Other Infections of the Liver

Michael S. Torbenson, MD

10.1 INTRODUCTION

This chapter discusses nonviral and nonparasitic infections of the liver, though infections that are primarily granulomatous are discussed with other granulomatous diseases in Chapter 11, including fungal infections, Mycobacterium tuberculosis, Mycobacterium leprae, Brucellosis, and Q fever. Of course, not all organisms that can possibly infect the liver can be covered in this chapter, because the list of specific organisms is vast and ever growing. Instead, this chapter will focus on the most common infections.

The histologic findings vary considerably with these infections. Many cases have only nonspecific findings such as mild portal and lobular chronic inflammation with Kupffer cell hyperplasia. In contrast, some biopsies will have findings that more strongly suggest infection (Table 10.1). Special stains are key tools in identifying organisms (Table 10.2). When infection is strongly considered clinically before the biopsy, an additional core of tissue for culture can be very helpful in establishing a diagnosis.

10.2 MALARIAL INFECTION

Malaria is caused by the protozoan parasite Plasmodium, of which there are four species: falciparum, vivax, malariae, and ovale. The organism is transmitted by the anopheline mosquito. The World Health Organization (WHO, http://www.who.int/malaria/en/) estimates that there are more than 200 million malarial infections per year worldwide, leading to approximately 438,000 deaths per year, 90% occurring in Africa. Almost all of the infections are in the tropical areas of the world. Malaria is very uncommon outside of the tropics but can be encountered because of the increasingly global nature of medicine, with patients traveling widely for health care. The large increase in vacations to endemic areas also increases exposure. Finally, the infection can be encountered as populations emigrate from endemic areas to nonendemic areas.

The classic clinical presentation for malaria is cyclic fevers that occur every 48 to 72 hours, often preceded by shaking chills. That being said, in many cases the presentation is not classic, consisting of milder and less-specific complaints. Jaundice is reported in about 5% of infected individuals but can be as high as 60% during epidemic

outbreaks.¹ Children are more likely than adults to be jaundiced.²

Table 10.1 Overview of histologic findings of infections in liver

Association with infection	Histologic findings
Common but nonspecific	Mild to moderate portal and mild lobular chronic inflammation Kupffer cell hyperplasia Cholestasis
Strongly suspicious for infection	Numerous small clusters of sinusoidal histiocytes (consider listeriosis, typhoid) Small abscesses (consider listeriosis, tularemia) Abscesses Necrotizing granulomas Irregular geographic areas of necrosis (viral infection and malignancy should also be excluded) Malakoplakia Inflammatory pseudotumor
Strongly suspicious for a specific organisms	Malarial pigment (malaria) Sulfur granules (Actinomyces)
Other findings	Peliosis Steatosis

Table 10.2 Special stains used to identify organisms

Stain	Comment
For fungi
Gomori Methenamine-Silver (GMS)	Fungi Pneumocystis carini Also stains some bacteria: Actinomyces and related species, Nocardia, some encapsulated bacteria
PAS	Fungi Foamy macrophages in Whipple’s disease
Alcian Blue	Mucoid capsule of Cryptococcus neoformans
Mucicarmine	Mucoid capsule of Cryptococcus neoformans
For bacteria
Gram-Weigert	Gram-positive organisms, blue. Fibrin also stains blue. Bacteria that are negative on the stain are assumed to be gram-negative. Some acid-fast bacteria can stain red.
Brown-Hopps	Gram-positive organisms, blue. Gram-negative organisms, red. Rickettsia are also positive.
Giemsa	Rickettsia lack cell walls so don’t stain with gram stains. Same for other organisms such as Leishmania, Plasmodium.
For acid-fast bacteria
Kinyoun/Ziehl Neelsen	Stains all mycobacteria red/purple. Non-acid-fast bacteria will be blue.
Fite	Nocardia, Mycobacterium leprae
For spirochetes
Warthin-Starry	Stain is dirty and hard to read, but can stain spirochetes including Bartonella, Treponema pallidum. Legionella also can stain. In fact, many different bacteria stain, so morphology of the organism is also important.
Dieterle	Similar to Warthin-Starry
Steiner Stains	Similar to Warthin-Starry
Immunostains
Treponema pallidum	Spirochetes
Tropheryma whipplei

Figure 10.1 Hemozoin or malarial pigment. This biopsy was prompted by unexplained liver enzyme elevations and showed malarial pigment.

The histologic findings in liver vary in severity and can be mild and subtle, even with fatal cases.³,⁴ The actual malarial organisms are generally not seen.³ The major pattern is that of variable degrees of Kupffer cell hyperplasia, sinusoidal congestion, and generally minimal to mild portal chronic inflammation.⁵ However, moderate to marked portal chronic inflammation has been reported in more severe cases.⁵ The Kupffer cells can show prominent hemophagocytosis. In some cases, the Kupffer cells or the portal macrophages will have distinctive brown-black malarial pigment, also called hemozoin (Fig. 10.1). Other lobular changes include cholestasis and, rarely, fatty change in more severe cases.⁶ In fatal cases, hemorrhagic necrosis of the zone 3 hepatocytes can be seen.³ Additional findings will be seen in those individuals with comorbid conditions, such as a more significant hepatitis in the setting of chronic viral hepatitis, or iron deposits in the setting of glucose-6-phosphate dehydrogenase deficiency.

10.3 TICK-BORNE DISEASES

Ticks can transmit a variety of infectious agents, including protozoa, bacteria, and viruses. Most tick-borne infections do not present with hepatitis as their primary clinical manifestation, but the liver is commonly involved, as evidenced by elevated liver enzymes. Of the tick-borne infections, the bacterial infections are particularly likely to involve the liver. Three of the tick-borne diseases that most commonly cause liver dysfunction are discussed later, but all known tick-borne diseases can lead to liver biochemical and histologic abnormalities.⁷

Clinical findings are quite variable and often quite confusing, but gastrointestinal manifestations are common, including nausea, vomiting, abdominal pain, diarrhea, and hepatomegaly. Unfortunately, the histologic findings remain incompletely defined because of the relative rarity of these diseases and the challenges of making a definite diagnosis. Nonetheless, our current state of knowledge is that the histologic changes range from mild nonspecific inflammatory changes to predominately cholestatic changes to small abscesses. Granulomas are not particularly common in any of the tick-borne diseases but can be seen in many of them, especially Lyme disease, ehrlichiosis, and tularemia. When granulomas are present, most are poorly formed and lack the circumscription and epithelioid morphology of fungal infection-associated granulomas. Q fever (Coxiella burnetii) is not transmitted directly by ticks, but ticks serve as a major reservoir, infecting domesticated sheep, goats, and cattle, with subsequent spread to human through unpasteurized milk, cheese, or undercooked meats. Q fever is discussed in more detail in Chapter 11.

Ehrlichiosis

Ehrlichiosis is a bacterial disease caused by Ehrlichia and Anaplasma organisms and transmitted by the lone star tick. The bacteria are obligate intracellular organisms that infect white blood cells. Mild and transitory elevations in liver enzymes are found in greater than 80% of infections.⁷ In about 3% of cases, the infection can be fatal.⁸,⁹ Liver biopsies are only rarely performed, so the full histologic spectrum of changes is unknown, but biopsy specimens can show lobular cholestasis and diffuse Kupffer cell hyperplasia. The cholestasis can be severe. The biopsies can also show mild lobular hepatitis, including scattered discrete foci of lymphocytes and macrophages (often 50 to 100 cells in size) associated with hepatocyte necrosis and drop out.⁸,¹⁰ The organisms are present in the liver and can be identified by immunostains,¹⁰ but can’t really be seen on the hematoxylin and eosin (H&E). They are best identified on peripheral blood smears, where cytoplasmic morulae are found in monocytes or granulocytes, with the infection burden ranging from 0.2% to 10% of cells.¹¹

Lyme disease

Lyme disease results from infection with the spirochete, Borrelia burgdorferi. At presentation, patients can have fevers, chills, headaches, arthralgias, and fatigue. The typical bull’s eye skin rash and a history of a tick bite are very helpful in suggesting a diagnosis, but are not evident in most cases. Gastrointestinal findings are also common at presentation but are not very
specific, including anorexia, nausea, and vomiting. About 1/3 of individuals with localized disease will have a mild hepatitis, whereas 2/3 of individuals with disseminated disease have a mild hepatitis, primarily with elevated aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in both cases.¹², ¹³, ¹⁴, ¹⁵ The enzyme elevations resolve within a few weeks following appropriate antibiotic therapy.⁷,¹⁴

The histologic findings have been described only in a few cases, but show a mild lobular predominant hepatitis with Kupffer cell hyperplasia.⁷,¹⁶ The lobular infiltrates are predominately lymphocytic but can also have admixed neutrophils. Granulomatous hepatitis has been reported in several cases,¹⁷, ¹⁸, ¹⁹ including one with large necrotizing granulomas, palisading histiocytes and multinucleated giant cells.¹⁸ In one case report with chronic infection, the biopsy showed portal-based inflammation that was initially interpreted as suggestive of primary biliary cirrhosis.¹⁹ In this same case, the authors identified mulberry shaped granules within the Kupffer cells on periodic acid-Schiff diastase (PASD) stain. In some reports, spirochetes have been identified on Dieterle silver stains and/or immunostains.¹⁶,¹⁹,²⁰

Rocky Mountain spotted fever

Rickettsia rickettsia is a gram-negative intracellular bacteria that is transmitted by the wood tick and the dog tick, causing Rocky Mountain spotted fever, a serious and sometimes life threatening illness. Risk factors for severe disease include older age, male gender, and glucose-6-phosphate dehydrogenase deficiency,²¹ which most commonly affects African Americans. In the first 2 to 3 days of illness, the clinical findings are largely gastrointestinal tract related, including anorexia, nausea, vomiting, and diarrhea. The classic constellation of findings takes longer to develop, but consists of fever, headache, and a rash following a tick bite. The liver is commonly involved in symptomatic individuals, as evidenced by hepatomegaly and abnormal liver enzymes.

The organism infects endothelial cells throughout the body. The resulting vasculitis can involve the stomach, pancreas, small bowel, and colon, leading to significant clinical disease. Within the liver, the histologic findings are often mild and not very specific. The histologic findings are primarily portal-based, showing mild to moderate inflammation with mixed lymphocytes and neutrophils.²²,²³ In some cases, the portal tract inflammation shows a prominent neutrophilia. Portal vein vasculitis and fibrin thrombi can occasionally be seen, with the inflammation composed of both lymphocytes and neutrophils. Cholestasis is not uncommon and can be striking.²⁴ Kupffer cell hyperplasia and erythrophagocytosis can be prominent.

Tularemia

Tularemia is caused by Francisella tularensis, a gram-negative coccobacillus. Francisella tularensis was first isolated in 1912 by GW McCoy of the US Public Health Services and named after Tulare County, California. However, the disease was well known anciently, though by different names of course, names that often included the term plague. As one example, tularemia infection has been proposed as the etiologic agent for the “Hittite plague.”²⁵

In the USA, the majority of tularemia cases are found in the southeast and southwest. Tularemia is not transmitted from humans to humans. However, the infection is highly contagious, transmitted to humans from rodents, rabbits, and deerfly or tick bites (Amblyomma americanum, Dermacentor andersoni, and Dermacentor variabilis). The organism can also live for many weeks in the soil, causing rare infections through aerosolization of organisms in the soil by gardeners, farmers, and construction workers. There is a bimodal epidemiologic distribution over the course of a year, reflecting these two primary sources for infection, with one peak in the summer driven by tick bites and a peak in the winter due largely to rabbit/rodent exposure. For the latter, there are a number of ways for disease transmission to occur, including skinning rabbits/rodents and recent contact with domestic cats that have eaten infected rodents.

The incubation period is usually short, averaging 3 to 5 days, but can extend out to 14 days. Tuleremia infection is broadly classified into a localized ulceroglandular pattern or a disseminated typhoidal pattern. The typhoidal pattern often has pneumonia as one of its manifestations, contributing to its overall worse prognosis.²⁶

Histologic descriptions are sparse, but there is hepatic involvement in more than 75% of cases.⁷ The liver shows small abscesses, 1 to 2 mm in size, with central necrosis surrounded by a thin rim of mixed neutrophils, lymphocytes, and macrophages.²⁷, ²⁸, ²⁹, ³⁰ Organisms are only rarely found on gram stain.⁷ Scattered granulomas can also be seen.³⁰ Outside of these abscesses/granulomatous areas, the lobules show mild nonspecific inflammatory changes and varying degrees of cholestasis.

10.4 HEPATIC ABSCESSES

An abscess is a localized collection of inflammatory exudate, often admixed with necrotic debris, which is surrounded by a rim of inflamed fibrous tissue. Liver abscesses can result from amebic, fungal, or bacterial infections. Mixed bacterial and fungal abscesses are also frequent but bacterial (or pyogenic) abscess are
the most common. The two major risk factors for hepatic abscesses are immunosuppression and chronic biliary tract disease. As an example, bacterial abscesses can result from biliary obstruction due to cancer involving the biliary tree or pancreas.³¹ Colon cancer is also associated with an increased risk for hepatic abscesses, even if there is no metastatic disease.³² The most common organisms in bacterial abscesses occurring in adults are streptococcal or Pseudomonas species, whereas in children, most hepatic abscesses are due to Staphylococcus aureus.³³

In many cases, hepatic abscesses are not biopsied because the clinical history and imaging studies can make the diagnosis. However, a number of abscesses remain challenging to diagnose by imaging findings and so undergo biopsy. On histology, an abscess is composed of a rim of inflamed fibrous tissue (Fig. 10.2), often with scattered reactive bile ducts (Fig. 10.3), and an inner layer of necrotic debris and inflammatory exudate (Fig. 10.4). The adjacent hepatic parenchyma also shows nonspecific inflammatory changes, edema, fibrosis, and sometimes cholestasis. This histologic pattern is very typical of a hepatic abscess and a diagnosis is usually straightforward. Gram and GMS stains are helpful to identify organisms (Fig. 10.5) and Table 10.2.

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