FUNCTIONAL AND ORGANIC DISEASES OF LIVER AND BILE DUCTS
Cholecystitis is an inflammation of the gallbladder, a small sack-like organ located in the upper right-hand side of the abdomen. In a healthy individual, the gallbladder temporarily stores bile, a substance produced by the liver that helps the body digest fat. After a meal, particularly a high-fat meal, bile passes from the gallbladder through the cystic and common bile ducts and into the small intestine where it helps process fats.
Cholecystitis, which has long been considered an adult disease, is quickly gaining recognition in pediatric practice because of the significant documented increase in nonhemolytic cases over the last 20 years. Gallbladder disease is common throughout the adult population, affecting as many as 25 million Americans and resulting in 500,000-700,000 cholecystectomies per year. Although gallbladder disease is much more rare in children, with 1.3 pediatric cases occurring per every 1000 adult cases, pediatric patients undergo 4% of all cholecystectomies. In addition, acalculous cholecystitis, uncommon in adults, is not that unusual in children with cholecystitis. Because of the increasing incidence of gallstones and the disproportionate need for surgery in the pediatric population, consider cholecystitis and other gallbladder diseases in the differential diagnosis in any pediatric patient with jaundice or abdominal pain in the right upper quadrant, particularly if the child has a history of hemolysis.
Pathophysiology: Cholecystitis is defined as inflammation of the gallbladder and is traditionally divided into acute and chronic subtypes. These subtypes are considered to be 2 separate disease states; however, evidence suggests that the 2 conditions are closely related, especially in the pediatric population. Most gallbladders that are removed for acute cholecystitis show evidence of chronic inflammation, supporting the concept that acute cholecystitis may actually be an exacerbation of chronic distension and tissue damage. Cholecystitis may also be considered calculous or acalculous, but the inflammatory process remains the same.
Chronic cholecystitis is most often related to gallstone disease but has been documented without gallstones. Its course may be insidious or involve several acute episodes of obstruction. The initiating factor is thought to be the supersaturation of bile, often with cholesterol crystals and/or calcium bilirubinate, which contributes to stone formation and inflammation. These processes lead to chronic obstruction, decreased contractile function, and biliary stasis, which contribute to further inflammation of the gallbladder wall. Biliary stasis also permits the increased growth of bacteria, usually Escherichia coli and enterococci, which may irritate the mucosa and increase inflammatory response. Chronic acalculous cholecystitis is less understood, but it may result from a functional deficiency of the gallbladder, which leads to spasm and an inability to appropriately empty its contents, causing chronic bile stasis.
Acute calculous cholecystitis results from a more sudden obstruction of the cystic duct by gallstones, which results in distension of the sac, edema, and bile stasis with bacterial overgrowth. These events lead to inflammation and a local release of lysolecithins, which further exacerbates the inflammatory process. In addition, edema of the wall and duct reinforces obstruction and may cause ischemia of the local tissue, releasing still more inflammatory mediators. Local lymph node hypertrophy and duct torsion or congenital anomalies may further complicate the obstructive process. As obstruction and inflammatory tissue damage progress, bacteria may proliferate. Bile cultures are positive in 75% of cases, usually with E coli, enterococci, or Klebsiella species. Bacterial infection most likely follows tissue damage, but after colonization, the severity of the disease can dramatically worsen. This cascade of events quickly leads pain and, possibly, a toxic appearance.
Acute acalculous cholecystitis develops in a similar manner but from different etiologic factors than acute calculous cholecystitis. Acute acalculous cholecystitis is most often associated with systemic illness, whether chronic or critical and acute. Increased mucous production, dehydration, and increased pigment load all are factors that increase cholesterol saturation and biliary stasis, whereas hyperalimentation, assisted ventilation, intravenous narcotics, ileus, and prolonged fasting contribute to cholestatic hypofunction. These conditions allow the formation of biliary sludge and may lead to obstruction. The resulting inflammation and edema lead to compromised blood flow and bacterial infection, as in acute calculous cholecystitis; however, the compromised blood flow appears more central in acute acalculous cholecystitis because acute acalculous cholecystitis can occur in vasculitides (eg, Kawasaki disease, periarteritis nodosa) presumably because of direct vascular compromise.
Physical: The physical examination in acute cholecystitis usually reveals right upper quadrant tenderness. The classic triad is right upper quadrant pain, fever, and leukocytosis. The patient may have abdominal guarding and a positive Murphy sign, ie, arrest of inspiration on deep palpation of the gallbladder in the right upper quadrant of the abdomen. Omental adherence to the inflamed gallbladder combined with distension may create a palpable mass between the 9th and 10th costal cartilages. The ductal system may become inflamed, causing cholangitis. In 50% of these cases, the examiner may find a Charcot triad.
Charcot triad: This combination of right upper quadrant pain, fever, and jaundice is indicative of obstruction to the common bile duct and the presence of acute cholangitis. The Charcot triad is considered a medical emergency, and patients require immediate intervention.
Biliary colic versus chronic cholecystitis: Performing a physical examination may be the only way to distinguish biliary colic from chronic cholecystitis. In chronic cholecystitis, the patient usually complains of tenderness to palpation in the right upper quadrant; however, the differentiation may be trivial given the high likelihood of chronic cholecystitis in the presence of recurring biliary colic.
Causes: Cholelithiasis is the most common cause of acute or chronic cholecystitis in adults and children. Three major types of gallstones may form, although most gallstones have components of more than one type. Cholesterol gallstones are radiolucent and are composed of cholesterol (>50%), calcium salts, and glycoproteins. They form within the gallbladder and migrate to the bile duct. Pigment gallstones are black, often radiopaque, and usually associated with hemolytic diseases. Radiopacity and color are related to an increased concentration of calcium bilirubinate, which interacts with mucin glycoproteins to form gallstones. These gallstones also form within the gallbladder and migrate to the ductal system. Brown gallstones, in contrast, form within the ductal system and are orange, soft, and greasy. They are composed of calcium salts of bilirubin, stearic acid, lecithin, and palmitic acid. These gallstones are more often associated with infection.
In rural Asia, infections with Opisthorchis sinensis or Ascaris lumbricoides are predisposing conditions. In the United States, these gallstones are more rare, although they have been found after cholecystectomy in which the bile was infected (most often by E coli) and in infants and children infected with Staphylococcus, Enterobacter, Citrobacter, and Salmonella species. In addition, chronic urinary tract infections may predispose individuals to the formation of these gallstones, and isolated gallstones associated with Ascaris have been recorded in the United States.
All gallstones require similar conditions to form. First, the bile must be supersaturated either by cholesterol or bilirubin. Second, chemical kinetics must favor nucleation of cholesterol. This occurs when cholesterol is no longer soluble in bile. Finally, stasis of the gallbladder allows cholesterol or calcium bilirubinate crystals to remain long enough to aggregate to form gallstones.
Many disease processes can precipitate or foster these events. Infection induces the deconjugation of bilirubin glucuronide, thereby increasing the concentration of unconjugated bilirubin in the bile. Hemolysis overwhelms the conjugation abilities of the liver, increasing the amount of unconjugated bilirubin in the bile. Hemolytic diseases include hereditary spherocytosis, sickle cell disease, thalassemia major, hemoglobin C disease, and possible uncontrolled glucose-6-phosphate dehydrogenase (G-6-PD) deficiency. Multiple blood transfusions also increase the pigment load, which predisposes the bile to the formation of biliary sludge.
Dehydration, whether primary or secondary to shock or sepsis, concentrates the bile, increasing viscosity and allowing supersaturation. CF is associated with increased mucous production and may cause a similar scenario. Gallstones remain the most common cause of cholecystitis. Although acalculous cases significantly contribute to incidence of cholecystitis, most acalculous cases are related to systemic illness and risk factors rather than epidemiologic determinants. Therefore, the discussion of epidemiology focuses on the development of cholelithiasis.
Acalculous cholecystitis
The aforementioned diseases may also contribute to the development of acalculous cholecystitis because the formation of gallstones is not necessary for the obstruction of the bile duct. In addition, acalculous cholecystitis has been heavily associated with local inflammation, endocarditis, vasculitides, and systemic infection. Implicated infections include those occurring in typhoid fever, scarlet fever, measles, and AIDS and those caused by mycoplasma, Streptococcus (groups A and B), and gram-negative organisms, such as Shigella and E coli.
Acalculous cholecystitis may also occur postoperatively. Tsakayannis et al observed acute cholecystitis occurring after open-heart surgery in 4 of their patients, although it is more commonly observed in other nonbiliary surgeries and trauma. Shock, sepsis, hyperalimentation, prolonged fasting, intravenous narcotics, and multiple transfusions were the most common risk factors for the development of acute acalculous cholecystitis. The presence of 4 or more of these risk factors is highly predisposing.
Other unusual causes
Gallstones may also be caused by medications. Furosemide, octreotide, ceftriaxone, and cyclosporine have all been associated with gallstone disease. Ceftriaxone causes a reversible pseudolithiasis through several mechanisms. Ceftriaxone displaces bilirubin on albumin, thereby increasing the blood concentration of unconjugated bilirubin. Ceftriaxone is also secreted in bile, and calcium salts of ceftriaxone have been found in biliary sludge.
Risk factors associated with gallstone formation are prolonged fasting and age older than 24 months. Lasix has also been implicated in gallbladder disease, but it usually is only a compounding factor in the presence of prematurity, sepsis, or small-bowel disease. Cyclosporine may be lithogenic, but it seems to require high drug levels and hepatotoxicity. Finally, ileal disease or resection has been correlated with cholelithiasis in adults and children, although the risks associated with resection seem to be highest after puberty. These patients have an increased cholesterol secretion and a lowered bile acid secretion, which leads to cholesterol supersaturation.
Lab Studies:
In assessing for cholecystitis, appropriate laboratory studies include a CBC, gamma-glutamyltransferase (GGT) assessment, amylase measurement, urinalysis, direct and indirect bilirubin tests, alkaline phosphatase measurement, and transaminase levels. In acute cholecystitis, the WBC count is elevated, with a predominance of polymorphonuclear cells and bands. Bilirubin, alkaline phosphatase and GGT levels rise secondary to a blocked biliary system. The traditional cholestatic picture involves direct hyperbilirubinemia, with a direct-to-indirect ratio approaching 1:1. Amylase may be elevated even in the absence of obstructive pancreatitis. In addition, transaminases may show mild elevation but not a significant increase, unless obstruction has been severe enough to cause hepatocyte damage. Transaminase levels are more likely to rise early in patients with obstruction of the common bile duct.
Imaging Studies:
Plain abdominal radiography may be used for initial screening in abdominal pain. Calcifications representing radiopaque gallstones may be observed in the gallbladder or ductal system. Radiopaque gallstones contain more calcium bilirubinate and are more common in the pediatric population, especially in infants and children. In addition, complications such as porcelain gallbladder and emphysematous cholecystitis may be visible on radiographs, although these complications are rare in children.
Abdominal ultrasonography has become the diagnostic tool of choice in evaluating cholelithiasis. The accuracy of abdominal ultrasonography in depicting gallstones is estimated to be more than 95%, but its reliability in the accurate diagnosis of acute cholecystitis is more limited. Ultrasonographic findings in acute cholecystitis include a discrete echodensity representing the gallstone, the presence of sludge, and, possibly, ductal anomalies or dilation. The gallbladder may be dilated with thickened walls. Imhof et al found gallbladder wall thickness of more than 3.5 mm to be a reliable independent diagnostic indicator of cholecystitis. Gallstones are often in a dependent position in the gallbladder and may move as the patient changes position. The reliability of ultrasonography is well established with both opaque and lucent gallstones. Results are immediate, and accessibility is usually excellent.
Oral cystography has been used in the past, but is now largely ignored because of the refinement of ultrasonography. Oral cystography involves the ingestion of contrast material that is secreted in the bile. Lack of visualization of the gallbladder indicates cholelithiasis. This procedure is limited by liver dysfunction and malabsorption. In addition, the contrast tablets have been associated with emesis and diarrhea, further complicating effectiveness.
The most accurate tool in the diagnosis of acute cholecystitis is biliary scintography, otherwise known as the hepatic 2,6-dimethyliminodiacetic acid or hepatoiminodiacetic acid (HIDA) scanning. This procedure involves the intravenous injection of substances labeled with technetium 99m, taken into the hepatocytes, and excreted into the biliary system. Normal hepatic uptake without gallbladder visualization is diagnostic, but false positive results occur with decreased biliary function secondary to prolonged fasting and the use of hyperalimentation. Morphine augmentation of this test has been shown to decrease false positive results. Induced spasm of the sphincter of Oddi increases biliary pressure and enhances gallbladder filling. This test may be unnecessary, however, because the clinical diagnosis and treatment are determined by the symptoms and presence of gallstones or sludge. Ultrasonography has proved its usefulness in depicting gallstones, does not rely on contrast, and, therefore, may be safer.
Other imaging techniques that can be used in the diagnosis of cholecystitis include MRI and CT, especially in cases in which ultrasonography is not helpful. Ultrasonographic results may be compromised by ileus, surgical incisions, and coexisting diseases, especially those found in patients who are critically ill. MRI and CT may be more sensitive than ultrasonography in detecting inflammation within and around the gallbladder. In addition, the presence of other sources of abdominal sepsis are more easily discovered and treated by means of MRI and CT.
Other Tests:
Other tests associated with the diagnosis and treatment of cholecystitis include cholecystokinin (CCK) stimulation, intraoperative cholangiography, and endoscopic retrograde cholangiopancreatography (ERCP). CCK stimulation may be employed during other imaging studies, such as cholescintigraphy. Gallbladder dyskinesia after CCK administration is diagnostic of gallbladder hypofunction and may be useful in discerning acalculous or chronic cholecystitis and acute inflammation.
Intraoperative cholangiography, whether intravenous or percutaneous, is widely used for the visualization of the gallbladder and ductal system. However, cholangiography can be time-consuming and an added expense to the patient, although some data show no statistical difference in operative time with and without its use. Consider cholangiography for any risk of obstruction of the common bile duct. Indications are a history of jaundice, pancreatitis, dilated common bile duct, and the presence of small gallstones. The benefits of using cholangiography have not been proven for routine cholecystectomy, routine screening for congenital anomalies, or assessment of the common bile duct for obstruction in the absence of clinical suspicion.
If the patient displays signs and symptoms of choledocholithiasis, ERCP may also be used preoperatively for exploration of the common bile duct. This procedure is both diagnostic and therapeutic because it may be used for stent placement, basket retrieval, or papillotomy to allow passage of gallstones; however, available choledochoscopes may be too large for small patients.
Procedures:
One alternative to cholecystectomy is percutaneous transhepatic cholecystostomy. In this approach, thread a catheter directly into the gallbladder and place it to allow gravity drainage. Cholecystostomy is especially useful in acalculous cholecystitis and in seriously ill patients with simple gallstones in whom obstruction of the common bile duct is ruled out. Because cholecystectomy is the standard of care for cholecystitis, cholecystostomy is usually reserved for seriously ill patients who may not tolerate surgery.
Choledocholithiasis complicates the picture of cholecystitis and usually requires adjunctive procedures to cholecystectomy. If obstruction of the common bile duct is suspected preoperatively, perform ERCP before surgery with papillotomy, stent placement, or basket retrieval. If gallstones are found intraoperatively, several techniques can be used. The common bile duct can be flushed with saline or opened and explored. Additionally, an endoscope or nephroureteroscope may be used intraoperatively for basket retrieval.
Biliary Dyskinesia
Definition – is a disorder of the sphincter’ tonus and kinetics of the gall-bladder and bile ducts.
Biliary dyskinesia is a quite common disease of the gallbladder. The gallbladder stores the bile which is released by the liver. The bile reaches the small intestine where it digests the fat from aliments. To reach the small intestine, the bile must pass through the common bile duct and if the bile caot be secreted by the gallbladder or caot flow through the common bile duct, then will return in the gallbladder, leading to biliary dyskinesia.
When a person eats, a hormone known as cholecystokinin is secreted by the cells from the intestine. The main action of cholecystokinin is activation of receptors that are distributed in the muscle of the gallbladder, thus producing contraction of gallbladder and the elimination of bile. Then, the bile is cleared from the gallbladder and will reach the small intestine. If a patient is suffering from biliary dyskinesia, then the gallbladder caot contract properly.
At the end of the common bile duct are three muscles that form the sphincter of Oddi. In its action to contract the gallbladder, cholecystokinin it binds to the receptors in the sphincter of Oddi and cause muscle relaxation. In this way the bile is eliminated from the gallbladder and will reach into the small intestine. If the sphincter of Oddi does not work properly, the bile will not pass through common bile duct and will remain in the gallbladder, which will cause biliary dyskinesia.
Biliary dyskinesia is often a symptom of disease rather than a disease itself. May signal the existence of gallbladder stones, acute or chronic pancreatitis and of other digestive disorders. However, symptoms can be induced by the consumption of certain types of food. Chronic inflammation may be another cause of biliary dyskinesia.
There is evidence that stress is a significant cause of biliary diskynesia. Some theorists believe that dopamine receptor dysfunction can trigger a biliary dyskinesia. Gallbladder function is likely to be damaged and caot receive appropriate signals from the brain when the bile will reach the gallbladder.
The most obvious sign of disease is the sharp pain in the right hypochondrium, intermittent cramps that are located under the right ribs. However, there are many patients who have no symptoms. Other patients may feel only a vague discomfort or a dull ache in right hypochondrium. Most often, pain occurs in approximately 40 minutes after the patient has eaten a meal high in fat. Rarely, may occur nausea and vomiting.
Most types of gallbladder disorders have symptoms similar to biliary dyskinesia. An extensive differential diagnosis is necessary to exclude other diseases such as cancer or gallstones. For the diagnosis, the doctor will ask, usually, blood tests and ultrasound. If the result of this investigations is negative, will be done other tests or ultrasound that evaluate the gallbladder function.
injection of a contrast substance into the bloodstream which will be transported to the liver cells and excreted trough gallbladder, which will allow the visualization of the gallbladder on a X-ray examination.
Although there are several risk factors for gallbladder disease in general, few of them are quite specific. Obesity, age and sex are known factors. Older women who are overweight are more likely to suffer from biliary dyskinesia than men. Treatment usually involves laparoscopic cholecystectomy (gallbladder removal complete).
Classification
n hypertonic-hyperkinetic dyskinesia
n hypotonic-hypokinetic dyskinesia
Clinical manifestation of hypertonic-hyperkinetic dyskinesia
n Duration of the disease up to 1 yr.
n Pain syndrome
n Dyspeptic syndrome
n Manifestations of vegetative dysfunction, neurotic symptoms
Clinical manifestation of hypotonic-hypokinetic dyskinesia
n Pain syndrome
n Dyspeptic syndrome
n Hepatomegaly
n Gallbladder symptoms are positive
Plan of examination
n Fool blood count
n Biochemical test of blood
n Serum aminotransferase
n Serum bilirubin (predominantly the direct reacting fraction)
n Serum alkaline phosphatase
n Albumin and globulin level
n Stool test
n USE of the abdominal cavity + cholekynetics for functional investigations
Treatment of hypertonic-hyperkinetic dyskinesia
1. Diet N 5
2. Spasmolitics:
platyphyllini hydrotartratis (amp. 0.2 % 1 ml)
papaverini hydrochloridum (tab. 0.01, amp. 2 % 2 ml)
no-spa (tab. 0.04 or amp. 2 % 2 ml)
3. Choleretic:
cholagon
allocholum
cholenzynum
galstena
hepabene
Treatment of hypotonic-hypokinetic dyskinesia
1. Diet N 5
2. Prokinetic: motilium, domperidone (tabl. 0.01 g) 1 mg/kg/day
3. Choleretic and cholekinetic drugs:
cholagon
allocholum
cholenzynum
galstena
hepabene
chophytol
Herbal remedies for biliary dyskinesia are using plants that are producing the contraction and relaxation of gallbladder and are regulating the liver secretion of bile. There are a number of plants with choleretic action and cholagogue effect (contributing to the contraction of gallbladder and evacuation of bile into the duodenum).
Artichokes – from this plant, with a good colecistokinetic effect, can be made teas. However, the taste is quite bitter, which is why many people avoid to drink it. The resulting liquid should be consumed with small sips, unsweetened, in the morning on an empty stomach. Then, the patient should stay on the right side about 30 minutes for maximum effect of the tea. The alternative would be capsules with artichokes, which can taken half an hour before each meal.
Yarrow – infusion may have a slightly sweet taste, according to some. Drink a cup of tea from this plant with a half hour before every meal to stimulate the evacuation of the bile. The infusion is prepared from a teaspoon of dried herb to a cup of boiling water. Cover the infusion and leave it untouched for 5 minutes. This is a very good tea for hyperacid gastritis, gastric and duodenal ulcer, hepatitis, abdominal bloating, nausea and loss of appetite.
Dandelion – is one of the most effective herbs for liver drainage and evacuation of bile in the digestive tract. Represents an excellent way to stimulate liver activity. For a cup of infusion will be use 2 teaspoons of herb. Drink 2-3 cups a day. You can follow a diet with fresh dandelion stems (10-15 strains per day) if you have hepatitis or biliary dyskinesia.
Other recommendations:
Because biliary dyskinesia can be triggered by the nervous system, try to be calm, at least until the pain relieves.
Take regular 4-5 meals per day and avoid foods with high level of fats.
Avoid fried foods, sauces and stews; prefer boiled or baked foods.
Stop smoking and try not to have a sedentary lifestyle.
For proper disposal of the bile, is indicated that after meals to lie on the right side for 30 minutes.
Treatment of hepatitis
Medical Care: No specific treatment is available for persons with acute HBV infection. Supportive and symptomatic care is the mainstay of therapy for most patients.
Surgical Care:
Liver transplantation for decompensated liver disease
Surgical resection of hepatocellular carcinoma
Diet: A high-energy diet is desirable, and because many patients may have nausea late in the day, they best tolerate their major caloric intake in the morning. Intravenous feeding is necessary in the acute stage if the patient has persistent vomiting and cannot eat.
Activity: Although forced and prolonged bed rest is not essential for full recovery, many patients feel better with restricted physical activity.
Alpha interferon (IFN-a) has been the mainstay of treatment for chronic hepatitis B since its introduction in the mid-1980s, although only 30-40% of patients respond to this therapy. Lamivudine and the newer nucleoside analogues famciclovir, lobucavir, and adefovir dipivoxil directly block the replication of HBV; they are highly effective, bioavailable, and extremely well tolerated. To date, only IFN-a and lamivudine are FDA-approved for this indication.
Interferon-therapy:
1. Intron А (α2b-Interferon),
Form of production – vial with 3 and 5 М units
2. Viferon (α2- Interferon+ vit. E and C)
Form of production rectal suppository
Viferon 1 – 150000 units
Viferon 2 – 500000 units
Viferon 3 – 1000000 units
Viferon 4 – 2000000 units.
3. Pegasis (peginterferon α-2а)
Form of production syrette with 135 mcg and 180 mcg
Hepatopronectors
n Heptral (tabl.- 0.4 g, amp.- 0.4 g) 1-2 tabl. 3 times a day (20-25 mg/kg/day)
n Ursophalk (cap. 250 mg) 8-10 mg/kg/day
n Essentiale (cap., amp.) 1-2 cap. 3 times a day
n Carsil (dragee) 1-2 dragee 3 times a day
n Hepabene 1-2 dragee 3 times a day
n Thiotriazolinum 1 tabl. 3 times a day
n Chophytol 1-2 tabl. 3 times a day
]Drug Category: Antiviral agents — Interferon may prevent the progression of acute hepatitis to the chronic stage and promote more rapid resolution of viremia and normalization of serum aminotransferase levels. Several nucleoside analogues are active against HBV. The most widely used and studied is lamivudine, which has produced promising responses. However, relapse rates tend to be high after treatment is discontinued.
DrugName
Alpha interferon 2b (Intron A) — Interferons (IFNs) are proteins produced by host cells in response to viral infection. Three interferons have been identified, and each has antiviral and immunoregulatory actions: IFN-a is produced by B lymphocytes and monocytes; IFN-b, by fibroblasts; and IFN-g, by T helper and NK cells. Immunomodulatory effects of IFNs are mediated by an increase in HLA class I antigen and FC receptor expression, an increased CD4/CD8 ratio, and activation of NK cell pathways. Ideally, candidates for IFN therapy have evidence of ongoing viral replication (presence of HBeAg or HBV DNA) for at least 6 mo and either persistently increased serum aminotransferase activity or evidence of chronic hepatitis B infection at liver biopsy. Before IFN therapy, screening patients for at least 4-6 mo to identify those who may be entering a period of spontaneous seroconversion to HBeAb is often beneficial.
Clinical variables associated with a favorable response to therapy are high pretherapy aminotransferase levels, low HBV DNA levels, and active disease at liver biopsy. Other less useful variables include female sex, acquisition of infection in adulthood, heterosexuality, HIV antibody negativity, and history of acute hepatitis. Responses to IFN-a-2b, is defined as a sustained loss of HBeAg and HBV DNA with a normalization or near normalization of ALT levels for at least 6 mo after therapy, is observed in 25-40% of patients. Controlled studies of IFN in children reveal comparable responses in primary non-Asian children. Chinese children respond poorly to IFN therapy. Safety and effectiveness in patients aged from 1-17 years have been established.
Pediatric Dose
High dose: 7.5-10 million U/m2 3 times per wk
Low dose: 3-6 million U/m2 3 times per wk; studies with both showed that the high dose was more effective
Contraindications
Documented hypersensitivity; decompensation (cirrhosis)
Interactions
Interactions with other medications have not been evaluated fully; use caution with potentially myelosuppressive agents such as zidovudine; combination with theophylline decreases theophylline clearance, increasing theophylline levels by 100%
Precautions
IFN does not appear to protect against hepatocellular carcinoma; treatment is associated with frequent adverse events; dose reduction is required in at least 20% of patients treated with recommended regimen; discontinuation of treatment is necessary in <5% of instances; most patients have influenza-like illness with fever, chills, myalgia, and headaches 6-8 hours after first injection; symptoms improve or disappear with subsequent injections; patients benefit from premedication with acetaminophen or NSAIDs
Psychiatric adverse effects, especially depression, occur in about 15% of patients; frank delirium and suicidal ideation have been reported IFN decreases the platelet count by 30-50%, total white cell count by 20-40%, and hematocrit level slightly; changes are clinically insignificant and often return to normal after treatment is discontinued; can induce an autoimmune diathesis; associated with clinically significant worsening or unmasking of autoimmune conditions; autoantibodies, such as antinuclear, anti√smooth muscle, antithyroid, and insulin antibodies, develop in> 50% of patients treated for 4 mo; thyroid abnormalities infrequent; evaluate serum TSH levels prior to therapy
Acute, serious, hypersensitivity reactions (rare) require immediate discontinuation; transient rashes have occurred after injection but have not required treatment interruption; may exacerbate preexisting psoriasis
Drug Name
Lamivudine (Epivir-HBV) — Only nucleoside analogue approved by the FDA for chronic HBV treatment. It inhibits HBV DNA polymerase. Lamivudine use should be considered in patients with ongoing HBV replication, elevated aminotransferase activity, and histologic evidence of liver injury. Lamivudine is now considered first-line therapy, eclipsing interferon. Consider lamivudine for cases that fail or are unlikely to respond to interferon or patients who cannot tolerate interferon. Discontinue lamivudine only when repeated assays demonstrate HBeAg loss or seroconversion to HBeAb.
Emergence of resistance is the major drawback of nucleoside analogue monotherapy. The proper management of viral breakthrough in patients treated with lamivudine is not yet defined. Continuation of lamivudine appears to be warranted in most cases because the resistant strains of HBV seem to be attenuated and are associated with only mild liver injury. Combination therapy with 2 or 3 nucleoside analogues may delay or prevent emergence of viral resistance, but clinical trials are needed.
Safe and effective in children aged 2-17 y. Epivir-HBV contains 100 mg/tab or 5 mg/mL in oral solution; Epivir contains 150 mg/tab or 10 mg/mL in oral solution.
Adult Dose
100 mg/d PO
Pediatric Dose
<12 years: 3 mg/kg/d PO
>12 years: Administer as in adults
Contraindications
Documented hypersensitivity
Interactions
Trimethoprim/sulfamethoxazole increases bioavailability of lamivudine; lamivudine increases concentration of zidovudine when administered concurrently
Precautions
Caution in pediatric patients with history of prior antiretroviral nucleoside exposure, pancreatitis, or other significant risk factors for pancreatitis; new-generatioucleoside analogues appear to be remarkably free of adverse effects; mild constitutional symptoms such as malaise, fatigue, headache, nausea, and abdominal discomfort have been reported; aminotransferase levels increase in 30-40% of patients; lactic acidosis/severe hepatomegaly with steatosis, including fatal cases, have been reported (mostly in women); obesity and prolonged exposure to nucleosides may be risk factors; physician experienced in managing chronic hepatitis B should assess patients before treatment; safety and efficacy is not established in patients with decompensated liver disease or organ transplants, in pediatric patients, and in patients dually infected with HBV, HCV, hepatitis delta, or HIV; reduced dose recommended in impaired renal function.
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