CHAPTER 15 The Liver in Systemic Disease and Pregnancy

Introduction

Liver biopsies are often obtained to evaluate abnormalities of liver function tests in patients with known or suspected systemic disease and in the investigation of pyrexia of unknown origin.¹^,² In the latter, liver biopsy provides diagnostic information in approximately 15–30% of cases.³ The hepatic changes associated with systemic diseases vary from obvious granulomas or steatosis (discussed in Ch. 7) to more subtle findings such as an increase in liver-cell mitoses. The pathologist will want to know, whenever possible, whether or not the biopsy changes are specific for a systemic disease. For example, when granulomas are present, their aetiology usually has important therapeutic implications. Liver biopsy in patients with AIDS may demonstrate suspected hepatotoxicity due to antiretroviral drugs or hepatic involvement by a micro-organism already identified elsewhere in the patient, or may disclose a new diagnosis such as lymphoma. Liver biopsy also provides tissue for culture and special stains. This chapter examines the pathology of hepatic granulomas, hepatic changes in a variety of infectious diseases, and liver involvement in gastrointestinal and haemopoietic diseases and the porphyrias.

In the unusual situation where liver dysfunction is found in pregnancy, the histopathologist may be called upon to differentiate intercurrent conditions such as viral hepatitis from several varieties of liver disease unique to pregnancy. This differential diagnosis is discussed later on in this chapter.

Granulomas

There are many causes of hepatic granulomas, including local irritants, infections, infestations and hypersensitivity to drugs. The constituents of these lesions, depending on the aetiology and inflammatory cytokines produced,⁴ include large epithelioid cells, multinucleated giant cells, varied numbers of mononuclear cells and eosinophils. Hepatic granulomas can be further morphologically classified as caseating (necrotising), non-caseating, lipogranulomas (Ch. 7) and fibrin-ring granulomas.⁵^–⁷ The causes vary in frequency from one country to another. Although the aetiology may be determined from the histological features, from special stains for micro-organisms, from culture of part of the biopsy specimen or polymerase chain reaction of the paraffin-embedded specimen,⁸ or from clinical and serological data, the cause of hepatic granulomas may remain unknown in some 10–36% of cases.⁹^,¹⁰

From a practical point of view biopsies containing granulomas fall into one of four groups:

1. The cause of the granuloma is seen under the microscope. Examples are the granulomas around schistosome ova, and the mineral oil lipogranulomas found in portal tracts or near terminal hepatic venules.

2. The cause is not seen, but other histological features and clinical circumstances make the diagnosis clear. For example, granulomas near damaged bile ducts in a patient with clinically and immunologically typical primary biliary cirrhosis are almost certainly due to this disease.

3. The cause is uncertain, but appearances favour one particular line of further investigation rather than another. For instance, sarcoidosis should be suspected when clusters of large granulomas with prominent epithelioid cells, large multinucleated giant cells and dense fibrosis are found in portal tracts.

4. The cause of the granulomas cannot be determined from the histological appearances. This is unfortunately common, and the help that the pathologist can then give to the clinician is limited.

These four circumstances can be summarised as see the cause, know the cause, suspect the cause and don’t know the cause. Some of the histological guidelines for evaluating granulomas are shown in Table 15.1.

Table 15.1 Histological features of hepatic granulomas

Aetiology	Favoured site(s)	Special features
Sarcoidosis	Portal/periportal	Clustering Hyalinisation Inclusions in giant cells May destroy bile ducts
Tuberculosis	None	Necrosis
PBC	Portal	Near damaged bile duct Lobular granulomas uncommon
Drug	None	Eosinophils Other lesions often present (hepatitis, fat, cholestasis)
Mineral oil	Portal, perivenous	Oil vacuoles
Q fever, CMV, Allopurinol, etc.	None	Fibrin-ring granuloma
CGDC	None	Brown pigment in macrophages May be necrotising
Cat-scratch disease, tularemia, yersinia	None	Purulent centre

CGDC, chronic granulomatous disease of childhood; CMV, cytomegalovirus; PBC, primary biliary cirrhosis.

Granulomas are found in up to 10% of liver biopsies.¹¹^,¹² They may be sparse, and suspicion of granulomatous disease is an indication for examining step sections from different levels of a paraffin block, if no lesions are seen initially. Because identifiable granulomas are generally more than 50 µm in diameter, serial sections 5 µm thick are unnecessary unless a single granuloma is to be further investigated.

Granulomas are commonly found in the liver in sarcoidosis and may even recur following liver transplantation.¹³ The liver is usually one of several organs involved, but occasionally extrahepatic lesions are difficult to demonstrate and chest X-ray may be normal.¹⁴ Liver biopsy is helpful for diagnosis, especially in patients with fever and arthralgia.¹⁵ The lesions may be found both in portal tracts and in lobules, and consist of well-defined, rounded granulomas with variable infiltration by inflammatory cells including plasma cells and eosinophils (Fig. 15.1). The granulomas contain reticulin fibres (Fig. 15.2). Multinucleated giant cells may contain inclusions of different types.¹⁶ Central necrosis may infrequently be present, but is never as extensive as in tuberculosis. The granulomas often cluster in portal and periportal regions¹⁷ (Fig. 15.2) and older lesions show dense hyalinised collagen. The fibrosis may extend to interfere with normal acinar structure, and in more severe cases may progress to cirrhosis.¹⁶^,¹⁸ A surprising degree of reactive portal and lobular inflammation may occasionally be seen in association with sarcoid granulomas, raising the question of concomitant hepatitis.¹⁸ The lobular component consists predominantly of hyperplastic Kupffer cells; acidophil bodies are rare. The portal tracts show considerable variability in the amount of lymphocytic inflammation and the most active portal inflammation is usually near granulomas. Serological tests for viral hepatitis should be obtained if there is serious diagnostic concern. In those few patients with sarcoidosis who develop portal hypertension,¹⁹^,²⁰ it may be related to portal and periportal fibrosis or to broad areas of replacement fibrosis,¹⁶ nodular regenerative hyperplasia²¹ or cirrhosis.¹⁶^,¹⁸ Another rare complication of sarcoidosis is a primary biliary cirrhosis-like lesion, with destruction of bile ducts and a clinical picture of chronic cholestasis.²² Portal features suggesting biliary obstruction may also be present.¹⁶^,¹⁸ It should be noted that a diagnosis of sarcoidosis cannot be proved by histological examination of the liver alone, because very similar lesions are found in other granulomatous diseases.

Figure 15.1 Sarcoidosis.

A cluster of epithelioid-cell granulomas with giant cells has expanded a portal tract and surrounded a bile duct (arrow). (Needle biopsy, H&E.)

Figure 15.2 Sarcoidosis.

The granulomas are clustered in the portal tract (P) and periportal region, a characteristic feature of sarcoidosis. They are associated with increased reticulin fibres. (Needle biopsy, reticulin.)

In chronic granulomatous disease of childhood, defective neutrophil leucocyte function leads to the development of infective granulomas of different sizes, containing homogeneous eosinophilic material, necrotic debris or pus. Portal tracts are inflamed and there may be fibrosis. A brown pigment of ceroid type accumulates in portal macrophages and to a lesser extent in Kupffer cells.²³^–²⁵ Abscesses and bile-duct fibroinflammatory lesions resembling primary sclerosing cholangitis are also seen.²⁶ The development of non-cirrhotic portal hypertension related to nodular regenerative hyperplasia and obliterative fibrosis of terminal venules and/or portal veins contributes to mortality.²⁷ Common variable immunodeficiency may be associated with portal and/or lobular epithelioid granulomas^27a as well as with nodular regenerative hyperplasia,^27b mild portal lymphocytic infiltrates with mild fibrosis^27c and, rarely, primary biliary cirrhosis or autoimmune hepatitis.^27d

A small number of patients with chronic hepatitis C may show non-caseating granulomas in the liver, either portal or lobular in location,²⁸^,²⁹ sometimes recurring after liver transplantation.³⁰ In one series, nearly 10% of granulomas were ascribed to this infection.¹⁰ Their pathogenesis is unknown. In some instances, other causes such as schistosomiasis may become apparent during a thorough evaluation.³¹

Drugs and toxins should be considered in the evaluation of hepatic granulomas (see Ch. 8), particularly if eosinophils are prominent.³² A diverse array of particulate materials may cause granulomas, including aluminium,³³ feldspar³⁴ and silicone.³⁵ Biopsies with granulomas should therefore be examined under polarised light for evidence of particulate material. Dense reactive fibrosis may develop in the form of sclerohyaline nodules in individuals exposed to silica, chromium, cobalt or magnesium, either in the workplace or by intravenous drug abuse.³⁶

The fibrin-ring granuloma is a distinctive though non-specific ³⁷ form described in Q fever,³⁷^–⁴² Hodgkin’s disease,⁴³ allopurinol hypersensitivity,⁴⁴ cytomegalovirus⁴⁵ and Epstein–Barr virus infections,⁴⁶ leishmaniasis,⁴⁷ toxoplasmosis,⁴³ hepatitis A,⁴⁸^,⁴⁹ giant-cell arteritis⁵⁰ and systemic lupus erythematosus.⁵¹ This granuloma is composed of a fat vacuole surrounded by a ring of fibrin, epithelioid cells, giant cells and neutrophils (Fig. 15.3). Serial sections may be needed to demonstrate the typical fibrin-ring or ‘doughnut’ lesion.³⁹

Figure 15.3 Q fever.

Small granulomas containing giant cells, fat vacuoles and neutrophil leucocytes are surrounded by rings of fibrin, stained red. (Needle biopsy, Martius scarlet blue.)

Simon and Wolff ⁵² described a syndrome characterised by fever, constitutional symptoms and hepatic granulomas, which does not respond to antituberculous drugs but improves on corticosteroid therapy or sometimes with methotrexate.⁵³ In some patients the syndrome resolves spontaneously without treatment.⁵⁴ The cause has not been established.

Viral diseases

The pathological changes in the liver resulting from virus infections other than hepatitis viruses have been reviewed by Lucas.⁵⁵ The viral haemorrhagic fevers, such as mosquito-borne flavivirus infection (Dengue fever⁵⁶) and rodent-borne hantavirus infections,⁵⁷ are characterised by mid-zonal or more extensive hepatic necrosis. In yellow fever, acidophil bodies are typically abundant; they were first described in this disease by Councilman over a 100 years ago.⁵⁸^,⁵⁹

Several viruses not normally associated with liver disease can occasionally cause liver damage. Examples include herpes simplex virus infection leading to irregular and randomly distributed areas of coagulative necrosis ⁶⁰^,⁶¹ (Fig. 15.4) and adenovirus infection.⁶²^,⁶³ In both infections, virus particles or antigens can be identified in hepatocytes. Paramyxovirus-like particles were described in adults with associated syncytial giant-cell hepatitis.⁶⁴ Multinucleated giant hepatocytes in liver biopsies from adults (post-infantile giant-cell hepatitis) may also be seen in hepatitis C virus mono-infection or co-infection with human immunodeficiency virus (HIV),^64a human herpes virus-6A infection,⁶⁵ in autoimmune hepatitis and in other liver diseases.⁶⁶^,⁶⁷

Figure 15.4 Herpes simplex hepatitis.

Pale, ground-glass-like intranuclear inclusions are present in a multinucleated hepatocyte (near centre) and elsewhere (arrows). An adjacent focus of necrosis with neutrophils is seen at the right of the field. (Needle biopsy, H&E.)

Cytomegalovirus infection

Cytomegalovirus (CMV) has been implicated in some children with neonatal hepatitis (see Ch. 13). Histological features include giant-cell formation as in other forms of neonatal liver damage, inflammation and cholestasis. Bile ducts are damaged and may be destroyed.⁶⁸ The CMV genome can be identified by the polymerase chain reaction in many cases.⁶⁹

In later life, CMV infection can present as a mononucleosis-like illness, but also as hepatitis. Asymptomatic infection is common in immunocompromised patients. In these, the histological changes are often mild, but typical CMV inclusions are found in hepatocytes, bile-duct epithelium and endothelial cells (Fig. 15.5). Specific immunocytochemical staining reveals CMV antigens, even in cells without inclusions,⁷⁰ but sometimes with an abnormal granular basophilic cytoplasm.⁷¹ Patients with CMV infection may also show aggregation of neutrophils in sinusoids, with or without evidence of CMV in neighbouring cells,⁷¹ an important diagnostic consideration in immunocompromised patients or individuals who have received organ transplants. Larger accumulations of macrophages and lymphocytes can be seen and epithelioid-cell granulomas have been reported.⁷² In immunocompetent patients, there are varying degress of focal liver-cell and bile-duct damage, portal inflammation, infiltration of sinusoids with lymphoid cells and increased mitoses in hepatocytes.⁷³ In such patients, it may not be possible to demonstrate CMV inclusions or antigen, a situation possibly analogous to hepatitis B virus infection where inclusions and antigen may be scanty or absent during the acute attack while characteristic of the carrier state.⁷³

Figure 15.5 Cytomegalovirus hepatitis in AIDS.

Numerous cytomegalovirus inclusions (arrows) are seen within bile-duct epithelial cells. (Needle biopsy, H&E.)

Infectious mononucleosis

The liver is histologically abnormal in infectious mononucleosis even when there is no clinical jaundice.⁷⁴ Dense accumulations of atypical lymphocytes are found in portal tracts and sinusoids (Fig. 15.6). Sinusoidal aggregates must be distinguished from the more heterogeneous collections of cells found in extramedullary haemopoiesis. The infiltration also mimics that of leukaemia. Kupffer cells are enlarged. Epithelioid-cell granulomas are occasionally present.¹² Small foci of hepatocellular necrosis and acidophil bodies may be seen, but the diffuse hepatocellular damage characteristic of viral hepatitis is usually absent and extensive necrosis⁷⁵ is rare. Cholestasis is absent or mild.

Figure 15.6 Infectious mononucleosis.

At left, a prominent sinusoidal ‘beads-on-a-string’ pattern is seen, consisting of atypical lymphocytes and hyperplastic Kupffer cells. Atypical lymphocytes are also present in the portal tract at right. (Needle biopsy, H&E.)

Acquired immune deficiency syndrome

A spectrum of hepatobiliary lesions has been associated with AIDS and HIV-1 infection since the onset of the epidemic ⁷⁶^–⁸⁵ (Table 15.2). Liver biopsy continues to play an important diagnostic role in the evaluation of abnormal liver function tests in these patients,^78,^79,⁸⁶ particularly in managing the potential hepatotoxicity of highly active antiretroviral therapy (HAART)⁸⁷^,⁸⁸ and concurrent chronic hepatitis B and/or C which may be present. Although Kupffer cells and endothelial cells⁸⁹^–⁹³ are potential target cells for HIV-1 infection, there are no specific hepatic lesions due to HIV-1, a few cases of alleged ‘HIV-1 hepatitis’⁹⁴^,⁹⁵ notwithstanding.

Table 15.2 Hepatobiliary lesions in HIV-1 infection and AIDS

Lesion	Cause(s) or type(s)
Granulomas	Mycobacteria, fungi, drugs
Abscesses	Staphylococci, streptococci, listeria
Bacillary peliosis	Bartonella henselae
Biliary tract disease (AIDS cholangiopathy)	CMV, cryptosporidia, microsporidia
Neoplasms	Kaposi’s sarcoma, lymphoma, smooth muscle tumours
Chronic viral hepatitis	HBV, HCV, HDV
Autoimmune hepatitis	Coexistent or following immune reconstitution
Other viral infections	CMV, herpes simplex virus, Epstein–Barr virus, adenovirus
Vascular lesions	Peliosis hepatis, sinusoidal dilatation
Drug toxicity	Sulfa agents, antiretrovirals
Miscellaneous	Steatosis, haemosiderosis, stellate cell hypertrophy, amyloidosis

Despite the reduction in morbidity and mortality due to antiretroviral therapy and prophylactic antibiotics,⁹⁶ opportunistic infections and neoplasms such as Kaposi’s sarcoma and lymphoma must still be excluded on liver biopsy. Specimens should routinely be studied with acid-fast and silver stains for detection of high-incidence pathogens such as mycobacteria and fungi. Other methods such as Gram or Warthin–Starry stains can be applied, depending on the clinical and histological indications. A portion of the biopsy should be sent for culture.

Drug-related hepatotoxicity

Antiretroviral drugs may need to be excluded as the cause of liver dysfunction in HIV-positive individuals, particularly in those with negative hepatitis virus serology. Combination therapy frequently presents the problem of distinguishing among various medications. In this instance it is helpful to consider the type of hepatic damage characteristic of the several classes of HAART agents.⁸⁸ The nucleoside reverse transcriptase inhibitors cause mitochondrial damage and microvesicular steatosis, while the non-nucleoside reverse transcriptase inhibitors may produce confluent necrosis. The lesions attributed to protease inhibitors are various, including bile-duct damage, hepatocyte necrosis and ballooning, Mallory body formation and perivenular fibrosis.⁸⁸ Since antiretroviral liver injury is often idiosyncratic, the Internet and other sources should be consulted for emerging descriptions of new cases.

Opportunistic infections and infestations

Opportunistic infections and infestations involving the liver and bile ducts in AIDS include Mycobacterium avium–intracellulare and Mycobacterium tuberculosis infections, cytomegalovirus infection, cryptococcosis, candidiasis, histoplasmosis, leishmaniasis,⁹⁷ malaria, cryptosporidiosis,⁹⁸ and microsporidiosis.⁹⁹^–¹⁰¹ Mycobacterial and fungal infections frequently produce granulomas. M. avium–intracellulare results in numerous granulomas and the organisms are readily demonstrated by staining with diastase–periodic acid–Schiff (PAS) or the Ziehl–Neelsen method¹⁰²^–¹⁰⁵ (Fig. 15.7). Each granuloma consists of foamy histiocytes with few lymphocytes. The histiocytes often show a striated appearance on haematoxylin and eosin (H&E) staining due to the abundant packing of organisms in each cell. M. avium–intracellulare organisms are also well stained with Gomori methenamine silver. For screening of liver biopsies, particularly for M. tuberculosis which may be present in fewer numbers than M. avium–intracellulare, the auramine–rhodamine fluorescent method ¹⁰⁶^,¹⁰⁷ gives excellent results. Careful examination of special stains is of particular importance, as some AIDS patients have mycobacterial infection without typical granuloma formation; scant, single mycobacteria may be present within sinusoids or portal tracts. Pneumocystis carinii may disseminate to the liver, producing acellular exudative masses which closely resemble the pulmonary alveolar exudates.¹⁰⁸

Figure 15.7 Mycobacterium avium–intracellulare in AIDS.

Abundant macrophages with densely packed mycobacteria are present within a granuloma. Individual organisms are best seen in the centre of the field. (Post-mortem liver, Ziehl–Neelsen.)

AIDS cholangiopathy

AIDS cholangiopathy resembles sclerosing cholangitis clinically and radiographically and is due to infections of the large bile ducts by several possible pathogens, including cytomegalovirus, cryptosporidia and microsporidia.99–101,109–111 Liver biopsy changes are those of large-duct obstruction. Cryptosporidia and microsporidia are best identified in aspirates obtained at endoscopy, duodenal biopsies, or post-mortem tissue samples of the major bile ducts.⁹⁹^–¹⁰¹

Peliosis hepatis

Peliosis hepatis ^104,^112,¹¹³ in AIDS has been postulated to be due to endothelial damage by HIV-1 infection.⁹³ Alternatively, bacillary peliosis hepatis may develop as a consequence of hepatic infection by the Gram-negative bacillus Bartonella henselae.¹¹⁴^–¹¹⁷ Smudge-like or granular pink-to-purple material associated with a myxoid stroma is seen within dilated vascular spaces (Fig. 15.8) and the Warthin–Starry stain shows clumped bacilli in these areas.

Figure 15.8 Bacillary peliosis in AIDS.

The portal tract is expanded by dilated blood vessels (left and right), chronic inflammatory cells and pink-grey smudge-like material (at centre) which contains bacilli. (Needle biopsy, H&E.)

Lymphomas

Lymphomas involve the liver as nodular masses or portal tract infiltrates (see Fig. 7.3) and are high-grade large-cell, immunoblastic and Burkitt types.¹¹⁸^,¹¹⁹

Chronic hepatitis

AIDS patients have many of the same risk factors for infection by hepatitis viruses, and serum markers of prior infection or active viral hepatitis are often present. While the liver biopsy lesions of chronic hepatitis B, C, and delta can vary considerably in persons infected with HIV,¹²⁰^–¹²² it is now recognised that HIV infection may exert an adverse effect.¹²³^–¹²⁵ Fulminant hepatitis may occur¹²⁶ and in drug addicts a propensity for more severe chronic hepatitis with progression to cirrhosis has been noted.¹²⁷ Coexistent autoimmune hepatitis may need exclusion when abnormal serum liver tests are found in the HIV-infected individual¹²⁸ and rarely de novo autoimmune hepatitis may develop because of immune reconstitution after antiretroviral therapy has begun.¹²⁹

Steatosis and other changes

Steatosis is common ¹³⁰ and may be periportal (see Fig. 7.3). Severe macrovesicular or microvesicular fat is cause for concern because this may reflect toxicity of anti-viral medications^87,^88,^131,¹³² and can be associated with liver failure.¹³³ Siderosis of Kupffer cells is related to transfusion or viraemia-associated erythrophagocytosis. In some cases, non-specific changes consisting of sparse portal or acinar lymphocytic inflammation with scattered apoptotic bodies are seen, with no apparent aetiology.

Other lesions reported include nodular regenerative hyperplasia,¹³⁴^,¹³⁵ amyloidosis¹³⁶ and hypertrophied perisinusoidal stellate (Ito) cells containing numerous lipid droplets.¹³⁷ In children, giant-cell hepatitis,⁹⁴^,¹³⁸ chronic hepatitis of uncertain cause¹³⁹ and primary leiomyosarcoma¹⁴⁰ are described.

Rickettsial, bacterial and fungal infections

Q fever

In Q fever, due to infection with Coxiella burnetii, liver involvement is common although only a few patients present clinically with liver disease. Histological changes include focal necrosis, non-specific inflammation and fatty change. The most characteristic lesion is the fibrin-ring granuloma³⁷^–⁴³ (see Fig. 15.3), a granulomatous lesion also seen in several other infections and in some patients taking allopurinol.⁴⁴ Atypical lesions without annular arrangement or a central clear area (but containing irregular fibrin strands) are also found, as are non-specific granulomas without fibrin. In chronic Q fever progressive fibrosis and cirrhosis have been reported.¹⁴¹

Brucellosis

In most patients with brucellosis, liver biopsy shows non-specific reactive changes comprising sinusoidal-cell hypertrophy, portal inflammation and focal necrosis. Non-necrotising granulomas, often small and located within the acini, are more commonly found in the acute phase of the infection.¹⁴²

Typhoid fever

Liver involvement is uncommon, but most patients with ‘typhoid hepatitis’ are jaundiced.¹⁴³ Liver biopsy shows a mild hepatitis with marked hyperplasia of mononuclear phagocytes, and lymphocytoid cells in sinusoids.¹⁴⁴ Characteristic granuloma-like collections of mononuclear cells, the typhoid nodules, are described.¹⁴⁵ Other features include fatty change and portal inflammation.¹⁴³^,¹⁴⁶

Cat-scratch disease

Infection by a short Gram-negative rod, Bartonella henselae, typically produces pyrexia and regional lymphadenopathy in children. Rarely, dissemination to the liver results in hepatic granulomas with central stellate microabscesses surrounded by palisaded macrophages, lymphocytes and an outer layer of fibroblasts.¹⁴⁷^,¹⁴⁸ The Warthin–Starry stain is used to identify the organisms.

Tuberculosis

Tuberculous lesions are present in the liver either as part of a generalised infection ¹⁴⁹ or, less often, in the hepatobiliary form of the disease.¹⁵⁰ A normal chest X-ray does not exclude the diagnosis.¹⁵¹ Granulomas are found randomly scattered in the parenchyma and also in the portal tracts. They range from small accumulations of macrophage-like cells to well-developed, large epithelioid-cell nodules with Langhans giant cells (Fig. 15.9). Central necrosis may or may not be present, and its absence does not exclude the diagnosis. Extensive necrosis (Fig. 15.10) is more likely to be seen when there are widely disseminated granulomas in the liver. Mycobacteria are seen in a minority of biopsies. Acute lesions contain little reticulin, while chronic ones undergo scarring. Remaining liver tissue shows non-specific reactive features and fatty change. Patients with AIDS sometimes have mycobacterial infection without typical granulomas, or may form tuberculous abscesses.¹⁵² In all patients in whom tuberculosis is suspected, part of the liver biopsy specimen should be cultured. Polymerase chain reaction studies may also be performed on biopsy samples.¹⁵³ Lesions similar to those of tuberculosis have been reported in patients given BCG immunotherapy.¹⁵⁴^–¹⁵⁷

Figure 15.9 Tuberculosis.

Three parenchymal granulomas abut a portal tract. Multinucleated giant cells are visible in two of the granulomas. (Needle biopsy, H&E.)

Figure 15.10 Tuberculosis.

There is extensive necrosis with little residual evidence of granulomas. (Needle biopsy, H&E.)

Leprosy

In lepromatous leprosy specific granuloma-like lesions composed of foam cells are found in the liver and often contain acid-fast bacilli.¹⁵⁸ Organisms are also seen in Kupffer cells. Epithelioid-cell granulomas of tuberculoid type, rare in lepromatous leprosy, are found in the livers of some patients with the tuberculoid form of the disease. Either type of granuloma is seen in borderline leprosy.¹⁵⁹

Spirochaetal infection

Syphilis

In congenital syphilis there is widespread fibrosis separating small groups of hepatocytes and spirochaetes are numerous. In early infections in adults, liver biopsies are normal or show non-specific changes.¹⁶⁰ Spirochaetes may be demonstrable histologically. In patients with secondary syphilis and jaundice or abnormal liver function tests, there is a variable degree of focal parenchymal inflammation, granuloma formation,¹⁶¹ hepatocellular necrosis and portal inflammation. The portal reaction may mimic that of biliary obstruction,¹⁶² and there may be inflammation of bile-duct epithelium as well as of the walls of small arteries and veins.¹⁶³^,¹⁶⁴ Because patients with syphilis often have other infections as well, lesions cannot always be confidently attributed to the syphilis itself.¹⁶⁵ The typical lesion of tertiary syphilis is the gumma, an area of necrosis surrounded by granulomatous tissue in which there is endarteritis. Healing is by fibrosis.

Leptospirosis

Most studies of the pathology of leptospirosis have dealt with autopsy material, in which disorganisation of liver-cell plates is a prominent feature. This is usually absent from liver biopsies.¹⁶⁶ Hepatocytes are swollen, especially in perivenular areas, and there is an increase in mitotic figures. A few acidophil bodies and fat vacuoles may be seen. Kupffer cells are prominent and there is a mild mononuclear-cell infiltrate in portal tracts. Cholestasis is common, which may persist after resolution of the other changes.¹⁶⁷ The diagnosis can be confirmed by demonstrating leptospiral antigen in paraffin sections by immunocytochemistry.¹⁶⁸

Lyme disease

Hepatomegaly, elevated serum aminotransferase activity and biopsy features resembling viral hepatitis may be seen in patients infected with the tick-borne spirochaete Borrelia burgdorferi.¹⁶⁹ Liver-cell ballooning and numerous mitoses are accompanied by sinusoidal inflammation (hyperplastic Kupffer cells, lymphocytes, plasma cells and neutrophilic leucocytes). Rarely, necrotising granulomas with multinucleated giant cells and many eosinophils develop.¹⁷⁰ The organism can be identified in liver tissue by Dieterle silver stain.

Candidiasis

The most common hepatic manifestations of candidiasis in immunocompromised hosts are microabscesses and granulomas.¹⁷¹^,¹⁷² The more acute lesions show microabscess formation with central necrosis, visible on gross examination as 1–2 mm yellow-white nodules. Yeasts and pseudohyphae can be seen in some, but not all, cases with diastase–PAS and Gomori methenamine silver stains. The predominantly neutrophilic infiltrates are replaced by epithelioid histiocytes and granulomas as the lesions evolve, sometimes surrounded by reactive fibrosis. Candidiasis is most often diagnosed post-mortem, but should be suspected in the presence of fever, abdominal symptoms and elevated serum alkaline phosphatase activity. Systemic candidiasis has been noted as an important cause of mortality in patients with zone 3 or multilobular hepatic necrosis due to exertional heatstroke.¹⁷³

Histoplasmosis

Hepatomegaly is common in disseminated histoplasmosis due to Histoplasma capsulatum. The disease is very occasionally seen in countries where it is not endemic.¹⁷⁴ The liver may rarely be the only organ clinically involved.¹⁷⁵ Liver biopsy shows non-specific inflammation as well as granulomas which may be mistaken for the lesions of tuberculosis.¹⁷⁶^,¹⁷⁷ The organisms may be scanty or abundant, and are found in Kupffer cells and granulomas. They are round or oval, 1–5 µm across, and have a capsule and central chromatin mass. Diastase–PAS and other stains for fungi can be used for their demonstration and differentiation from Leishman–Donovan bodies; the latter are PAS-negative in tissues.¹⁷⁸ Disseminated infection with Histoplasma duboisii, seen in Africa, also involves the liver. Nodular lesions contain the much larger and easily demonstrable organisms.¹⁷⁹

Fibrous, calcified and even bony nodules are sometimes found in and deep to the liver capsule in long-standing histoplasmosis. The nodules, 1–3 mm in diameter, may have a necrotic core surrounded by granulomatous tissue, and the organism is demonstrable in some instances.¹⁸⁰

The liver in sepsis

Hepatic changes in sepsis are the result of infection of the liver itself, of circulating toxins, of ischaemia, or of a combination of these factors. In many patients the exact cause cannot be established.

Infective lesions include liver abscess and bacterial cholangitis. Less commonly, infection produces a diffuse bacterial hepatitis in which bacterial colonisation of the liver is associated with portal inflammation.¹⁸¹ Infection in areas drained by the portal venous system can give rise to pylephlebitis (see Fig. 12.3). Rarely, cholangiographic and histological features resembling primary sclerosing cholangitis develop in sepsis, possibly related to ischaemic damage to large ducts.¹⁸² Post-mortem liver sections from septic patients may show neutrophils aggregated within sinusoids and in sparse numbers dispersed throughout the connective tissue of portal tracts.

Patients with extrahepatic sepsis are often jaundiced, especially when the infection is due to Gram-negative organisms.¹⁸³ Three histological patterns have been described in such patients. The commonest is canalicular cholestasis, most severe in perivenular areas. This is associated with various degrees of Kupffer-cell activation, fatty change and portal inflammation, but usually little or no hepatocellular necrosis.¹⁸⁴

The second pattern is one of ductular cholestasis and inflammation.¹⁸³^,¹⁸⁵ Bile ductular structures and canals of Hering at the margins of portal tracts are dilated and filled with bile, often in the form of dense, highly pigmented deposits, and neutrophils are seen within and around the affected ductules (Fig. 15.11). Perivenular cholestasis is usually present. Periportal canalicular bile is also sometimes present. These changes are not seen in uncomplicated bile-duct obstruction. They are common in the terminal stages of fatal acute or chronic liver disease complicated by sepsis. Damage to bile-duct epithelium has been reported¹⁸⁶ but in most instances the interlobular bile ducts are not affected. Patients with the ductular cholestasis pattern have disproportionately elevated serum bilirubin levels compared with alkaline phosphatase and aminotransferases.¹⁸⁷ Because of its dire implications, this biopsy finding should be communicated rapidly to the clinician and sepsis should be investigated.

Figure 15.11 Bile ductular cholestasis in sepsis.

Proliferated bile ductules at the edge of the portal tract contain inspissated bile. The patient died of septicaemia. (Post-mortem liver, H&E.)

The third pattern is non-bacterial cholangitis, seen in the toxic shock syndrome.¹⁸⁸ The histological features are similar to those of bacterial cholangitis, but the biliary tree is anatomically normal and the lesion is attributed to a circulating staphylococcal toxin rather than to bacteraemia. In many patients, but not all, the underlying lesion is a staphylococcal vaginitis associated with the use of tampons.

Parasitic diseases

Toxoplasmosis

Toxoplasma gondii is occasionally responsible for neonatal liver injury. In adults, hepatic changes include extensive lymphocytic infiltration of sinusoids, evidence of mild liver-cell damage and granuloma formation.¹²^,¹⁸⁹ Trophozoites may be seen within necrotic hepatocytes and can be identified by specific immunocytochemical methods.¹⁹⁰^,¹⁹¹

Malaria

In non-immune patients with malaria there is hypertrophy of Kupffer cells and these contain malarial pigment (haemozoin) in the form of fine, dark brown or black pigment granules (Fig. 15.12). In acute malaria due to Plasmodium falciparum they also contain erythrocytes, parasites and iron. Malarial pigment closely resembles schistosomal pigment. It often gives pin-point birefringence and, like formalin pigment, is soluble in alcoholic picric acid. This distinguishes it from carbon, with which it may be confused.¹⁹² Other black pigment in Kupffer cells, portal tract macrophages or granulomas can be seen after gold salt therapy or following knee or hip replacement with titanium-containing prostheses.¹⁹³ Following an attack of malaria the pigment clears from the acini but can be found in portal macrophages.

Figure 15.12 Malaria.

Kupffer cells contain abundant dark granules of malarial pigment. (Needle biopsy, H&E.)

The tropical splenomegaly syndrome (hyper-reactive malarial splenomegaly) probably represents an abnormal immune response of the patient to the malarial parasite.¹⁹⁴ Large numbers of small T-lymphocytes are seen in dilated hepatic sinusoids (Fig. 15.13). Kupffer cells are enlarged but hepatocytes remain normal. Malarial pigment is scanty or absent. The differential histological diagnosis is from leukaemia, hepatitis C virus infection, infectious mononucleosis, cytomegalovirus infection and toxoplasmosis.