Hemosiderosis Hepática
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Este documento describe la hemosiderosis hepática, una condición en la que se acumula hierro en el hígado. Explica que puede ocurrir por sobrecarga hereditaria o secundaria a otras enfermedades. Se definen los patrones de depósito de hierro (parenquimatoso, mesenquimático, mixto) y sus causas. También analiza el papel de la biopsia hepática para documentar la presencia de hierro y detectar otras patologías hepáticas.
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Hemosiderosis Hepática
- 1. Hemosiderosis hepáticaHemosiderosis hepática Revisión bibliográfica. M. Mónica García Falcone
- 2. DefinicionesDefiniciones • Hemosiderosis: presencia de pigmento granular férrico. • No es una enfermedad, es un Dx histopatológico. • Hemocromatosis hereditaria: enfermedad hereditaria autosómica recesiva que ocurre por mutaciones en el gen HFE, determinando absorción intestinal aumentada de Fe. • Sinonimia: hemocromatosis 1ria . • Enf. hereditaria monogénica + frecuente en caucásicos. • Hemocromatosis 2ria : hemosiderosis hepática NO genética. HIERRO EN EL HIGADO HEMOSIDEROSIS
- 3. Categorías de sobrecarga Categorías de sobrecarga Hemocromatosis hereditaria Hemosiderosis secundaria a enfermedadees sistémicas Hemosiderosis realacionada a CIRROSIS • Relacionada a HFE (tipo 1), • No relacionada a HFE (tipo 2 A, 2 B, 3 y 4). • Tranfusiones, • Trr eritrocitarios (hemólisis, eritropoyesis infectiva), • Anemia de los ttr. crónicos. • Hemocromatosis neonatal, • Hemosiderosis asociada a hepatitis viral crónica o hígado graso, • Sobrecarga de hierro alimentario africana, • Misceláneos.
- 4. GeneralidadesGeneralidades • El Fe se puede acumular en el hígado en muchos trastornos, el clínicamente más importante es HH. • Hepatocito: • Fe soluble (ferritina, no-granular) + insoluble (hemosiderina, granular). • Puede acumularse en hepatocitos, epitelio de ductus biliares, células endoteliales de venas potales o hepáticas, células endoteliales sinusoidales, células de Kupffer, y macrófagos tisulares en los tractos portales.
- 5. Homeostasis del FeHomeostasis del Fe
- 6. Interpretación MOInterpretación MO Parenquimatoso Mesenquimático Mixto ↑ de absorción Fe, que es llevado al hígado por el sistema porta y se deposita 1ero periportal, en la Zona 1. GRADIENTE ↑ Z3-Z1, deposito en polo biliar del hepatocito. Asociado a hemólisis, hemosiderina en células de Kupffer y/o macrófagos portales. No hay una zona de preferencia. Cnd están implicados los HC es cerca de los macrófagos. Se observa en enfermedades complejas o cuando el depósito es muy extenso. Una vez que se determinó la presencia de HIERRO…Una vez que se determinó la presencia de HIERRO… DEFINIR el PATRON del depósito:DEFINIR el PATRON del depósito:
- 7. Sobrecarga parenquimatosa de FeSobrecarga parenquimatosa de Fe
- 8. Sobrecarga mesenquimática de Fe Sobrecarga mesenquimática de Fe • HH tipo 4 (ganancia de función de ferroportina): • Las mutaciones de la ferroportina producen cualquiera de los dos patrones. • Autosómico dominante, mutación más frecuente en asiáticos y africanos con mutación HH. • Sobrecarga relacionada a transfusiones, anemias hemolíticas, hemodiálisis, y anemia de células falciformes. • Hemosiderina en las células de Kupffer, si es muy severo se forman “nódulos sideróticos” y cuando se sobrepasa la capacidad del SRE comienza a acumularse en hepatocitos.
- 9. Patrón mixto de sobrecargaPatrón mixto de sobrecarga • Condiciones genéticas: • Sobrecarga de hierro africana (Bantu siderosis): sobrecarga de ingesta, genes no identificados, cirrosis. • Porfiria cutánea tarda: 20% mutación que codifica uroporphyrinogen III decarboxylase, inclusiones intrahepatocitarias, esteatosis y esteatohepatitis. • Condiciones no-genéticas: • Síndrome dismetabólico de sobrecarga de hierro: pac con sn. metabólico, predomina depósito sinusoidal. • Hígado graso alcohólico: 5-20%, vino=Fe, coexiste c/HH. • Hígado graso no alcohólico: 1-95%, depósito decreciente de zona 1 a 3, pero en zona 1 no es continuo en todos los hepatocitos. • Hepatitis viral crónica: mayor depósito en el endotelio de la vena portal.
- 10. Cirrosis + hemosiderosisCirrosis + hemosiderosis • La cirrosis independientemente de su etiología puede provocar depósitos significativos de hierro, similares a los hallados en HH (10%) o menos prominentes (2/3). • La hemosiderosis se relaciona con mayor grado de fibrosis y disfunción hepática; se correlacionó en varios estudios con mayor mortalidad.
- 11. Rol actual de la Bx hepática en HH Rol actual de la Bx hepática en HH • Documentar la presencia de hierro, el patrón de distribución, proveer un método semi-cuantitativo de la cantidad de hierro. • Método de Searle modificado Scheuer, etc. • Detectar enfermedades hepáticas coexistentes (patología dual). • Determinar de forma fidedigna el grado de fibrosis (GOLD STANDARD).
- 12. Análisis cuantitativo de Fe hepático: índice hepático férrico (HII) Análisis cuantitativo de Fe hepático: índice hepático férrico (HII) • Espectofotometrometo atómico de absorción, taco de parafina. • Los resultados se obtienen en umg/g o ug/g de peso seco e indican la cantidad de deposito férrico. • Luego, se calcula el HII (1986, Basset et. al) que estima la progresión del depósito a lo largo del tiempo e identifica los pacientes en riesgo de padecer complicaciones.
- 14. ResumenResumen
- 15. Bibliografía (1)Bibliografía (1) Libros: 1.Geller, Stephen A.; Petrovic, Lydia M. Biopsy Interpretation of the Liver, 2nd Edition. 2009 Lippincott Williams & Wilkins. 2.Romil Saxena. Practical Hepatic Pathology, a diagnostic aproach. Pattern recognition series. Ed. Churchil L, 2009. Publicaciones científicas: 1.Batts KP. Iron overload syndromes and the liver. Mod Pathol. 2007 Feb;20 Suppl 1:S31-9. 2.Nair V, Fischer SE, Adeyi OA. Non-viral-related pathologic findings in liver needle biopsy specimens from patients with chronic viral hepatitis. Am J Clin Pathol. 2010 Jan;133(1):127-32. 3.Butensky E, Fischer R, Hudes M, Schumacher L, Williams R, Moyer TP, Vichinsky E, Harmatz P. Variability in hepatic iron concentration in percutaneous needle biopsy specimens from patients with transfusional hemosiderosis. Am J Clin Pathol. 2005 Jan;123(1):146- 52. Libros: 1.Geller, Stephen A.; Petrovic, Lydia M. Biopsy Interpretation of the Liver, 2nd Edition. 2009 Lippincott Williams & Wilkins. 2.Romil Saxena. Practical Hepatic Pathology, a diagnostic aproach. Pattern recognition series. Ed. Churchil L, 2009. Publicaciones científicas: 1.Batts KP. Iron overload syndromes and the liver. Mod Pathol. 2007 Feb;20 Suppl 1:S31-9. 2.Nair V, Fischer SE, Adeyi OA. Non-viral-related pathologic findings in liver needle biopsy specimens from patients with chronic viral hepatitis. Am J Clin Pathol. 2010 Jan;133(1):127-32. 3.Butensky E, Fischer R, Hudes M, Schumacher L, Williams R, Moyer TP, Vichinsky E, Harmatz P. Variability in hepatic iron concentration in percutaneous needle biopsy specimens from patients with transfusional hemosiderosis. Am J Clin Pathol. 2005 Jan;123(1):146- 52.
- 16. Bibliografía (2)Bibliografía (2) 1. Theise ND. Liver biopsy assessment in chronic viral hepatitis: a personal, practical approach. Mod Pathol. 2007 Feb;20 Suppl 1:S3-14. 2. Bergmann OM, et al. Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis? Lab Invest. 2008 Dec;88(12):1349-57. 3. Lobo C, et. Al.; RELATH Investigators. Retrospective epidemiological study of Latin American patients with transfusional hemosiderosis: the first Latin American epidemiological study in iron overload--the RELATH study. Hematology. 2011 Sep;16(5):265-73. 1. Theise ND. Liver biopsy assessment in chronic viral hepatitis: a personal, practical approach. Mod Pathol. 2007 Feb;20 Suppl 1:S3-14. 2. Bergmann OM, et al. Altered expression of iron regulatory genes in cirrhotic human livers: clues to the cause of hemosiderosis? Lab Invest. 2008 Dec;88(12):1349-57. 3. Lobo C, et. Al.; RELATH Investigators. Retrospective epidemiological study of Latin American patients with transfusional hemosiderosis: the first Latin American epidemiological study in iron overload--the RELATH study. Hematology. 2011 Sep;16(5):265-73.
Notas del editor
- ● 1/220 of Northern European ancestry are homozygous for mutation; 1/11 are heterozygous; thus disease is very common
- Friedrich Daniel von Recklinghausen Patólogo alemán 1833-1920. Describio exceso de hierro en higados en autopsia y lo denomino “ hemocromatose ” . Ferritin, the soluble form of iron, cannot be seen on a hematoxylin and eosin stain; a Prussian blue reaction[25] demonstrates a nongranular, pale blue cytoplasmic “ blush ” in hepatocytes and/or macrophages (Fig. 14-2). Hemosiderin, the insoluble form of iron sequestered within cells in membrane-bound lysosomes, appears as golden-brown, refractile granules on a hematoxylin and eosin stain (Fig. 14-3) and as coarse, dark blue particles and granules on a Perls' stain (see Fig. 14-2).
- Los humanos regulamos el hierro variando su absorción intestinal. La única manera de perder hierro es perdiendo sangre y a través del recambio de células intestinales. Absorción diaria baja: 1-2mg/día, pero puede retroalimentarse positivamente. DMT-1 : divalent metral transporter 1. Su presencia deviene de la cantidad de hierro que posee la celula criptica, si hay bajo hierro luminar se produce más. Mutaciones que producen HH se identificaron en todos menos DMT-1 (ferroportina, TRF2, hepcidina, HFE). Ferroportina : transportador de hierro localizado en la zona basal de los enterocitos y en células que exportan hierro, su gen es el SLC40A1. Su expresion es paralela a la de DMT-1. Hay una mutacion en este gen, llamada tipo 4, que produce una acumulación predominantemente en los macrófagos, y se parece al patron de la hemocromatosis secundaria. La hepcidina circulante depternina cuanto funciona el transportador ferroportina. Hepcidina aumenta en inflamación e hipoxia (anemia), es un reactante de fase aguda.
- Pathogenic mutations of FPN, which characterize type 4 HH, are of two types: loss-of-function mutations and gain-of-function mutations. Both are transmitted as autosomal dominant traits. FPN allows export of iron out of cells, and it is present on the basolateral surface of duodenal enterocytes, which export absorbed iron into blood, as well as on macrophages and other storage cells, which export stored iron into the circulation. Loss-of-function mutations reduce cell surface localization of FPN, reducing the cells' ability to export iron.[41–43] These mutations show a mixed pattern of iron accumulation and are discussed later. Gain-of-function mutations do not alter cell surface expression of FPN but rather abolish hepcidin-induced internalization and degradation of FPN.[44–46] Thus, iron continues to be absorbed regardless of need and is stored in a parenchymal distribution similar to HFE-HH. Hereditary aceruloplasminemia is transmitted as an autosomal recessive trait and is characterized by complete absence of ceruloplasmin in serum. Ceruloplasmin is a ferroxidase, which catalyzes the oxidation of ferrous iron to ferric iron, and has a role in uptake of ferric iron by transferrin. The essential role of ceruloplasmin in iron metabolism is demonstrated in copper-deficient animals whose anemia does not respond to administration of iron but is correctable by ceruloplasmin. Microscopically, iron is found predominantly in parenchymal cells.[47,][48] No case of liver cirrhosis has been described even in the most iron-overloaded cases.
- Dysmetabolic Iron Overload Syndrome Dysmetabolic iron overload syndrome (DIOS) is unexplained hepatic iron overload associated with features of metabolic syndrome.[55,][56] Transferrin saturation is usually normal. There is an association between several components of the insulin resistance syndrome (overweight status, hyperlipidemia, and abnormal glucose metabolism) and the development of hepatic iron overload. HFE mutations (C282Y and H63D) involved in HH are not responsible for the development of insulin resistance–hepatic iron overload syndrome, but compound heterozygosity may play a role in the overexpression of iron burden.[55] Features of fatty liver disease, steatosis, or steatohepatitis are present in approximately 50% of cases. However, not all patients reported with DIOS have hepatic steatosis, and patients with fatty liver disease may be regarded as a subset of DIOS. Compared with patients free of steatosis, patients with steatosis were older and more overweight; had higher serum enzyme and ferritin levels; had a higher incidence of periportal fibrosis, portal and lobular inflammation, hepatocytic ballooning, and sinusoidal iron; and had a lower incidence of the C282Y mutation (C282Y heterozygosity and compound heterozygosity).[57] Hepatocellular iron deposits were located mostly in the periportal area with a heterogeneous pattern from one cell to another, whereas sinusoidal deposits were distributed throughout the lobule. In contrast to HH, sinusoidal iron deposition was proportionately higher than hepatocellular deposition; this disparity between hepatocellular and sinusoidal iron deposition may be considered the hallmark of the syndrome.[57] Iron excess is usually mild. However, the hepatic iron index (HII) approaches a value of 2 in 30% of cases. Bridging fibrosis and cirrhosis occur in 12% of cases. The contribution of iron overload in the development and progression of fibrosis in patients with DIOS is not entirely clear. Alcoholic Liver Disease Mild hepatic siderosis in a mixed parenchymal-mesenchymal distribution is seen in 5% to 20% of chronic alcoholics, even when cirrhosis is not present; one study reported a 57% incidence.[58] Animal studies have shown down-regulation of hepcidin by alcohol, and a similar effect is postulated in humans.[58] Alcohol-induced liver disease and genetic hemochromatosis may coexist; in one study, heavy alcohol consumption was found in 15% of hemochromatosis patients.[59] This is pertinent because alcohol is perhaps the single most important factor that induces the phenotypic expression of HH both in terms of accumulation of iron and progression of fibrosis. In one study, HH patients who consumed more than 60 g of alcohol per day were nine times more likely to develop cirrhosis even at a modestly increased HIC than were HH patients who consumed less than 60 g of alcohol per day. HIC was highest in those subjects with heavy alcohol intake; however, not all studies have found a difference in HIC and HII between HH patients who consume alcohol and those who do not.[59] In addition, alcoholic patients developed cirrhosis at a younger age than HH patients who did not consume excess alcohol.[60] In a study of C282Y homozygous relatives of probands with HFE-associated hemochromatosis, 36% of persons who consumed more than 60 g of alcohol had cirrhosis or advanced fibrosis.[61] Alcohol consumption accentuates iron overload, and the two probably have an additive effect, causing oxidative stress, hepatic stellate cell activation, and hepatic fibrogenesis. There is growing evidence that a mild degree of iron overload is sufficient to enhance alcohol-induced liver injury. In alcoholic liver disease, stainable hepatic iron was positively correlated with fibrosis in a multivariate analysis of risk factors in 268 French alcoholic patients.[62] The presence of typical histologic features of alcoholic liver disease (Mallory hyaline, perivenular fibrosis, neutrophils, and steatosis) are indicative of concurrent alcohol use because these findings are not a part of the spectrum of uncomplicated HH.[59] On the other hand, these typical features may disappear in end-stage alcoholic disease; therefore, their absence does not rule out alcohol use. In addition, because cirrhosis of any etiology may demonstrate severe siderosis without underlying HH (as discussed later), the presence of siderosis in cirrhosis does not favor one etiology over the other, especially the distinction of alcoholic cirrhosis with severe iron overload from cirrhosis due to genetic hemochromatosis. Nonalcoholic Fatty Liver Disease Granular iron deposits in hepatocytes and/or RES similar to alcoholic liver disease have been reported in 1% to 95% of patients with nonalcoholic fatty liver disease (NAFLD). The distribution of hepatocellular iron is more or less similar to that of genetic hemochromatosis with a decreasing gradient from periportal zone 1 to zone 3; however, parenchymal zone 1 involvement is not homogeneous. Iron deposition within sinusoidal lining cells is usually panacinar (Fig. 14-10).[33,][63] Iron deposition noted in NAFLD is rarely as marked as in advanced alcoholic liver disease or hereditary hemochromatosis.[64,][65] Increased hepatic iron concentration in nonalcoholic steatohepatitis (NASH) is associated with increased portal hepatic fibrosis.[66] It has been proposed that iron, in relatively low concentrations, could synergize with lipid overload and induction of CYP2E1 to increase oxidative stress in hepatocytes.[67] Iron may contribute to the development or exacerbation of insulin resistance, which is the most important risk factor for development of NAFLD and NASH.[68] Conclusions regarding the presence and possible role of HFE mutations; abnormal indices of iron metabolism, most commonly hyperferritinemia; and alterations of insulin metabolism with both the presence and progression of fibrosis continue to vary in different studies.[68–70] Some studies show associations between C282Y or H63D, iron accumulation, and severity of liver disease in patients with NASH. In one study, there was a higher prevalence of homozygotes and heterozygotes for C282Y in a study of Australian patients with NASH.[66] Bonkovsky and colleagues reported a significantly increased prevalence of H63D heterozygosity in patients with NASH versus controls. Heterozygosity for C282Y was not statistically different between the two groups.[71] Other investigators have failed to find significant associations between hepatic iron accumulation, HFE mutations, and the severity of liver disease in patients with NASH.[72–75] Chronic Viral Hepatitis Chronic viral hepatitis is not uncommonly accompanied by mild hemosiderin deposition, which may occur in hepatocytes with zone 1 predominance, in Kupffer cells, or in portal macrophages.[76] There may be evidence of iron overload in the form of elevations in serum ferritin and iron saturation. However, most patients with these characteristics do not have elevations of HIC; when an increase in HIC does occur, it is usually mild. A higher incidence of hemosiderin deposition in portal vein endothelium has been noted in chronic hepatitis B, chronic hepatitis C, and autoimmune hepatitis but not in primary biliary cirrhosis or alcoholic liver disease. This pattern of iron has been associated in some studies with disease progression as assessed by fibrosis stage and with the presence of interface activity in chronic hepatitis C and B. Endothelial cell iron loading and a lack of response to interferon therapy have been shown to play a role by some, but not all, authors.[77] This is a subtle pattern and requires attention to detect. Yano and associates reported that depletion of the iron through phlebotomy appears to lower serum transaminase values and decrease inflammation, and may slow progression of hepatitis C.[78] Several studies[79–81] have shown an increased prevalence of the C282Y mutation in patients with chronic hepatitis C. These patients have higher serum iron saturations, more stainable iron, and more advanced fibrosis at a younger age compared with patients without the genetic mutation; this is especially true for those who are homozygous for C282Y. Whether the observations reflect the effect of iron on hepatic disease, or whether HFE mutations and iron overload in some way contribute to susceptibility for developing chronic hepatitis C after an acute infection, is currently not known.
- In the case of end-stage cirrhosis, the predominantly hepatocellular loading most likely results from decreased hepcidin production as a result of both a decreasing liver mass and abnormal liver function. As cirrhosis progresses, the situation is accentuated by the presence of infections, which cause further decrease in hepcidin levels, and by intrahepatic vascular events, which further reduce hepatic mass by causing drop-out of parenchymal nodules (parenchymal extinction).[89] The potential causes for hepatic iron overload in alcoholic liver disease and alcoholic cirrhosis are detailed in several reviews. In a sampling of one such review,[91] the causes of iron overload included increased ingestion of iron, increased intestinal iron absorption, up-regulation of hepatic transferrin receptor 1, secondary anemia caused by hemolysis, hypersplenism, ineffective erythropoiesis, and hypoxemia resulting from intrapulmonary shunts and portosystemic shunts. Increased iron absorption could arise through three main mechanisms: (1) an increase in the reduction of luminal iron to the ferrous state, (2) up-regulation of DMT1 in duodenal enterocytes, and (3) up-regulation of FPN in duodenal enterocytes. The latter mechanism may be influenced by down-regulation of hepcidin production by ethanol.
- Differential Diagnosis Prior to the availability of genetic testing for HFE mutations, liver biopsy had been the gold standard for diagnosis of HH, which was established by estimating the HII and evaluating the histologic pattern of iron distribution. This role is now supplanted by genetic tests; however, because of the low phenotypic penetrance of the HFE genes, the mere presence of genetic mutations does not equate to iron overload. Thus, irrespective of the presence or absence of genetic mutations, the degree of iron overload is established by the levels of serum ferritin, serum iron, and transferrin saturation. Ferritin is an acute phase reactant, and its value may be affected by inflammatory conditions; however, in the absence of these confounding conditions, ferritin remains a sensitive indicator of iron stores. These serum markers of iron overload are also used to monitor phlebotomy therapy. Reliable noninvasive markers of fibrosis have not yet been defined; therefore, the liver biopsy continues to provide important information on the presence and progression of fibrosis, albeit in selected patients with the usual genotypes of HH.[92] An algorithm as when to obtain a liver biopsy in genetic hemochromatosis with regard to HFE genotype has been proposed in a French study. In C282Y homozygotes, liver biopsy is no longer necessary for diagnosis but remains suitable with respect to prognosis. Guyader and coworkers[93] found that no significant fibrosis was present in C282Y homozygotes that had normal aspartate aminotransferase levels, serum ferritin levels less than 1000 ng/mL, and no hepatomegaly. On the contrary, when one, two, or all these conditions were not met, there was a significant risk of fibrosis as calculated by a mathematical equation. As such, there is consensus to perform liver biopsy for evaluation of fibrosis in C282Y homozygotes with increased liver size, serum ferritin levels higher than 1000 ng/mL, or abnormal serum aspartate aminotransferase levels except when the diagnosis of cirrhosis is clinically obvious or when the predictive equation gives a risk close to 100%. In a C282Y-H63D compound heterozygote presenting with mild increase in transferrin saturation (between 45% and 60%) and in serum ferritin (usually <500 ng/mL) but with no biochemical abnormalities or clinical liver symptoms, it can be reasonably assumed that the HFE genotype is responsible for the abnormalities in iron metabolism and that the patient is free of risk of fibrosis. A liver biopsy is not necessary in these cases. In all other cases, a liver biopsy must be obtained irrespective of the HFE genotype.[28] The role of liver biopsy has therefore changed from an essential diagnostic tool to a method of estimating prognosis and evaluating coexistent disease. The availability of a definite genetic test for HH has allowed for correlation with histologic features and better understanding of the pathophysiology of iron accumulation. These findings, some of which are contrary to historical paradigms, are: • Considerable overlap exists in patterns of iron deposition between genetic and nongenetic causes of hepatic iron overload. • There is evidence to show that although predominant RES iron deposition may serve as a strong negative predictor of HFE-related HH, the reverse is not necessarily true.[40] In Brunt's series, approximately 22% of patients with predominantly hepatocellular iron deposition had the wild-type HFE gene. Thus, the HH pattern of iron deposition may be seen in other forms of liver disease besides HH. As discussed previously, nongenetic disorders such as thalassemia or spur cell anemia in cirrhosis may closely mimic HH. • A subset of patients with type 4 HH, characterized by loss-of-function mutations of FPN, result in iron deposition primarily in macrophages, thus mimicking the pattern seen in iron overload secondary to transfusion and hemolytic blood disorders. • One pattern can evolve over time into another. For example, a parenchymal pattern may evolve into a mixed pattern with progressive iron overload. • The extent of iron deposition in patients with genetic hemochromatosis is variable. First of all, penetrance of the genotypes is neither uniform nor absolute, and secondly, the genotype is modified significantly by environmental factors.[94–96] Thus, many heterozygotes turn out to be homozygotes as a result of low phenotypic penetrance of the genes. Males are affected more often and severely than females, who are protected from severe iron deposition because of the blood loss from menstruation and pregnancy. Thus, liver biopsy alone is not enough to diagnose with specificity the underlying cause of iron overload and must be combined with additional tests. The role of the pathologist is to document the presence of excess iron, its pattern of distribution (cellular and acinar localization), and to provide a semiquantitative assessment of amount to alert the clinician to the possibility of a significant condition. The pathologist should be aware of the patterns of iron deposition (see Table 14-2) and their predictive values, especially the negative predictive value.[40] The liver biopsy remains the only diagnostic tool for evaluation of fibrosis in many cases and can detect coexistent chronic liver disease that may contribute to liver injury.