Critical Care in Acute Liver Failure || Histopathological basis of syndrome

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Alberto QuagliaLead Consultant HistopathologistInstitute of Liver StudiesKing’s College Hospital NHS Foundation TrustLondon, UK

Bernard PortmannProfessor EmeritusKing’s College London, School of MedicineFormer Lead Consultant HistopathologistInstitute of Liver StudiesKing’s College Hospital NHS Foundation TrustLondon, UK

About the Authors

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© 2013 Future Medicine

doi:10.2217/EBO.12.382

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Histopathological basis of syndrome

Alberto Quaglia & Bernard PortmannThe syndrome of acute liver failure may follow severe liver injury due to a broad range of etiologies from viral, drug and toxic insults to metabolic conditions, through rarer malignant infiltration and vascular compromise, with a significant number of cases remaining of indeterminate cause [1]. Although etiologies are multiple and varied, the morphologic repertoire of tissue response is somewhat limited. Nevertheless, there are patterns of histological changes that may permit the allocation of individual cases into a diagnostic category, to help understand the pathogenetic mechanisms and the potential for tissue repair. Major histological patterns are reviewed in conjunction with their most likely etiology.

Coagulative necrosis with minimal inflammation 20Severe hepatitis with confluent cell dropout (diffuse) 21Severe hepatitis, ‘map-like’ pattern 22Acute on chronic ‘hepatitis’ 22Venous outflow block 23Malignant infiltration 24Microvesicular steatosis 24Periportal necrosis 25Severe necroti zing hepatitis with inclusions 26Extensive parenchymal loss with giant-cell formation 27Extensive parenchymal loss with massive hemosiderosis 27Role of liver morphologic findings in ALF 28

Chapter 2

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Coagulative necrosis with minimal inflammationThe lesion consists of eosinophilic necrosis of hepatocytes from the perivenular region to the whole lobule, sleeves of spared and regenerating hepatocytes being often seen around the portal areas. Hepatocytes appear as eosinophilic bodies having lost their nuclei. The liver on gross examination shows a discrete nutmeg appearance due to sinusoidal congestion in acinar zones three and two (Figure 2.1A). The sequential changes have been described in a comprehensive study including variable

degree of injury [2]. Within 4–5 days of the acute injury, most of the eosinophilic cells will have been removed, leaving confluent areas of cell dropout with stromal collapse. Tissue examined at this stage will underestimate the extent of necrosis present earlier due to shrinkage of the collapsed area and re-expansion of the spared periportal parenchyma. Should necrosis include periportal hepatocytes, small cells with scanty amphophilic cytoplasm (oval cells) are seen at the portal margins, the result of activation of bipotential progenitor cells forming abortive ductular structures (Figure 2.1B). Inflammation is minimal at this stage, at worst a

few neutrophils within and at the margin of the portal tracts, but activated macrophages engaged in dead tissue removal are prominent; these cells recruited from proliferation and circulating monocytes play a major role in future tissue repair [3]. The inflammatory cell infiltration progressively increases with time to become similar to that seen in viral hepatitis approximately 2–3 weeks after the initial insult. Whatever the extent of necrosis, the anatomical relationship between central venules and portal tracts is maintained, an explanation for the good repair with near complete restoration of the liver tissue in those patients who survived acute liver failure (ALF) without the need for liver transplantation [2].

Eosinophilic necrosis: the changes associated with hepatocyte death due to breakdown of

the plasma membrane osmotic regulatory mechanisms and cell rupture. This is observed in conditions such as ischemia or oxidative stress. Morphologically dead hepatocytes have an eosinophilic appearance, with nuclei lacking or having a picnotic appearance. The appearance of eosinophilic necrosis is different from the parenchymal injury observed in conditions such as viral hepatitis. Confluent dropout of hepatocyte plate often referred to as confluent or bridging necrosis or collapse is associated with heavy infiltration by inflammatory cells, and hepatocyte apoptosis with formation of acidophilic bodies.

Histological patterns of liver injury are often described in relation to the way they affect the

liver microscopy anatomy. The terminology varies depending on which microscopy anatomical model is used. According to the ‘lobular’ model, a terminal hepatic venule is placed in the center of an approximately hexagonal area, the angles of which correspond to the surrounding portal tracts. The lobule is further divided into three regions, centrilobular, midlobular and periportal. According to the acinar model, the parenchyma is divided into approximately triangular areas in which the base corresponds to portal vein radicles branching into the parenchyma and the apex to the nearby centrilobular venule. The aspect closest to the portal vein branches is called acinar zone 1, and the one closest to the centrilobular venule acinar zone 3, with acinar zone 2 inbetween. The acinar or lobular terminology is often used to describe the pattern of liver injury, with some patterns fitting best with the shape of the acinar zones and others with the lobular regions.


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This type of lesion pattern generally follows a single, time-limited insult such as is observed after an acetaminophen overdose or less commonly after mushroom poisoning due to Amanita phalloides toxins, in which case prominent steatosis is an additional feature. Carbon tetrachloride, a rare industrial or intentional exposure, produces similar changes.

Severe hepatitis with confluent cell dropout (diffuse)In most instances necrotic cells have been removed, leaving confluent areas of bridging to panacinar cell loss and stromal collapse. Heavy infiltration by mixed inflammatory cells is seen throughout (Figure 2.2). Surviving, pale staining hepatocytes occur singly or in clusters within the postnecrotic areas, a layer of spared hepatocytes around the hepatic venules having been characteristically associated with viral hepatitis A. Ductular reaction is often seen at portal tract margins and a variable degree of cellular or canalicular cholestasis may be spotted in the surviving parenchyma. Frequent cholangiolar bile casts either reflect the severity of the parenchymal damage or septic complications.

This pattern is mostly associated with fulminant hepatitis due to hepatitis viruses A, B at times with superimposed hepatitis D, and hepatitis E, particularly in pregnant women [4].

A similar picture may follow exposure to drugs acting through immunological or metabolic idiosyncrasy. Their list is long, some drugs having been the

Ductular reaction: the presence of an increased number of ductules, usually at the margin of

portal tracts, in response to a range of acute or chronic insults. Reaction as opposed to proliferation acknowledges the fact that the ductules may variably derive from proliferation of cholangiocytes, proliferation and differentiation of progenitor cells and/or hepatocyte metaplasia.

Figure 2.1. Liver removed at transplantation due to acute liver failure caused by acetaminophen overdose.

A B

On macroscopic examination (A) the parenchymal surface shows a diffuse ‘nutmeg’ appearance due to perivenular/midzonal necrosis and congestion alternating with (B) periportal spared parenchyma.

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object of single or a few case reports, others being well or increasingly recognized as the culprit. These include anesthetics (halothane), antituberculous drugs (isoniazid), herbal remedies and antimicrobial agents (amoxycillin) to name but a few.

Severe hepatitis, ‘map-like’ patternThis unique lesion encompasses broad areas of multiacinar hepatitis with confluent cell dropout, stromal collapse and inflammation similar to that described in the previous section (Figure 2.3A), except that they are intermingled with confluent areas of apparently spared parenchyma showing features of regeneration [5]. A map-like pattern is seen on gross examination, the irregular dark-red collapsed areas alternating with more or less

nodular and green areas of regenerative parenchyma (Figure 2.3B). The distribution of the two distinct areas appears random, an extreme situation being that of almost complete collapse of one lobe while the other is essentially regenerative. Histologically, the regenerative areas show little evidence of previous cell loss, mild inflammation and subtle ductular reaction in a patchy distribution (Figure 2.3C); thickened liver cell plates with high hepatocyte proliferation rate often exhibit cholestasis, including cholangiolar bile casts. The variable amount of spared parenchyma accounts for the fluctuating functional impairment observed clinically. Unfortunately, the uneven distribution of the lesions leads to major sampling variation, and needle liver biopsy specimens do not provide useful information as to the respective proportion of collapsed and regenerative areas and potential outcome.

Although distinctive, this lesion pattern remains most often of indeterminate cause. A few cases may represent an acute onset of autoimmune hepatitis [6], whereas drugs are occasionally incriminated, the evidence being mostly circumstantial.

Acute on chronic ‘hepatitis’Apparent ALF with no clinical evidence of previous liver impairment may

histologically manifest as acute necro-inflammatory changes superimposed on a more chronic process, with bridging fibrosis or an established cirrhosis. Such a

Bridging fibrosis: formation of new collagen linking portal tracts reciprocally or to hepatic

venules, typically observed during progression of chronic hepatitis.

Figure 2.2. Severe hepatitis B virus hepatitis.

An area of confluent parenchymal collapse is associated with a florid mixed inflammatory cell infiltrate. Canalicular bile plugs are present in nearby preserved hepatocellular plates.



combination is observed in so-called fulminant Wilson’s disease and acute flare-up of a previously undiagnosed autoimmune hepatitis. Acute hepatitis B virus flare-up is another possible cause in immunocompromised carriers of hepatitis B virus after withdrawal of chemotherapy given for hematological malignancy or in HIV patients after therapeutic restoration of serum CD4 levels. This is now exceptional due to awareness and the availability of antiviral agents.

In Wilson’s disease, the liver is generally cirrhotic with either features of chronic hepatitis or steatohepatitis of variable severity. The patchy deposition of copper or copper-associated protein demonstrated in both hepatocytes and macrophages is characteristic. This morphological picture may allow a retrospective diagnosis and subsequent family screening, should clinical features remain inconclusive. Patients are most often adolescent or young adults. A single case with features of severe hepatitis and confluent cell loss has been reported in an unusually young girl in whom fulminant hepatitis E was complicating Wilson’s disease [7].

Venous outflow block Hepatic vein branches and sinusoids are dilated and congested with apparent extravasation of red blood cells into atrophied hepatic plates. Variable degree of cell loss occurs, but inflammation is inconspicuous and portals tracts are remarkably normal. Acute or organizing thrombi can occasionally be seen in small hepatic or portal venules. Although ALF may be the clinical presentation,

Figure 2.3. Liver removed at transplantation due to acute liver failure of unknown etiology.

A B C

(A) Large confluent areas of stromal collapse include a mixed inflammatory cell infiltrate and a ductular reaction. (B) These areas alternate with nodular areas of parenchymal regeneration giving a ‘map-like’ appearance to the parenchymal surface on macroscopic examination. (C) The areas of regeneration consist of hepatocellular plates with little sign of liver injury. Sampling variation is a major issue in the interpretation of liver biopsy samples from livers with this pattern of injury.

Presence of bridging fibrosis in liver tissue from patients with acute liver failure suggests acute

exacerbation of an underlying chronic disease. Autoimmune hepatitis and Wilson’s disease are two examples.

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explanted livers often demonstrate older lesions in a patchy distribution with areas of hepatocyte loss, stromal collapse and collagenization, suggesting that the

thrombotic process has evolved for some time prior to the acute presentation.

ALF is an uncommon presentation of Budd–Chiari syndrome, hepatomegaly being noticeable in that situation. A correct diagnosis is important in terms of both management and the need to investigate the patient for an underlying hypercoagulable state.

Malignant infiltrationSinusoid spaces are infiltrated by atypical cells diffusely or discretely, but in a widespread distribution throughout both lobes of the liver. This infiltration pattern is mostly associated with lymphoma, and less often with metastatic epithelial neoplasm, in particular occult breast carcinoma. ALF is rarely a complication, hepatomegaly being a salient feature.

Microvesicular steatosisThe term microvesicular steatosis should be reserved for a faint vesiculation or foamy appearance of liver cell cytoplasm without nuclear displacement. The accumulated lipids can be demonstrated as finely dispersed red globules using Oil red O staining of fresh or formalin-fixed liver tissue prior to paraffin embedding as the latter removes the fat. The liver involvement is widespread, but periportal hepatocytes are generally spared. Ultrastructurally, the fat is not membrane bound and pleomorphic mitochondria have few or no cristae and a fluffy matrix [8]. Unlike its macrovesicular counterpart, microvesicular steatosis is associated with a profound functional impairment and, potentially, ALF. Mitochondrial defects, whether inherited or acquired, are generally responsible. Clinically the change is observed in the following conditions:

nAcute fatty liver of pregnancy. This rare condition develops in the last trimester of pregnancy and is likely associated with acquired or inherited fatty acid oxidation defect. Oxidative stress in placental mitochondria and peroxisomes is accompanied by accumulation of toxic mediators, such as arachidonic acid, which may play a causative role in maternal liver damage of acute fatty liver of pregnancy [9]. A sharply delineated zone of unaffected hepatocytes is often present around the portal tracts and, when repair occurs within days of parturition, fat will disappear progressively from the periportal to the perivenular zones;

nReye syndrome. First described on postmortem findings in 17 children from Australia, it was soon recognized to have a worldwide distribution,

Malignant infiltration is a rare cause of acute liver failure and usually associated with

hepatomegaly.



and a link to aspirin given in children with influenza or varicella was later highlighted. Subsequently, metabolic defects such as urea cycle or fatty acid oxidation disorders were demonstrated in many patients who had survived an acute disease attributed to Reye syndrome. Consequently, early literature is in part historical, as it is largely based on data collected at a time when our knowledge of metabolic disorders and their diagnostic tools were limited. Nevertheless, it seems likely that idiopathic Reye syndrome exists and may reflect a pharmaco- or immuno-genetic susceptibility in those who do not have a demonstrable metabolic disorder;

nDrugs. A number of drugs especially tetracycline, soldium valproate, salicylates, antiretroviral agents (nucleoside reverse transcriptase) and methylenedioxymethamphetamine (‘ecstasy’) have been incriminated as a cause of microvesicular steatosis leading to ALF (Figure 2.4). The compounds may be either directly toxic to mitochondria or may unmask an unrecognized underlying mitochondrial defect [10];

nMitochondrial metabolic disorders: Mitochondrial disorders (mitochondriopathies) are defined as a disorder of mitochondrial function or structure that may be confined to the liver or affect multiple organ systems resulting in combinations of many diverse symptoms, including hepatic failure. They comprise a broad array of diseases and tend to present clinically in infancy or childhood [11]. Histology is variable. In addition to a marked microvesicular steatosis, there are intermingled oxyphilic cells and groups of smaller hepatocytes with basophilic cytoplasm (Figure 2.5A) whereas dissection by fibrous septa and ductular reaction may be conspicuous (Figure 2.5B). This constellation of features, although not specific will points toward a possible mitochondriopathy and may direct further investigations, if a full metabolic screen has not been performed, in particular to a defect confined to the liver.

Periportal necrosis Necrosis confined to the periportal areas has been rarely associated with ALF. In addition to eosinophilic necrosis and cell dropout, a hemorrhagic appearance is frequently seen.

Figure 2.4. Microvesicular steatosis, char-acterized by faint cytoplasmic vesiculation of hepatocyte cytoplasm and a centrally placed nucleus.

This pattern is usually observed as a consequence of inherited or acquired mitochondrial dysfunction.

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In severe eclampsia, the distinctive liver lesion comprises periportal intrasinusoidal fibrin deposition with irregular areas of liver-cell necrosis exciting a minimal inflammatory reaction (Figure 2.6). The hepatic arteries and arterioles in the adjacent portal tract show seepage of fibrin into and through their walls. The vascular changes are similar to those occurring in other organs in severe toxemia and are the result of endothelial cell damage and activation of intravascular coagulation. Distinction from the changes of acute fatty liver of pregnancy is important clinically [12].

Phosphorus poisoning changes in the liver include periportal necrosis associated with severe steatosis. It is a rare cause of ALF following the accidental or suicidal ingestion of fireworks powder containing yellow phosphorus [13].

Iron toxicity, not uncommon in infants and children, produces predominantly periportal, hemorrhagic necrosis, which, at times, can involve most of the acini and lead to ALF [14]. Occasional cases are reported in adults [15].

Severe necrotizing hepatitis with inclusions Here the lesion consists of focally confluent areas of necrosis with inflammation and viral nuclear inclusions in the surrounding viable hepatocytes (Figure 2.7A). It is a rare cause of

Figure 2.5. Liver biopsy from a child with mitochondrial disorder.

A B

(A) Hepatocytes show a heterogenous appearance with larger cells with eosinophilic cytoplasm alternating with smaller basophilic ones. (B) Bridging fibrosis and ductular reaction are seen elsewhere.Reprinted from [22] with permission from Elsevier.

Figure 2.6. Periportal injury in a liver biopsy from a pregnant woman with eclampsia-related acute liver failure.



ALF mainly due to adenovirus [16] or herpes viruses [17] occurring in immunocompromised hosts. Both types of viruses may be detected by immunohistochemistr y using antiadenovirus-group (Figure 2.7B) or specific antiherpes virus antibodies.

Extensive parenchymal loss with giant-cell formation (neonatal hepatitis)The pattern of giant-cell hepatitis with severe widespread and bridging confluent cell loss mostly affects neonates and infants, although a few syncytial giant hepatocytes may be spotted in adult livers with confluent and map-like necrosis at the margins of cell loss areas. In infants, the cause is most often indeterminate, rarely a metabolic disorder already alluded to above is responsible, and may be suspected should marked steatosis be associated. A distinctive form is associated with autoimmune (Coombs positive) hemolytic anemia. The disease is somewhat refractory to conventional immunosupressive therapy, but may be controlled with a stronger therapy regimen. Disease recurrence has been observed after liver transplantation [18].

Extensive parenchymal loss with massive hemosiderosis (perinatal hemochromatosis)This rare condition is characterized by severe hepatic parenchymal loss with variably patchy and confluent stromal collapse. Surviving hepatocytes, often multinucleated and forming rosettes, are markedly

Figure 2.7. Adenovirus infection.

A B

(A) Confluent hepatocellular necrosis alternates with viable hepatocellular plates in which hepatocytes show nuclear inclusions. (B) Immunohistochemistry confirms adenovirus infection.

Some patterns of liver injury are associated with a specific etiology of acute liver failure but

liver biopsy usually does not contribute to the clinical management of these patients.

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loaded with hemosiderin, which is also found in parenchymal cells of the heart, pancreas, thyroid and salivary glands (Figure 2.8). Surgical lip biopsies with demonstration of iron in accessory salivary glands and increased pancreatic MRI density are helpful diagnostic tests. The disease, which manifests as intrauterine fetal demise or ALF at or shortly after birth, has a high rate of recurrence in subsequent pregnancies. It is thought to result from congenital alloimmune hepatitis. Morphological confirmation of the diagnosis is important as gestational administration of hyperimmune globulin may prevent recurrence [19].

Role of liver morphologic findings in ALFDramatic progress over the past 10 years in serological testing for hepatitis viruses and immune, enzymatic and genetic markers have made liver biopsy in ALF somewhat redundant [20]. When comprehensive investigations have been performed in adult or pediatric centers with an expertise in ALF, morphological findings will rarely provide additional information for cases whose etiology remained indeterminate. Exceptions may be for the confirmation of neonatal hemochromatosis, suggestion a mitochondrial disorder confined to the liver and the diagnosis of Wilson’s disease, should clinical parameters remain doubtful. Nevertheless, examination of livers removed at transplantation or liver specimens taken shortly after death are often essential to confirm the clinical diagnosis and are bound to yield complementary information. Such material is essential to study the duality of liver regeneration; actively dividing matured hepatocytes versus

activation of bipotential stem cells; the role and outcome of reactive ductules and the potential of liver restoration according to the pattern of injury present earlier. Availability of tissue from native liver after auxiliary transplantation has been rewarding in that respect [21]. In addition, a thorough morphological evaluation is likely to provide historical data that may turn out to have prognostic value or to be potentially useful to dictate future therapy.

Financial & competing interests disclosure

The authors have no relevant affiliations or finan-cial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in

Figure 2.8. Perls’ staining demonstrates hemo-siderin deposition in the residual hepatocytes of a neonate liver removed at transplanta-tion for acute liver failure, in a clinical picture consistent with neonatal hemochromatosis.



the manuscript. This includes employment, consultancies, honoraria, stock owner-ship or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.

Summary.

� Acute liver failure is associated with a relatively limited range of patterns of histological injury.� The histological patterns of liver injury include coagulative necrosis with minimal inflammation,

severe hepatitis with diffuse confluent cell dropout, severe hepatitis in a ‘map-like ‘pattern, acute on chronic hepatitis, venous outflow block, malignant infiltration, microvesicular steatosis, periportal necrosis, severe necrotizing hepatitis with inclusions, extensive parenchymal loss with giant-cell formation, and massive hemosiderosis (perinatal hemochromatosis).� Some patterns are characteristic of particular diagnostic categories, but in a significant number

of cases the etiology remains indeterminate.� Liver biopsy does not usually contribute to the management of patients with acute liver failure.� Examination of tissue removed at transplantation or after death is essential to confirm the

clinical diagnosis or provide additional information, and to investigate the pathogenesis of liver injury and aspects of liver regeneration.

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