1 Insuficiencia Hepática e Hipertensión PortalDr. Michel Baró A

2 Daño Hepático agudo necrosis Insuficiencia hepáticaregeneración Insuficiencia hepática encefalopatía hepática crónico cirrosis hipertensión portal hepatocarcinoma

3 Funciones del hígado: Digestión Síntesis de la bilisDetoxificación hormonas y compuestos extraños Biosíntesis Síntesis factores de coagulación, albúmina Energía del Metabolismo Metabolismo de glúcidos, proteínas, grasas Otras Funciones Filtración y almacenamiento de sangre Almacenamiento de vitaminas y hierro

4 Tests de evaluación del hígado“Pruebas (daño) hepáticas” Tests de función hepática GOT/ASAT GPT/ALAT Bilirrubina total Bilirrubina directa Fosfatasas alcalinas GGT LDH Albúmina Protrombina Colesterol total Amonemia Bromosulftaleína Verde indocianina

5 Insuficiencia hepática hipoglicemia hemorragia Disminución síntesisedema Insuficiencia hepática ictericia Disminución depuración encefalopatía hiperestrogenismo

6 Estimated prevalence of common causes of acute liver failure worldwideFigure 7-1. Estimated prevalence of common causes of acute liver failure worldwide. Great variation is observed between the United Kingdom (high prevalence of acetaminophen toxicity) and India (predominantly hepatitis B and others, including a large percentage of hepatitis E cases) [24]. An increasing proportion of acute liver failure in the United States is attributable to acetaminophen. Although generally with better outcomes, these cases may account for more than 50% of patient hospital admissions for acute liver failure in certain urban areas [2], [13]. Furthermore, significant numbers of unintentional acetaminophen poisoning cases are being recognized, in which the medication is taken to relieve pain, without suicidal intent. Whether ethanol abuse is a cofactor in these cases is not entirely clear. References: [24]. Lee WM, Schiodt FV, Fulminant hepatic failure. In Schiff's Textbook of Liver Diseases. Edited by Schiff ER, Sorrell MF, Maddrey WC. New York: Lippincott-Raven; 1999 [2]. Lee WM, Medical progress: acute liver failure. N Engl J Med [13]. Schiodt FV, Rochling FA, Casey DL, Lee WM, Acetaminophen toxicity in an urban county hospital. N Engl J Med

7 Principal causes of acute liver failureTable 7-2. Principal causes of acute liver failure. Cause of acute liver failure is important because it determines prognosis. In some instances, initial management must be directed at the specific cause. Disease-specific treatments include antidotes to acetaminophen and mushroom poisoning that must be given immediately on patient admission to the hospital. Identification of severe heart failure as the cause indicates proper resuscitation and correction of any fluid balance disturbance. Likewise, recognition of acute fatty liver of pregnancy leads to consideration of delivery of the mother as the logical treatment for this condition. Patients with fulminant Wilson disease carry such a poor prognosis that urgent listing for transplantation must be immediately undertaken once this diagnosis is made, although therapy with trientine or penicillamine is often initiated. Toxinas (micetismo)

8 Reactivation of inactive hepatitis B after chemotherapy (A)Figure 7-3. Reactivation of inactive hepatitis B after chemotherapy. Patients with fulminant hepatitis B infection often clear the virus rapidly, presumably as the result of a vigorous immune response. In these patients, hepatitis B surface antigen (HBsAg) and even hepatitis B virus DNA may be undetectable on or shortly after presentation. Anti-hepatitis B core IgM antibodies (anti-HBcIgM) will usually be positive in these cases and may aid in diagnosing HBV as the cause of acute liver failure. If liver transplantation is required for patients with early clearance, prognosis is generally good in that infection of the new liver graft rarely occurs. Intravenous drug users are sometimes found to have combined hepatitis B and D or B and C infections. The combination of these infections tends to carry a higher morbidity than either alone, but hepatitis C by itself virtually never causes true acute liver failure [3], [4], [17]. The combination of acute hepatitis B with acute hepatitis D is also an uncommon cause of acute liver failure; clearance of hepatitis B infection aborts continued delta infection, and each virus appears to inhibit replication of the other to some extent, thus facilitating clearance of both. Mutations in the hepatitis B virus precore and core promoter regions are common in cases of acute liver failure secondary to hepatitis B, and these variants are usually hepatitis B early antigen negative on serologic analysis [25].It is not clear whether these mutations are directly related to the fulminant course.Another scenario in which hepatitis B may cause acute liver failure is through reactivation of inactive hepatitis B during or after certain regimens of cancer chemotherapy. The patient in this figure developed acute liver failure from reactivated hepatitis B after receiving CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy for lymphoma. A, Prominent ground-glass cytoplasmic inclusions of the virus in a background of acute hepatitis (hematoxylin and eosin, ×400). B, Architectural disruption with intracellular fibrosis and hepatocyte necrosis (trichrome, ×100). C, Immunohistochemical stain for hepatitis B surface antigen showing diffuse strong cytoplasmic reactivity (×100). D, Immunohistochemical stain for hepatitis B core antigen showing nuclear reactivity (×100).The antiviral agents lamivudine and adefovir, used widely in the treatment of chronic active hepatitis B, may be considered in patients with fulminant hepatitis B, although experience with these drugs in severe hepatitis or acute liver failure is still quite limited. (Courtesy of Guy Lindberg, MD; University of Texas Southwestern Medical Center, Dallas.)CHOP—cyclophosphamide, doxorubicin, vincritine, prednisone; DNA—deoxyribonucleic acid; HbcIgM—anti hepatitis B core IgM antibodies; HBsAg—hepatitis B surface antigen; HBV—hepatitis B virus; IgM—immunoglobulin M. References: [3]. Ostapowicz GA, Fontana RJ, Schiodt FV, and the US Acute Liver Failure Study Group, Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States. Ann Intern Med [4]. Lee WM, Acute liver failure in the United States. Semin Liver Dis in press [17]. Schiodt FV, Davern TA, Shakil O, et al. Viral hepatitis-related acute liver failure. Am J Gastroenterol [25]. Teo EK, Ostapowicz G, Hussain M, et al. Hepatitis B infection in patients with acute liver failure in the United States. Hepatology

9 Acetaminophen metabolic pathwayFigure 7-4. Acetaminophen metabolic pathway. The main metabolic pathways for xenobiotic metabolism by the liver are divided into phase I (using cytochromes P-450), phase II (sulfation and glucuronidation), and the glutathione-S-transferase system. Acetaminophen is a prime example of a well-understood metabolic pathway that uses all three mechanisms. Acetaminophen in therapeutic doses undergoes sulfation and glucuronidation (phase II reactions) but is metabolized by cytochrome P-450 2E1 (phase I reaction) to the toxic metabolite N-acetyl-p-benzoquinoneimine (NAPQI) if the capacity of the phase II reactions is exceeded or if the cytochrome is induced. Glutathione-S-transferase is capable of detoxifying NAPQI to mercapturic acid if glutathione is available; N-acetylcysteine is an excellent source of glutathione substrate. Acetaminophen serves as an example of a direct toxin, one in which toxicity occurs in all individuals and is dose related, and in which all animal models demonstrate similar reactions. In alcoholic patients or individuals who are malnourished, glutathione depletion accentuates the liver injury. In addition, induction of P-450 2E1 by ethanol and some other drugs may enhance formation of NAPQI. This metabolite may cause hepatocyte damage via covalent binding to intracellular proteins [26]. Derangements in the regulation of apoptosis may also contribute to hepatocyte destruction [27], and the xenobiotic receptor CAR (constitutive androstane receptor) has recently been identified as a key regulator of acetaminophen metabolism and hepatoxicity in mice, suggesting new possibilities for potential hepatoprotective therapies in humans [28].CAR—constitutive androstane receptor; NAPQI—N-acetyl-p-benzoquinoneimine. References: [26]. Ostapowicz G, Lee WM, Management of acetaminophen toxicity. In Drugs and the Liver. Edited by Deleve L, Kaplowitz N. : ; [27]. Reed JC, Apoptosis-regulating proteins as targets for drug discovery. Trends Mol Med [28]. Zhang J, Huang W, Chua SS, et al. Modulation of acetaminophen-induced hepatotoxicity by the xenobiotic receptor CAR. Science N-acetyl-p-benzoquinoneimine

10 Acetaminophen toxicity nomogramFigure 7-5. Acetaminophen toxicity nomogram. This nomogram aids in determining the likelihood of serious acetaminophen hepatotoxicity using plasma levels and the estimated time of the ingestion-to-sampling interval. Levels falling in the lower zone indicate that the liver damage should be mild, and those falling in the upper zone indicate that damage will be severe. Use of N-acetylcysteine (NAC) as an antidote is indicated in either case, because it is quite safe and acetaminophen toxicity is sometimes unpredictable, particularly when the interval from ingestion to clinical presentation is long or unknown, or when it has occurred over several days, rather than at a single timepoint. NAC may still have some value 48 hours or more following ingestion. (Adapted from Zimmerman [29].)NAC—N-acetylcycteine. References: [29]. Zimmerman HJ, The adverse effects of drugs on the liver. In Hepatotoxicity New York: Appleton Century Crofts;

11 Drugs implicated in idiosyncratic liver injury leading to acute liver failureTable 7-6. Drugs implicated in idiosyncratic liver injury leading to acute liver failure. A wide variety of medications have been associated at one time or another with acute liver injury. Although some drugs have never been implicated, others are well known as occasional acute hepatotoxins. The frequency of such reactions may vary from one in 100 patients receiving isoniazid to one in 10,000 patients receiving halothane, or less with many other compounds. Implication of a given drug requires that the physician make a careful listing of all agents taken by the patient, the time period involved, and the quantity ingested. Most examples of hepatotoxicity occur within the first 4 to 8 weeks of drug initiation. Combination agents may have enhanced toxicity in comparison to that experienced with either ingredient alone. It is important to note that certain herbal preparations and other nutritional supplements have been implicated in causing liver injury, so that inquiry about such substances must be made during a complete medication history [30]. References: [30]. Stedman C, Herbal hepatotoxicity. Semin Liver Dis

12 Acute liver failure caused by Wilson diseaseTable 7-7. Acute liver failure caused by Wilson disease. Although Wilson disease is an uncommon cause of acute liver failure, early diagnosis is crucial, as it is almost universally fatal without hepatic transplantation. This diagnosis should be considered in all young individuals (& 30 years of age) with acute liver failure. Wilson disease is often accompanied by a non-immune hemolytic anemia thought to be due to increased levels of plasma copper, which results in an exaggerated high bilirubin level. A depressed serum alkaline phosphatase is also seen. Serum ceruloplasmin may be normal in up to 15% of cases, and high serum and urinary copper levels as well as a high hepatic copper level are helpful in diagnosis [31]. References: [31]. Schilsky ML, Diagnosis and treatment of Wilson's disease. Pediatr Transplant

13 Basic physical findings in acute liver failureFigure 7-8. Basic physical findings in acute liver failure. Typical features observed in the patient with acute liver failure include confusion, agitation, and possibly hallucination. Mental status may deteriorate quickly to coma, making history taking difficult. Most patients will be icteric, although some barely so. Spider angiomata as seen in cirrhotic patients should be absent. Tachycardia, tachypnea, and relative hypotension are common. Asterixis, so commonly observed in chronic hepatic encephalopathy, is rarely seen. Fetor hepaticus, a sweet but pungent odor caused by mercaptans excreted in the breath, is often noted. Percussion over the rib cage to detect hepatic dullness may reveal a considerably decreased liver span; at times no dullness may be appreciated as evidence of the loss of hepatic mass. At autopsy, the normal liver mass of approximately 1600 g may be reduced to as little as 600 g. Edema is not observed initially but may develop during the course. Although the extremities are often cold, after resuscitation "warm shock" is the rule.

14 Cerebral edema on CT scanning in a patient with acute liver failure (A)Figure Cerebral edema on CT scanning in a patient with acute liver failure. A, CT of a normal brain showing clear demarcation between gray and white matter. B, A similar section showing obliteration of gray and white matter demarcation caused by increased cerebral water. Obliteration of brain sulci is also seen but is a less consistent finding. Evidence of edema using CT is a late and inconstant finding in cerebral edema patients and thus is not a reliable guide to therapy. The presence of edema has two possible adverse effects. First, it decreases cerebral blood flow and may result in brain anoxia. The cerebral perfusion pressure (systemic blood pressure minus intracerebral pressure) should be maintained above 40 mm Hg to preserve adequate brain oxygenation. Second, herniation of the brain stem through the falx cerebri caused by cerebral edema is uniformly fatal. Erratic changes in blood pressure, temperature, or breathing pattern imply impending herniation.

15 Physical findings in patients with advanced hepatic encephalopathy and cerebral edemaFigure Physical findings in patients with advanced hepatic encephalopathy and cerebral edema. Typically, patients experience a brief period of agitation before the development of coma. Hepatic coma is usually graded as I through IV. Grade I is signified by altered personality and subtle changes in cognition. Grade II includes frank disorientation, slurred speech, inappropriate behavior, and occasionally asterixis, but the patient remains able to follow commands. Grade III is characterized by deepening confusion with incoherent verbalizations, sleeping most of the time but responsive to strong stimuli. Grade IV patients are completely comatose and unresponsive even to pain. Hyperventilation is universal in all stages. In grade IV (and sometimes in grade III) hepatic coma, changes in breathing pattern, seizures, and pupillary abnormalities all may occur in the setting of cerebral edema. Grade IV patients may demonstrate decorticate or decerebrate posturing. These signs, alone or in association with systemic hypertension, warrant immediate evaluation for and pursuit of transplantation, if possible, and careful management of intracranial hypertension. Mannitol is still the mainstay of therapy, but other measures such as careful hemodynamic and renal monitoring, raising the head of the bed to 30°, maintaining a low stimulus environment, and managing seizure activity are important as well [18]. Patients in stage III or IV encephalopathy may have subclinical seizure activity; routine electroencephalogram monitoring and prophylaxis with phenytoin may be considered [32]. References: [18]. Hay JE, McGuire B, Ostapowicz G, Lee WM, Management of fulminant hepatic failure in the USA: results from a survey of 14 liver transplant programs. Gastroenterology (suppl 1) 542A [32]. Ellis AJ, Wendon JA, Williams R, Subclinical seizure activity and prophylactic phenytoin infusion in acute liver failure: a controlled clinical trial. Hepatology

16 Oxygen delivery curve Figure Oxygen delivery curve. Patients with acute liver failure (ALF) develop a pathologic oxygen supply-dependency curve and extract oxygen over a wider range of delivery than normal. Hypoxia occurs in peripheral tissues frequently leading to lactic acidosis. Changes in peripheral oxygenation are poorly understood but appear to be the result of vasodilatation, low perfusion pressure caused by low systemic arterial pressure, platelet plugging of capillaries, and interstitial edema, all of which result in shunting of blood and, subsequently, tissue hypoxia. The same abnormalities in oxygen delivery can be observed in adult respiratory distress syndrome (ARDS) and in sepsis. To optimize fluid intake in these patients, it is important to perform pulmonary artery pressure monitoring. Use of a-adrenergic agents is discouraged because it may worsen peripheral oxygen delivery. (Adapted from MacNaughton and Evans [33].)ALF—acute liver failure; ARDS—adult respiratory distress syndrome. References: [33]. MacNaughton PD, Evans TW, Management of adult respiratory distress syndrome. Lancet

17 Renal parameters in acute liver failureTable Renal parameters in acute liver failure. Massive alterations in hemodynamics occur in acute liver failure and the mechanisms underlying these changes are incompletely understood. In many respects, these patients resemble those with hepatorenal syndrome caused by advanced cirrhosis. Fluid deficits occur initially because of altered mental status leading to decreased per os intake, transudation of fluid into the extravascular space, and possibly gastrointestinal bleeding; most patients require extensive fluid resuscitation on hospital admission. Low systemic vascular resistance exacerbates this problem, and it may be necessary to place a pulmonary artery catheter to properly assess fluid needs. Fluid replacement should emphasize colloid, rather than crystalloid, although intravenous glucose may also be required for maintenance of satisfactory blood glucose levels. Diuretics should be considered only if intravascular volume has been fully restored and pulmonary or cerebral edema is a consideration. Direct renal toxicity is sometimes observed in acetaminophen overdose and will manifest as oliguria. Although few patients die as the result of renal failure alone, it often contributes to mortality; both renal failure and lactic acidosis are ominous signs in patients with acute liver failure [34]. References: [34]. O'Grady JG, Gimson AES, O'Brien CJ, et al. Controlled trials of charcoal hemoperfusion and prognostic factors in fulminant hepatic failure. Gastroenterology

18 Intraoperative photographs of related living-donor liver transplantation (A)Figure Intraoperative photographs of related living-donor liver transplantation. Orthotopic liver transplantation is now the accepted treatment for acute liver failure in individuals who are unlikely to survive otherwise, but there are still many patients who die without receiving a graft. Although some of these patients are not suitable candidates for various reasons, numerous others do not undergo transplantation because of logistical problems (eg, difficulty in transporting a patient to a transplantation center, failure to obtain an organ donor within the critical time period). Furthermore, transplantation is costly and carries with it the problems of lifelong immunosuppression for a condition that may be self-limited. Patients who recover from acute liver failure apparently do so completely; therefore, less dramatic modes of treatment are more preferable if safe and effective.Auxiliary heterotopic transplantations, which entail the placement of a graft in the abdomen without removal of the native liver, may serve as a temporary bridge, allowing support for 4 to 6 months as the native liver recovers (see Figure 7-11). In the absence of immunosuppression, the transplanted organ will eventually be rejected. Partial organ transplants, in which a left or right lobe is replaced in the orthotopic position, may also enable liver function to be maintained until the patient's own liver returns to normal [35].Extracorporeal liver-assist devices, consisting of cartridges employing living hepatocytes from other species or tissue culture lines, hold promise for providing temporary liver support until transplantation can be carried out or the native liver regenerates. Temporary support can also be provided by extracorporeal whole-organ perfusion. Another treatment in the early stages of development is hepatocyte transplantation. This involves the infusion of liver cells into the peritoneum or splenic pulp. These cells have been shown to carry out some liver functions until the host rejects them.Several hepatocyte growth factors have been identified that may aid hepatic regeneration, but preliminary studies do not show significant efficacy. Because growth factor levels tend to be elevated in acute liver failure, the likelihood of real benefit is small. In contrast, N-acetylcysteine, routinely used for acetaminophen toxicity, has also been shown to result in hemodynamic improvements and greater oxygen delivery in patients with non-acetaminophen-induced acute liver failure. Its effect on survival is still not known, and a clinical trial is currently addressing this issue.Grafts from living donors are often used in pediatric liver transplantation, but this practice in adult patients continues to generate controversy. A recent survey found that performance of living-donor liver transplantation in adults is increasing in frequency in the United States, although it is concentrated in relatively few high-volume centers [36]. Nonfatal complications in donors are relatively common, and although donor mortality is low, any death of a previously healthy individual under such circumstances understandably raises great concern. A, Right lobe graft. B, Left lobe graft. (Courtesy of Robert S. Brown, Jr., MD, MPH; Columbia University College of Physicians and Surgeons, Columbia-Presbyterian Medical Center, New York.) References: [35]. Jaeck D, Boudjema K, Audet M, et al. Auxiliary partial orthotopic liver transplant (APOLT) in the treatment of acute liver failure. J Gastroenterol [36]. Brown RS, Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med

19 Intraoperative photographs of related living-donor liver transplantation (B)Figure Intraoperative photographs of related living-donor liver transplantation. Orthotopic liver transplantation is now the accepted treatment for acute liver failure in individuals who are unlikely to survive otherwise, but there are still many patients who die without receiving a graft. Although some of these patients are not suitable candidates for various reasons, numerous others do not undergo transplantation because of logistical problems (eg, difficulty in transporting a patient to a transplantation center, failure to obtain an organ donor within the critical time period). Furthermore, transplantation is costly and carries with it the problems of lifelong immunosuppression for a condition that may be self-limited. Patients who recover from acute liver failure apparently do so completely; therefore, less dramatic modes of treatment are more preferable if safe and effective.Auxiliary heterotopic transplantations, which entail the placement of a graft in the abdomen without removal of the native liver, may serve as a temporary bridge, allowing support for 4 to 6 months as the native liver recovers (see Figure 7-11). In the absence of immunosuppression, the transplanted organ will eventually be rejected. Partial organ transplants, in which a left or right lobe is replaced in the orthotopic position, may also enable liver function to be maintained until the patient's own liver returns to normal [35].Extracorporeal liver-assist devices, consisting of cartridges employing living hepatocytes from other species or tissue culture lines, hold promise for providing temporary liver support until transplantation can be carried out or the native liver regenerates. Temporary support can also be provided by extracorporeal whole-organ perfusion. Another treatment in the early stages of development is hepatocyte transplantation. This involves the infusion of liver cells into the peritoneum or splenic pulp. These cells have been shown to carry out some liver functions until the host rejects them.Several hepatocyte growth factors have been identified that may aid hepatic regeneration, but preliminary studies do not show significant efficacy. Because growth factor levels tend to be elevated in acute liver failure, the likelihood of real benefit is small. In contrast, N-acetylcysteine, routinely used for acetaminophen toxicity, has also been shown to result in hemodynamic improvements and greater oxygen delivery in patients with non-acetaminophen-induced acute liver failure. Its effect on survival is still not known, and a clinical trial is currently addressing this issue.Grafts from living donors are often used in pediatric liver transplantation, but this practice in adult patients continues to generate controversy. A recent survey found that performance of living-donor liver transplantation in adults is increasing in frequency in the United States, although it is concentrated in relatively few high-volume centers [36]. Nonfatal complications in donors are relatively common, and although donor mortality is low, any death of a previously healthy individual under such circumstances understandably raises great concern. A, Right lobe graft. B, Left lobe graft. (Courtesy of Robert S. Brown, Jr., MD, MPH; Columbia University College of Physicians and Surgeons, Columbia-Presbyterian Medical Center, New York.) References: [35]. Jaeck D, Boudjema K, Audet M, et al. Auxiliary partial orthotopic liver transplant (APOLT) in the treatment of acute liver failure. J Gastroenterol [36]. Brown RS, Russo MW, Lai M, et al. A survey of liver transplantation from living adult donors in the United States. N Engl J Med

20 Massive liver necrosis secondary to halothane anesthesiaFigure Massive liver necrosis secondary to halothane anesthesia. This 55-year-old woman died 35 days after halothane anesthesia for a cholecystectomy. Twenty years prior, she had undergone a hysterectomy with halothane. The patient became ill 2 weeks after her surgery and became comatose 2 weeks later, never regaining consciousness. The liver was small and shrunken, with a wrinkled capsule, and weighed only 680 g (normal liver weight, 1400–1600 g). This finding was formerly referred to as acute yellow atrophy.

21 Histologic findings in a selection of patients with acute liver failure (A)Figure Histologic findings in a selection of patients with acute liver failure. A, Normal liver for comparison. In this photomicrograph of a normal hepatic lobule, a portal tract (P) and hepatic venule (V) are highlighted. The liver cells appear uniform and cuboid in single-cell plates lining the sinusoids. Very few inflammatory cells are present, and no signs of hepatocyte regeneration exist (hematoxylin and eosin, ×145). B, Autopsy specimen from a young girl who died of cerebral edema 7 days after an apparent acetaminophen ingestion. Moderately severe centrilobular necrosis is present, but viable hepatocytes are seen in the periportal regions (hematoxylin and eosin, ×145). C and D, Massive hepatic necrosis caused by halothane. The patient (whose liver is shown in Figure 7-13) died 35 days after a cholecystectomy during which she had received halothane anesthesia, probably representing her second exposure to the drug. Virtually the entire hepatic lobule appears necrotic, with fibrinoid cellular debris interspersed between portal tracts that appear to be in close proximity because of massive collapse of the intervening hepatocytes (Masson's trichome, C, ×145; D, ×185). E, Reye's syndrome. This infant was admitted with liver failure shortly after developing an upper respiratory infection that was treated with aspirin. Massive infiltration of hepatocytes with microvesicular fat is seen as pale areas within cells. There is little inflammation or evidence of necrosis. The finding of microvesicular fat is characteristic of Reye's syndrome as well as of fatty liver of pregnancy and exposure to certain nucleoside analogues (fialuridine, didanosine, and possibly zidovudine) (hematoxylin and eosin, ×185). F, Wilson disease. This autopsy photomicrograph is of a 16-year-old girl with a 2-week illness characterized by fatigue, confusion, and deep jaundice. Bilirubin level on admission to the hospital was 38 mg/dL, and she died on the fifth hospital day. Widespread hepatocyte necrosis and bile staining are present. There is evidence of some increased fibrosis and early cirrhosis in other sections. As in the halothane case, few remaining viable hepatocytes are seen (hematoxylin and eosin, ×185). G, Metastatic melanoma. This 58-year-old man presented with altered mental status, hepatomegaly, and jaundice 6 months after enucleation of his right eye for melanoma. The sinusoids are packed with malignant cells that appear to contain pigment (melanin). Ischemic necrosis of hepatocytes is presumed to result from sinusoidal obstruction. Liver biopsy is indicated in fulminant hepatic failure if the liver is massively enlarged, thus suggesting an infiltrative process. Transplantation would be inappropriate here and biopsy would therefore clarify the diagnosis (hematoxylin and eosin, ×145). H, Advanced tuberculosis. This 63-year-old man presented with a febrile illness of 2 weeks' duration, accompanied by jaundice and obtundation. At autopsy, massive replacement of the liver by granulomas containing tubercle bacilli was present. The patient had no other associated illnesses (hematoxylin and eosin, ×145). I, Amyloidosis. Massive infiltration of the hepatic sinusoids with amyloid appears to displace hepatocytes and cause atrophy of cells (hematoxylin and eosin, ×185). J, Ischemic myocardiopathy causing ischemic necrosis of hepatocytes. This 54-year-old overweight man complained of fatigue and somnolence but was not found to be short of breath and had no history of heart failure. Prothrombin time was 16 seconds, alanine aminotransferase was 1830 IU/L, serum ammonia was 135 mg/dL (normal & 30), and the ejection fraction was determined to be 16%. The centrilobular region shows dilated sinusoids and considerable necrosis of hepatocytes. His symptoms resolved with a cardiotonic regimen.

22 Histologic findings in a selection of patients with acute liver failure (B). AcetoaminofenoFigure Histologic findings in a selection of patients with acute liver failure. A, Normal liver for comparison. In this photomicrograph of a normal hepatic lobule, a portal tract (P) and hepatic venule (V) are highlighted. The liver cells appear uniform and cuboid in single-cell plates lining the sinusoids. Very few inflammatory cells are present, and no signs of hepatocyte regeneration exist (hematoxylin and eosin, ×145). B, Autopsy specimen from a young girl who died of cerebral edema 7 days after an apparent acetaminophen ingestion. Moderately severe centrilobular necrosis is present, but viable hepatocytes are seen in the periportal regions (hematoxylin and eosin, ×145). C and D, Massive hepatic necrosis caused by halothane. The patient (whose liver is shown in Figure 7-13) died 35 days after a cholecystectomy during which she had received halothane anesthesia, probably representing her second exposure to the drug. Virtually the entire hepatic lobule appears necrotic, with fibrinoid cellular debris interspersed between portal tracts that appear to be in close proximity because of massive collapse of the intervening hepatocytes (Masson's trichome, C, ×145; D, ×185). E, Reye's syndrome. This infant was admitted with liver failure shortly after developing an upper respiratory infection that was treated with aspirin. Massive infiltration of hepatocytes with microvesicular fat is seen as pale areas within cells. There is little inflammation or evidence of necrosis. The finding of microvesicular fat is characteristic of Reye's syndrome as well as of fatty liver of pregnancy and exposure to certain nucleoside analogues (fialuridine, didanosine, and possibly zidovudine) (hematoxylin and eosin, ×185). F, Wilson disease. This autopsy photomicrograph is of a 16-year-old girl with a 2-week illness characterized by fatigue, confusion, and deep jaundice. Bilirubin level on admission to the hospital was 38 mg/dL, and she died on the fifth hospital day. Widespread hepatocyte necrosis and bile staining are present. There is evidence of some increased fibrosis and early cirrhosis in other sections. As in the halothane case, few remaining viable hepatocytes are seen (hematoxylin and eosin, ×185). G, Metastatic melanoma. This 58-year-old man presented with altered mental status, hepatomegaly, and jaundice 6 months after enucleation of his right eye for melanoma. The sinusoids are packed with malignant cells that appear to contain pigment (melanin). Ischemic necrosis of hepatocytes is presumed to result from sinusoidal obstruction. Liver biopsy is indicated in fulminant hepatic failure if the liver is massively enlarged, thus suggesting an infiltrative process. Transplantation would be inappropriate here and biopsy would therefore clarify the diagnosis (hematoxylin and eosin, ×145). H, Advanced tuberculosis. This 63-year-old man presented with a febrile illness of 2 weeks' duration, accompanied by jaundice and obtundation. At autopsy, massive replacement of the liver by granulomas containing tubercle bacilli was present. The patient had no other associated illnesses (hematoxylin and eosin, ×145). I, Amyloidosis. Massive infiltration of the hepatic sinusoids with amyloid appears to displace hepatocytes and cause atrophy of cells (hematoxylin and eosin, ×185). J, Ischemic myocardiopathy causing ischemic necrosis of hepatocytes. This 54-year-old overweight man complained of fatigue and somnolence but was not found to be short of breath and had no history of heart failure. Prothrombin time was 16 seconds, alanine aminotransferase was 1830 IU/L, serum ammonia was 135 mg/dL (normal & 30), and the ejection fraction was determined to be 16%. The centrilobular region shows dilated sinusoids and considerable necrosis of hepatocytes. His symptoms resolved with a cardiotonic regimen.

23 Histologic findings in a selection of patients with acute liver failure (C): HalotanoFigure Histologic findings in a selection of patients with acute liver failure. A, Normal liver for comparison. In this photomicrograph of a normal hepatic lobule, a portal tract (P) and hepatic venule (V) are highlighted. The liver cells appear uniform and cuboid in single-cell plates lining the sinusoids. Very few inflammatory cells are present, and no signs of hepatocyte regeneration exist (hematoxylin and eosin, ×145). B, Autopsy specimen from a young girl who died of cerebral edema 7 days after an apparent acetaminophen ingestion. Moderately severe centrilobular necrosis is present, but viable hepatocytes are seen in the periportal regions (hematoxylin and eosin, ×145). C and D, Massive hepatic necrosis caused by halothane. The patient (whose liver is shown in Figure 7-13) died 35 days after a cholecystectomy during which she had received halothane anesthesia, probably representing her second exposure to the drug. Virtually the entire hepatic lobule appears necrotic, with fibrinoid cellular debris interspersed between portal tracts that appear to be in close proximity because of massive collapse of the intervening hepatocytes (Masson's trichome, C, ×145; D, ×185). E, Reye's syndrome. This infant was admitted with liver failure shortly after developing an upper respiratory infection that was treated with aspirin. Massive infiltration of hepatocytes with microvesicular fat is seen as pale areas within cells. There is little inflammation or evidence of necrosis. The finding of microvesicular fat is characteristic of Reye's syndrome as well as of fatty liver of pregnancy and exposure to certain nucleoside analogues (fialuridine, didanosine, and possibly zidovudine) (hematoxylin and eosin, ×185). F, Wilson disease. This autopsy photomicrograph is of a 16-year-old girl with a 2-week illness characterized by fatigue, confusion, and deep jaundice. Bilirubin level on admission to the hospital was 38 mg/dL, and she died on the fifth hospital day. Widespread hepatocyte necrosis and bile staining are present. There is evidence of some increased fibrosis and early cirrhosis in other sections. As in the halothane case, few remaining viable hepatocytes are seen (hematoxylin and eosin, ×185). G, Metastatic melanoma. This 58-year-old man presented with altered mental status, hepatomegaly, and jaundice 6 months after enucleation of his right eye for melanoma. The sinusoids are packed with malignant cells that appear to contain pigment (melanin). Ischemic necrosis of hepatocytes is presumed to result from sinusoidal obstruction. Liver biopsy is indicated in fulminant hepatic failure if the liver is massively enlarged, thus suggesting an infiltrative process. Transplantation would be inappropriate here and biopsy would therefore clarify the diagnosis (hematoxylin and eosin, ×145). H, Advanced tuberculosis. This 63-year-old man presented with a febrile illness of 2 weeks' duration, accompanied by jaundice and obtundation. At autopsy, massive replacement of the liver by granulomas containing tubercle bacilli was present. The patient had no other associated illnesses (hematoxylin and eosin, ×145). I, Amyloidosis. Massive infiltration of the hepatic sinusoids with amyloid appears to displace hepatocytes and cause atrophy of cells (hematoxylin and eosin, ×185). J, Ischemic myocardiopathy causing ischemic necrosis of hepatocytes. This 54-year-old overweight man complained of fatigue and somnolence but was not found to be short of breath and had no history of heart failure. Prothrombin time was 16 seconds, alanine aminotransferase was 1830 IU/L, serum ammonia was 135 mg/dL (normal & 30), and the ejection fraction was determined to be 16%. The centrilobular region shows dilated sinusoids and considerable necrosis of hepatocytes. His symptoms resolved with a cardiotonic regimen.

24 Histologic findings in a selection of patients with acute liver failure (D): HalotanoFigure Histologic findings in a selection of patients with acute liver failure. A, Normal liver for comparison. In this photomicrograph of a normal hepatic lobule, a portal tract (P) and hepatic venule (V) are highlighted. The liver cells appear uniform and cuboid in single-cell plates lining the sinusoids. Very few inflammatory cells are present, and no signs of hepatocyte regeneration exist (hematoxylin and eosin, ×145). B, Autopsy specimen from a young girl who died of cerebral edema 7 days after an apparent acetaminophen ingestion. Moderately severe centrilobular necrosis is present, but viable hepatocytes are seen in the periportal regions (hematoxylin and eosin, ×145). C and D, Massive hepatic necrosis caused by halothane. The patient (whose liver is shown in Figure 7-13) died 35 days after a cholecystectomy during which she had received halothane anesthesia, probably representing her second exposure to the drug. Virtually the entire hepatic lobule appears necrotic, with fibrinoid cellular debris interspersed between portal tracts that appear to be in close proximity because of massive collapse of the intervening hepatocytes (Masson's trichome, C, ×145; D, ×185). E, Reye's syndrome. This infant was admitted with liver failure shortly after developing an upper respiratory infection that was treated with aspirin. Massive infiltration of hepatocytes with microvesicular fat is seen as pale areas within cells. There is little inflammation or evidence of necrosis. The finding of microvesicular fat is characteristic of Reye's syndrome as well as of fatty liver of pregnancy and exposure to certain nucleoside analogues (fialuridine, didanosine, and possibly zidovudine) (hematoxylin and eosin, ×185). F, Wilson disease. This autopsy photomicrograph is of a 16-year-old girl with a 2-week illness characterized by fatigue, confusion, and deep jaundice. Bilirubin level on admission to the hospital was 38 mg/dL, and she died on the fifth hospital day. Widespread hepatocyte necrosis and bile staining are present. There is evidence of some increased fibrosis and early cirrhosis in other sections. As in the halothane case, few remaining viable hepatocytes are seen (hematoxylin and eosin, ×185). G, Metastatic melanoma. This 58-year-old man presented with altered mental status, hepatomegaly, and jaundice 6 months after enucleation of his right eye for melanoma. The sinusoids are packed with malignant cells that appear to contain pigment (melanin). Ischemic necrosis of hepatocytes is presumed to result from sinusoidal obstruction. Liver biopsy is indicated in fulminant hepatic failure if the liver is massively enlarged, thus suggesting an infiltrative process. Transplantation would be inappropriate here and biopsy would therefore clarify the diagnosis (hematoxylin and eosin, ×145). H, Advanced tuberculosis. This 63-year-old man presented with a febrile illness of 2 weeks' duration, accompanied by jaundice and obtundation. At autopsy, massive replacement of the liver by granulomas containing tubercle bacilli was present. The patient had no other associated illnesses (hematoxylin and eosin, ×145). I, Amyloidosis. Massive infiltration of the hepatic sinusoids with amyloid appears to displace hepatocytes and cause atrophy of cells (hematoxylin and eosin, ×185). J, Ischemic myocardiopathy causing ischemic necrosis of hepatocytes. This 54-year-old overweight man complained of fatigue and somnolence but was not found to be short of breath and had no history of heart failure. Prothrombin time was 16 seconds, alanine aminotransferase was 1830 IU/L, serum ammonia was 135 mg/dL (normal & 30), and the ejection fraction was determined to be 16%. The centrilobular region shows dilated sinusoids and considerable necrosis of hepatocytes. His symptoms resolved with a cardiotonic regimen.

25 Histologic findings in a selection of patients with acute liver failure (E): sindrome de ReyeFigure Histologic findings in a selection of patients with acute liver failure. A, Normal liver for comparison. In this photomicrograph of a normal hepatic lobule, a portal tract (P) and hepatic venule (V) are highlighted. The liver cells appear uniform and cuboid in single-cell plates lining the sinusoids. Very few inflammatory cells are present, and no signs of hepatocyte regeneration exist (hematoxylin and eosin, ×145). B, Autopsy specimen from a young girl who died of cerebral edema 7 days after an apparent acetaminophen ingestion. Moderately severe centrilobular necrosis is present, but viable hepatocytes are seen in the periportal regions (hematoxylin and eosin, ×145). C and D, Massive hepatic necrosis caused by halothane. The patient (whose liver is shown in Figure 7-13) died 35 days after a cholecystectomy during which she had received halothane anesthesia, probably representing her second exposure to the drug. Virtually the entire hepatic lobule appears necrotic, with fibrinoid cellular debris interspersed between portal tracts that appear to be in close proximity because of massive collapse of the intervening hepatocytes (Masson's trichome, C, ×145; D, ×185). E, Reye's syndrome. This infant was admitted with liver failure shortly after developing an upper respiratory infection that was treated with aspirin. Massive infiltration of hepatocytes with microvesicular fat is seen as pale areas within cells. There is little inflammation or evidence of necrosis. The finding of microvesicular fat is characteristic of Reye's syndrome as well as of fatty liver of pregnancy and exposure to certain nucleoside analogues (fialuridine, didanosine, and possibly zidovudine) (hematoxylin and eosin, ×185). F, Wilson disease. This autopsy photomicrograph is of a 16-year-old girl with a 2-week illness characterized by fatigue, confusion, and deep jaundice. Bilirubin level on admission to the hospital was 38 mg/dL, and she died on the fifth hospital day. Widespread hepatocyte necrosis and bile staining are present. There is evidence of some increased fibrosis and early cirrhosis in other sections. As in the halothane case, few remaining viable hepatocytes are seen (hematoxylin and eosin, ×185). G, Metastatic melanoma. This 58-year-old man presented with altered mental status, hepatomegaly, and jaundice 6 months after enucleation of his right eye for melanoma. The sinusoids are packed with malignant cells that appear to contain pigment (melanin). Ischemic necrosis of hepatocytes is presumed to result from sinusoidal obstruction. Liver biopsy is indicated in fulminant hepatic failure if the liver is massively enlarged, thus suggesting an infiltrative process. Transplantation would be inappropriate here and biopsy would therefore clarify the diagnosis (hematoxylin and eosin, ×145). H, Advanced tuberculosis. This 63-year-old man presented with a febrile illness of 2 weeks' duration, accompanied by jaundice and obtundation. At autopsy, massive replacement of the liver by granulomas containing tubercle bacilli was present. The patient had no other associated illnesses (hematoxylin and eosin, ×145). I, Amyloidosis. Massive infiltration of the hepatic sinusoids with amyloid appears to displace hepatocytes and cause atrophy of cells (hematoxylin and eosin, ×185). J, Ischemic myocardiopathy causing ischemic necrosis of hepatocytes. This 54-year-old overweight man complained of fatigue and somnolence but was not found to be short of breath and had no history of heart failure. Prothrombin time was 16 seconds, alanine aminotransferase was 1830 IU/L, serum ammonia was 135 mg/dL (normal & 30), and the ejection fraction was determined to be 16%. The centrilobular region shows dilated sinusoids and considerable necrosis of hepatocytes. His symptoms resolved with a cardiotonic regimen.

26 Histologic findings in a selection of patients with acute liver failure (F): Enfermedad de WilsonFigure Histologic findings in a selection of patients with acute liver failure. A, Normal liver for comparison. In this photomicrograph of a normal hepatic lobule, a portal tract (P) and hepatic venule (V) are highlighted. The liver cells appear uniform and cuboid in single-cell plates lining the sinusoids. Very few inflammatory cells are present, and no signs of hepatocyte regeneration exist (hematoxylin and eosin, ×145). B, Autopsy specimen from a young girl who died of cerebral edema 7 days after an apparent acetaminophen ingestion. Moderately severe centrilobular necrosis is present, but viable hepatocytes are seen in the periportal regions (hematoxylin and eosin, ×145). C and D, Massive hepatic necrosis caused by halothane. The patient (whose liver is shown in Figure 7-13) died 35 days after a cholecystectomy during which she had received halothane anesthesia, probably representing her second exposure to the drug. Virtually the entire hepatic lobule appears necrotic, with fibrinoid cellular debris interspersed between portal tracts that appear to be in close proximity because of massive collapse of the intervening hepatocytes (Masson's trichome, C, ×145; D, ×185). E, Reye's syndrome. This infant was admitted with liver failure shortly after developing an upper respiratory infection that was treated with aspirin. Massive infiltration of hepatocytes with microvesicular fat is seen as pale areas within cells. There is little inflammation or evidence of necrosis. The finding of microvesicular fat is characteristic of Reye's syndrome as well as of fatty liver of pregnancy and exposure to certain nucleoside analogues (fialuridine, didanosine, and possibly zidovudine) (hematoxylin and eosin, ×185). F, Wilson disease. This autopsy photomicrograph is of a 16-year-old girl with a 2-week illness characterized by fatigue, confusion, and deep jaundice. Bilirubin level on admission to the hospital was 38 mg/dL, and she died on the fifth hospital day. Widespread hepatocyte necrosis and bile staining are present. There is evidence of some increased fibrosis and early cirrhosis in other sections. As in the halothane case, few remaining viable hepatocytes are seen (hematoxylin and eosin, ×185). G, Metastatic melanoma. This 58-year-old man presented with altered mental status, hepatomegaly, and jaundice 6 months after enucleation of his right eye for melanoma. The sinusoids are packed with malignant cells that appear to contain pigment (melanin). Ischemic necrosis of hepatocytes is presumed to result from sinusoidal obstruction. Liver biopsy is indicated in fulminant hepatic failure if the liver is massively enlarged, thus suggesting an infiltrative process. Transplantation would be inappropriate here and biopsy would therefore clarify the diagnosis (hematoxylin and eosin, ×145). H, Advanced tuberculosis. This 63-year-old man presented with a febrile illness of 2 weeks' duration, accompanied by jaundice and obtundation. At autopsy, massive replacement of the liver by granulomas containing tubercle bacilli was present. The patient had no other associated illnesses (hematoxylin and eosin, ×145). I, Amyloidosis. Massive infiltration of the hepatic sinusoids with amyloid appears to displace hepatocytes and cause atrophy of cells (hematoxylin and eosin, ×185). J, Ischemic myocardiopathy causing ischemic necrosis of hepatocytes. This 54-year-old overweight man complained of fatigue and somnolence but was not found to be short of breath and had no history of heart failure. Prothrombin time was 16 seconds, alanine aminotransferase was 1830 IU/L, serum ammonia was 135 mg/dL (normal & 30), and the ejection fraction was determined to be 16%. The centrilobular region shows dilated sinusoids and considerable necrosis of hepatocytes. His symptoms resolved with a cardiotonic regimen.

27 Histologic findings in a selection of patients with acute liver failure (G): MelanomaFigure Histologic findings in a selection of patients with acute liver failure. A, Normal liver for comparison. In this photomicrograph of a normal hepatic lobule, a portal tract (P) and hepatic venule (V) are highlighted. The liver cells appear uniform and cuboid in single-cell plates lining the sinusoids. Very few inflammatory cells are present, and no signs of hepatocyte regeneration exist (hematoxylin and eosin, ×145). B, Autopsy specimen from a young girl who died of cerebral edema 7 days after an apparent acetaminophen ingestion. Moderately severe centrilobular necrosis is present, but viable hepatocytes are seen in the periportal regions (hematoxylin and eosin, ×145). C and D, Massive hepatic necrosis caused by halothane. The patient (whose liver is shown in Figure 7-13) died 35 days after a cholecystectomy during which she had received halothane anesthesia, probably representing her second exposure to the drug. Virtually the entire hepatic lobule appears necrotic, with fibrinoid cellular debris interspersed between portal tracts that appear to be in close proximity because of massive collapse of the intervening hepatocytes (Masson's trichome, C, ×145; D, ×185). E, Reye's syndrome. This infant was admitted with liver failure shortly after developing an upper respiratory infection that was treated with aspirin. Massive infiltration of hepatocytes with microvesicular fat is seen as pale areas within cells. There is little inflammation or evidence of necrosis. The finding of microvesicular fat is characteristic of Reye's syndrome as well as of fatty liver of pregnancy and exposure to certain nucleoside analogues (fialuridine, didanosine, and possibly zidovudine) (hematoxylin and eosin, ×185). F, Wilson disease. This autopsy photomicrograph is of a 16-year-old girl with a 2-week illness characterized by fatigue, confusion, and deep jaundice. Bilirubin level on admission to the hospital was 38 mg/dL, and she died on the fifth hospital day. Widespread hepatocyte necrosis and bile staining are present. There is evidence of some increased fibrosis and early cirrhosis in other sections. As in the halothane case, few remaining viable hepatocytes are seen (hematoxylin and eosin, ×185). G, Metastatic melanoma. This 58-year-old man presented with altered mental status, hepatomegaly, and jaundice 6 months after enucleation of his right eye for melanoma. The sinusoids are packed with malignant cells that appear to contain pigment (melanin). Ischemic necrosis of hepatocytes is presumed to result from sinusoidal obstruction. Liver biopsy is indicated in fulminant hepatic failure if the liver is massively enlarged, thus suggesting an infiltrative process. Transplantation would be inappropriate here and biopsy would therefore clarify the diagnosis (hematoxylin and eosin, ×145). H, Advanced tuberculosis. This 63-year-old man presented with a febrile illness of 2 weeks' duration, accompanied by jaundice and obtundation. At autopsy, massive replacement of the liver by granulomas containing tubercle bacilli was present. The patient had no other associated illnesses (hematoxylin and eosin, ×145). I, Amyloidosis. Massive infiltration of the hepatic sinusoids with amyloid appears to displace hepatocytes and cause atrophy of cells (hematoxylin and eosin, ×185). J, Ischemic myocardiopathy causing ischemic necrosis of hepatocytes. This 54-year-old overweight man complained of fatigue and somnolence but was not found to be short of breath and had no history of heart failure. Prothrombin time was 16 seconds, alanine aminotransferase was 1830 IU/L, serum ammonia was 135 mg/dL (normal & 30), and the ejection fraction was determined to be 16%. The centrilobular region shows dilated sinusoids and considerable necrosis of hepatocytes. His symptoms resolved with a cardiotonic regimen.

28 Histologic findings in a selection of patients with acute liver failure (H): TuberculosisFigure Histologic findings in a selection of patients with acute liver failure. A, Normal liver for comparison. In this photomicrograph of a normal hepatic lobule, a portal tract (P) and hepatic venule (V) are highlighted. The liver cells appear uniform and cuboid in single-cell plates lining the sinusoids. Very few inflammatory cells are present, and no signs of hepatocyte regeneration exist (hematoxylin and eosin, ×145). B, Autopsy specimen from a young girl who died of cerebral edema 7 days after an apparent acetaminophen ingestion. Moderately severe centrilobular necrosis is present, but viable hepatocytes are seen in the periportal regions (hematoxylin and eosin, ×145). C and D, Massive hepatic necrosis caused by halothane. The patient (whose liver is shown in Figure 7-13) died 35 days after a cholecystectomy during which she had received halothane anesthesia, probably representing her second exposure to the drug. Virtually the entire hepatic lobule appears necrotic, with fibrinoid cellular debris interspersed between portal tracts that appear to be in close proximity because of massive collapse of the intervening hepatocytes (Masson's trichome, C, ×145; D, ×185). E, Reye's syndrome. This infant was admitted with liver failure shortly after developing an upper respiratory infection that was treated with aspirin. Massive infiltration of hepatocytes with microvesicular fat is seen as pale areas within cells. There is little inflammation or evidence of necrosis. The finding of microvesicular fat is characteristic of Reye's syndrome as well as of fatty liver of pregnancy and exposure to certain nucleoside analogues (fialuridine, didanosine, and possibly zidovudine) (hematoxylin and eosin, ×185). F, Wilson disease. This autopsy photomicrograph is of a 16-year-old girl with a 2-week illness characterized by fatigue, confusion, and deep jaundice. Bilirubin level on admission to the hospital was 38 mg/dL, and she died on the fifth hospital day. Widespread hepatocyte necrosis and bile staining are present. There is evidence of some increased fibrosis and early cirrhosis in other sections. As in the halothane case, few remaining viable hepatocytes are seen (hematoxylin and eosin, ×185). G, Metastatic melanoma. This 58-year-old man presented with altered mental status, hepatomegaly, and jaundice 6 months after enucleation of his right eye for melanoma. The sinusoids are packed with malignant cells that appear to contain pigment (melanin). Ischemic necrosis of hepatocytes is presumed to result from sinusoidal obstruction. Liver biopsy is indicated in fulminant hepatic failure if the liver is massively enlarged, thus suggesting an infiltrative process. Transplantation would be inappropriate here and biopsy would therefore clarify the diagnosis (hematoxylin and eosin, ×145). H, Advanced tuberculosis. This 63-year-old man presented with a febrile illness of 2 weeks' duration, accompanied by jaundice and obtundation. At autopsy, massive replacement of the liver by granulomas containing tubercle bacilli was present. The patient had no other associated illnesses (hematoxylin and eosin, ×145). I, Amyloidosis. Massive infiltration of the hepatic sinusoids with amyloid appears to displace hepatocytes and cause atrophy of cells (hematoxylin and eosin, ×185). J, Ischemic myocardiopathy causing ischemic necrosis of hepatocytes. This 54-year-old overweight man complained of fatigue and somnolence but was not found to be short of breath and had no history of heart failure. Prothrombin time was 16 seconds, alanine aminotransferase was 1830 IU/L, serum ammonia was 135 mg/dL (normal & 30), and the ejection fraction was determined to be 16%. The centrilobular region shows dilated sinusoids and considerable necrosis of hepatocytes. His symptoms resolved with a cardiotonic regimen.

29 Histologic findings in a selection of patients with acute liver failure (I): AmiloidosisFigure Histologic findings in a selection of patients with acute liver failure. A, Normal liver for comparison. In this photomicrograph of a normal hepatic lobule, a portal tract (P) and hepatic venule (V) are highlighted. The liver cells appear uniform and cuboid in single-cell plates lining the sinusoids. Very few inflammatory cells are present, and no signs of hepatocyte regeneration exist (hematoxylin and eosin, ×145). B, Autopsy specimen from a young girl who died of cerebral edema 7 days after an apparent acetaminophen ingestion. Moderately severe centrilobular necrosis is present, but viable hepatocytes are seen in the periportal regions (hematoxylin and eosin, ×145). C and D, Massive hepatic necrosis caused by halothane. The patient (whose liver is shown in Figure 7-13) died 35 days after a cholecystectomy during which she had received halothane anesthesia, probably representing her second exposure to the drug. Virtually the entire hepatic lobule appears necrotic, with fibrinoid cellular debris interspersed between portal tracts that appear to be in close proximity because of massive collapse of the intervening hepatocytes (Masson's trichome, C, ×145; D, ×185). E, Reye's syndrome. This infant was admitted with liver failure shortly after developing an upper respiratory infection that was treated with aspirin. Massive infiltration of hepatocytes with microvesicular fat is seen as pale areas within cells. There is little inflammation or evidence of necrosis. The finding of microvesicular fat is characteristic of Reye's syndrome as well as of fatty liver of pregnancy and exposure to certain nucleoside analogues (fialuridine, didanosine, and possibly zidovudine) (hematoxylin and eosin, ×185). F, Wilson disease. This autopsy photomicrograph is of a 16-year-old girl with a 2-week illness characterized by fatigue, confusion, and deep jaundice. Bilirubin level on admission to the hospital was 38 mg/dL, and she died on the fifth hospital day. Widespread hepatocyte necrosis and bile staining are present. There is evidence of some increased fibrosis and early cirrhosis in other sections. As in the halothane case, few remaining viable hepatocytes are seen (hematoxylin and eosin, ×185). G, Metastatic melanoma. This 58-year-old man presented with altered mental status, hepatomegaly, and jaundice 6 months after enucleation of his right eye for melanoma. The sinusoids are packed with malignant cells that appear to contain pigment (melanin). Ischemic necrosis of hepatocytes is presumed to result from sinusoidal obstruction. Liver biopsy is indicated in fulminant hepatic failure if the liver is massively enlarged, thus suggesting an infiltrative process. Transplantation would be inappropriate here and biopsy would therefore clarify the diagnosis (hematoxylin and eosin, ×145). H, Advanced tuberculosis. This 63-year-old man presented with a febrile illness of 2 weeks' duration, accompanied by jaundice and obtundation. At autopsy, massive replacement of the liver by granulomas containing tubercle bacilli was present. The patient had no other associated illnesses (hematoxylin and eosin, ×145). I, Amyloidosis. Massive infiltration of the hepatic sinusoids with amyloid appears to displace hepatocytes and cause atrophy of cells (hematoxylin and eosin, ×185). J, Ischemic myocardiopathy causing ischemic necrosis of hepatocytes. This 54-year-old overweight man complained of fatigue and somnolence but was not found to be short of breath and had no history of heart failure. Prothrombin time was 16 seconds, alanine aminotransferase was 1830 IU/L, serum ammonia was 135 mg/dL (normal & 30), and the ejection fraction was determined to be 16%. The centrilobular region shows dilated sinusoids and considerable necrosis of hepatocytes. His symptoms resolved with a cardiotonic regimen.

30 Histologic findings in a selection of patients with acute liver failure (J): MiocardiopatíaFigure Histologic findings in a selection of patients with acute liver failure. A, Normal liver for comparison. In this photomicrograph of a normal hepatic lobule, a portal tract (P) and hepatic venule (V) are highlighted. The liver cells appear uniform and cuboid in single-cell plates lining the sinusoids. Very few inflammatory cells are present, and no signs of hepatocyte regeneration exist (hematoxylin and eosin, ×145). B, Autopsy specimen from a young girl who died of cerebral edema 7 days after an apparent acetaminophen ingestion. Moderately severe centrilobular necrosis is present, but viable hepatocytes are seen in the periportal regions (hematoxylin and eosin, ×145). C and D, Massive hepatic necrosis caused by halothane. The patient (whose liver is shown in Figure 7-13) died 35 days after a cholecystectomy during which she had received halothane anesthesia, probably representing her second exposure to the drug. Virtually the entire hepatic lobule appears necrotic, with fibrinoid cellular debris interspersed between portal tracts that appear to be in close proximity because of massive collapse of the intervening hepatocytes (Masson's trichome, C, ×145; D, ×185). E, Reye's syndrome. This infant was admitted with liver failure shortly after developing an upper respiratory infection that was treated with aspirin. Massive infiltration of hepatocytes with microvesicular fat is seen as pale areas within cells. There is little inflammation or evidence of necrosis. The finding of microvesicular fat is characteristic of Reye's syndrome as well as of fatty liver of pregnancy and exposure to certain nucleoside analogues (fialuridine, didanosine, and possibly zidovudine) (hematoxylin and eosin, ×185). F, Wilson disease. This autopsy photomicrograph is of a 16-year-old girl with a 2-week illness characterized by fatigue, confusion, and deep jaundice. Bilirubin level on admission to the hospital was 38 mg/dL, and she died on the fifth hospital day. Widespread hepatocyte necrosis and bile staining are present. There is evidence of some increased fibrosis and early cirrhosis in other sections. As in the halothane case, few remaining viable hepatocytes are seen (hematoxylin and eosin, ×185). G, Metastatic melanoma. This 58-year-old man presented with altered mental status, hepatomegaly, and jaundice 6 months after enucleation of his right eye for melanoma. The sinusoids are packed with malignant cells that appear to contain pigment (melanin). Ischemic necrosis of hepatocytes is presumed to result from sinusoidal obstruction. Liver biopsy is indicated in fulminant hepatic failure if the liver is massively enlarged, thus suggesting an infiltrative process. Transplantation would be inappropriate here and biopsy would therefore clarify the diagnosis (hematoxylin and eosin, ×145). H, Advanced tuberculosis. This 63-year-old man presented with a febrile illness of 2 weeks' duration, accompanied by jaundice and obtundation. At autopsy, massive replacement of the liver by granulomas containing tubercle bacilli was present. The patient had no other associated illnesses (hematoxylin and eosin, ×145). I, Amyloidosis. Massive infiltration of the hepatic sinusoids with amyloid appears to displace hepatocytes and cause atrophy of cells (hematoxylin and eosin, ×185). J, Ischemic myocardiopathy causing ischemic necrosis of hepatocytes. This 54-year-old overweight man complained of fatigue and somnolence but was not found to be short of breath and had no history of heart failure. Prothrombin time was 16 seconds, alanine aminotransferase was 1830 IU/L, serum ammonia was 135 mg/dL (normal & 30), and the ejection fraction was determined to be 16%. The centrilobular region shows dilated sinusoids and considerable necrosis of hepatocytes. His symptoms resolved with a cardiotonic regimen.

31 Encefalopatía hepáticaNEUROTOXINAS: Amomio Aumento transporte aa neutrales (BHE) Aumento osmolalidad astrocitos Alteración actividad electrica Oxindole ALTERACIÓN DE LA BHE ALTERACIÓN DE LA NEUROTRANSMISIÓN: GABA Glutamato Catecolaminas Serotonina Histamina Melatonina ALTERACIÓN DEL METABOLISMO ENERGÉTICO CEREBRAL EDEMA CEREBRAL HIPOPERFUSIÓN CEREBRAL ATROFIA CORTICAL

32 Encefalopatía hepáticaAmonio, Producido en: intestino Enterocitos flora comensal, H. pylori Detoxificación Hepática Glutamina (interfiere fx mitocondrial del astrocito) Muscular Aumenta por Disminución del aclaramiento hepático Shunting (TIPS)

33 Encefalopatía hepáticaAumento transporte aa neutrales (BHE) Aumento actividad transportador de L-aminoácidos Aumento transporte de triptófano, tirosina y fenilalanina Alteración síntesis dopamina, norepinefrina y serotonina Aumento osmolalidad astrocitos Acumulación de glutamina en astrocitos Efecto sólo en ratas con shunt Vasodilatación cerebral vía NO Alteración actividad electrica Inhibición de potenciales postsinápticos excitatorios e inhibitorios Oxindole: Metabolito tóxico del triptófano

34 Encefalopatía hepáticaALTERACIÓN DE LA NEUROTRANSMISIÓN: GABA: Producido por flora comensal del intestino y detoxificado en el hígado Complejo neurotransmisor GABA-benzodiacepina: inhibidor SNC Animales expuestos al amonio o manganeso aumentan la expresión del gen del receptor de benzodiazepina del astrocito Glutamato Disminución del glutamato cerebral total Aumento del glutamato extracelular Catecolaminas Disminución de la norepinefrina cerebral

35 Ammonia and glutamate metabolism in the brainFigure Ammonia and glutamate metabolism in the brain. Ammonia crosses from blood through intracranial capillary circulation and is taken up by astrocytes where it is converted to glutamine. Glutamine is transported out of astrocytes and is taken up by presynaptic neurons from which they are released as glutamate, which bind to glutamate receptors on postsynaptic neurons. Excess glutamate is taken up by astrocytes and converted to glutamine. (Adapted from Butterworth [41].) References: [42]. Butterworth RF, Hepatic encephalopathy: disorder of multiple neurotransmitter systems. In Advances in Hepatic Encephalopathy and Metabolism in Liver Disease. Edited by Christopher R, Al-Mardinii H. Newcastle on Tyne: Ipswich Book Company;

36 Hepatic encephalopathy: assessment of mental statusFigure Hepatic encephalopathy: assessment of mental status. The grade of portosystemic encephalopathy (PSE) is indicated on the left. Each of the three components of mental state plus neuromuscular abnormalities are shown in the four columns. Within each column the grade at which specific abnormalities usually appear is shown by the tail of the arrow. The length of the arrow indicates the range of grades through which each abnormality may persist. Many features of PSE are not detectable or measurable because testing may require cooperation not possible in comatose patients [37], [38]. (Adapted from Conn and Lieberthal [37].) References: [38]. Conn HO, Lieberthal MM, In The Hepatic Coma Syndromes and Lactulose Baltimore: Williams & Wilkins; [39]. Conn HO, Bircher J, Quantifying the severity of hepatic encephalopathy. In Hepatic Encephalopathies: Syndromes and Therapies Bloomington: Medi-Ed Press;

37 Asterixis Figure Asterixis. Asterixis is a nonspecific neurologic sign that appears to result, at least in part, from dysfunction of the descending reticular system [39]. It may be seen in almost all types of metabolic encephalopathy of both hepatic and nonhepatic origin. A, Asterixis is defined as a defect of movement that is characterized by an inability to sustain a fixed posture such as holding one's hand in a dorsiflexed position at the wrist. Within 30 seconds, repetitive, irregular, involuntary movements of the hand occur. They appear to be flapping motions, hence its colloquial name, the "flapping tremor." Both the active and opposing muscles are activated. When asterixis is present, transient interruptions in electrical current, which last from 50 to 100 ms, occur. When the current is cut off, the hand falls forward by force of gravity; when the current returns, the position is resumed. Similar abnormalities can be induced in experimental animals by infusion of ammonium salts [40]. References: [40]. Leavitt S, Typer HR, Studies in asterixis. Arch Neurol [41]. Stahl J, Studies of the blood ammonia in liver disease: its diagnostic, prognostic, and therapeutic significance. Ann Intern Med

38 Blood ammonia concentration in hepatic encephalopathyFigure Blood ammonia concentration in hepatic encephalopathy. Association of blood ammonia concentrations and the grade of hepatic encephalopathy in untreated cirrhotic patients. There is a step-wise progression between the arterial ammonia levels and the degree of portosystemic encephalopathy (PSE) (columns 1, 3, 5, 7) [40]. There is, however, much overlap in ammonia concentrations between the adjacent grades of PSE. With venous ammonia levels (columns 2, 4, 6, 8), the same trend is evident, but the degree of overlap is even greater. Arterial ammonia levels correlate much more closely with the degree of hepatic encephalopathy than venous levels. It is not possible to predict these gradients. (Adapted from Stahl [40].) References: [41]. Stahl J, Studies of the blood ammonia in liver disease: its diagnostic, prognostic, and therapeutic significance. Ann Intern Med

39 Laennec’s cirrhosis and encephalopathy (A)Figure Computed tomography (CT) scans of the brain of a 42-year-old man with Laennec’s cirrhosis and encephalopathy are shown. The image on the left demonstrates atrophy of the frontal cortex; the right image shows cerebellar atrophy.

40 Laennec’s cirrhosis and encephalopathy (B)Figure Computed tomography (CT) scans of the brain of a 42-year-old man with Laennec’s cirrhosis and encephalopathy are shown. The image on the left demonstrates atrophy of the frontal cortex; the right image shows cerebellar atrophy.

41 Factors precipitating acute episodes of encephalopathyFigure Factors precipitating acute episodes of encephalopathy. Precipitants of hepatic encephalopathy in 100 consecutive patients with hepatic encephalopathy at the West Haven Veterans Administration Hospital, West Haven, Connecticut. The most common precipitant was azotemia, which occurred in one third of the patients [42]. In about half of them the azotemia had been precipitated by diuretic agents such as furosemide. Precipitation of hepatic encephalopathy by tranquilizers, sedatives, or analgesic agents appears to be primarily responsible for induction of impaired mental state in a quarter of the episodes. Ninety-seven episodes had occurred in cirrhotic patients, 13 of whom had portacaval anastomoses. The severity of the encephalopathy tended to be milder in the azotemic and drug-induced patients. Hypokalemic alkalosis, which had been caused by vomiting, diarrhea, or diuretic drugs, was seen in 10% of the patients. The most severe encephalopathy occurred in association with gastrointestinal bleeding, infection, or azotemia. (Adapted from Fessel and Conn [42].) References: [43]. Fessel JM, Conn HO, An analysis of the causes and prevention of hepatic coma [abstract]. Gastroenterology (diuréticos)

42 Precipitants of hepatic encephalopathy in cirrhotic patientsDrugs Benzodiazepines Narcotics Alcohol Increased ammonia production, absorption or entry into the brain Excess dietary intake of protein Gastrointestinal bleeding Infection Electrolyte disturbances such as hypokalemia Constipation Metabolic alkalosis Dehydration Vomiting Diarrhea Hemorrhage Diuretics Large volume paracentesis Portosystemic shunting Radiographic or surgically placed shunts Spontaneous shunts Vascular occlusion Portal vein thrombosis Hepatic vein thrombosis Primary hepatocellular carcinoma