CHRONIC HEPATITIS
Definition
Chronic hepatitis is a broad clinical and pathologic syndrome that encompasses an etiologically diverse group of diseases characterized by long-term elevation of liver chemistries and the finding of hepatic inflammation on liver biopsy. Chronic hepatitis is generally defined as disease that has lasted for 6 months or longer; in many cases, however, the diagnosis can be established earlier.
Anatomy of the liver and portal venous system
VIDEO 1 VIDEO 2 (liver cellular structure)
Anatomy of the liver and portal venous system
Etiology
The most important groups of diseases that cause chronic hepatitis are autoimmune hepatitis (previously called autoimmune chronic active hepatitis) and chronic viral hepatitis, which is caused by infection with hepatitis B virus (HBV), with or without coinfection with hepatitis D virus (HDV), or by infection with hepatitis C virus (HCV) [see Table 1]. Less commonly, chronic hepatitis is cryptogenic or caused by drugs, Wilson disease, á1-antitrypsin deficiency, or early-stage primary biliary cirrhosis or primary sclerosing cholangitis. Over the past several years, international working groups have substantially modified the terminology of chronic hepatitis to reflect an etiologic basis rather than a pathologic basis.
CLASSIFICATION
Chronic Viral Hepatitis B
Chronic Viral Hepatitis C
Chronic Viral Hepatitis D
Chronic Viral Hepatitis nonidentificated
Autoimmune Hepatitis (type 1, 2 ,3)
Toxic Hepatitis, Drug-Induced Hepatitis
Cryptogenic Hepatitis
Alcoholic Hepatitis
Metabolic Hepatitis
Cholestatic Hepatitis
Nonspecific Reactive Hepatitis
Grades of Inflammation
and Stages of Fibrosis on Liver Biopsies
COMPLICATIONS
HEPATIC ENCEPHALOPATHY
VARICEAL BLEEDING
ASCITES
GLOMERULONEPHRITIS
OTHERS
LABORATORY SYNDROMES:
Cytolitic syndrome (↑AST, ↑ALT, ↑GGT, ↑Bilirubin, ↑Iron, ↑ vit. B12)
Cholestatic syndrome (↑Bilirubin (сonjugated), ↑Alkaline phosphatase, ↑GGT, ↑cholesterol)
Liver cellular insufficiency syndrome (↓Albumine, ↓prothrombin, ↓cholesterol, ↓fibrinogen)
Mesenchyme-inflammatory syndrome (↑ESR, ↑ﻻ-globulins, ↑timol test ↑Le)
Hypersplenism (anemia, thrombocytopenia, leukocytopenia)
Approach to Chronic Hepatitis
Diagnosis
Clinical Manifestations. Clinical manifestations of chronic hepatitis are diverse, ranging from asymptomatic stable disease characterized by mildly elevated aminotransferase levels (the usual pattern seen in the early stages of chronic viral hepatitis) to severe, rapidly progressive illness with fulminant hepatic failure. The most common symptoms of chronic hepatitis are fatigue, malaise, and mild abdominal pain. Patients with mild forms of chronic hepatitis are usually asymptomatic or have minimal symptoms with no stigmas of chronic liver disease on physical examination. In more advanced cases, the symptoms and signs of chronic hepatitis include anorexia, jaundice, spider angiomas, palmar erythema, ascites, edema, hepatomegaly, and encephalopathy. Pruritus is unusual, unless the patient has primary biliary cirrhosis or primary sclerosing cholangitis. A small number of patients with autoimmune hepatitis have an acute fulminant course and are critically ill at initial presentation. Extrahepatic manifestations of chronic hepatitis are common and include arthralgias, arthritis, glomerulonephritis, skin rashes, amenorrhea, acne, hirsutism, and thyroiditis.
Mild jaundice
Jaundiced patient
Spider naevus in the ventral side of the
left shoulder
Palmar erythema
Table 1 Summary of the Types, Diagnosis, and Treatment of Chronic Hepatitis
*Anti-LKM1 was called anti-LKM before LKM2 (associated with tienilic acid) and LKM3 (associated with hepatitis D) were identified.
†The role of a non-A through -E hepatitis agent (hepatitis F or G) remains speculative.
(+)—present (–)—absent (±)—present or absent AMA—antimitochondrial antibody ANA—antinuclear antibody anti-GOR—antibody to GOR protein anti-HBc—antibody to hepatitis B core antigen anti-HBe—antibody to HBeAg anti-HCV—antibody to HCV anti-HDV—antibody to hepatitis D virus anti-LKM—antibody to liver/ kidney microsome anti-LKM1—antibody to liver/kidney microsome type 1 anti-LP—antibody to liver/pancreas antigen anti-SLA—antibody to soluble liver antigen ASMA—anti–smooth muscle antibody ELISA—enzyme-linked immunosorbent assay HBeAg—hepatitis B e antigen HBsAg—hepatitis B surface antigen HBV—hepatitis B virus HCV—hepatitis C virus LKM2—liver/kidney microsome type 2 LKM3—liver/kidney microsome type 3 RIBA—recombinant immunoblot assay
Routine Laboratory Tests
The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels are usually elevated in patients with chronic hepatitis, although a small number of patients with histologic chronic hepatitis have transiently normal aminotransferase levels. Even a mild elevation of aminotransferase levels (5 to 10 IU/L higher than the upper limit of normal) should lead the physician to consider the presence of chronic hepatitis. Elevations of more than 400 IU/L are common in cases of untreated autoimmune hepatitis and severe chronic viral hepatitis. Substantial increases in the aminotransferase levels herald an exacerbation of disease. The serum bilirubin level is usually normal (0.0 to 1.0 mg/dl) in chronic viral hepatitis but is higher than 3 mg/dl in patients with moderately severe autoimmune hepatitis. A characteristic feature of autoimmune hepatitis, but not of chronic viral hepatitis, is an increased ã-globulin level (> 1.6 g/dl), which may be markedly increased (3 to 7 g/dl). In the most severe forms of chronic hepatitis, hepatic synthetic function is impaired; this condition is demonstrated by a low serum albumin level and prolongation of the prothrombin time. Imaging studies of the abdomen show variable degrees of hepatomegaly with or without splenomegaly; irregularity of liver density or contour; and evidence of portal hypertension with ascites, an increased number of portal collateral vessels, or both.
Liver Biopsy
The specific etiology of chronic hepatitis can usually be determined by clinical evaluation combined with immunologic and serologic testing, but liver biopsy helps confirm certain diagnoses (e.g., Wilson disease or á1-antitrypsin deficiency) and establish histologic grading and staging. It has been proposed that the etiologic terminology be supplemented by a histologic description of the grade of inflammatory activity and of the stage of fibrosis or cirrhosis. Thus, the diagnosis of chronic hepatitis in a given patient might be autoimmune hepatitis (etiology) with severe activity (grade) and cirrhosis (stage). The grade and stage of chronic hepatitis can be assessed with various semiquantitative scoring systems. In the histology activity index, also known as the Knodell score, the grades of inflammation range from 0 to 18, and the stages of fibrosis range from 0 to 4. This scoring system is often used in clinical research studies, but other scoring systems are more commonly applied in routine practice.2 The most popular scoring system for chronic hepatitis generates two scores from 1 to 4—one for the degree of inflammation and the other for the degree of fibrosis [see Table 2]. The various numerical scoring systems have been critically important in research, particularly in treatment trials, and are now often used by pathologists in the routine interpretation of liver biopsy specimens from patients with chronic hepatitis. However, it is also important that the final evaluation of a liver biopsy specimen from a patient with chronic hepatitis include descriptive terminology characterizing the etiology, grade, and stage of disease.
DIFFERENTIAL DIAGNOSIS
Primary Biliary Cirrhosis
Primary biliary cirrhosis most often occurs in women between 30 and 50 years of age.7 The presence of serum autoantibodies, an association with other autoimmune diseases, and the resemblance of the bile duct lesions in primary biliary cirrhosis to those seen in chronic graft versus host disease suggest that immune mechanisms play an important role in the pathogenesis of this disorder. Studies have also shown that primary biliary cirrhosis is associated with the HLA-DR8 haplotype, suggesting a genetic predisposition to the disease.
Diagnosis
Clinical features Presenting complaints in patients with primary biliary cirrhosis are fatigue and generalized pruritus. Jaundice may not develop until 5 to 10 years after the onset of pruritus and systemic symptoms. Some patients experience bone pain, multiple fractures, and vertebral collapse. The usual cause of primary biliary cirrhosis is osteoporosis, which occurs in 20% to 30% of patients. Less commonly, osteomalacia is also present. Factors that give rise to the bone abnormalities include malabsorption of calcium and phosphate, altered vitamin D metabolism, cholestyramine therapy, and poor nutrition. Physical examination often reveals xanthelasma, xanthomas, hepatosplenomegaly, hyperpigmentation, and excoriation of the skin [see Figure 2]. If the disease is advanced, scleral icterus, ascites, and edema will also be present.
Figure 1 Alcoholic cirrhosis in the liver of a 58-year-old man produces distortion with scar tissue (arrows) that spreads through the parenchyma and outlines small regenerating nodules.
Figure 2 This patient with advanced primary biliary cirrhosis demonstrates some characteristic signs of the disease: (a) xanthelasma, a common finding, and (b) xanthomas, which are prominent on the elbows.
Laboratory tests.
Typical laboratory findings of primary biliary cirrhosis include an elevated alkaline phosphatase level (usually > 300 IU/L and often > 700 IU/L), a serum cholesterol level above 300 mg/dl, an elevated IgM level, and antimitochondrial antibody detectable at high titer (in 90% to 95% of patients). A moderate number of patients with primary biliary cirrhosis have concomitant disease, such as renal tubular acidosis, cleroderma, CREST syndrome (calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia), or Sjögren syndrome. Primary biliary cirrhosis may have clinical and laboratory features similar to those of cirrhosis secondary to chronic biliary tract disease. Indeed, carcinoma of the pancreas or biliary tree, common duct stones, postoperative bile duct stricture, and primary sclerosing cholangitis or pericholangitis secondary to inflammatory bowel disease may all mimic some of the laboratory and histologic features of primary biliary cirrhosis. There is seldom a need, however, to directly visualize the biliary tree in patients who display the typical clinical, laboratory, and histologic features of primary biliary cirrhosis.
Liver biopsy.
Liver biopsy may reveal bile duct destruction with lymphocytic-plasmacytic infiltration of portal areas, periportal granuloma formation, and portal scarring with linking of portal tracts [see Figure 3]. Ductular proliferation is common. When scarring is extensive, nodule formation, often with retention of the central veins, can be found. Bile stasis is usually periportal and indicates advanced disease.
Treatment
The management of primary biliary cirrhosis includes ursodiol therapy and nonspecific treatment of pruritus, malabsorption, bone disease, and portal hypertension.
Specific treatment
Ursodiol, a hydrophilic bile acid, has been given to patients with primary biliary cirrhosis on the premise that altering the composition of the endogenous bile acid pool may prove beneficial by reducing the concentration of potentially toxic endogenous hydrophobic bile acids. In one large placebo-controlled trial, 2 years of treatment with ursodiol at a dosage of 13 to 15 mg/kg daily resulted in clinical, biochemical, and histologic improvement; decreased need for liver transplantation; and increased survival. These favorable results were confirmed by two additional large trials—a Canadian multicenter trial and a Mayo Clinic trial12—which showed trends toward increased survival and decreased need for liver transplantation in the ursodiol treatment group. Most patients are given ursodiol because it appears to be effective, is safe, and may relieve pruritus. In a small pilot study, methotrexate appeared to be of benefit in patients with primary biliary cirrhosis, but therapy was associated with a number of side effects, including bone marrow suppression and pulmonary toxicity.13 In a 2-year study of the use of methotrexate in combination with ursodiol, no benefit was noted over the use of ursodiol alone, and methotrexate toxicity was substantial. General use of methotrexate is not warranted until its efficacy and safety profile is further studied. Corticosteroids, azathioprine, penicillamine, cyclosporine, and colchicines have been used to treat patients with primary biliary cirrhosis. Corticosteroids do not alter the course of the disease, and they accelerate the onset of osteoporosis. Azathioprine, cy closporine, and penicillamine are not used for therapy. Two randomized clinical trials evaluated the efficacy of colchicine therapy at a dosage of 0.6 mg twice daily. Colchicine improved the results of liver tests but without improvement in symptoms or histology. There was the suggestion that survival was enhanced. However, a long-term follow-up of one of the randomized colchicine trials did not confirm a survival benefit. Colchicine produced only minor side effects, which were easily controlled by dose reduction in these studies.
Figure 3 Dense portal inflammatory reaction (thin arrow) and portal granulomas (thick arrow) characterize primary biliary cirrhosis affecting the liver of a 29-year-old woman who underwent a cholecystectomy.
Nonspecific treatment.
Nonspecific therapy is directed at relieving symptoms during the slow but relentless course of the disease. The anion exchange resin cholestyramine may help alleviate pruritus. The usual dosage is
Prognosis
The prognosis varies, but the clinical course is generally indolent. Major hepatic dysfunction usually does not occur until very late. The median survival time is about 10 years. Hemochromatosis Hepatic iron overload may be primary (most often caused by hereditary hemochromatosis) or secondary (related to transfusional iron loading, ineffective erythropoiesis, or end-stage liver disease—particularly alcoholic liver disease, chronic hepatitis C, and nonalcoholic steatohepatitis).19 Patients with these chronic liver diseases may have abnormal iron study results and elevated serum ferritin levels, but hepatic iron concentration measured from a liver biopsy specimen is most ofteormal or only slightly elevated. Hereditary hemochromatosis is characterized by the deposition of large amounts of iron in the liver parenchymal cells [see Figure 5]. The accumulation leads to periportal cell destruction and hepatic scarring, culminating in cirrhosis. The disease occurs 10 times more often in males than in females. Symptoms generally appear between 40 and 60 years of age in men or after menopause in women. Occasionally, the disease is manifested at a much earlier age.
Etiology and Genetics
Hereditary hemochromatosis is inherited as an autosomal recessive defect that affects approximately one in 300 persons. 19,20 The heterozygote carrier rate is estimated to be one in 10 to 12 of the white population. Heterozygotes may show some abnormalities of iron storage, but clinical disease does not develop under normal circumstances. In
Diagnosis
Clinical features In advanced disease, bronze discoloration of the skin secondary to deposition of both melanin and iron appears. The liver is moderately enlarged; splenomegaly is noted in about half of patients. When disease is less advanced, the skin may have normal color, and the liver may be barely palpable. Signs of portal hypertension eventually develop in most cases. Primary liver cell cancer occurs in about 15% to 20% of patients.
Laboratory tests.
Laboratory analysis reveals an increase in serum iron associated with an 80% to 90% saturation of serum transferrin (15% to 47% saturation is normal). Serum ferritin is usually elevated as well. An elevated mean linear attenuation coefficient (CT number) on CT scanning of the liver may signal the presence of increased hepatic iron stores. MRI may also demonstrate iron overload in hereditary hemochromatosis. Mild elevations of serum aminotransferase and alkaline phosphatase levels are not uncommon, but jaundice is unusual. The serum albumin level and the prothrombin time remain in the normal range until late in the course. Serum iron concentration and total iron-binding capacity can be used to screen populations for hemochromatosis. A fasting transferrin saturation of 62% or higher in men (and perhaps 50% in women) identifies a high proportion of patients who are homozygous for hemochromatosis. The serum ferritin concentration has not proved to be an effective screening tool, because too few homozygous individuals have elevated levels before clinical disease develops. Identifying a homozygous individual warrants investigating his or her siblings, because 25% of siblings are expected to be homozygous for the disease as well.
Figure 4 (a) A percutaneous liver biopsy specimen was taken from a 30-year-old woman with hepatosplenomegaly and amenorrhea of 6 months’ duration. Pigment both in hepatic parenchymal cells (thick arrow) and in bile duct cells (thin arrow) is apparent. (b) Higher-magnification iron stain of the specimen confirms that the pigment is iron both in parenchymal cells (thick arrow) and in bile duct cells (thin arrow). The woman, who also had hemochromatosis, required removal of 72 units of blood over 1.5 years to render her liver free of excess iron.
An elevated serum iron or serum ferritin level is not diagnostic, because these values can be raised in a wide variety of liver diseases marked by hepatic cell death. An elevated serum iron or ferritin level is not uncommon in decompensated alcoholic liver disease, acute viral hepatitis, or chronic active hepatitis. The widely accepted criteria for the diagnosis of iron overload caused by hereditary hemochromatosis include
Liver biopsy
The characteristic finding on liver biopsy is a heavy deposit of hemosiderin granules in hepatocytes and bile duct cells. Fibrosis may range from minimal to well-established cirrhosis. At times, hereditary hemochromatosis is difficult to distinguish from cirrhosis with secondary iron overload. A preponderance of parenchymal iron relative to the amount of scar tissue and the presence of iron in the bile duct cells characterize hereditary hemochromatosis. Iron overload secondary to underlying cirrhosis is usually associated with advanced cirrhosis, relatively less stainable iron, and absence of iron in the bile ducts. When excess hepatic iron derives from an exogenous source, such as a series of massive transfusions for chronic hemolytic anemia, iron is prominent in the Kupffer cells. When the morphologic features of the liver biopsy do not clearly distinguish between hereditary hemochromatosis and secondary iron overload, quantitative analysis of the hepatic iron content may prove he lpful. Patients with hemochromatosis typically have quantitative hepatic iron values ranging from 200 to 800 μmol/g dry weight (normal, < 35 μmol/g), whereas patients with alcoholic siderosis have hepatic iron content ranging from 40 to 100 μmol/g. Another useful diagnostic test for hemochromatosis is calculation of the hepatic iron index; this value is usually greater than
Treatment
Early detection and treatment of patients with hereditary hemochromatosis is essential. The usual therapy is removal of the excess iron by weekly phlebotomy. Because each pint of blood contains 250 mg of iron, removal of
Primary biliary cirrhosis may be indistinguishable from chronic hepatitis on liver biopsy. Characteristic hyperpigmentation, pruritus, marked elevation of serum alkaline phosphatase, and high titers of antimitochondrial antibody (AMA) (> 1:160) are helpful in making the differential diagnosis.
Primary Sclerosing Cholangitis
Primary sclerosing (skluh-ROHS-ing) cholangitis (koh-lan-JIE-tis) is a disease of the bile ducts in your liver. The term “cholangitis” in primary sclerosing cholangitis refers to inflammation of the bile ducts, while the term “sclerosing” describes the hardening and scarring of the bile ducts that result from chronic inflammation.
Primary sclerosing cholangitis is a progressive disease that leads to liver damage and, eventually, liver failure. Liver transplant is the only known cure for primary sclerosing cholangitis, but transplant is typically reserved for people with severe liver damage.
Researchers continue looking for treatments to slow or reverse bile duct damage caused by primary sclerosing cholangitis. But until a treatment is found, doctors care for people with primary sclerosing cholangitis by reducing signs and symptoms of complications.
Figure Proposed pathogenesis of primary sclerosing cholangitis
Factors that may increase the risk of primary sclerosing cholangitis include:
age. Primary sclerosing cholangitis can occur at any age, but it’s most commonly diagnosed in people ages 25 to 45.
sex. Primary sclerosing cholangitis occurs more often in men than it does in women.
Inflammatory bowel disease. The great majority of people with primary sclerosing cholangitis also have inflammatory bowel disease, which includes ulcerative colitis and Crohn’s disease. Still, primary sclerosing cholangitis is rare among people with inflammatory bowel disease, and most won’t develop primary sclerosing cholangitis. It’s not clear why these diseases occur together. If you’ve been diagnosed with primary sclerosing cholangitis, your doctor may recommend testing for inflammatory bowel disease, even if you have no signs or symptoms.
Signs and symptoms of primary sclerosing cholangitis include:
· Abdominal pain
· Chills
· Diarrhea
· Fatigue
· Fever
· Itchiness
· Weight loss
· Yellowing of your eyes and skin (jaundice)
Primary sclerosing cholangitis may not cause any symptoms in its early stages. In some cases, the only indication of this disorder may be abnormal blood tests suggesting that your liver isn’t functioning well.
Diagnosed primary sclerosing cholangitis include:
Liver function blood tests. A blood test to check your liver function, including levels of your liver enzymes, can give your doctor clues about your diagnosis.
X-rays of bile ducts. Injecting a dye into your bile ducts helps make them visible on an X-ray. To inject the dye, your doctor may recommend endoscopic retrograde cholangiopancreatography. During this procedure, your doctor guides a flexible tube down your throat and through your stomach to the area of your small intestine where your bile ducts empty. Using the tube and special tools, your doctor injects dye into the bile ducts.
MRI of bile ducts. Magnetic resonance cholangiopancreatography uses magnetic resonance imaging (MRI) to make images of your liver and bile ducts.
MR Imaging of sclerosing cholangitis
Magnetic resonance cholangiopancreatography shows a normal-sized common bile duct, but strictures of both the left and right ducts are noted as well as a dilated proximal left hepatic duct.
Intrahepatic bile duct changes demonstrated on CT scans reflect cholangiography features with pruning and beading of the ducts. Pruning on CT scans is defined as the presence on a single CT slice of a 4-cm or longer segment of dilated duct (excluding the main right and left ducts) that lacks the expected side branching. Beading is defined as at least 3 closely alternating regions of change in caliber in an intrahepatic duct on a single CT slice.
Skip dilatations, defined as isolated dilated peripheral bile ducts with no visible connection to the other dilated ducts on contiguous images, are strongly suggestive of PSC.
CT appearances of extrahepatic bile duct involvement by PSC include focal or diffuse eccentric or concentric involvement and wall thickening (>
Contrast enhancement of the bile duct is a nonspecific finding that can be observed in normal and abnormal bile ducts.
As many as 65% of patients with PSC may have benign celiac, gastrohepatic ligament, porta hepatis, periaortic, pancreaticoduodenal, and mesenteric lymphadenopathy.
Lymph nodes are usually homogeneous and isodense with the pancreas.
Ultrasonography (US) is the initial examination modality of choice in patients presenting with jaundice and right upper quadrant pain. The liver may demonstrate nonspecific abnormalities on US, which infrequently leads to definitive diagnosis. The primary role of US is in helping clinicians make the diagnosis of other bile duct mechanical obstructions, such as gallstones and neoplasia.
Ultrasound of Cholangitis
Plain radiographs have little role to play in the diagnosis of PSC. Cholangiography in PSC is performed using either PTC or ERCP. ERCP is preferable because of its higher success rate in the absence of dilated intrahepatic bile ducts.
Endoscopic retrograde cholangiopancreatography performed in a patient with abnormal liver function test results shows multiple intrahepatic bile duct strictures and beading
Double-contrast barium enema shows filiform polyps and an ahaustral colon resulting from ulcerative colitis.
Testing a sample of liver tissue. A liver biopsy is a procedure to remove a piece of liver tissue for laboratory testing. Your doctor inserts a needle through your skin and into your liver to extract a tissue sample. Liver biopsy can help determine the extent of damage to your liver.
Treatment
Treatments for primary sclerosing cholangitis focus on reducing signs and symptoms of the disease as it progresses. Primary sclerosing cholangitis progresses slowly, but it usually ends in liver failure and the need for a liver transplant. Many medications have been studied in people with primary sclerosing cholangitis, but so far none has been proved to slow or reverse the liver damage associated with this disease.
Treatment for itching
Medications that may help control itching include:
Antihistamines, such as diphenhydramine (Benadryl, others)
Bile-acid-binding drugs, such as cholestyramine (Locholest, Questran, others)
Treatment for infections
Bacterial infections can occur frequently in people with primary sclerosing cholangitis. Antibiotics may be prescribed to treat an infection. If you’ve had repeated infections, your doctor may recommend antibiotics before procedures that are likely to cause infection, such as endoscopic procedures or surgery.
Treatment for malnutrition
Primary sclerosing cholangitis makes it difficult for your body to absorb certain vitamins. Even though you may eat a healthy diet, you may find that you can’t get all the nutrients you need. Your doctor may recommend vitamin supplements that you take as tablets or that you receive as an infusion through a vein in your arm.
Treatment for bile duct blockages
Blockages that occur in your bile ducts can be treated with:
Balloon dilation and stent placement. These procedures can open blockages in the larger bile ducts. Balloon dilation is a procedure in which your doctor runs a slender tube with an inflatable balloon at its tip (balloon catheter) through an endoscope and into a blocked bile duct. Once the balloon catheter is in place, the balloon is inflated. Small plastic tubes called stents may be placed in bile ducts to keep them open.
Bile duct surgery. In certain situations, blockages in bile ducts may need to be removed surgically. After removing a blockage, the surgeon connects the remaining portions of bile duct so that bile can still flow through the duct.
Liver transplant
A liver transplant is the only treatment known to cure primary sclerosing cholangitis. During a liver transplant, surgeons remove your diseased liver and replace it with a healthy liver from a donor. Liver transplant is reserved for people with liver failure or other severe complications of primary sclerosing cholangitis. Though uncommon, it’s possible for primary sclerosing cholangitis to recur after a liver transplant.
Drug-Induced Chronic Hepatitis
The liver helps the body break down certain medicines. These include some drugs that you buy over-the-counter or your health care provider prescribes for you. However, the process is slower in some people. This can make you more likely to get liver damage.
Some drugs can cause hepatitis with small doses, even if the liver breakdown system is normal. Large doses of many medications can damage a normal liver.
Many different drugs can cause drug-induced hepatitis.
Painkillers and fever reducers that contain acetaminophen are a common cause of liver inflammation. These medications can damage the liver when taken in doses that are not much greater than the recommended dose. People who already have liver disease are most likely to have this problem.
Nonsteroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen and naproxen, may also cause drug-induced hepatitis.
Drug-induced chronic hepatitis constitutes a small but important category of chronic hepatitis.3 Methyldopa, trazodone, and isoniazid are well-recognized causes. In addition, cases have occasionally been reported after therapy with sulfonamides, propylthiouracil, nitrofurantoin, acetaminophen, aspirin, and dantrolene; other drugs are also likely to be implicated. Thus, it is reasonable to discontinue as many medications as possible when chronic hepatitis is first diagnosed. If a patient’s hepatitis is drug related, liver function abnormalities and the clinical course of disease frequently improve after the causative agent has been withdrawn.
Wilson Disease
When neurologic abnormalities are absent, Wilson disease mimics chronic hepatitis. It is critical to establish the diagnosis of Wilson disease, because specific treatment with penicillamine, trientine, or zinc is available. Measurement of the hepatic copper content in a needle biopsy specimen is definitive. If a biopsy specimen is not available, the serum ceruloplasmin and 24-hour urinary copper levels should be obtained and slitlamp examination for Kayser-Fleischer rings performed in all patients younger than 35 years for whom the cause of chronic hepatitis remains obscure after the usual testing. If the results of all three tests are normal, Wilson disease is virtually excluded.
Wilson disease, or hepatolenticular degeneration, is an autosomal recessive disorder found in about one in 30,000 to 50,000 persons, with a gene frequency of 1:90 to 1:15
Etiology and Genetics
The genetic defect for Wilson disease is located on chromosome 13, where disease-specific mutations in a gene that codes for a copper-binding P-type adenosine triphosphatase protein have been identified. In this disorder, the excretion of copper into the bile appears to be defective, leading to an accumulation of excess copper in most body tissues. The incorporation of copper into ceruloplasmin is also impaired.
Diagnosis
Clinical features By 15 years of age, affected persons have usually experienced symptoms caused by either neurologic or hepatic dysfunction. Although Wilson disease occasionally presents for the first time in persons as old as 30 years, this late an onset is the distinct exception. In about 40% of patients, the first manifestations of the disease are symptoms related to hepatic dysfunction. The hepatic disease is usually a chronic disorder manifested by fatigue, jaundice, spider nevi, ascites, edema, splenomegaly, and variceal hemorrhage. Associated hemolytic anemia is a clue to the diagnosis. Occasionally, the liver disease mimics severe acute hepatitis and progresses to death in a few days to weeks. Neurologic symptoms include tremors, rigidity, gait disturbances and clumsiness, slurring of speech, and personality changes. The pathognomonic sign is the Kayser-Fleischer ring, a thin, brown crescent of pigmentation at the periphery of the cornea. Although this feature is usually circumferential, it may be located only superiorly and inferiorly. Early in the disease, a slitlamp examination may be required to identify the telltale ring. It may be particularly difficult to detect on routine eye examination in brown-eyed patients.
Laboratory tests
On first examination, at least 50% of patients have hepatosplenomegaly and moderate liver function abnormality. Two distinguishing laboratory findings are depression or absence of serum ceruloplasmin and an increase of urinary copper levels from a normal value of less than 50 mg/day to as high as 1,000 mg/day. In a small percentage of patients with Wilson disease, serum ceruloplasmin or urinary copper levels may be normal, and Kayser-Fleischer rings may be absent. Hence, it is wise to evaluate all three of these factors because it is likely that at least one will be abnormal. In problematic cases, finding excess urinary copper after the administration of 1,000 mg of penicillamine may also help establish the diagnosis.29 If doubt persists, the ultimate standard is an increase in hepatic tissue copper concentration; however, this finding is conclusive only if the patient does not have long-standing cholestasis, which can also increase the hepatic copper concentration.
Treatment
Treatment of Wilson disease requires the administration of either trientine or penicillamine, chelating agents that bind copper and promote the urinary excretion of 1,000 to 3,000 mg of copper a day. The usual dosage for either drug is 1 g/day. Clinical improvement generally parallels depletion of the tissue copper buildup. Trientine has become the preferred drug because penicillamine therapy is associated with significant side effects— most commonly, nausea and abdominal discomfort immediately after taking the medication. More serious side effects of penicillamine include leukopenia and thrombocytopenia, which may, in a rare case, lead to aplastic anemia. A small percentage of patients experience the nephrotic syndrome. All patients with Wilson disease should be followed closely with routine urinalyses and blood counts, particularly during the first few months of therapy. Because penicillamine is a pyridoxine antagonist, 50 mg of pyridoxine should be given once a week. If trientine and penicillamine cannot be tolerated, oral zinc therapy should be considered. Elemental zinc may be administered in the form of zinc acetate in three divided doses on an empty stomach for a total daily dose of 150 mg. Zinc therapy increases fecal copper loss and induces a negative copper balance in patients with Wilson disease.30 The onset of action is delayed, however, and the longterm efficacy of zinc therapy is unknown.
α1-Antitrypsin Deficiency
Homozygous α 1-antitrypsin deficiency is associated with a rare syndrome of progressive cirrhosis.2 Although originally described in children with juvenile cirrhosis, the combination of α 1-antitrypsin deficiency and cirrhosis has been reported in adults. Adult patients usually have accompanying emphysema. The diagnosis of α 1-antitrypsin deficiency should always be considered in cases in which the cirrhosis does not have an obvious antecedent. On first presentation, most patients have moderate hepatomegaly and mild abnormality of liver function. Absence of α 1-antitrypsin globulin on protein electrophoresis makes the diagnosis very likely. Specific measurements of α 1-antitrypsin levels in the
Figure 1 (a) Nodules of liver tissue surrounded by scar tissue—a feature of cirrhosis—are seen in a surgical liver biopsy specimen from a 67-year-old man with emphysema and mild hepatomegaly. (b) In a higher-magnification view of the specimen, multiple, round, hepatic cell inclusion bodies (arrows) are distinctive for á1-antitrypsin globulin deficiency.
blood confirm the diagnosis. Genetic variants have been found, reflecting the existence of more than 75 different alleles for the gene that controls production of á1-antitrypsin. Protease inhibitor type ZZ (PiZZ) is the genotype generally associated with cirrhosis and emphysema. An amino acid substitution in the Z variant protein allows the α1-antitrypsin protein molecules to polymerize within the liver cell, thereby impairing excretion of the protein from the liver. Characteristic periodic acid–Schiff positive (diastase- resistant) inclusion bodies containing abnormal α1-antitrypsin globulin can be seen in the hepatocytes Individuals carrying a single PiZ allele may also be at risk for cirrhosis and liver failure.33 A significant proportion of patients homozygous for PiZZ who also have chronic liver disease show evidence of hepatitis B or hepatitis C infection. The most important treatment for α1-antitrypsin deficiency is avoidance of cigarette smoking, which markedly accelerates coexistent lung disease. There is no specific treatment for liver disease associated with α1-antitrypsin deficiency, and thus, therapy is supportive and includes avoidance of alcohol. Augmentation therapy to increase the circulating levels of α1-antitrypsin is used to treat emphysema but not liver disease in patients with antitrypsin deficiency. Patients with end-stage liver disease and liver failure caused by α1-antitrypsin deficiency are candidates for liver transplantation, and long-term survival is excellent.
Autoimmune Hepatitis
The wide spectrum of clinical and immunoserologic manifestations of autoimmune hepatitis has led investigators to characterize types of the disease4,5 [see Tables 1 and 3]. Three types have been described, but only types 1 and 2 have sufficiently distinct features to warrant formal recognition. Whether patients with type 3 autoimmune hepatitis are truly a distinct subpopulation remains uncertain.
type 1 autoimmune hepatitis
Type 1, or classic, autoimmune hepatitis is the most common form of the disease in the United States.4,5 It is characterized by hypergammaglobulinemia; the presence of antinuclear antibody (ANA), anti–smooth muscle antibody (ASMA), or both; and a bimodal age at onset (adolescence and around late middle age). In type 1 autoimmune hepatitis, aminotransferase levels are three to 10 times higher thaormal, and the á-globulin level is increased more than twofold. The presentation may be acute or subacute but is more commonly chronic. Other autoimmune diseases may be present concurrently, and associations between type 1 autoimmune hepatitis and the presence of human leukocyte antigen profiles have been identified. Liver biopsy is a useful prognostic tool because patients with portal or mild periportal hepatitis have a benign course, whereas those with bridging or multilobular necrosis or cirrhosis are at high risk for progressive liver disease. Patients with severe disease who are treated with corticosteroids have a 10-year survival rate of 60% to 70%, whereas untreated patients have a survival rate of less than 30%.
type 2 autoimmune hepatitis
Type 2 autoimmune hepatitis [see Tables 1 and 3] is characterized by the absence of ANA and ASMA and by the presence of antibody to liver/kidney microsome type 1 (anti-LKM1). The target antigen of type 2 autoimmune hepatitis is P-450 IID6. Anti-LKM1 and AMA reactivity may be difficult to distinguish on immunofluorescence, especially in cases of strong reactivity, and patients with anti-LKM1 may be falsely positive for AMA, which suggests the incorrect diagnosis of primary biliary cirrhosis.
Type 2 autoimmune hepatitis appears to be much less common than type 1 and has been observed primarily in Europe. It appears to be predominant in children and is frequently associated with other autoimmune diseases. The onset of type 2 autoimmune hepatitis is often acute and may be associated with liver failure, and there is a propensity for the disease to progress rapidly to cirrhosis.
type 3 autoimmune hepatitis
Type 3 autoimmune hepatitis is the most recently encountered and least established type of autoimmune hepatitis. It is characterized by the presence of antibody to a soluble liver antigen (anti-SLA), to a recently characterized liver/pancreas antigen (anti-LP), or to both. Approximately one third of patients also are positive for ASMA, AMA, or both. The presence of anti-SLA or anti-LP antibody identifies this small group of patients with autoimmune hepatitis and serves to distinguish them from patients who have chronic hepatitis of an indeterminate viral cause or an unclassified, truly cryptogenic variety of disease.
DIFFERENTIAL DIAGNOSIS
Occasionally, physicians have difficulty distinguishing between type 1 or 2 autoimmune hepatitis and chronic hepatitis C. The distinction is important because autoimmune hepatitis responds to immunosuppressive drugs but may be exacerbated by treatment with interferon. Enzyme-linked immunosorbent assay (ELISA) for antibody to HCV (anti-HCV) may be reactive in patients with untreated type 1 autoimmune hepatitis, but HCV infection can be excluded iearly all of these patients by the findings of a negative result for anti-HCV on second-generation recombinant immunoblot assay (RIBA) and absent serum HCV RNA. The false positive anti-HCV test result is associated with the hypergammaglobulinemia of autoimmune disease. The distinction between chronic hepatitis C and type 1 autoimmune hepatitis may be further confused by the finding that ANA is present in some patients with HCV infection; however, the ANA titer in patients with chronic hepatitis C is typically lower (i.e., ≤ 1:160), and significant hypergammaglobulinemia is not present. Although it has been speculated that HCV infection might induce the development of autoimmune markers or disease, this hypothesis remains unproved.
More of a problem is the observation that anti-LKM1 is found in some patients with chronic HCV infection, which causes diagnostic confusion between type 2 autoimmune hepatitis and chronic hepatitis C.6 Worldwide, the prevalence of markers of HCV infection in patients with detectable anti- LKM1 varies widely—from 0% to more than 80%. Conversely, the prevalence of anti-LKM1 in patients with chronic hepatitis C varies from 0% to 5%. Anti-LKM1–positive, anti-HCV–positive serum reacts significantly less often with P-450 IID6, the target of anti-LKM1, than does anti-LKM1–positive, anti- HCV–negative serum. In particular, serum from patients with type 2 autoimmune hepatitis reacts with a linear epitope contained within P-450 IID6, whereas serum from patients with HCV markers and anti-LKM1 does not. Moreover, anti-GOR, an antibody to GOR protein found in patients with HCV infection, is frequently present in anti-LKM1–positive patients who are positive for anti-HCV but is absent in those who are negative for anti-HCV. Thus, in some patients, HCV seems to induce autoimmunity to both GOR and LKM1.
These findings support the division of type 2 autoimmune hepatitis into two subtypes [see Tables 1 and 4].
TREATMENT
Immunosuppressive Therapy
Most patients who have the clinical, biochemical, and histologic features of type 1 autoimmune hepatitis should be treated with corticosteroids.2,4 Patients with type 2a or type 3 autoimmune hepatitis are treated in a similar fashion. The usual regimen consists of prednisone (15 to 20 mg/day). Although 10% to 20% of patients do not show improvement with this regimen, some show improvement with higher corticosteroid dosages (approximately 60 mg/day). A combination of prednisone at a lower dosage (5 to 10 mg/day) and azathioprine (50 to 100 mg/day) may be given to patients who experience intolerable side effects from prednisone. Azathioprine alone will not induce remission, but long-term therapy is effective in maintaining remission and sparing the use of corticosteroids. Clinical, biochemical, and histologic remission occurs in 65% of patients within 18 months to 2 years after treatment. In general, symptoms are reduced within 3 months, liver chemistry test results improve within 3 to 6 months, and histologic resolution occurs within 18 months to 2 years. The presence of serum autoimmune markers, such as ANA, does not appreciably influence the initial response to corticosteroids in patients with autoimmune hepatitis.
Complications of treatment.
Corticosteroid treatment is not without risk. Obesity, cushingoid facies, acne, or striae develop within 2 years in at least 80% of patients. When treatment is continued for longer than 18 months, one or more severe complications (e.g., diabetes, hypertension, cataracts, psychosis, infections, or osteoporosis with vertebral collapse) develop in more than 50% of patients. The risk of complications increases with the duration of treatment. In addition, azathioprine may cause severe bone marrow depression or pancreatitis.
Contraindications for treatment
Not all patients with presumed autoimmune hepatitis should be treated with immunosuppressive drugs. Treatment of elderly patients should be considered very carefully because serious side effects are likely to occur. Patients with advanced cirrhosis and relatively modest abnormalities in serum aminotransferase levels (< 100 IU/L) are also not good candidates; in such patients, severe fibrosis does not resolve, the sequelae of portal hypertension cannot be prevented, and the hepatitis component (against which the anti-inflammatory effect of the corticosteroids is most effective) is not marked. Finally, the benefit of treatment of asymptomatic patients is also questionable. These patients already functioormally, their disease appears to progress slowly, and the risk associated with long-term therapy is substantial.
Overlap Syndromes
In hepatology, the term overlap syndrome describes variant forms of the major hepatobiliary autoimmune diseases, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Patients with overlap syndromes present with both hepatitic and cholestatic biochemical and histological features of AIH, PBC, and/or PSC, and usually show a progressive course toward liver cirrhosis and liver failure without adequate treatment. AIH-PBC overlap syndromes have been reported in almost 10% of adults with AIH or PBC, whereas AIH-PSC overlap syndromes were found in 6 to 8% of children, adolescents, and young adults with AIH or PSC. A minority of patients may also show transition from stable PBC to AIH, AIH to PBC, or AIH to PSC, as documented by single case reports and small case series. Single cases of AIH and autoimmune cholangitis (antimitochondrial antibody-negative PBC) overlap have also been reported. Empiric medical treatment of AIH-PBC and AIH-PSC overlap syndromes includes anticholestatic therapy with ursodeoxycholic acid and immunosuppressive therapy with corticosteroids and azathioprine. In end-stage disease, liver transplantation is the treatment of choice
The term overlap syndrome has been adopted by hepatologists to describe variant forms of autoimmune hepatitis (AIH) that present with characteristics of AIH and primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC). It remains unclear whether these overlap syndromes form distinct entities or are only variants of the major autoimmune hepatopathies. Standardization of diagnostic criteria for overlap syndromes has not been achieved so far, and misuse of the term overlap syndrome is common in clinical practice.
A careful data analysis revealed that variant forms of AIH form a considerable fraction of autoimmune liver diseases. In addition to AIH-PBC and AIH-PSC overlap syndromes, the outlier syndrome autoimmune cholangitis (AIC), today mainly regarded as antimitochondrial antibody [AMA]-negative PBC, has been a matter of debate. Overlap of AIC and AIH has also been reported. Whether overlap between PBC and PSC exists remains unclear. Transitions from one to another autoimmune hepatopathy (e.g., from PBC to AIH and from AIH to PSC) have also been reported and are discussed here together with the respective overlap syndromes. The term overlap syndrome appears to be misused when characteristic features of an autoimmune hepatopathy are detected together with those of a second liver disease (e.g., chronic hepatitis C).
This article is an extension of a recent review and includes a series of case reports that may illustrate typical features of different overlap syndromes. It summarizes current views on overlap syndromes and the outlier syndrome AIC, and also discusses several controversial issues in this field.
A diagnosis of AIH, PBC, or PSC in a patient with liver disease always requires careful exclusion of other major causes of liver damage, including alcoholic, viral, drug- and toxin-induced, hereditary metabolic, and nonalcoholic fatty liver disease. The diagnosis of AIH, PBC, and PSC is then based on clinical, biochemical, histopathological, and cholangiographic findings. None of these findings alone is diagnostic, and most criteria are of limited sensitivity and specificity for the diseases under discussion. Thus, a diagnosis of AIH, PBC, or PSC requires a pattern of characteristic, although not highly specific features (Table 1]
|
Clinical, Biochemical, Histologic, and Cholangiographic Criteria of Autoimmune Liver Diseases* |
||||
|
Criteria |
AIH |
PBC |
PSC |
AIC |
|
Female: male |
4:1 |
9:1 |
1:2 |
9:1 |
|
Predominant serum liver test elevation |
ALT, AST |
ALP, γ-GT |
ALP, γ-GT |
ALP, γ-GT |
|
Serum Ig elevation |
IgG |
IgM |
IgG, IgM |
IgM |
|
Autoantibodies |
ANA, ASMA, LKM, |
AMA, AMA-M2 |
pANCA |
ANA, ASMA |
|
HLA association |
A3, B8, DR3, DR4 |
DR8 |
DR52 |
B8, DR3, DR4 |
|
Histology |
Lymphocytic interface hepatitis (moderate/severe) |
Florid bile duct lesion |
Fibrosing bile duct lesion |
Florid bile duct lesion |
|
Diagnosis |
AIH score > 15 |
AMA-M2, cholestatic serum enzyme pattern, compatible histology |
Bile duct stenoses/dilatations (cholangiography), cholestatic serum enzyme pattern, inflammatory bowel disease, pANCA |
Cholestatic serum enzyme pattern, AMA negative, ANA or ASMA positive, histology compatible with PBC |
|
First-line medical therapy |
Corticosteroids + azathioprine |
UDCA |
UDCA |
UDCA |
AIH, autoimmune hepatitis; PBC, primary biliary cirrhosis; PSC, primary sclerosing cholangitis; AIC, autoimmune cholangitis; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALP, alkaline phosphatase; γ–GT, gamma–glutamyl transferase; IgG, immunoglobulin G; ANA, antinuclear antibody; ASMA, anti–smooth muscle antibodies; HLA, histocompatibility leucocyte antigen; AMA, antimitochondrial antibody; LKM, anti–liver–kidney microsomal antibodies; SLA, anti–soluble liver antigen; pANCA, perinuclear antineutrophil cytoplasmic antibodies; UDCA, ursodeoxycholic acid.
Overlap syndromes show characteristics of both autoimmune hepatitis (AIH) and primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), or autoimmune cholangitis (AIC). (From Beuers U. Hepatic overlap syndromes. J Hepatol 2005;42(suppl 1):S93-S99).
Criteria for the diagnosis of PBC include (1) a cholestatic serum enzyme pattern, (2) elevated serum IgM, (3) the presence of AMAs detected by immunofluorescence (> 1:40) or PBC-specific AMA-M2 directed against the E2 subunit of the pyruvate dehydrogenase complex and detected by enzyme-linked immunosorbent assay or immunoblotting, and (4) a florid bile duct lesion of mid-sized intrahepatic bile ducts and bile duct paucity. The cholestatic serum enzyme pattern, serum AMAs, and a compatible histology (Table 1) are regarded as mandatory for the diagnosis of PBC. A granulomatous cholangitis is not specific for PBC and is only observed in fewer than one third of biopsies from PBC patients. PBC frequently is associated with other autoimmune disorders, such as Sjögren syndrome, Hashimoto thyroiditis, and celiac disease.
Overlap syndrome autoimmune hepatitis-primary biliary cirrhosis. A 57-year-old woman presented with elevated γ-GT (2 × ULN) and transaminases (AST 2.5 × ULN, ALT 5.5 × ULN), and normal bilirubin. Serum AMA (1:3840), AMA-M2,ASMA and
Therapy.
When coexistence of AIH and chronic hepatitis C is assumed, treatment should be adapted to three groups of patients: (1) patients with true AIH and a false-positive anti-HCV test should be treated with immunosuppressive drugs; (2) patients with true chronic hepatitis C and autoantibodies at low titers, but no other signs of AIH, should undergo antiviral treatment (e.g., pegylated interferon and ribavirin); and (3) patients with true chronic hepatitis C and clear signs of AIH including young age, female gender, high autoantibody titers (ANA, SMA, LKM1) ≥ 1:320, hypergammaglobulinemia, and a history of extrahepatic autoimmune disorders, should first be treated with an immunosuppressive regimen under careful control of clinical and biochemical features.
Chronic Hepatitis B
Hepatitis B is irritation and swelling (inflammation) of the liver due to infection with the hepatitis B virus (HBV).
Other types of viral hepatitis include:
Causes
Hepatitis B infection is caused by the hepatitis B virus (HBV).You can catch hepatitis B through contact with the blood or body fluids (such as semen, vaginal fluids, and saliva) of a person who has the virus.
Exposure may occur:
After a needle stick or sharps injury
If any blood or other body fluid touches your skin, eyes or mouth
People who may be at risk of hepatitis B are those who:
Have unprotected sex with an infected partner
Receive blood transfusions (not common in the
Have contact with blood at work (such as health care workers)
Have been on long-term kidney dialysis
Get a tattoo or acupuncture with uncleaeedles
Share needles during drug use
Share personal items (such as toothbrush, razor, and nail clippers) with a person who has the virus
Were born to a hepatitis-B infected mother
Epidemiology
Chronic hepatitis B is a major global health care problem: 5% of the world’s population, or approximately 300 million persons, are chronic carriers.9 In the United States, 300,000 new cases of acute disease are reported to the Centers for Disease Control and Prevention (CDC) each year; 5% of these patients, or 15,000 persons, become new chronic carriers. The prevalence of hepatitis B surface antigen (HBsAg) carriers in the United States is 0.2% to 0.5% of the general population; approximately 1.25 million persons have chronic HBV infection. However, carrier rates five to 10 times higher have been identified among certain groups, including Asian Americans, persons who have received multiple blood transfusions or hemodialysis, intravenous drug users, homosexual men, and patients with AIDS. In addition, carrier rates of 5% to 20% have been recognized in certain populations in some states, such as Alaska and Hawaii.
DIAGNOSIS
Chronic hepatitis B can be reliably diagnosed with serologic testing [see Table 1]. In patients with chronic HBV infection, HBsAg remains detectable for more than 6 months. After 6 months, HBsAg clears spontaneously in 1% to 2% of patients each year. Persons who continue to test positive for HBsAg, are asymptomatic, and have normal aminotransferase levels are termed HBsAg carriers. Other chronically infected, HBsAg-positive individuals may have clinical or laboratory evidence of chronic hepatic disease (i.e., elevated aminotransferase levels) and are given a diagnosis of chronic hepatitis B.
NATURAL HISTORY
Chronic HBV infection can be divided into two phases. The first phase is a highly infectious, active replicative phase characterized by high levels of circulating virions; the presence of circulating HBV DNA, DNA polymerase, and hepatitis B e antigen (HBeAg); and the presence of free, episomal DNA in hepatocytes. The second phase is a minimally infectious, low replicative phase characterized by few circulating virions; undetectable levels of circulating HBV DNA, DNA polymerase, and HBeAg; the presence of circulating antibody to HBeAg (anti-HBe); and the presence of integrated HBV DNA in hepatocytes. Age at the time of initial HBV infection is the major determinant of chronicity. Although as many as 90% of infected neonates become carriers, the carrier rate falls with increasing age at the time of infection, so that only 3% to 5% of newly infected adults fail to clear HBsAg. Another important risk factor for chronicity is the presence of intrinsic or iatrogenic immunosuppression. Gender is also a well-established but poorly understood determinant of chronicity; women are more likely than men to clear HBsAg. As a result, men predominate in all populations of HBsAg carriers. In some patients with chronic HBV infection who have lost previous markers of HBV replication (e.g., HBV DNA and HBeAg), biochemical, clinical, and histologic exacerbations that mimic acute hepatitis have beeoted. These exacerbations, termed reactivation, appear spontaneously but also have been reported in oncology patients after withdrawal of chemotherapy. Reactivation appears to be a consequence of increased HBV replication because HBV DNA, DNA polymerase, and HBeAg usually reappear in the serum concurrently with elevation of the ALT level. Persistent HBV infection is an important risk factor for the development of hepatocellular carcinoma, the most prevalent nondermatologic carcinoma in the world. In Taiwan, the relative risk of hepatocellular carcinoma is about 200 times higher in carriers of HBV than ioncarriers.9 In addition, very high risk areas for hepatocellular carcinoma have been identified in sub-Saharan Africa and Asia, where a strong correlation between hepatocellular carcinoma rates and HBV carrier rates has been recognized. Several lines of evidence suggest that the use of screening tests, including ultrasonography and serum α-fetoprotein, may be useful in the early diagnosis of hepatocellular carcinoma, which can then be treated.
TREATMENT
The ultimate goal of treatment of chronic hepatitis B is to eradicate HBV infection and prevent the development of cirrhosis or hepatocellular carcinoma.9,11 Although currently available therapies, such as interferon and lamivudine, have not been proved to achieve these goals, they can suppress HBV replication and lead to improvement in the clinical, biochemical, and histologic features of chronic hepatitis B.
Interferon Therapy
A large number of trials have demonstrated the efficacy of interferon alfa-2b in the treatment of HBV DNA–positive, HBeAg-positive chronic hepatitis B. The dosage is 30 to 35 million U/wk (subcutaneously or intramuscularly for 4 months) given as 5 million U/day or 10 million units three times weekly. Treatment results in loss of HBV replication (loss of HBeAg and HBV DNA) in 40% of patients and loss of HBsAg in approximately 10%. Predictors of a response to interferon include an HBV DNA level of lower than 100 pg/ml, an ALT level higher than 200 IU/L, a short duration of infection, heterosexual orientation, and female gender. Studies show that after several years, as many as 60% of patients who responded to interferon lose HBsAg, and many of these persons develop antibody to HBsAg (anti-HBs).
Fortunately, relapse with reappearance of HBeAg is very unusual. In a meta-analysis of interferon trials, loss of viral markers of replication and normalization of the ALT level occurred about 20% more often in treated patients than in control subjects. Moreover, interferon has also been shown to prolong life and lower treatment costs for patients with chronic hepatitis B who have detectable HBeAg. It should be noted that interferon is considerably less effective in Chinese patients with chronic hepatitis B than in white patients, with sustained loss of HBeAg occurring in only 15% of Chinese patients. However, Chinese patients with an elevated ALT level have a response rate similar to that of whites, whereas Chinese patients with a normal ALT level (and probable immune tolerance to HBV) respond poorly.
Most patients who have anti-HBe have inactive liver disease and are therefore unlikely to benefit from interferon. An exception, however, is the subgroup of anti-HBe–positive patients who harbor a precore mutant, recognized by the absence of HBeAg but the presence of HBV DNA in high concentrations.
These patients experience a good response to interferon, although the relapse rate is high.Finally, patients with mildly decompensated cirrhosis can be treated with low, titrated doses of interferon. One third of such patients will respond and have a sustained loss of HBV DNA and HBeAg that is associated with resolution of the symptoms of cirrhosis. These patients must be monitored closely, however, because bacterial infections and exacerbation of hepatitis are common, serious complications.
Interferon and corticosteroid combination therapy
Because studies found that corticosteroid withdrawal was frequently associated with a flare in liver disease and spontaneous clearance of HBeAg, trials were initiated to evaluate the role of a short course of corticosteroids in enhancing the effectiveness of interferon in patients with chronic HBV infection. The majority of studies have showo difference between use of corticosteroid priming followed by interferon and use of interferon alone in the treatment of patients with chronic hepatitis B.Therefore, the combination of prednisone and interferon is generally not used, although this combination may increase HBeAg loss in patients who have a low ALT level (< 100 IU/L).
Side effects of interferon therapy
influenzalike symptoms (fever, myalgia, arthralgia, and headache),
hematologic toxicity (granulocytopenia, leukopenia, and thrombocytopenia),
systemic symptoms (fatigue and hair loss),
neurologic signs (decreased concentration, depression, and irritability),
and immune system disorders (development of autoantibodies, thyroid disease, or other autoimmune diseases)
Contraindications to interferon therapy:
hypersensitivity to interferon
decompensated cirrhosis
immunosuppression associated with organ transplantation
active autoimmune disease
significant psychiatric disease, including depression
Lamivudine Therapy
Lamivudine, a nucleoside analogue that inhibits viral DNA synthesis, was approved in late 1998 for the treatment of chronic hepatitis B. A dose of 100 mg/day achieves maximal suppression of HBV DNA. Lamivudine is readily absorbed from the gastrointestinal tract and may be taken with or without food. Lamivudine is cleared mainly in urine, and thus, dose adjustments are required for patients with significant renal failure. In three placebo-controlled studies, improved liver histology occurred in a significantly higher percentage of patients given lamivudine than patients who received placebo. Improvements in liver histology were similar in treatment-naive patients, relapsers, and nonresponders to prior interferon therapy, and the improvements occurred independently of HBeAg seroconversion. Serum HBV DNA levels fell rapidly and remained at least 94% below baseline values, and serum ALT levels also decreased during therapy, with 50% of patients achieving and maintaining normal ALT levels after 2 years of therapy. Patients receiving lamivudine for 1 year experienced a 17% to 33% rate of loss of HBeAg. It is generally thought that patients who achieve HBeAg seroconversion (loss of HBeAg and HBV DNA, with development of anti-HBe) can discontinue lamivudine therapy. Relapse appears to occur in 15% to 20% of patients, but more data are needed to define the durability of HBeAg seroconversion.
The efficacy of lamivudine therapy after 1 year is similar to that of interferon therapy after 4 to 6 months. However, the cumulative HBeAg seroconversion rate is higher in patients who had elevated baseline ALT levels before treatment, and the seroconversion rate increases progressively with additional years of lamivudine therapy. In 58 patients treated for 3 years with lamivudine, the cumulative HBeAg seroconversion rate increased from 22% after 1 year of therapy to 27% after 2 years and to 40% after 3 years. Within this group, 38% of patients with pretreatment ALT levels greater than twice the upper limit of normal experienced HBeAg seroconversion after 1 year of therapy, with the rate increasing to 42% after 2 years and to 65% after 3 years. The serum levels of ALT and HBV DNA return to pretreatment levels if lamivudine is discontinued before HbeAg loss or seroconversion is achieved. Some patients may experience serum ALT levels that are transiently higher after treatment than before treatment, as do patients who receive interferon. Generally, no adverse effects have been associated with these elevations, although there are rare reports of severe flares of hepatitis B.
Lamivudine and interferon combination therapy.
Lamivudine and interferon alfa-2b in combination should theoretically have synergistic effects against HBV. Unfortunately, this combination failed to show greater efficacy than either drug used alone.
Complications of lamivudine therapy.
Variant strains of HBV that demonstrate changes near the YMDD motif (the amino acid sequence tyrosine-methionine-aspartate-aspartate) may appear after 6 to 8 months of lamivudine therapy. YMDD variants of HBV occur in 27% to 32% of patients after 1 year of therapy. The median serum ALT and HBV DNA levels were lower than pretreatment levels in patients who developed YMDD variants, but these improvements were not as significant as those in patients who maintained the wild-type HBV. In spite of developing HBV variants, liver histology after 1 year of therapy was still better in patients who received lamivudine than in patients who received placebo. Because the variant HBV is less replication-efficient, it is generally recommended that lamivudine therapy be continued. If therapy is stopped, the wild-type HBV returns and may be associated with a flare of chronic hepatitis B.
Lamivudine and end-stage liver disease
Lamivudine may play a role in patients with chronic hepatitis B who have endstage liver disease, according to preliminary evidence of stabilization and improvement of biochemical and clinical features as well as occasional deferral of the need for liver transplantation. Lamivudine therapy may serve as a bridge to transplantation for patients with decompensated cirrhosis while they await a donor liver.
Liver Transplantation
Liver transplantation can be performed for liver failure associated with chronic hepatitis B, but HBV infects the allograft in 80% to 100% of cases (if antiviral prophylaxis is not given), and long-term survival is only 45% to 50% (compared with 80% to 85% in transplant patients with other types of cirrhosis). The HBV reinfection often is accelerated and progresses to cirrhosis. As a result, most transplant centers now implement prophylactic antiviral strategies to reduce reinfection. Two such strategies are (1) the intraoperative, immediately postoperative, and long-term administration of high-dose hepatitis B immune globulin (HBIG) (to maintain an anti-HBs level > 100 to 200 mIU/ml over the long term) and (2) the short-term administration of HBIG with lamivudine, with later discontinuance of HBIG. A number of trials using these prophylaxis strategies against HBV reinfection suggest that the reinfection rate can be reduced to 10% to 20% and that 1-year and 3-year survival rates are improved.
Chronic Hepatitis D
Hepatitis D (delta hepatitis) appears to respond at least temporarily to high doses of interferon alfa (9 million units three times a week for 48 weeks). In one study, aminotransferase levels returned to normal in 71% of patients; in 50% of these patients, aminotransferase levels were still normal an average of 39 months later. However, the clearance of HDV RNA from the serum that occurred immediately after treatment was not sustained; HDV RNA was found in the serum of all treated patients at long-term follow-up. Lamivudine is not effective in patients with delta coinfection.
Causes and symptoms
The delta virus is a small and incomplete viral particle. Perhaps this is why it cannot cause infection on its own. Its companion virus, HBV, actually forms a covering over the HDV particle. In chronically ill patients (those whose virus persists longer than six months), the combined viruses cause inflammation throughout the liver and eventually destroy the liver cells, which are then replaced by scar tissue. This scarring is called cirrhosis.
When HBV and HDV infections develop at the same time, a condition called coinfection, recovery is the rule. Only 2-5% of patients become chronic carriers (have the virus remain in their blood more than six months after infection). It may be that HDV actually keeps HBV from reproducing as rapidly as it would if it were alone, so chronic infection is less likely.
When HBV infection occurs first and is followed by HDV infection, the condition is called superinfection. This is a more serious situation. Between half and two-thirds of patients with superinfection develop severe acute hepatitis. Once the liver cells contain large numbers of HBV viruses, HDV tends to reproduce more actively. Massive infection and liver failure are more common in superinfection. The risk of liver cancer however, is no greater than from hepatitis B alone.
As with other forms of hepatitis, the earliest symptoms are nausea, loss of appetite, joint pains, and tiredness. There may be fever (not marked) and an enlarged liver may cause discomfort or actual pain in the right upper part of the abdomen. Later, jaundice (a yellowing of the skin and whites of the eyes that occurs when the liver is no longer able to eliminate certain pigmented substances) may develop.
Diagnosis
HDV infection may be diagnosed by detecting the antibody against the virus. Unfortunately this test cannot detect acute coinfection or superinfection as early as when symptoms first develop. Antibody against HDV usually is found no sooner than 30 days after symptoms appear. Until recently, the virus itself could only be identified by testing a small sample of liver tissue. Scientists now are developing a blood test for HDV that should make diagnosis faster and easier. When HDV is present, liver enzymes (proteins made by the liver) are present in abnormally high amounts. In some patients with coinfection, the enzyme levels peak twice, once when HBV infection starts and again at the time of HDV infection.
Chronic Hepatitis C
Hepatitis C is an infection caused by a virus that attacks the liver and leads to inflammation. Most people infected with the hepatitis C virus (HCV) have no symptoms. In fact, most people don’t know they have the hepatitis C infection until liver damage shows up, decades later, during routine medical tests.
Hepatitis C is one of several hepatitis viruses and is generally considered to be among the most serious of these viruses. Hepatitis C is passed through contact with contaminated blood — most commonly through needles shared during illegal drug use.
Hepatitis C infection is caused by the hepatitis C virus (HCV). HCV is spread when you come in contact with blood contaminated with the virus.
Risk of hepatitis C infection is increased if:
Are a health care worker who has been exposed to infected blood, such as may happen if an infected needle pierces your skin
· Have ever injected illicit drugs
· Have HIV
· Received a piercing or tattoo in an unclean environment using unsterile equipment
Epidemiology
Approximately 30,000 new cases of acute HCV infection are reported annually to the CDC. Of these patients, at least 85% develop chronic HCV infection.33 Approximately 4 million persons in the United States (1.8%) have been infected with HCV, and 74% of these individuals (1.4% of the population) are viremic.34 The high chronicity rate of HCV infection makes chronic hepatitis C a much more prevalent disease than chronic hepatitis B (0.2% to 0.5% of the general population).
DIAGNOSIS
The diagnosis of chronic hepatitis C is typically made by the finding of persistently or intermittently elevated aminotransferase levels in association with reactive anti-HCV on secondgeneration ELISA. Samples from a small percentage of patients with chronic HCV infection are nonreactive on ELISA but are reactive for anti-HCV on second-generation RIBA or show detectable serum HCV RNA. Chronic hepatitis C is often silent; half of infected patients are asymptomatic. In addition, 20% to 30% of patients who test positive for anti-HCV and are viremic with detectable HCV RNA have persistently normal aminotransferase levels. Liver biopsies demonstrate the full spectrum of disease severity, ranging from mild portal tract inflammation to cirrhosis. Histologic features such as bile duct damage, lymphoid follicles or aggregates, and large droplets of fat are suggestive of chronic hepatitis C.
NATURAL HISTORY
After the onset of acute HCV infection, the infection resolves in 15% to 30% of patients and there is a loss of HCV RNA, although anti-HCV remains detectable. The natural history of chronic hepatitis C appears to typically span several decades.34 In general, liver disease progresses insidiously, and cirrhosis may not develop for 2 or more decades. The natural history may be more prolonged when HCV infection occurs earlier in life. In a Japanese study, the mean interval from blood transfusion to development of chronic hepatitis was 10 years; to development of cirrhosis, 21 years; and to development of hepatocellular carcinoma (a late risk factor), 29 years. Similar results were found in a population of patients seen in a referral liver center in the United States: the mean interval from transfusion to cirrhosis was 21 years; and for progression to hepatocellular carcinoma, the mean interval was 28 years. In contrast to these reported outcomes, an analysis of posttransfusion studies in the United States found that over 18 years of follow-up, the survival rate of patients who developed non-A, non-B hepatitis after blood transfusion was no different from the survival rate of control subjects who did not develop hepatitis after transfusion.37 However, mortality in the patients who had posttransfusion hepatitis was significantly more often caused by liver disease than by other forms of disease. In a large cross-sectional European study designed to study the natural progression of hepatic fibrosis in patients with chronic hepatitis C, the median interval from the presumed time of infection to cirrhosis, identified by liver biopsy, was 30 years.38 The rate of progression to fibrosis and cirrhosis was not normally distributed; findings suggested at least three populations of patients: rapid fibrosers (median time to cirrhosis < 30 years), intermediate fibrosers, and slow fibrosers (no progression to cirrhosis, or at least 50 years from infection to cirrhosis). Three independent factors were associated with an increased rate of progression to cirrhosis: age older than 40 years at the time of infection, daily alcohol consumption of
TREATMENT
Many subtypes of interferon have been evaluated for their effectiveness in treating chronic hepatitis C, including interferon alfa-2b, interferon alfa-2a, interferon alfacon-1 (consensus interferon), and interferon alfa-n1; these interferons appear to be relatively similar with respect to their therapeutic indices. On the basis of recent studies, interferon monotherapy has been superseded by interferon and ribavirin combination therapy.
Interferon and Ribavirin Combination Therapy
Beginning in late 1998, the combination of interferon alfa-2b and ribavirin became the standard therapy for chronic HCV infection in patients with no contraindications. Ribavirin (1,000 to 1,200 mg daily in two divided doses) combined with interferon alfa-2b (3 MU three times weekly) for 6 months was found to provide significantly better biochemical and virologic sustained response rates than interferon used alone. Approximately 40% of patients treated for 1 year with combination therapy had sustained virologic response 6 months after the end of treatment. The 1998 studies of interferon and ribavirin combination therapy showed important differences in the outcome based on genotype; that is, approximately 30% of patients with genotype 1 and approximately 65% with genotype 2 or 3 had sustained virologic responses. In addition, patients with genotype 1 had higher rates of sustained virologic response with 48 weeks of combination therapy than with 24 weeks of therapy, whereas patients with other genotypes achieved no additional benefit beyond 24 weeks of therapy. These studies have led to the practice of administering therapy for 12 months to patients with genotype 1 but for only 6 months to those with genotype 2 or 3. Factors in addition to genotype are known to predict the likelihood of successful therapy with ribavirin and interferon [see Table 5].
Side effects of combination therapy.
Side effects are common with interferon and ribavirin combination therapy and may necessitate discontinuance of therapy in 10% to 15% of patients. The major side effect of ribavirin is a dose-dependent hemolytic anemia, which is reversible and usually stabilizes after 6 weeks of treatment. If severe anemia develops, treatment must be discontinued. Ribavirin is teratogenic; therefore, pregnancy must be avoided. Combination therapy should be used cautiously in patients with depression, because interferon can exacerbate depression. These patients can often be managed with antidepressants, with or without reduction in interferon dosage. Patients with preexisting anemia usually cannot tolerate the degree of hemolysis that occurs with ribavirin therapy, which can be dangerous. Moreover, patients with significant
cardiovascular disease are particularly at risk should severe anemia develop during therapy. Patients with chronic hepatitis C and comorbid conditions preventing the use of ribavirin can be treated with interferon monotherapy. Contraindications to combination therapy are summarized [see Table 6].
Sustained response to combination therapy.
The persistence of a biochemical (normal ALT) or virologic (undetectable HCV RNA) response for 6 months or more after cessation of therapy is the operational definition of a sustained response. In two studies of patients who had an initial posttreatment 6- month sustained response, including a mean 4-year follow-up study of 80 patients and a 10-year follow-up study of five patients, long-term virologic sustained response rates were 96% and 100%, respectively.41,42 In addition, there was improvement of liver histology, including evidence of regression of hepatic fibrosis in noncirrhotic patients. These studies suggest that some patients may indeed be cured of chronic hepatitis C and that a mortality benefit should be expected if cirrhosis, with its risk of hepatocellular carcinoma, can be prevented.
Treatment after Relapse
Relapse after a course of therapy is defined by an elevated ALT level, which was normal during treatment, and detectable levels of HCV RNA, which were undetectable during treatment. Re-treatment using standard interferon monotherapy is ineffective, but an extended 12-month course of interferon alfa- 2b or interferon alfacon-1 resulted in sustained response rates of 32% and 58%, respectively.43,44 Re-treatment with interferon and ribavirin combination therapy is more commonly employed and gave sustained response rates of 24% to 95%, depending on viral genotype
Management Options after Nonresponse to Therapy
Nonresponse to antiviral therapy is defined as persistently elevated ALT levels, detectable serum HCV RNA levels, or both during therapy. A variant of nonresponse called breakthrough is characterized by an initial decrease of ALT levels into the normal range or the disappearance of HCV RNA, with subsequent elevation of ALT or reappearance of HCV RNA while the patient is still being treated. Ionresponse or breakthrough patients given interferon alfa-2b initially, re-treatment with interferon alfacon-1 yielded sustained virologic response rates of 13% to 27%. There is some evidence that histologic improvement may occur with longer therapy despite nonresponse after 6 months of treatment, thus implying that indefinite low-dose interferon maintenance therapy may be beneficial. Recent trials even demonstrate that interferon therapy may delay or prevent decompensation from cirrhosis and the development of hepatocellular carcinoma, particularly in patients who show a sustained response. Finally, studies have demonstrated that sustained virologic response rates to interferon monotherapy are lower in African Americans than in whites.
Emerging Treatment Options
A number of future options may become available for the treatment of chronic hepatitis C over the next several years.The most promising new treatment soon to be licensed is pegylated interferon. Polyethylene glycol (PEG) is a water-soluble polymer that can be covalently linked to proteins such as interferon, which markedly increases the half-life, resulting in sustained serum levels and allowing once-weekly administration. Two PEG interferons have been studied: the branched 40 kd PEG interferon alfa-2a (Pegasys) and the linear 12 kd PEG interferon alfa-2b (PEG-Intron). Phase 2 studies revealed that the appropriate dosage of PEG interferon alfa-2a was 180 ìg once weekly, resulting, after 48 weeks of therapy, in a sustained virologic response rate of 36% ioncirrhotic patients and 30% in cirrhotic patients. A large study of 531 treatmentnaive patients who were given PEG interferon alfa-2a or standard interferon alfa-2a for 48 weeks showed a sustained virologic response rate of 39% with PEG interferon alfa-2a versus 19% with standard interferon alfa-2a. In an international study of PEG interferon alfa-2b given once weekly versus interferon alfa-2b given three times weekly for 48 weeks in 1,219 patients with untreated chronic hepatitis C, the sustained virologic response rates were 25% with PEG interferon alfa-2b, 1.0 ìg/kg, and 23% with PEG interferon alfa-2b, 1.5 ìg/kg, versus 12% with interferon alfa-2b. Thus, PEG interferons achieve sustained virologic response rates that are approximately twice that achieved with standard interferons (39% versus 19% with PEG interferon alfa-2a, and 23% and 25% versus 12% with PEG interferon alfa-2b). In both studies, patients with genotype 1 and higher viral loads had reduced response rates. Both PEG interferons were tolerated as well as the standard interferons, with discontinuance rates ranging from 6% to 11% in all treatment groups. It is likely that the efficacy of the PEG interferons will be enhanced by the addition of ribavirin to treatment regimens, and sustained virologic response rates may approach 50%. The results of ongoing large studies of combination therapy with PEG interferon alfa-2a or PEG interferon alfa-2b and ribavirin are under way and will likely lead to a new standard therapy of combination pegylated interferon and ribavirin in 2001.
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2. Harrison’s Principles of Internal Medicine. Dan L.Longo M.D. –
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Charles M. WienerAnthony S. FauciEugene BraunwaldDennis L. KasperStephen L. HauserDan L. LongoJ.Larry JamesonJoseph LoscalzoCynthia Brown, 18th Revised edition. – New York : McGraw-Hill Education – Europe, 2012. – 512 p
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6 Textbook of Clinical Gastroenterology and Hepatology (2nd Revised edition) /
