across the genome have limited molecular genetic diagnosis to kindreds of known patients. The DNA-based diagnostic test can be done only in siblings of an index patient whose diagnosis was made according to phenotypic criteria and only if DNA from both patients is available :

Presymptomatic risk

Siblings of WD patients have a 25% chance of having the disease. Since both of a sibling's parents are carriers, ¼ have the disease, 2/4 will be carriers, and ¼ will have no WD gene.

Children of WD patients have a 1/200 chance of having the disease : from the patient, their children will definitely inherit the abnormal gene; for the patient's spouse, a normal person, the chance of carrying the gene is 1/100 and the chance they will pass it on ½.

Grandchildren of WD patients have a 1/400 chance of having the disease ; all children of the patient are carriers; from the patient's child, grandchildren have a 50% chance of inheriting a gene; from the other parent, a normal person, they have a 1/200 chance of inheriting the gene.

Presymptomatic Screening

All siblings, aunts, uncles, children, nieces, nephews and cousins should be screened for WD, because those with even mild or non-apparent WD will ultimately become seriously ill if not treated.

The most appropriate screening test is 24-hor urine measurement of copper, which should be performed in asymptomatic individuals at about age 5 years and again at age 15 years. Blood ceruloplasmin is helpful but is normal in 5-10% of WD patients. Screening can begin for low ceruloplasmin and abnormal liver function tests at age 2 years. Ophthalmologic assessment for K-F rings can be diagnostic but they do not have to present to have WD.

Treatment

WD is a manifestation of copper toxicosis and, in most cases, symptoms can be prevented or reversed by achieving and maintaining a negative copper balance.

Presymptomatic

· Reduction of dietary copper to less than 1 mg/day : copper-rich foods (liver, mushrooms, cocoa, chocolate, nuts and shellfish).
· Zinc sulfate, 200 mg orally, three times daily, blocks copperabsorption from the gut. Adverse effects : epigastric pain, nausea, vomiting, and sideroblastic anemia.

Symptomatic
Medical
Limit dietary copper to less than 1 mg/day

Chelating agents :
Penicillamine can be taken orally. Begin with 250 mg orally twice a day before food and increase slowly over a few weeks to 1.0-2.0 g daily in 2 - 4 divided doses. Add pyridoxine 25 mg daily, particularly during pregnancy, a growth spurt, malnutrition or prolonged intercurrent illness. Pyridoxine deficiency, due to d-pencillamine, can be detected early by the presence of abnormal tryptophan metabolites in the urine. About 10% develop penicillamine sensitivity: temporarily reduce the dose or try a course of cortisone. Reinstitute in low dose with small, widely spaced increases. If the pencillamine sensitivity persists or if severe immune-mediated reactions occur, the drug should be discontinued and zinc acetate or trientene substituted.

Triethylene tetramine dihydrochloride is a seffective as penicillamine and has fewer adverse effects, but is expensive. It is taken orally, 1.2-2.4 g daily in 2 -4 divided doses before food. It is poorly absorbed from the gut. TETA reduces intestinal copper absorption and increases urinary copper excretion. Add zinc acetate 50 - 150 mg as a single dose at night to prevent zinc deficiency. Toxic reactions, are rare : sideroblastic anemia, reactivation of penicillamine-induced lupus, colitis and duodenitis.

Metal to metal antagonists :
Zinc sulfate or acetate can be used if penicillamine or trientene toxicity occurs. Doses are taken orally, 200 mg three times daily. It blocks copper absorption from the gut. Toxic reactions are rare : nausea, epigastric pain, vomiting, sideroblastic anemia. It is useful for maintenance therapy, treatment of the pregnant patient, and the initial as well as maintenance treatment of the presymptomatic patient. It does not seem to be optimal for initial treatment because it is somewhat slow acting and may take several months to control copper toxicity.

Ammonium tetrathiomolybdate blocks intestinal absorption of copper and binds copper present in tissues. Early studies suggested it may depress bone marrow and cause serious epiphyseal deformities in growing animals. A safe and effective initial treatment in a recent open of 33 patients.

Metal-binding agent :

British antilewisite (BAL) (dimercaprol) : if advanced neurologic lesions which have failed to respond to other treatments. Crosses the blood-brain barrier better than chelating agents.

· Monitor clinical response, full blood count, proteinuria, and urine copper excretion.
· A further 8% or so show no response to treatment.
· The appropriate drug needs to be continued for the patient's life time.

In about 20% of patients, chelation treatment results in an initial
worsening of neurologic symptoms before improvement begins, and a few may deteriorate rapidly once treatment is started. This is thought to reflect the mobilization of copper from tissues, e.g. liver, and its redistribution in the brain, and for the redistribution of copper within neurons themselves.

Chelating agents have been used during pregnancy in WD patients without teratogenic effects.

Surgical

Liver transplantation : cures WD by removing the site of the metabolic lesion; chelation therapy need not be continued. If there is irreversible liver damage due to acute and chronic liver failure its place in the management of advanced neurologic disease is less clear.

Clinical course and prognosis

Course and prognosis vary greatly. Untreated, the course is invariably progressive and fatal. Most patients reach a terminal stage with severe dystonia and constractures, though a few may become akinetic. The disease may last from a few months to many years with occasional periods of relative remission. With treatment, most patients improve or recover completely, but some do not. Some get worse before they get better, some get worse and do not get better, remaining permanently disabled, and some die, fortunately very few. Pseudosclerotic patients have a better prognosis than the dystonic.

Prevention

Younger siblings can now be identified by means of molecular DNA techniques as normal, heterozygous or presymptomatic carriers of the WD gene. For the latter and relatives detected by screening, prophylactic treatment can be started. Experience to date shows that such patients remain in good health so long as they take their medication.

VIRAL HEPATITIS

Essential of Diagnosis

· Prodrome of anorexia, nausea, vomiting, malaise, symptoms of upper respiratory infection or flu-like syndrome, aversion to smoking.
· Fever, enlarged and tender liver, jaundice.
· Normal to low white cell count ; abnormal liver tests, especially markedly elevated aminotransfetases early in the course.
· Liver biopsy shows characteristic hepatocellular necrosis and mononuclear infiltrate but is rarely indicated.

General Considerations

Hepatitis can be caused by many drugs and toxic agents as well as by numerous viruses, the clinical manifestations of which may be quite similar. The specific viruses causing viral hepatitis are (1) hepatitis A virus (HAV); (2) hepatitis B virus (HBV); (3) hepatitis C virus (HCV); (4) hepatitis D virus (HDV); and (5) hepatitis E virus ( an enterically transmitted hepatitis seen in epidemic from in Asia, North Africa, and Mexico). The designation hepatitis G virus (HGV) ; also known as the CB - C virus) has been applied to an agent that rarely, if ever, causes frank hepatitis. A DNA virus designated the TT virus (TTV) has been identified in up to 7.5% of blood donors and found to be transmitted readily by blood transfusions, but an association between this virus and liver disease has not been established. Recently, a new virus known as SEN-V has been reported to account for a substantial proportion of cases of transfusion -associated hepatitis. In immunocompromised and rare immunocompetent hosts, cytomegalovirus, Epstein-Barr virus, herpes simplex virus should be considered in the differential diagnosis of hepatitis. As yet unidentified agents accounts for a small percentage of cases of apparent acute viral hepatitis.

A. Hepatitis A :

HAV is a 27 - nm RNA hepatovirus (in the picornavirus family) that may cause epidemics or sporadic cases of hepatitis. Transmission of the virus is usually but the fecal -oral route, and spread is favored by crowding and poor sanitation. Common source outbreaks may result from contaminated water or food. The incubation period averages 30 days. Hepatitis A virus (HAV) is excreted is feces for up to 2 weeks before the onset of clinical illness. HAV is rarely demonstrated in feces after the first week of illness. The mortality rate for hepatitis A is low, and fulminant hepatitis A is uncommon except perhaps for rare instances in which acute hepatitis A occurs in a patient with chronic hepatitis C. Chronic hepatitis A does not occur, and there is no carrier state. Clinical illness is more severe in adults than in children, in whom hepatitis A is often asymptomatic.

Antibody to hepatitis A appears early in the course of the illness. Both IgM and IgG anti HAV are detectable in serum soon after the onset of the illness. Peak titers of IgM anti-HAV occur during the first week of clinical disease and usually disappear within 3-6 months. Detection of IgM anti-HAV is an excellent test for diagnosting acute hepatitis A. Titers of IgG anti-HAV peak after 1 month of the disease and may persist for years. The presence of IgG anti-HAV alone indicates previous exposure to HAV, non-infectivity, and immunity to recurring HAV infection. In the USA, about 33% of the population have serologic evidence of previous infection.

B. Hepatitis B :

Hepatitis B virus (HBV) is a 42 nm hepadnavirus with partially double-stranded DNA genome, inner core protein and outer surface coat. HBV is usually transmitted by inoculation of infected blood or blood products or by sexual contact and is present in saliva, semen, and vaginal secretions. HbsAg-positive mothers may transmit HBV to their neonates at the time of delivery ; the risk of chronic infection in the infant is as high as 90%. Hepatitis B virus (HBV) is highly prevalent in homosexuals and intravenous drug users, but most cases reported in the USA now result from heterosexual transmission. Other groups at high risk include patients and staff at hemodialysis centers, physicians, dentists, nurses, and personnel working in clinical and pathology laboratories and blood banks. The risk of HBV infection from a blood tranfusion is less than one in 60,000 units tranfused in the USA. The incubation period of hepatitis B is 6 weeks of 6 months.

Clinical features of hepatitis A and B are similar ; however, the onset in hepatitis B tends to be more insidious and the aminotransferase levels higher. The risk of fulminant hepatitis is less than 1%, with a mortality rate of up to 60%. Following acute hepatitis B, HBV infection may persist in 1 - 2% of immunocompetent adults but a higher percentage of immunocompromised adults or children. Persons with chronic hepatitis B, particularly when HBV infection is acquired early in life and viral replication persists, are at substantial risk of cirrhosis and hepatocellular carcinoma. Infection caused by HBV may be associated with arthritis, glomerulonephritis, and polyarteritis nodosa.

There are three distinct antigen - antibody systems that relate to HBV infection and a variety of circulating markers that are useful in diagnosis.

1. HBsAg - The appearance of HBsAg is the first evidence of HBV infection, appearing before biochemical evidence of liver disease. HBsAg persists throughout the clinical illness. Persistence of HBsAg after the acute illness may be associated with clinical and laboratory evidence of chronic hepatitis for variable periods of time. The detection of HBsAG establishes injection with HBV and implies infectivity.

2. Anti-HBs - Specific antibody to HBsAg appears in most individuals after clearance of HBsAg and after successful vaccination against hepatitis B. Disappearance of HBsAg and the appearance of anti-HBs signals recovery from HBV infection, noninfectivity, and protection from recurrent HBV infection.

Table : Common serologic patterns in hepatitis B virus infection and their interpretation.

HbsAg Anti-HBs Anti-Abc HbeAg Anti-Hbe Interpretation
+ - IgM + - Acute hepatitis B
+ - IgG1 + - Chronic hepatitis B with active viral replicaton
+ - IgG - + Chronic hepatitis B with low viral replication
+ + IgG + or - + or - Chronic hepatitis B with heterotypic anti-HBs (about 10% of cases)
- - IgM + or - - Acute hepatitis B
- + IgG - +or - Recovery from hepatitis B (immunity)
- - - - - Vaccination (immunity)
- - IgG - - False - positive less commonly, infection in remote past

3. Anti-HBc - IgM anti-HBc appears shortly after HbsAg is detected. Its presence in
the setting of acute hepatitis indicates a diagnosis of acute hepatitis B, and it fills the serologic gap in patients in protein who have cleared HbsAG but do not yet have detectable anti-HBs. IgM anti-HBc can persist for 3 months or more. IgM anti-HBc may also reappear during flares of previously inactive chronic hepatitis B. IgG anti-HBc also appears during acute hepatitis B nut persists indefinitely, whether the patient recovers or develops chronic hepatitis B. In asymptomatic blood donors, an isolated anti-HBc with no other positive HBV serologic results may represent a falsely positively result or latent infection in which HBV DNA is detectable is serum only by polymerase chain reaction methodology.

4. HbeAg - HbeAg is a soluble protein found only in HbsAg - positive sera. It represents a secretory form of HbcAg that appears during the incubation period shortly after the detection of HbsAg indicates viral replication and infectivity. Persistence of HbeAg is serum beyond 3 months suggests an increased likelihood of chronic hepatitis B. Disappearance of HbeAG is often followed by the appearance of anti-Hbe, signifying diminished viral replication and decreased infectivity.

5. HBV DNA - The rpesence of HBV DNA is serum generally parallels the presence of HbeAg, though HBV DNA is a more sensitive and precise marker of viral replication and infectivity. Very low levels of HBV DNA, detectable only by polymerase chain reaction methodology, may persist in serum after a patient has recovered from acute hepatitis B, but the BV DNA is bound to IgG and rarely infectious. In some patients with chronic hepatitis B, HBV DNA may be present in high levels without HbeAg in serum because of a muration that prevents synthesis of HbeAg in infected hepatocytes. The pre-core mutant appears during the course of chronic "wild-type" HBV infection, presumably as a result of immune pressure. When additional mutations in the core gene are present, the pre-core mutant enhances the severity of HBV and increases the risk of cirrhosis.

C. Hepatitis D (Delta Agent) :

Hepatitis D virus (HDV) is a defective RNA virus that causes hepatitis only in association with hepatitis B infection and specifically only in the presence of HbsAg; it is cleared when the latter is cleared.

HDV may co-infect with HBV or may superinfect a person with chronic hepatitis B, usually by percutaneous exposure. When acute hepatitis D is coincident with acute HBV infection, the infection is generally similar in severity to acute hepatitis B alone. In chronic hepatitis B, superinfection by HDV appears to carry a worse short-term prognosis, often resulting in fulminant hepatitis that progresses rapidly to cirrhosis. In the 1970s and early 1980s, HDV was endemic in some areas, such as the Mediterranean countries, where up to 80% of HBV carries were superinfected with it. In the united States, HDV occurred primarily among intravenous drug users. However, new cases of hepatitis D are now infrequent, and cases seen today are usually from cohorts infected years ago who survived the initial impact of hepatitis D and now have inactive cirrhosis. These patients have a threefold increased risk of hepatocellular carcinoma. Diagnosis is by detection of antibody to hepatitis D antigen or, where available, HDV RNA in serum.

D. Hepatitis C (HCV) :

The hepatitis C virus is a single-stranded RNA virus with properties similar to those of flavivirus. At least six major genotypes of HCV have been identified. In the past, HCV have been identified. In the past, HCV was responsible for over 90% of cases of posttransfusion hepatitis, yet only 4% of cases of hepatitis C were attributable to blood transfusions. Over 50% of cases are in fact attributable to past intravenous drug use. Intranasal cocaine use and body piercing also are risk factors for transmission. The risk of sexual and materal - neonatal transmission is low and may be greatest in a subset of patients with high circulating levels of HCV RNA. Having multiple sexual partners may increase the risk of HCV infection. Transmission via breast feeding has not been documented. An outbreak of hepatitis C in patients with immune deficiencies occurred in some recipients of intravenous immune globulin, and nosocomial transmission via multidose vials of saline used to flush Portacaths has been reported. Covert transmission during bloody fisticuffs has been reported. In many patients, the source of infection is uncertain. There are about 2.7 million HCV carriers in the USA and another 1.3 million previously exposed persons who have cleared the virus.

The incubation period averages 6 - 7 weeks, and clinical illness is often mild, usually asymptomatic, and characterized by waxing and waning aminotransferase elevations and a high of chronic hepatitis. In pregnant patients, serum aminotransferase levels frequently normalize despite persistence of viremia, only to increase again after deliver, HCV is thought to be a pathogenetic factor in cryoglobulinemia and glomerulonephritis and may be involved in autoimmune thyroiditis, lymphocytic sialadenitits, idiopathic pulmonary fibrosis, sporadic porphyria cutanea tarda, monoclonal gammopathies, and probably lymphoma. The risk of type 2 diabetes mellitus appears to be increased in persons with chronic hepatitis C.

Diagnosis of hepatitis C is based on an enzyme immunoassay that detects antibodies to HCV. Anti-HCV is not a protective antibody, and in patients with acute or chronic hepatitis the presence of anti-HCV in serum generally signifies that HCV is the cause. Limitations of the enzyme immunoassay include moderate sensitivity for the diagnosis of acute hepatitis C early in the course and in healthy blood donars and low specificity in some persons with elevated gamma globulin levels. In these situations, a diagnosis of hepatitis C may be confirmed by use of a supplemental recombinant immunoblot assay. Most RIBA-positive persons are potentially infectious, as confirmed by use of polymerase chain reaction-based tests to detect HCV RNA. Occasional persons are found to have anti-HCV in serum, confirmed by RIBA, without HCV RNA in serum, suggesting recovery form HCV infection in the past. Testing of donated blood for HCV has helped reduce the risk of transfusion-associated hepatitis C from 10% a decade ago to less than one per 100,000 units of transfused blood today.

E. Hepatitis E (HEV) :

HEV is a 29 to 32 -nm RNA virus similar to calicivirus and responsible for waterborne hepatitis outbreaks in India, Burma, Afghanistan, Algeria, and Mexico. Hepatitis E is rare in the USA but should be considered in patients with acute hepatitis after a trip to an endemic area. Illness is self-limited with a high mortality rate in pregnant women

F. Hepatitis G :

The designation hepatitis G virus (HGV) has been applied to a flavivirus that is percutaneously transmitted and associated with chronic viremia lasting at least 10 years. HGV has been detected in 1.5% of blood donors, 50% of intravenous drug users, 30% of hemodialysis patients, 20% of hemophiliacs, and 15% of patients with chronic hepatitis B or C, but it does not appear to cause important liver disease or affect the response of patients with chronic hepatitis B or C to antiviral therpay.

Clinical Findings

The clinical picture of viral hepatitis is extremely variable, ranging from asymptomatic infection without jaundice to a fulminating disease and death in a few days.

A. Symptoms :

1. Prodromal phase - The onset may be abrupt or insidious, with general malaise, myalgia, arthralgia, easy fatigability,upper respiratory symptoms, and anorexia. A distaste for smoking, paralleling anorexia, may occur early. Nausea and vomiting are frequent, and diarrhea or constipation may occur. Skin rashes, arthritis, or serum sickness may be seen early in acute hepatitis B. Fever is generally present but is rarely over 39.5 C save in occasional cases of hepatitis A. Defervescence often coincides with the onset of jaundice. Chills or chilliness may mark an acute onset.

Abdominal pain is usually mild and constant in the right upper quadrant or epigastrium and is often aggravated by jarring or exertion.

2. Icteric phase - Clinical jaundice occurs after 5 - 10 days but may appear at the same times as the initial symptomatology. Most patients nerve develop clinical icterus. With the onset of jaundice, there is often worsening of the prodromal symptoms, followed by progressive clinical improvement.

3. Convalescent phase - There is an increasing sense of well-being return of appetite, and disappearance of jaundice, abdominal pain and tenderness, and fatigability.

4. Course and complications - The acute illness usually subsides over 2 - 3 weeks
with complete clinical and laboratory recovery by 9 weeks in hepatitis A and by 16 weeks in hepatitis B. In 5 - 10% of cases, the course may be more protracted, and less than 1% will have a fulminant course. In some cases of acute hepatitis A, clinical, biochemical, and serologic recovery may be followed by one or two relapses, but ultimate recovery is the rule. Hepatitis B, D, and C may become chronic.

B. Signs :

Hepatomegaly - rarely marked - is present in over half of cases. Liver tenderness is usually present. Splenomegaly is reported in 15% of patients, and soft, enlarged lymph nodes - especially in the cervical or epitrochlear areas - may occur. Signs of general toxemia vary from minimal to severe.

C. Laboratory Findings :

The white blood cell count is normal to low, especially in the preicteric phase. Large atypical lymphocytes, such as are found in infectious mononucleosis, may occasionally be seen. Mild proteinuria is common, and bilirubinuria often precedes the appearance of jaundice. Acholic stools are often present during the icteric phase. Blood studies reflect hepatocellular damage often with strikingly elevated AST or ALT values. Bilirubin and alkaline phosphatase are elevated and, in a minority of patients, remain so after aminotransferase levels have normalized. Cholestasis is occasionally marked in acute hepatitis A. Marked prolongation of the prothrombin time in severe hepatitis correlates with increased mortality.

Differential Diagnosis

The differential diagnosis of hepatitis include other viral diseases such as infectious mononucleosis, cytomegalovirus infection, and herpes simplex virus infection; spirochetal diseases such as leptospirosis and secondary syphilis ; brucellosis ; rickettsial diseases such as Q fever ; drug - induced liver disease ; and shock liver. Occasionally , autoimmune hepatitis may have an acute onset mimicking acute viral hepatitis. Rarely, metastatic cancer of the liver may present with a hepatitis - like picture.

The prodromal phase of viral hepatitis must be distinguished form other infectious disease such as influenza, upper respiratory infections, and the prodromal stages of the exanthematous disease. Occasionally, cholestasis may be prominent, particularly in hepatitis A, and mimic obstructive jaundice.

Prevention

Strict isolation of patients is not necessary, but hand washing after bowel movements is required. Thorough hand washing by medical attendants who come into contact with contaminated utensils, bedding, or clothing is essential. Careful handling of disposable needles - including not recapping used needles - i9s important for medical personnel. Screening of donated blood for HbsAG, and anti-HBc, and anti-HCV has reduced the risk of transfusion-associated hepatitis markedly. Unnecessary transfusions and commerically obtained blood should be avoided. All pregnant women should undergo testing for HbsAg, HBV- and HCV-infected persons should practice "safe sex", but there is little evidence that HCV is spread easily by sexual contact. Vaccination against HAV and HBV is recommended for patients with chronic hepatitis C, and vaccination against HAV is recommended for patients with chronic hepatitis B.

A. Hepatitis A :

Immune globulin should be given routinely to all close personal contacts of patients with hepatitis. The recommended dose of 0.02 mL.Kg intramuscularly has been found to be protective for hepatitis A if administered during the incubation period. Two effective inactivated hepatitis A vaccines are available and recommended for persons living in or traveling to endemic areas, patients with chronic liver disease, persons with clotting-factor disorders who are treated with concentrates, homosexual and bisexual men, animal handlers, illicit drug users, sewage workers, food handlers, and children and caregivers in day care centers and institutions. Routine vaccination of all children has been recommended in states with a high incidence of hepatitis A. The HAV vaccine has also been reported to be effective in the prevention of secondary spread to houshold contacts of primary cases. The recommended dose for adults is 1 mL or 0.5 mL of Vaqta intramuscularly, followed by a booster dose at 6 - 12 months.

B. Hepatitis B :

Hepatitis B immune gloublin may be protective - or may at least attenuate the severity of illness if given in large doses within 7 days after exposure followed by initiation of the HBV vaccine series. At present, this approach is recommended for individuals exposed to hepatitis B surface antigen - contaminated material via the mucous membranes or through breaks in the skin and for persons who have had sexual contact with patients with HBV infection. HBIG is also indicated for newborn infants of HbsAg-positive mothers followed by initiation of the vaccine series.

The currently used vaccines are recombinant -derived. Initially, the vaccine was targeted to persons at high risk, including renal dialysis patients and attending personnel, patients, requiring repeated transfusions, spouses of HbsAg-positive individuals, male homosexuals, intravenous drug users, newborns of HbsAg-positive mothers, entering medical and nursing students, as well as all medical technologists. Because this strategy failed to lower the incidence of hepatitis B, the CDC recommended universal vaccination of infants and children in the USA. Over 90% of recipients of the vaccine mount protective antibody to hepatitis B. The standard regimen for adults is 10 - 20 g initially and again at 1 and 6 months, but alternative schedules have been approved ; for greatest reliability of absorption, the deltoid muscle is the preferred site of injection. Vaccine formulations free of the mercury-containing preservative thimerosal are preferred in infants less than 6 months of age. When documentation of seroconversion is considered desirable, postimmunization anti-HBs titers may be checked. Protection appears to be excellent even if the titer wanes - at least for 10 years - and booster reimmunization is not routinely recommended but is advised for immunocompromised persons in whom anti-HBs titers fall below 10 ml mlU/mL. Universal vaccination of neonates in countries that are endemic for HBV reduces the incidence of hepatocellular carcinoma.

Treatment

Bed rest is recommended only on an as-needed basis during the acute initial phase of the disease, when symptoms are most severe. Return to normal activity during the convalescent period should be gradual. If nausea and vomiting are pronounced or if oral intake is substantially decreased, intravenous administration of 10% glucose solution is indicated. If the patient shows signs of encephalopathy or severe coagulopathy, acute hepatic failure should be suspected, and hospitalization is mandatory.

In general, dietary management consists of giving palatable meals as tolerated, without overfeeding. Patients should avoid strenuous physical exertion, alcohol, and hepatotoxic agents. While the administration of small doses of oxazepam is safe, morphine sulfate should be avoided.

In controlled studies, corticosteroids have demonstrated no benefit in patients with viral hepatitis, including those with fulminant hepatitis. Treatment of patients with acute hepatitis C with alpha interferon appears to decrease the risk of chronic hepatitis.

Prognosis

In most cases, clinical recovery is complete in 3 - 16 weeks. Laboratory evidence of liver dysfunction may persist for a longer period, but most patients recover completely. The overall mortality rate is less than 19%, but the rate is reportedly higher in older people.

Hepatitis A does not progress to chronic liver disease, though hepatitis A may persist for up to 1 year, and clinical and biochemical relapses may occur before full recovery. The mortality rate is less than 0.2%. the mortality rate for acute hepatitis B is 0.1 - 1%, but it is higher for superimposed hepatitis D. Fulminant hepatitis C is rare in the USA. For unknown reasons, the mortality rate for hepatitis E is especially high in pregnant women.

Chronic hepatitis, characterized by elevated amino transferase levels for more than 6 months, develops in 1 - 2% of immunocompetent adult patients with acute hepatitis B but in as many as 90% of infected neonates and infants and a substantial proportion of immunocompromised adults with acute hepatitis B. Over 80% of all persons with acute hepatitis C develop chronic hepatitis, which in many cases progresses very slowly. Ultimately, cirrhosis may develop in up to 30% of those with chronic hepatitis C and 40% of those with chronic hepatitis B ; the risk of cirrhosis is even higher in patients coinfected with both viruses or with HIV. Patients with cirrhosis are at risk of hepatocellular carcinoma. Even in the absence of cirrhosis, patients with chronic hepatitis B - particularly those with active viral replication - are at increased risk of hepatocellular carcinoma.

Reference

Branch AD et al : Hepatitis C : state of the art at the millennium. (Parts 1 and 2.) Semin Liver Dis 2000; 201, 127. (Detailed reviews covering epidemiology, virology, immunology, diagnosis, treatment, and prevention).

Di Bisceglie A : Natural history of hepatitis C : its impact on clinical management. Hepatology 2000;31:1014. (PMID : 10733560) (Over a 20-year period, 6% of patients with chronic hepatitis C can be expected to develop decompensated cirrhosis.)

Gecta GB et al : Chronic hepatitis D : a vanishing disease? An Italian mutlicenter study, Hepatology 2000;32:824. (PMD : 11003629) (Since 1987 the frequency of anti-HDV antibodies in HBV carries in Italy has declined from 23% to 8%, with most of the decline in persons under age 50.)

Hunt CM et al : Clinical relevance of hepatitis B viral mutations. Hepatology 2000;31:1037. (PMID : 1096877) (Discusses the significance of the pre-core mutant as well as mutations conferring resistance to antiviral therapy.)

Koff RS : Hepatitis A. Lancet 1998;351:1643. (NLM Cit ID : 98282054)

Lee W (editor) : Hepatitis B. Clin Liver Dis 1999;3:179. (Reviews of epidemiology, virology, immunopathogenesis, clinical features, natural history, treatment, and prevention.)

Liang TJ et al : Pathogenesis, natural history, treatment, and prevention of hepatitis C. Ann Intern Med 2000; 132:296. (NLM Cit ID : 20132334)

Myers RP et al : The cost-effectiveness of hepatitis A vaccination in patients with chronic hepatitis C. Hepatology 2000;31:834. (PMID : 10733536) (This decision analysis concludes that vaccination C against hepatitis A is not cost-effective.)

CHRONIC HEPATITIS

By K. Gireesh

Chronic hepatitis is defined as a chronic inflammatory reaction of the liver of more than 3 - 6 months' duration, as demonstrated by persistently abnormal serum aminotransferase levels and characteristic histologic findings. The causes of chronic hepatitis include HBV, HCV, and HDV, autoimmune hepatitis, chronic hepatitis associated with certain medications, Wilson's disease, and -antiprotease deficiency. Traditionally, chronic hepatitis has been categorized histologically as chronic persistent hepatitis and chronic active hepatitis. However, with improved serologic and autoimmune markers, more precise categorization is preferred, based on etiology ; the grade of portal, periportal, and lobular inflammation; and the stage of fibrosis .

Clinical findings & Diagnosis

A. Autoimmune Hepatitis :

This is generally a disease of young women but can occur in either sex at any age. Affected persons are often positive for HLA - B8 and -DR3 or, in older patients. HLA - DR4. The principal susceptibility allele among white Americans and northern Europeans is HLA DRB1 *0301. The onset is usually insidious, but about 25% of cases present as an acute attack of hepatitis and some cases follow a viral illness such as hepatitis A, Epstein -Barr infection, or measles or exposure to a drug or toxin such as nitrofurantoin. The serum bilirubin is usually increased, but 20% of patients are anicteric. In classic cases, examination reveals a helathy-appearing young woman with multiple spider nevi, cutaneous striae, acne, hirsutism, and hepatomegaly. Amenorrhea may be a presenting feature. Extrahepatic features may include arthritis. Sjogren's syndrome, thyroiditis, nephritis, ulcerative colitis, and Coombs-positive hemolytic anemia. In classic autoimmune hepatitis, antinuclear antibody or smooth muscle antibody is detected in serum. Serum gamma globulin levels are typically elevated. In patients with high gamma globulin levels, the enzyme immunoassay for antibody to HCV may be falsely positive. Other antibodies, including antineurtrophil cytoplasmic antibodies, may be found. A second type, infrequently seen in the United States but more common in Europe, is characterized by circulating antibody to liver-kidney microsomes without anti-smooth muscle antibody or ANA. Concurrent primary biliary cirrhosis or primary sclerosis cholangitis has been recognized in up to 13% of patients with autoimmune hepatitis.

B. Chronic Hepatitis B :

Chronic hepatitis B chiefly affects males and afflicts nearly 400 million people world wide and 1.25 million in the USA. It may be noted as a continuum of acute hepatitis or may be diagnosed on evaluation of persistently elevated aminotransferase levels.

Early in the course, HbeAg and HBV DNA are present in serum, indicative of active viral replications. Low-level IgM anti - HBc is also present in about 70%. In some patients, clinical and biochemical improvements coincides with disappearance of HbeAg and HBV DNA from serum, appearance of anti-Hbe, and integration of the HBV genome in to the host genome in infected hepatocytes. Such patients may still be at increased risk for the development of cirrhosis and hepatocellular carcinoma. As discussed above, infection by a pre-core mutant of HBV or spontaneous mutation of the pre-core region of the HBV genome during the course of chronic hepatitis caused by wild-type HBV may result in particularly severe chronic hepatitis with rapid progression to cirrhosis, particularly when additional mutation in the core gene of HBV are present.

C. Hepatitis D :

Acute hepatitis D infection superimposed on chronic HBV infection may result in severe chronic hepatitis, which may progress rapidly to cirrhosis and may be fatal. The diagnosis is confirmed by detection of anti HDV in serum.

D. Chronic Hepatitis C :

At least 80% of patients with acute hepatitis C develop chronic hepatitis C. It is clinically indistinguishable from chronic hepatitis due to other causes and able from chronic hepatitis due to other causes and may be the most common. In up to 40% of cases serum aminotransferase levels are persistently normal. The diagnosis is confirmed by detection of anti-HCV by enzyme immunoassay. In rare cases of suspected chronic hepatitis C but a negative EIA, the diagnosis may be confirmed by a positive recombinant immunoblot assay or detection of HCV RNA in serum by polymerase chain reaction. Progression to cirrhosis occurs in 20% of affected patients after 20 years with an increased risk in men, those who drink more than 50 g of alcohol daily, and possibly those who acquire HCV infection after age 40. Immunosuppressed persons - including patients with hypogammaglobulinemia, with HIV infection and a low CD4 count, or with organ transplants and receiving immunosuppressants - appear to progress more rapidly to cirrhosis than immunocompetent persons with chronic hepatitis C. Affected persons with persistently normal serum aminotransferase levels usually have mild chronic hepatitis with slow or absent progression to cirrhosis ; however, cirrhosis is found in 10 - 20% of these patients.

Treatment

Activity should be modified according to the patient's symptoms, but strict bed rest is not necessary. The diet should be well balanced, without specific limitations other than sodium or protein restriction as dictated by fluid overload or encephalopathy.

A. Autoimmune Hepatitis :

Prednisone with or without azathioprine has been shown to improve symptoms, decrease the serum bilirubin, aminotransferase, and gamma globulin levels, and reduce hepatic inflammation. Symptomatic patients with serum aminotransferase levels elevated tenfold are optimal for therapy, and patients who are symptomatic or who have modest enzyme elevations may be considered for therapy depending on the clinical circumstances.

Prednisone or an equivalent drug is given initially in doses of 30 mg orally daily with azathioprine or mercaptopurine, 50 mg/d orally, which are generally well tolerated and permit the use of lower corticosteroid doses. Complete blood counts should be monitored weekly for the first 8 weeks of therapy and monthly thereafter because of the small risk of bone marrow suppression. The dose of predinose is lowered from 30 mg/d after 1 week to 20 mg/d and again after 2 or 3 weeks to 15 mg/d. Ultimately, a maintenance dose of 10 mg/d is achieved. While symptomatic improvement is often prompt, biochemical improvement is more gradual, with normalization of serum aminotransferase levels after several months in many cases. Histologic resolution of inflammation may take up to 18 - 24 months, the time at which repeat liver biopsy is recommended. Failure of aminotransferase levels to normalize invariably predicts lack of histologic resolution.

The response rate to therapy with prednisone and azathioprine is 80 - 90%. Cirrhosis, however, does not reverse with therapy and may even develop after apparent biochemical and histologic remission. Once remission is achieved, therapy may be withdrawn, but the subsequent relapse rate is 50 - 90%. Relapses may again be treated in the same manner as the initial episode, with an expected remission rate sign of 80 - 90%. After successful treatment of a relapse, the patient may be kept indefinitely on axathioprine up to 2 mg/kg and the lowest dose of prednisone needed to maintain aminotransferase levels as close to normal as possible. Nonresponders to prednisone and azathioprine may be considered for a trial of cyclosporine, tacrolimus, or methotrexate. Mycophenolate mofetil appears to be an effective alternative to azathioprine in patients who cannot tolerate or do not respond to azathioprine. Liver transplantation may be required for treatment failures, and the disease has been recognized to recur in up to one-third of transplanted livers as immunosuppression is reduced.

B. Chronic Hepatitis B :

Patients with active viral replication may be treated with recombinant human interferon alfa - 2b in a dose of 5 million units a day or 10 million units three times a week intramuscularly for 4 months. About 40% of treated patients will respond with normalization of aminotransferase levels, disappearance of HbeAg and HBV DNA from serum, appearance of anti-Hbe, and improved survival. A response is most likely in patients with an HBV DNA level under 200 pg/mL and high aminotransferase levels. Moreover, over 60% of these responders may eventually clear HbsAg from serum and liver, develop anti-HBs in serum, and thus be cured of the infection. Relapses are uncommon in such complete responders.

The nucleoside analog lamivudine, 100 mg orally daily as a single dose, may be used instead of interferon for the treatment of chronic hepatitis B and is much better tolerated. This agent reliably suppresses HBV DNA in serum, improves liver histology in 40% of patients, and leads to normal ALT levels in over 40% and HbeAg seroconversion in 20% of patients after 1 year of therapy. However, 1 - 30% of responders experience a mild relapse during therapy as a result of mutation in HBV DNA that confers resistance to lamivudine. Moreover, hepatitis activity may recur when the drug is stopped, and long-term, perhaps indefinite treatment despite a high rate of resistance over time may be required to suppress the disease when treatment does not result in HbeAg seroconversion. The drug is well tolerated even in patients with decompensated cirrhosis, and it may be effective in patients with rapidly progressive hepatitis B following organ transplantation. There is no clear evidence that combined use of interferon and lamivudine offers an advantage over the use of either drug alone. Other antiviral agents such as adefovir dipivoxil are under study, and strategies employing multiple drugs are likely to be tried in the future.

Recombinant interferon alfa - 2a may lead to normalization of serum aminotransferase levels, histologic improvement, and elimination of HDV RNA from serum in about 50% of patients with chronic hepatitis D, but relapse is common after therapy is stopped. Lamivudine is not effective in chronic hepatitis D.

C. Chronic Hepatitis C :

Treatment of chronic hepatitis C is generally considered in patients under age 70 with elevated serum aminotransferase levels and more than minimal inflammation or fibrosis on liver biopsy. Standard therapy is with a combination of interferon alfa and ribavirin. Recombinant human interferon alfa - 2b or alfa 2a in a dose of 3 million units three times a week for 24 weeks and "consensus" interferon in a dose of 9 mg three times a week have been shown to induce biochemical, virologic, and histologic improvement in up to 50% of patients. Most experience has been with interferon alfa-2b. Factors that predict an increased chance of responding to therapy include the absence of cirrhosis on liver biopsy, low serum HCV RNA levels, and infection by genotypes of HCV other than 1 a, 1 b or 4. After stopping the medication at 24 weeks, only 30 - 50% of the treated responders will maintain the improvement. More prolonged treatment has been shown to increase the durability of remission. The use of higher doses of interferon alfa - 2b increases toxicity and does not appear to increase the rate of sustained responses substantially. Response rates among blacks appear to be lower than those among whites, in part because of a higher rate of genotype 1 among infected black patients.

A slow - release, long acting "pegylated" formulation of interferon taken only once a week is now available and is more effective than standard interferon, presumably because of sustained high blood levels. With one formulation of pegylated interferon administered in a dose of 180 mg once per week for 48 weeks, a sustained biochemical and virologic response was achieved in 38% of patients with chronic hepatitis C compared with 17% of those treated with standard interferon.

Addition of the nucleoside analog ribavirin, 1000 - 1200 mg daily in two divided doses, results in higher sustained response rates than interferon alone in previously untreated patients with chronic hepatitis C or patients who have had a relapse after an initial response to interferon -alfa alone. Sustained response rates are 40% and 50%, respectively, following combination therapy consisting of standard interferon and ribavirin. Higher rates can be expected with a combination of pegylated interferon and ribavirin. Patients with repeatedly normal serum aminotransferase levels before treatment appear to respond to combination therapy as well as those with elevated levels. Patients taking ribavirin must be monitored for hemolysis, and, because of teratogenic effect in animals, men and women taking the drug must practice strict contraception until they have been off the drug for at least 6 months.

Interferon alfa with ribavirin may be beneficial in the treatment of cryoglobulinemia associated with chronic hepatitis C. On the other hand, treatment of patients with chronic hepatitis C and persistently normal serum aminotransferase level ("chronic carriers") is of uncertain long-term benefit. Patients with both HCV and HIV infections may benefit from treatment of HCV if the CD4 count is not low. Treatment with interferon alfa plus ribavirin is costly, and side effects, which include flulike symptoms, are almost universal ; more serious side effects - psychiatric symptoms, thyroid dysfunction, and bone marrow suppression - are less common. Interferon is contraindicated in patients with decompensated cirrhosis, profound cytopenias, psychiatric disease, and autoimmune diseases. Ribavirin should be avoided in persons over age 65 or others in whom hemolysis could pose a risk of angina or stroke.

In nonresponders to interferon-based therapy for chronic hepatitis C, early experience suggests that treatment with interleukin - 10 may normalize aminotransferase levels, improve liver histology, and even reduce fibrosis.

Prognosis

The course of chronic hepatitis is variable and unpredictable. Untreated autoimmune hepatitis has a 5-year mortality rate of 50%, which decreases markedly with treatment. The sequelae of chronic hepatitis secondary to hepatitis B include cirrhosis, liver failure, and hepatocellular carcinoma. Up to 40 - 50% of patients with chronic hepatitis B and cirrhosis die within 5 years after the onset of symptoms, though predictive models suggest that therapy with interferon improves the prognosis is responders. Chronic hepatitis C is an indolent, often subclinical disease that may lead to cirrhosis and hepatocellular carcinoma after decades. In one study, the mortality rate from transfusion - associated hepatitis C was no different from that of an age-matched control population. Nevertheless, mortality rates clearly rise once cirrhosis develops, and mortality from cirrhosis and hepatocellular carcinoma due to hepatitis C is expected to triple in the next 10 - 20 years. Recent data suggest that treatment with interferon plus ribavarin has a beneficial effect on survival and quality of life, is cost - effective, and in responders may reduce the risk of hepatocellular carcinoma.

References

Alvarrez F et al : International Autoimmune Hepatitis Group report : Review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999 ; 31 : 929. (NLM Cit ID : 20046538) (Detailed review of the clinical, biochemial, serologic, and histologic criteria for the diagnosis of autoimmune hepatitis.

Baffis V et al : Use of interferon for prevention of hepatocellular carcinoma in cirrhotic patients with hepatitis B or hepatitis C virus infection. Ann Intern Med 19999 ; 131 : 691. (NLM Cit ID 99456453) (Review evidence suggesting that interferon therapy may prevent hepatocellular carcinoma in patients with cirrhosis, particularly those infected with hepatic C).

Bonancini M et al : Hepatitis C in patients with human immunodeficiency virus infection : diagnosis, natural history, meta-analysis of sexual and vertical transmission, and therapeutic issues. Arch Intern Med 2000;160:3365. (PMID : 11112228) (Coinfection leads to more severe liver disease ; therapy with interferon and ribavarin is indicated in patients without low CD4 counts but may not be tolerated well by patients receiving highly active antiretroviral therapy.)

Cummings KJ et al : Interferon and ribavirin vs, interferon alone in the re-treatment of chronic hepatitis C previously nonresponsive to interferon : A meta-analysis of randomized trails. JAMA 2001;285:193. (Sustained virologic response with re-treatment was achieved in 14% of cases. The best results were achieved with use of interferon alfa - 2a or -2b and standard rather than reduced doses of ribovirin.)

Czaja AJ et al : Autoimmune hepatitis : th einvestigational and clinical challenges. Hepatology 2000;31:1194. (PMID : 10796898) (Lucid review of pathogenesis).

Czaja AJ : Drug therapy in the management of type 1 autoimmune hepatitis. Drugs 1999;57:49. (NLM Cit ID : 99135433) (In-depth overview of indications for treatment, preferred drug regimens, complications, treatment results, and management of relapses and nonresponse.

DeBisceglie AM (editor) : Treatment advances in chronic hepatitis C. Semin Liver Dis 1999;19 (Suppl 1) :1, (Reviews of all aspects of drug therapy for chronic hepatitis C.)

Dienstag JL et al : Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256. (NLM Cit ID: 99442269) (After 1 year of treatment, lamivudine, 100 mg orally daily, led to HbeAg seroconversion with loss of serum HBV DNA in 17%, sustained normalization of ALT levels in 41%, and histologic improvement in 52% of patients).

Howell C et al : Hepatitis C in African Americans : summary of a workshop. Gastroenterology 2000;119:1385. (PMID : 11054398) (Hepatitis C is two or three times more common in blacks than in whites, more likely to become chronic but with a slower rate of progression to cirrhosis, and poorly responsive to treatment with interferon alone; however, response rates to interferon and ribavirin may be comparable in blacks and whites.)

Keeffe EB (editor) : Treatment of chronic hepatitis C. Clin liver Dis 1999;3:693. (Collection of reviews on various aspects of drug therapy for hepatitis C.)

Malik AH et al : Chronic hepatitis B virus infection : treatment strategies for the new millennium. Ann Intern Med 2000;132:723. (PMID : 10787366) (Recommends interferon alfa for patients with a serum ALT>200 units/L and HBV DNA < 200 pg/mL and lamivudine for the rest and for nonresponders to interferon alfa.)

McHutchinson JG et al : Interferon alfa - 2b alone or in combination with ribavirin as initial treatment for chronic hepatitis C. N Engl J Med 1998;339:1485. (NLM Cit ID : 99025346) (Sustained virologic response after 48 weeks of therapy was achieved in 38% of patients given interferon and ribavirin compared with 13% of those given interferon alone.)

Zeuzem S et al : Peginteriferon alfa - 2 a in patients with chronic hepatitis C. N Engl J Med 2000;343:1666. (PMID : 11106715) (With a dose of 180 mg once per weeks a sustained biochemical response was achieved in 38% of patients as compared with 17% treated with standard interferon.)