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Usefulness of liver biopsy in chronic hepatitis C
Edna Strauss
,
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ednastrauss@gmail.com

Correspondence and reprint request:
* Department of Internal Medicine. Universidade de São Paulo, Brazil.
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">Introduction</span><p id="p0005" class="elsevierStylePara elsevierViewall">The possibility of evaluating hepatic lesions by means of liver percutaneous biopsy started in 1883 when Paul Ehrlich intended to study glycogen content of hepatocytes in diabetes&#46; In the second half of last century risk of bleeding was minimized and the procedure permitted the analysis of structural alterations&#44; inflammatory processes and other various hepatic lesions&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Little by little indications of liver biopsy became more and more frequent&#44; since it was a precious instrument of making correct diagnosis as well as prognostic evaluations and therapeutic monitoring in clinical practice&#46;</p><p id="p0010" class="elsevierStylePara elsevierViewall">Liver biopsy is indicated in a wide variety of clinical conditions and the basic requirements for its performance are the benefits for the patient and the impossibility of having the same information by less invasive procedures&#46; The patient must be aware of its indication&#44; its risks and benefits and nowadays an informed written consent is demanded&#46;</p><p id="p0015" class="elsevierStylePara elsevierViewall">Most of the knowledge about chronic hepatitis was obtained with data derived from liver biopsies&#46; On the other hand&#44; acceptance of the procedure by the patients has been a challenge&#44; due to its invasiveness&#46; Another complain&#44; easy to be removed&#44; is the fear of malignancy&#44; since biopsy procedures in other organs is frequently linked to diagnosis of cancer&#46;</p><p id="p0020" class="elsevierStylePara elsevierViewall">When the patient has symptoms and feels sick it is easier to indicate invasive procedures&#46; It is not the case of chronic hepatitis C&#46; This disease is usually asymptomatic with few laboratory alterations&#46; In the last two decades physicians have faced the difficult task of convincing a patient positive for hepatitis C&#44; with minimal clinical or laboratory alterations to be submitted to liver biopsies in order to evaluate the status of the disease for therapeutic management&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">Relevance of Different Types of Procedures and Needles</span><p id="p0025" class="elsevierStylePara elsevierViewall">Percutaneous liver biopsy can be performed as a &#8220;day-clinic&#8221; procedure&#46; General requirements include a hemogram with platelet count&#44; prothrombin time and bleeding time&#44; some days before the procedure&#46; Fasting is required&#44; although only local anesthesia is necessary&#46; Pre-medication and sedation of the patient is optional&#46; Hemodynamic control at short intervals is advisable&#44; meaning pulse and blood pressure during the first six hours&#44; at hospital&#46; As bed rest is essential to control bleeding&#44; patient will be allowed to go home but with minimal physical efforts for the next five days&#46;</p><p id="p0030" class="elsevierStylePara elsevierViewall">In the last decade&#44; with popularization of ultrasound machines and its usefulness in taking hepatic images&#44; with growing degrees of perfection&#44; many physicians preferred to make liver biopsies guided by ultrasound&#46; Replacing the old liver percussion&#44; the use of ultrasound allows the choice of the best place to put the needle&#44; avoiding great vessels&#44; as well as other structures as gall bladder and kidney&#44; sometimes found together with the liver fragment by the pathologist&#46; It also permits the analysis of the liver and its surroundings after the procedure&#46; Early bleeding can be detected as well as hematomas near the capsule&#44; sometimes the cause of a more severe local pain&#46; Nevertheless&#44; it is not mandatory to use ultrasound or other image guiding during routine liver biopsies&#46;</p><p id="p0035" class="elsevierStylePara elsevierViewall">As chronic hepatitis C becomes more common through the years&#44; the therapeutic consensuses have stressed on the need of liver biopsy before treatment&#44; and therefore ultrasound clinics started making liver biopsies&#46; Although they usually use thin needles with imaging control&#44; it is not advisable to make this procedure far from surgical facilities&#44; usually found in a hospital center&#44; since unexpected hemorrhagic complications needing surgical intervention may occur&#46;</p><p id="p0040" class="elsevierStylePara elsevierViewall">Either at surgery or during laparoscopy&#44; wedged liver biopsies may take large fragments of liver&#44; offering also the possibility of liver direct visualization with evaluations of alterations in color&#44; parenchyma consistency and presence of nodules&#44;&#46; It has been largely used in the 70s and 80s&#46; Nevertheless&#44; those advantages are not particularly important in chronic hepatitis C and some disadvantages have to be pointed out&#46; Fear of hemorrhage may lead to very superficial resections or small fragments of liver&#46; The subcapsular area may present structural alterations not representing the whole liver parenchyma&#46; When specific needles are used for biopsy it is advisable to take fragments at least two centimeters deep in the liver&#46; Another advantage of the needle is regular cut and proximity of the areas&#44; allowing prompt clotting and regeneration&#46;</p><p id="p0045" class="elsevierStylePara elsevierViewall">The transjugular access to make liver biopsies may be indicated in patients with coagulation problems or in cases of intractable ascites&#46; These conditions are usually found in decompensated cirrhosis&#44; but patients with chronic hepatitis C very seldom will need a liver biopsy when they achieve that condition&#46; Another possible indication for transjugular access would be in hemophiliacs with hepatitis C&#44; in which therapeutic doubts or the need of better prognostic evaluation are demanded&#46;</p><p id="p0050" class="elsevierStylePara elsevierViewall">Concerning the needles currently used for liver biopsy different mechanisms can be found&#46; The old Vim-Silverman needle&#44; maintaining the guillotine mechanism&#44; was replaced by Tru-cut needles&#46; They cut a linear fragment of liver avoiding fragmentation and allowing a better evaluation of fibrous septa&#46; The other common type of needle uses the aspiration procedure as in the old Menguini type&#46; It is assumed they are related to less bleeding tendency&#44; but fragmentation is more common and large fibrous septa may be over passed&#46; Metallic needles have been replaced by dischargeable ones&#46; The expertise of manual handling has been replaced by semi-automatic needles&#44; mainly used by experts in ultrasound&#46;</p><p id="p0055" class="elsevierStylePara elsevierViewall">The characteristics of the needle may interfere with accuracy of diagnosis&#46; It is increasingly recognized that longer biopsy samples with larger bore needles are needed to accurately stage and grade the extension of liver damage&#46; In hepatitis C it was shown that biopsies with 15mm length may have only four to six portal tracts&#46; In these specimens grading and staging may be underscored&#46; Validity was achieved with fragments about 25mm with more than 10 portal tracts&#44; what is now mandatory in the evaluation of the representativity of liver biopsy&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Contraindications and Complications</span><p id="p0060" class="elsevierStylePara elsevierViewall">For liver biopsy in general and also in chronic hepatitis C&#44; the main contraindications are coagulation disorders and tense ascites&#46; Prolongation of prothrombin time as well as very low platelet counts are risk factors for bleeding&#46; As patients with clinical evident cirrhosis do not require liver biopsy for treatment purposes&#44; these situations are very rare&#46;</p><p id="p0065" class="elsevierStylePara elsevierViewall">Morbidity due to liver biopsy is mainly related to bleeding&#46; Slight to moderate bleedings can be controlled clinically&#44; but some cases of bleeding urge for surgical intervention and death is rare&#44; mainly linked to advanced liver disease or hemorrhagic tumors&#46;</p><p id="p0070" class="elsevierStylePara elsevierViewall">Local pain or referred pain in the right shoulder are common and may happen in up to 50&#37; of patients&#44; sometimes due to capsule hematomas&#44; seen in ultrasound&#46; Other less frequent related complications are hemoperitoneum&#44; biliary peritonitis&#44; arteriovenous fistulas and septicemia&#46; A nationwide prospective study in France&#44; involving more than two thousands biopsies have shown no deaths but severe complications in 0&#46;57&#37; of cases&#44; that increased with number of passes and decreased with experience of operator and US-guidance&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Sampling and Observation Errors</span><p id="p0075" class="elsevierStylePara elsevierViewall">Considering the whole liver weight&#44; the liver fragment collected in a biopsy represents about 1&#58;50&#46;000 of the liver parenchyma&#46; Although chronic hepatitis C is a diffuse disease&#44; the various areas of the liver may not be equally affected&#46; Unfortunately macroscopic analysis on surgery or laparoscopy does not evidenciate these small differences&#46; So&#44; there are possibilities of sampling errors&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="p0080" class="elsevierStylePara elsevierViewall">On the other hand&#44; especially for chronic hepatitis C&#44; a good representativity of the liver fragment may be a guarantee for the accuracy concerning the degrees of alterations&#46; In small fragments that contain less than 10 portal spaces underscoring is frequent&#46; Besides length of the liver fragment&#44; needle bore larger than 18 gauges is also relevant&#46; If the needle is thin or the fragment is short&#44; a second or third pass will be needed to obtain more material for accuracy of diagnosis&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="p0085" class="elsevierStylePara elsevierViewall">Another potential limitation of liver biopsy is the discordance between pathologists in its interpretation&#46; Several studies have shown that observer variation is higher for grading than staging&#46; So&#44; fibrosis scores are usually less affected&#46; Training of pathologists in liver disease is of major importance to reduce observer variations&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="p0090" class="elsevierStylePara elsevierViewall">Due to those various limitations of liver biopsy&#44; many panels of surrogate markers have been described in literature and some are routinely used in clinical practice of some hepatology centers&#46; Their aim is to identify the extent of fibrosis and inflammations replacing liver biopsy&#46; Among them&#44; the direct markers of extracellular matrix turnover&#44;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> the indirect markers of fibrosis or inflammation<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> as well as combination of direct with indirect methods and elastography to evaluate liver stiffness<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> all of them have used liver biopsy as their &#8220;gold standard&#8221;&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Indications of Liver Biopsy in Chronic Hepatitis C</span><p id="p0095" class="elsevierStylePara elsevierViewall">The diagnosis of chronic hepatitis C is often made on clinical&#44; laboratory and serological grounds&#46; As the disease develops without symptoms in the great majority of patients the evaluation of real liver damage must be made by liver biopsy&#46; But it would not be necessary if all patients could be safely and efficiently treated&#44; eliminating this viral infection&#46; Much progress has been achieved in the treatment of hepatitis C in the last years&#44; but efficiency could only be reached in small groups of patients&#46; For the great majority of them&#44; side effects and low efficacy levels persists&#46; There are mainly three drawbacks for universal treatment of all patients with a diagnosis of chronic hepatitis C&#46; Overall efficacy is as low as 50&#37;&#44; many side effects may be present&#44; some of them severe&#44; and the costs of the treatment are not easily affordable&#46;</p><p id="p0100" class="elsevierStylePara elsevierViewall">Patients with persistently normal transaminases may have severe hepatic damage&#59; according to some authors a systematic indication of liver biopsy has been proposed&#46; Nevertheless&#44; some recent works&#44; studying paired liver biopsies have found that patients with persistently normal ALT experience significantly milder disease when compared to patients with elevated levels of ALT&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Another frequent concern is the cut-off to define normal levels of ALT&#44; which should be lowered when evaluating chronic hepatitis C&#46; Physicians face a dilemma with those patients in terms of an early indicating of liver biopsy and surrogate markers of fibrosis could play a role&#44; in terms of postponing this indication&#46;</p><p id="p0105" class="elsevierStylePara elsevierViewall">On the other extreme&#44; patients with clinical evidences of cirrhosis but without signs of decomposition are candidates for treatment&#46; In these cases there is little profit in confirming the nodular architectural changes of the liver&#44; since F4 cases should be treated&#46; So&#44; liver biopsy is not necessary&#44; considering this approach&#46;</p><p id="p0110" class="elsevierStylePara elsevierViewall">In chronic hepatitis C patients with genotypes 2 or 3 and other indicators of good response&#44; in which therapeutic efficacy reaches 80 to 90&#37;&#44; a liver biopsy is not really needed&#46; Some authors differentiate between genotype 2 more benign and genotype 3&#44; which may have greater percentages of relapses or no response&#46; For genotype 3&#44; in particular&#44; it is important to have histopathological differentiation&#44; since in cases with cirrhosis or even with F3 and some nodules&#44; a prolongation of treatment for 48 weeks is advisable&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Diagnosis of Associated Diseases in Chronic Hepatitis C</span><p id="p0115" class="elsevierStylePara elsevierViewall">Histological diagnosis of associated diseases may be relevant in the management of chronic hepatitis C&#46; In cases of elevated titers of auto antibodies other clinical data may not be sufficient to assure a correct diagnosis of autoimmune hepatitis and a liver biopsy is mandatory&#46;</p><p id="p0120" class="elsevierStylePara elsevierViewall">A more frequent association is between chronic hepatitis C and steatosis or steatohepatitis&#46; Although epidemiological data can exclude alcohol intake&#44; the diagnosis of nonalcoholic steatohepatitis is made on histopathological grounds&#46; Lately&#44; this association is recognized as relatively frequent and linked to more advanced histopathological changes&#46;<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">12</span></a></p><p id="p0125" class="elsevierStylePara elsevierViewall">Other metabolic diseases as iron overload and &#945;1 anti-tripsin deficiency can also be easily detected when liver biopsy is available&#46; Although the diagnosis of hepatocelular carcinoma is currently made by use of imaging methods&#44; for small lesions a liver biopsy is still indicated&#44; allowing the detection of very early cases of liver tumor&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Conclusion</span><p id="p0130" class="elsevierStylePara elsevierViewall">Liver biopsy is the only approach enabling direct assessment of liver injury&#46; In addition to fibrosis it allows a full histopathological evaluation&#46; In Hepatitis C&#44; besides staging fibrosis and grading necro-inflammatory activity&#44; it may reveal and&#47;or confirm associated liver diseases as steatohepatitis&#44; auto-immune hepatitis&#44; alfa1 antitripsine deficiency&#44; iron overload and others&#46; It is useful not only for diagnosis and treatment indications but also for prognosis and general management&#46; The acceptability of the biopsy by the patient is highly dependent on the physician&#8217;s conviction and belief in biopsy usefulness&#46;</p></span></span>"
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        "resumen" => "<span id="abs0005" class="elsevierStyleSection elsevierViewall"><p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Major requirements for performance of liver biopsy &#40;LB&#41; are the benefits for the patient and the impossibility of having the same information by less invasive procedures&#46; In the last two decades physicians have faced the difficult task of convincing a patient positive for hepatitis C&#44; with minimal clinical or laboratory alterations to be submitted to LB in order to evaluate the status of the disease for therapeutic management&#46; The characteristics of the needle used for percutaneous LB interferes with the accuracy of diagnosis&#46; In chronic hepatitis C &#40;CHC&#41;&#44; validity is achieved with liver fragments about 25mm in length containing more than 10 portal tracts&#46; Morbidity due to LB is mainly related to bleeding but death is very rare&#46; Severe complications are also uncommon&#44; increasing with number of passes and decreasing with experience of operator and ultrasound guidance&#46; Although CHC is a diffuse disease&#44; the various areas of the liver may not be equally affected and sampling errors are possible&#46; Another potential limitation of LB is the discordance between pathologists in its interpretation&#46; To replace LB&#44; many panels of surrogate markers have been described&#44; aiming to identify extent of fibrosis and inflammation&#46; All of them have used LB as their &#8220;gold standard&#8221;&#46; Liver biopsy continues to be the most reliable method to evaluate the possibility of therapy for CHC&#46; Universal treatment of all patients with diagnosis of CHC would be ideal&#46; But&#44; there are mainly three drawbacks&#46; Overall efficacy is as low as 50&#37;&#44; side effects are common and may be severe and treatment is prolonged and expensive&#46; The acceptability of the biopsy by the patient is highly dependent on the physician&#8217;s conviction of its usefulness&#46;</p></span>"
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