Seminario Central de Clínica Médica Presenta: Dra EugeniaFurno Discute: Dr Bruno Levy

Resumen del caso Paciente masculino 56 años Ingresa con diagnóstico anatomopatológico de cirrosis sin antecedentes de etilismo Presenta además fiebre y hematuria que resuelven de forma espontánea durante la internación

Cirrosis de causa desconocida Virus hepatitis B y C Esteatohepatitis no Alcohólica Cirrosis biliar primaria Colangitis esclerosante primaria Hepatitis autoinmune Hemocromatosis Enf de Wilson Déficit de Alfa 1 antitripsina

Esteatohepatitis no alcohólica Se denomina con este nombre a la entidad clínica en la que los pacientes presentan hallazgos anatomopatológicos en biopsia de hígado compatible con esteatosis hepática sin que exista el antecedente de ingesta alcohólica significativa Su etiología no está clara Es frecuente su asociación con el sindrome metabólico

Esteatohepatitis no alcohólica La mayor parte de los pacientes se encuentran asintomáticos al momento del diagnóstico En los que presentan síntomas, predominan la astenia, malestar general y un leve e inconstante dolor en hipocondrio derecho La forma más frecuente de presentación es el hallazgo de elevación de transaminasas en un control de laboratorio de rutina Habitualmente presenta hepatomegalia De forma infrecuente puede aparecer elevaciones de FAL e hiperbilirrubinemia

Esteatohepatitis no alcohólica La ecografía tiene baja sensibilidad, aunque alta especificidad para la esteatosis, pero no sirve para evaluar severidad o establecer un pronóstico claro La TAC y la RMI aportan sensibilidad, pero su especificidad varía El gold standard sigue siendo la biopsia hepática, permitiendo establecer no sólo el diagnóstico, sino evaluar la severidad y el pronóstico

Cirrosis Biliar Primaria Se caracteriza por un ataque mediado por linfocitos T sobre los conductos biliares, que lleva a destrucción y desaparición graduales Se presenta predominantemente en mujeres (95% de los casos) Habitualmente se presenta entre los 30 y los 65 Los síntomas más frecuentes son fatiga, prurito e hiperpigmentación de la piel, aunque más de la mitad de los pacientes se encuentran asintomáticos al momento del diagnóstico

Fantasm Es muy frecuente la presencia de hepatomegalia al momento de la presentación, no así la esplenomegalia Fuerte asociación con la patología reumática: el 40-60% de los pacientes presentan síntomas de Sjögren; 5-15% presentan esclerodermia cutánea y 5-10% presentan artritis reumatoidea

Cirrosis Biliar Primaria Casi siempre presenta marcadas elevaciones de FAL y GGT La elevación de transaminasas, si existe, es en general menor a 5 veces el valor normal Más del 50% de los pacientes presentan hiperlipemia, pudiendo llegar a valores extremos (>a 1000mg/dL de colesterol). Generalmente, la HDL se eleva más que la LDL La presencia de anticuerpos antimitocondriales es casi constante (más del 95% de los pacientes), por lo que deberían pedirse siempre que se sospeche este diagnóstico Puede presentar elevación de la ceruloplasmina sérica

La elevación de la bilirrubina se da con la progresión de la enfermedad y es un marcador de mal pronóstico El FAN se encuentra en el 70% de los pacientes

Cirrosis Biliar Primaria Diagnóstico: Requiere dos de los siguientes: Evidencia bioquímica de colestasis (FAL, GGT) Anticuerpos antimitocondriales Biopsia que evidencia colangitis destructiva no supurativa, con destrucción de conductors biliares interlobares

Colangitis esclerosante primaria Se trata de una patología progresiva crónica de causa desconocida que se caracteriza por inflamación, fibrosis y estenosis de los conductos biliares medianos y grandes intra y extra hepáticos Tiene una fuerte asociación con colitis ulcerosa – Hasta el 90% de los pacientes con CEP presentan colitis ulcerosa, aunque sólo el 5% de los pacientes con colitis ulcerosa desarrollan CEP Los síntomas más frecuentes son la fiebre, fatiga, prurito y dolor en hipocondrio derecho, aunque la mayor parte de los pacientes se encuentran asintomáticos al momento del diagnóstico En la mayoría de los casos el diagnóstico se hace en el marco del estudio de la enfermedad inflamatoria intestinal

Colangitis esclerosante primaria Habitualmente presenta alteración del hepatograma con patrón colestásico con hiperbilirrubinemia y transaminasas menores a 5 veces el valor normal Puede presentar disminución de la ceruloplasmina sérica Para el diagnóstico son útiles la colangioRMI y colangioendoscopía, que revelan la estenosis de los conductos biliares La biopsia puede apoyar el diagnóstico, pero rara vez alcanza para confirmarlo

The diagnosis of PSC is established by the demonstration of characteristic multifocal stricturing and dilation of intrahepatic and/or extrahepatic bile ducts on cholangiography (picture 2). Abnormal bile ducts may also be suggested on ultrasound (picture 3A-B), although findings are usually not diagnostic. Magnetic resonance cholangiography may be an alternative to endoscopic cholangiography, particularly if the image quality continues to improve The gallbladder and cystic duct may also be involved (picture 4). A study of 286 patients with PSC found one or more gallbladder abnormalities in 41 percent of patients [13]. Gallbladder findings were more common in those with extrahepatic PSC. A gallbladder mass lesion was found in 18 patients (6 percent), ten of which represented gallbladder carcinoma suggesting that cholecystectomy should be performed when such lesions are detected. Similar results have been reported by others [14]. Va a transplante

Hepatitis autoinmune Se trata de una hepatopatía crónica, que puede presentarse a cualquier edad Su forma de presentación varía desde pacientes asintomáticos hasta aquellos que debutan con una hepatitis aguda con falla hepática (infrecuente) Puede asociarse a arttritis reumatoidea, anemia hemolítica, PTI, celiaquía, DBT I y colitis ulcerosa Se dividen en Tipo I (FAN y/o AntiSm +) y Tipo II (ALKM-1 y/o ALC-1 +) De forma habitual cursa con elevación de las globulinas (particularmente, con aumento de los gamma)

Type 1 autoimmune hepatitis – Type 1, or classic autoimmune hepatitis, is characterized by circulating antibodies to nuclei (ANA) and/or smooth muscle (ASMA); the latter are thought to be reflective of more specific antiactin antibodies (AAA). AAA is not generally measured in most clinical laboratories, but ASMA with titers of 1:320 or greater generally reflect the presence of AAA. An ELISA technique for detecting antiactin antibodies (IgG anti F- actin) is available in some laboratories and is being used more frequently in commercial laboratories in North America. Other autoantibodies can occur in conjunction with or independent of ANA and ASMA. (See 'Autoantibodies' below and "Serologic markers of autoimmune hepatitis".) Type 2 autoimmune hepatitis – Type 2 autoimmune hepatitis is defined by the presence of antibodies to liver/kidney microsomes (ALKM-1) and/or to a liver cytosol antigen (ALC-1)

Extrahepatic disorders associated with autoimmune hepatitis Ulcerative colitis Hemolytic anemia Idiopathic thrombocytopenic purpura Type 1 diabetes mellitus Thyroiditis Hyperthyroidism Diabetes insipidus Primary adrenal insufficiency Polyglandular autoimmune syndrome, type I Celiac disease Systemic lupus erythematosus Rheumatoid arthritis Polymyositis Mixed connective tissue disease Pulmonary fibrosis Glomerulonephritis Behcet's disease Febrile panniculitis Skin diseases Pityriasis lichenoides et variola Vitiligo Urticaria pigmentosa Sweet's syndrome

Score diagnóstico del Autoimmune Hepatitis Group Hepatitis autoinmune Score diagnóstico del Autoimmune Hepatitis Group  Variable Puntaje ANA/SMA + 1:40 1 ANA/SMA + 1:80 o LKM 1:40 2 IgG > VN IgG > 1.10 veces el VN Biopsia compatible con HAI Biopsia típica de HAI Ausencia de hepatitis viral Diagnóstico probable: 6 ptos Diagnóstico seguro: >= 7 ptos Sensibilidad: 88% Especificidad: 97 %

Liver histology (evidence of hepatitis is a mandatory condition): assign one point if the histological features are compatible with autoimmune hepatitis OR two points if the histological features are typical of autoimmune hepatitis. Typical histologic features were defined as the presence of interface hepatitis, lymphocytic/lymphoplasmacytic infiltrates in the portal tracts and extending into the lobule, emperipolesis (active penetration of one cell into and through a large cell), and hepatic rosette formation. Compatible features were defined as a picture of chronic hepatitis with lymphocytic infiltration without all the features considered typical.

AASLD recommendations — We generally agree with the following recommendations, which have been proposed in a 2010 consensus statement issued by the American Association for the Study of Liver Diseases, except for the comments noted below [2]. The recommendations are based mainly on results of controlled trials of patients with severe disease and observational studies of patients with disease of varying severity. These guidelines can be accessed through the AASLD web site at www.aasld.org/practiceguidelines/Pages/default.aspx. Immunosuppressive treatment should be instituted in patients with serum aminotransferases greater than 10-fold the upper limit of normal, at least five-fold the upper limit of normal in conjunction with serum gamma-globulin levels at least two-fold the upper limit of normal, and/or histologic features of bridging necrosis or multilobular necrosis. Immunosuppressive treatment can be considered in adults without symptoms and mild laboratory and histological changes. The decision should be individualized and balanced against the risks of therapy. The AASLD recommends referral of such patients to a hepatologist. Immunosuppressive treatment should NOT be instituted in patients with minimal or no disease activity or inactive cirrhosis, but such patients should be followed every three to six months. Immunosuppressive treatment should NOT be instituted in patients with serious preexisting comorbid conditions (vertebral compression, psychosis, brittle diabetes, uncontrolled hypertension) or previous known intolerances to prednisone unless the disease is severe and progressive and adequate control measures for the comorbid conditions can be instituted. Azathioprine should NOT be started in patients with severe pretreatment cytopenia (white blood cell counts below 2.5 X 10(9)/L or platelet counts below 50 X 10(9)/L) or known complete deficiency of thiopurine methyltransferase activity. Immunosuppressive treatment should be instituted in children at diagnosis regardless of symptoms. One concern with this approach is that the level of serum aminotransferase or gamma globulin elevation does not correlate perfectly with the degree of histologic injury. In many cases, we have found that therapy may be required when serum aminotransferases are elevated to a lesser degree than suggested by the AASLD guideline and/or when serum gamma globulin levels are less than twice the upper limit of normal. We believe that treatment is also warranted in certain patients with milder features of inflammation than suggested in the AASLD guideline, particularly if they have symptoms.

Inactive cirrhosis — A subset of patients with cirrhosis has inactive disease characterized by the absence of inflammatory cells on liver biopsy and normal or near- normal serum aminotransferases. The diagnosis of AIH may be presumed in such patients based upon the clinical setting, the presence of serologic markers of AIH, and the absence of other causes of liver disease. Such patients may be at increased risk for the development of glucocorticoid-related side effects while the benefit of treatment is uncertain. On the other hand, treatment should not be withheld from patients with decompensated cirrhosis who have active disease. The response may be excellent even in those who have already experienced bleeding from esophageal varices or who have significant ascites. Many patients respond when treatment is initiated, and the 10-year survival for treated patients, including those with cirrhosis, exceeds 90 percent (figure 1) [4]. In one series of 97 patients, actual reversibility of fibrosis was demonstrated in 8 of 14 patients who had evaluable biopsies both before and after treatment [8]. Although sampling error could not be absolutely excluded, the biopsies were evaluated in a blinded fashion by two pathologists. An additional 25 patients with cirrhosis had successful medical treatment but without biopsies performed after response.

Hemocromatosis Se trata de un desorden hereditario, recesivo, que provoca un aumento en la absorción del hierro a nivel intestinal Sus manifestaciones clínicas pueden incluir hepatopatía crónica, hiperpigmentación cutánea, diabetes mellitus, artralgias, impotencia, cardiomegalia y astenia El depósito excesivo de hierro en el hígado aumenta de 20 a 200 veces el riesgo de desarrollar hepatocarcinoma

The hepatic iron content is preferably reported as micromoles of iron per gram dry weight of liver. Normal values are <36 micromol/g, while values >71 micromol/g are highly suggestive of homozygous HH [58]. This value can be divided by the subject's age in years to give the hepatic iron index (HII); a value ≥1.9 is consistent with, but not diagnostic of homozygous HH.

Suspecting iron overload from iron studies — (see 'Cutoff levels for screening purposes' above) A fasting transferrin saturation ≥60 percent in men or ≥50 percent in women is accurate in detecting over 90 percent of patients with homozygous HH who have clinical symptoms and/or documented iron overload. Many investigators, including a Practice Guideline from the American Association for the Study of Liver Disease have advocated using a lower "cutoff" value of 45 percent transferrin saturation for both men and women, which will lead to fewer patients being missed, although at the expense of an increased false positive rate (algorithm 1). Some institutions have developed expertise in the use of MRI techniques for assessing cardiac and liver iron, although MRI techniques cannot detect tissue or cellular damage due to tissue iron overload. If direct or indirect markers of liver disease are present (ie, subjects who drink alcohol, serum ferritin >1000 ng/mL, abnormal serum AST and ALT levels), we suggest that those diagnosed with the C282Y/C282Y HFE genotype should undergo a liver biopsy. (See 'Liver biopsy' above.) We suggest screening of all first degree relatives of patients with the C282Y/C282Y HFE genotype, although the vast majority of those so diagnosed may not need immediate treatment. 

Hemocromatosis Para el diagnóstico de certeza en general es necesaria la biopsia de hígado Son sugestivos del diagnóstico: Aumento de las concentraciones séricas del Fe > 150micg/dL Saturación de transferrina > 45% (más significativo si >60%) Concentraciones de ferritina > 200 micg/L

RATIONALE FOR TREATMENT Symptomatic patients — A number of observations provide compelling reasons for early detection and therapy of symptomatic hereditary hemochromatosis (HH): The major causes of death in HH are decompensated cirrhosis, hepatocellular carcinoma, diabetes mellitus, and cardiomyopathy [4-6]. Survival was normal in HH patients in whom treatment was initiated before the development of cirrhosis or diabetes [5]. Despite prior reports to the contrary [7,8], data from the United Network for Organ Sharing, covering all liver transplants performed in the United States between 1997 and 2006, have indicated that the 217 recipients with a diagnosis of hemochromatosis had one-, three- and five-year survivals comparable to all other transplant recipients [9]. Phlebotomy has a variety of benefits, including improvement in or resolution of varices [10], reduction in the degree of hepatic fibrosis if cirrhosis is absent [11], reversal of left ventricular dysfunction [12-14], and some reversal of secondary hypogonadism in men (table 2) [15- 17]. However, not all patients improve and not all responders have complete recovery, particularly in patients with advanced disease. In a review of 30 patients with HH, cirrhosis, and varices, the varices improved or completely reversed in only 26 percent [10]. Similarly, hypogonadism typically improves in younger men but may be unlikely to improve in men over the age of 40 [17], and isolated reports suggest that some patients with severe cardiomyopathy do not improve with phlebotomy [18]. The arthritis does not usually improve. PHLEBOTOMY — The simplest, cheapest, and most effective way to remove accumulated iron in non-anemic patients with iron overload is via therapeutic phlebotomy. Each 500 mL of whole blood removed contains 200 to 250 mg of iron. In providing replacement for the hemoglobin lost along with the phlebotomized red cells, the body mobilizes an equal amount of iron from tissue stores, thereby reducing the degree of iron overload. Thus, for a patient with HH and estimated iron stores of 10 grams, one phlebotomy per week for 50 weeks should fully deplete the patient's accumulated iron stores. Patient selection — Most patients who have a clinical phenotype consistent with hemochromatosis (regardless of their genotype) will benefit from therapeutic phlebotomy. Possible exceptions include patients who have limited life expectancy due to other diseases, and/or those who are anemic or otherwise do not tolerate phlebotomy (eg, ferroportin mutations, aceruloplasminemia, congestive failure with hemodynamic instability). Such patients may instead respond to iron chelation therapy. (See "Genetics of hereditary hemochromatosis", section on 'Ferroportin mutations' and "Genetics of hereditary hemochromatosis", section on 'Aceruloplasminemia' and "Chelation therapy for iron overload states".) Phlebotomy should not be withheld based upon advanced age alone or in patients who are asymptomatic. Criteria for initiating therapeutic phlebotomy have been proposed by a panel of experts who formed the Hemochromatosis Management Working Group (table 3) [24]. Schedule — Therapeutic phlebotomy can be performed in a physician's office, blood bank or other hospital facility, or at home by a well- trained phlebotomist. Patients should be encouraged to maintain hydration, and avoid vigorous exercise within 24 hours of phlebotomy. Symptoms of hypovolemia are more likely in patients who have a hemoglobin concentration less than 11 g/dL or a hematocrit less than 33 percent prior to treatment. The optimal regimen for phlebotomy in HH has not been established. However, it is preferable that patients be depleted of iron as quickly as possible [4,24]. Removal of one unit of blood every one or two weeks usually suffices. A weekly phlebotomy removing 50 units of blood per year will remove approximately 10 to 12.5 g of iron. Male patients and those with large body mass may tolerate removal of 1.5 to 2 units per week, whereas women, the elderly, and those with a low body mass or cardiopulmonary disease may only tolerate removal of 0.5 units per week. The development of erythroid hyperplasia after a few weeks of phlebotomy often permits a more accelerated phlebotomy schedule.

Enf de Wilson Se trata de una enfermedad autosómica recesiva en la que existe una excreción biliar deficiente de cobre, el cuál se acumula inicialmente en hígado y luego en otro órganos La afectación hepática es muchas veces subclínica, pero siempre está presente La afectación neuropsiquiátrica es más tardía, y aunque puede ser el motivo de consulta inicial, siempre se acompaña de una enfermedad hepática avanzada

 They are rare before age 6 and almost always present before the age of 30, although it has been described in those as young as age 3 and patients presenting in their seventies

Diagnóstico de Enf de Wilson a partir de una afectación hepática de causa desconocida

Molecular testing means confirming homozygosity for one mutation or defining two mutations constituting compound heterozygosity. Conversion to SI units: CPN <20 mg/dL or 0.2 g/L; 24-hour urinary Cu >40 micrograms/day or 0.6 micromol/day. Note that normal ranges for CPN may vary slightly between laboratories.CPN: ceruloplasmin; KF: Kayser-Fleischer. * Assure adequacy of urine collection. TREATMENT — Lifetime therapy is required in patients with Wilson disease and treatment should be given in two phases: removing the tissuecopper that has accumulated and then preventing reaccumulation. Copper removal is achieved by the administration of potent chelators. The primary chelator that has been used is D-penicillamine. However, approximately 30 percent of patients do not tolerate long-term therapy because of side-effects and it may not be the treatment of choice in patients with neurologic symptoms. Trientine has traditionally been used as a second-line agent but is also a reasonable option for primary therapy, and may be the preferred treatment because of its lower incidence of side effects. There are few controlled trials that have compared these agents to one another and thus recommendations for their use are based mainly on observational data and clinical experience [4]. Patients who stop taking chelating treatment may develop new neurologic abnormalities. Rapidly progressive hepatic decompensation refractory to treatment may also occur. Prevention of reaccumulation during the maintenance phase can be achieved with either lower doses of chelators or zinc. Oral zinc acts by preventing copper absorption. A newer agent, tetrathiomolybdate (another metal antagonist) is still being evaluated. Patients with Wilson disease should also be maintained on a low copper diet and avoid copper-rich foods such as liver, kidney, shellfish, nuts, dried fruits or beans, peas, unprocessed wheat, chocolate, cocoa, and mushrooms

Déficit de Alfa 1 Antitripsina La afectación hepática es la forma más frecuente de afectación extrapulmonar del déficit de A1AT Frecuentemente tiene una evolución asintomática hasta la cirrosis Aumenta en 8-12 veces el riesgo de hepatocarcinoma El diagnóstico se hace al constatar A1AT en suero <50 mg/dL

SKIN DISEASE — The major dermatologic manifestation of AAT deficiency, although rare, is necrotizing panniculitis. Other possible dermatologic associations with AAT deficiency include systemic vasculitis, psoriasis, urticaria, and angioedema OTHER ASSOCIATIONS — Associations between AAT and vascular disease, inflammatory bowel disease, glomerulonephritis, and vasculitis have been proposed but not definitively established. Vascular disease — Vascular complications are a less well-established consequence of the PI*ZZ phenotype [35,36]. A number of vascular abnormalities have been suggested, including abdominal and intracranial aneurysms and arterial fibromuscular dysplasia, all based on the principle that unopposed proteolytic activity damages vessel walls in severely deficient individuals [8,30]. In addition, one allele (so-called AAT Pittsburgh) is characterized by substitution of an arginine for a methionine at position 358, causing the protein to mimic the hemorrhagic effects of antithrombin III [37]. Two individuals with AAT Pittsburgh have thus far been identified, one of whom died of massive bleeding when the acute phase reactant properties of the AAT protein caused levels of the Pittsburgh variant to rise after a viral infection [37]. Inflammatory bowel disease — It has been hypothesized that decreased antiprotease activity in the bowel may promote local injury and progression to inflammatory bowel disease, although data have been conflicting regarding an association between AAT and inflammatory bowel disease [38]. One case control study from Sweden found that significantly more patients with ulcerative colitis were PI*MZ than in the general population (8.5 versus 4.7 percent), and that PI*MZ individuals tended to have more severe colitis [39]. However, a second study from Germany comparing 135 patients with either Crohn's disease or ulcerative colitis with controls found no such associations [40]. Glomerulonephritis — Glomerular disease is an uncommon finding in AAT. Two different types have been described, one related to AAT and the other to the development of liver failure

¿Cómo seguimos? Resultado de autoanticuerpos y resto del inmunológico Nuevo estudio del Fe + ferritina fuera de la intercurrencia Evaluación con lámpara de hendidura ¿Cobre en orina de 24hs? Dosaje de Alfa 1 Antitripsina

Muchas Gracias!