—  SPECIALTY CONFERENCE  —

Liver Pathology

Case 4 - Reactive, Granulomatous Hepatitis Due to Chronic Granulomatous Disease with Sclerosing Cholangitis-like Changes

David Kleiner
National Cancer Institute


Click on each slide thumbnail image for an enlarged view
Case Summary
The patient is a 23 year old man with a history of recurrent pulmonary, hepatic and bone infections since young childhood. These infections have required repeated hospitalizations and chronic administration of antibiotics and antifungals. This time he was admitted for investigation of sinusitis and during the work-up was noted to have an elevated liver associated enzymes (Alkaline phosphatase 866 (range 37-116), ALT 52 (range 6-41), AST 37 (range 9-34) and total bilirubin of 0.6 mg/dL). Imaging using ultrasound, CT and MRI showed multiple hepatic lesions consistent with abscesses. A CT guided aspirate grew Staph. aureus and Strep. mitis. He was started on Ceftriaxone, Vancomycin and Rifampin and discharged, but returned one week later with right upper quadrant pain, fatigue and chills. He was taken to surgery where drains were placed and wedge resections of liver were performed. One of the specimens was a wedge of liver measuring 7 x 4.5 x 3 cm. Sectioning revealed multiple small firm white nodules measuring up to 0.4 cm, but no frank abscesses. Hemorrhage and fibrosis was noted on one edge of the specimen. The section submitted for review was selected from an area without obvious gross parenchymal lesions.


Case 4 - Figure 1 - Hepatic abscess from one of the other liver specimens submitted on this patient (10x, H&E)
Case 4 - Figure 2 - Low power overview of hepatic parenchyma (4x, H&E)
Case 4 - Figure 3 - Low power overview of hepatic parenchyma (4x, H&E)



Case 4 - Figure 4 - One of numerous collections of pigmented macrophages (40x, H&E)
Case 4 - Figure 5 - Scattered granulomas were seen. This one may have been located in or near a portal area (20x, H&E)
Case 4 - Figure 6 - Another example of the granulomatous inflammation (20x, H&E)



Case 4 - Figure 7 - Central vein with inflammation (40x, H&E)
Case 4 - Figure 8 - Portal area with obliterated duct (10x, H&E)



Case 4 - Figure 9 - Large duct with inflammation (10x, H&E)
Case 4 - Figure 10 - Small duct with periductal fibrosis and inflammation (40x, H&E)


Pathology
The section provided for evaluation shows a large variety of changes. At the edges of the section there is extensive hemorrhage with fibrin deposition and areas of coagulative necrosis. The hemorrhage tracks deeper into the specimen along portal tracts and large central veins. These changes are all acute and probably related to the surgical procedure. The liver parenchyma is involved by a diffuse inflammatory process. The portal areas are expanded by a mild to moderate infiltrate consisting of lymphocytes and macrophages. Granulomas are common. Some portal areas contain collections of eosinophils. At the edges of nearly all of the portal areas, there is infiltration and disruption of the limiting plate by lymphocytes. The sinuses are mildly dilated and there are foci of spotty necrosis associated with lymphocytes and micro-granulomas. Many of the large central veins show perivenular inflammation and granuloma formation. The granulomas themselves show a variety of morphologies, from aggregates of large pigmented macrophages, to small, well-defined epithelioid giant-cell granulomas, to larger, more ill-defined epithelioid granulomas that are infiltrated by lymphocytes and eosinophils. Some of the portal granulomas seem to be occupying positions where ducts ought to be and a number of smaller portal tracts lack an identifiable duct. In some large portal areas, there is periductal edema and inflammation with infiltration of the duct by lymphocytes. Other portal areas show constriction of the duct by concentric fibrosis to the point of complete obliteration of the lumen and replacement of the duct by a round fibrotic scar. The hepatocytes at the edges of these portal areas have pale rarefied cytoplasm (cholatestasis, pseudoxanthomatous change). Rare cholestatic rosettes can be seen in the parenchyma. Sections taken from the abscesses (one digital slide provided) showed multiple, large necrotizing granulomas with irregular borders surrounded by a cuff of fibroinflammatory granulation tissue that varied from several millimeters to more than a centimeter in thickness.

Diagnosis
Reactive, Granulomatous Hepatitis Due to Chronic Granulomatous Disease with Sclerosing Cholangitis-like Changes

Discussion
The pathologic differential diagnosis should always begin with a careful consideration of the pathologic changes first and only after that adding the clinical information. In this case, the liver is diffusely involved by a necroinflammatory process that is characterized by portal and lobular lymphocytic inflammation, interface hepatitis and lobular spotty necrosis, non-necrotizing granulomas and duct injury with duct loss. The broadest differential would include chronic hepatitic diseases such as chronic viral and autoimmune hepatitis, granulomatous diseases such as sarcoidosis and disseminated granulomatous infections and chronic cholestatic diseases such as primary biliary cirrhosis (PBC), sclerosing cholangitis and others (see Table below).

Differential Diagnosis of (Non-Steatotic) Chronic Necroinflammatory Diseases in Adults, adapted from Snover, DC. Biopsy Diagnosis of Liver Disease, Williams & Wilkins, Baltimore, MD. 1992, pp 23-37.

Basic Pattern of Injury
Chronic Hepatitic Granulomatous Chronic Cholestatic
Hallmark: Portal-dominant chronic inflammation with interface hepatitis Hallmark: Granulomas, without associated duct involvement Hallmark: Duct injury and or duct loss as dominant finding
Resolving acute hepatitis Infectious diseases (mycobacterial, fungal, viral (EBV, CMV), rickettsial) Primary biliary cirrhosis
Chronic viral (B, C or D) hepatitis Sarcoidosis Primary sclerosing cholangitis
Autoimmune hepatitis Idiopathic granulomatosis Acute cholangitis
Early stages of PBC or primary sclerosing cholangitis Primary biliary cirrhosis Graft-vs-host disease
Wilson's disease Foreign material Idiopathic adulthood ductopenia
Drug injury Drug Injury Drug Injury
Reactive hepatitis adjacent to mass lesion Malignancy (especially lymphoma) Secondary (acquired) sclerosing cholangitis
Chronic intermittent duct obstruction Crohn's disease Sarcoidosis
Chronic granulomatous disease
Common variable immunodeficiency

In this case, although multiple inflammatory features are observed, the presence of duct injury and loss takes the differential diagnosis out of the purely hepatitic disease into the granulomatous and/or cholestatic diseases. Some diseases, such as sarcoidosis and PBC may have cholestatic and granulomatous features. Once the basic pattern of injury has been defined, individual entities can be included or excluded based on features that are more specific for particular diseases. The granulomas of sarcoidosis typically are well-circumscribed cellular spheres of epithelioid histiocytes with little or no infiltration by lymphocytes or eosinophils. They may be found in portal areas or in the lobular parenchyma and tend to be of the same degree of size and cellularity. True necrosis is generally not seen, although there may be collagen degeneration in the centers of larger or coalescent granulomas. Patients with hepatic sarcoidosis have developed chronic cholestasis from secondary involvement of ducts by granulomas [1]. Infectious granulomas may come in all sizes and shapes, and with or without necrosis. They do not, however, typically cause duct injury or paucity. Nevertheless, special stains for fungi, mycobacteria and atypical bacteria should be done whenever faced with a biopsy full of granulomas, particularly one from a patient with a history of recurrent infections. Primary biliary cirrhosis is a progressive, chronic autoimmune disease of the liver characterized by destruction of small ducts [2, 3] . The hallmark lesion consists of an injured duct with reactive epithelial changes associated with an epithelioid cell granuloma. Ducts may be incomplete or injured and ultimately disappear from the portal areas completely. Portal based lymphoid follicles are common and are sometimes associated with injured ducts. Eosinophils may be seen mixed into the portal inflammation. As the disease progresses, there is duct loss, ductular reaction and cholatestasis. Fibrosis begins as expansion of portal areas and progresses to portal-portal bridging and cirrhosis. Primary sclerosing cholangitis (PSC) is a disease of large and small ducts, although there is a variant which is limited mainly to small ducts [2, 3] . The larger ducts become surrounded by a cuff of edematous, mildly inflamed connective tissue, given the duct an "onion-skin" appearance. There is frequently evidence of epithelial damage, with infiltration of the epithelium by lymphocytes or neutrophils. Gradually there is constriction of the duct to the point where the lumen disappears completely and the duct is replaced by a dense collagenous scar. Granulomas are not generally seen in PSC and the inflammation is usually sparse. As with PBC, as the ducts disappear, there is ductular reaction and progressive fibrosis. Patients with PSC are at risk for the development of cholangiocarcinoma.

Once the pathologist has reviewed the histologic features and formulated a pathologic differential diagnosis, then the clinical history and laboratory data should be reviewed. This is particularly critical with non-neoplastic liver disease. In this case, the history indicated that the patient had an underlying immunodeficiency, chronic granulomatous disease (CGD). Chronic granulomatous disease is a rare (incidence ~1 in 200,000 to 250,000) defect in intracellular killing of pathogens by neutrophils [4, 5, 6, 7] . It is inherited through both X-linked and autosomal recessive mechanisms. The specific functional defect is in NADPH oxidase, a membrane-bound enzyme that catalyzes the oxidation of O2 to superoxide anion, O-2. NADPH oxidase has four subunits, gp91phox, which is on the X-chromosome and p22phox, p47phox and p67phox, which are on chromosomes 16, 7 and 1 respectively. About 70% of patients have the X-linked form of the disease. Because patients with CGD cannot generate superoxide, they are particularly susceptible to infections from certain catalase-positive organisms such as Staph. aureus, Burkholderia sp., Serratia marcescens, Nocardia sp., and Aspergillus sp. About a quarter of patients with CGD will develop hepatic abscesses, which frequently require surgical intervention due to the fact that CGD abscesses are multiloculated and embedded in a thick cuff of fibrous tissue and so are not amenable to percutaneous drainage [8, 9] . Aside from abscesses, which can be life-threatening, patients with CGD can also develop granulomatous enteritis and genitourinary obstruction. They heal wounds poorly, in part from the exuberant inflammatory response that develops against any infection or injury. Biopsies will show a large variety of granulomatous reactions and typically there are collections of pigmented macrophages at sites of inflammation and at sites of cell turnover or bacterial surveillance, such as the mucosa of the GI tract. Beyond the development of hepatic abscesses and the presence of granulomas and pigmented macrophages, little has been reported on the hepatic pathology of CGD.

In a patient with a systemic disease who develops manifestations of disease not previously associated with the systemic disease, there are three general possibilities for interpretation of the new lesion.
  1. The systemic disease is unrelated to the development of the new lesion and the association is only coincidental.

  2. The systemic disease may modify the natural history and/or histologic appearance of the new lesion, but the new lesion is one that may be seen in individuals without the systemic disease.

  3. The new lesion is a manifestation of the systemic disease, possibly unreported.
The case under consideration has features of both PBC (granulomatous inflammation in portal areas with duct loss) and PSC (injury of large ducts with progressive sclerosis and duct loss). There are also clearly manifestations of the patient's systemic illness with both granulomatous inflammation and numerous collections of pigmented macrophages. Given that the patient was young, male, AMA-negative (determined later) and that his CGD might account for the presence of granulomas, the cholestatic injury seemed to be more like PSC than PBC or other granulomatous or cholestatic disease. PSC is a rare disease, and it is associated with underlying ulcerative colitis or Crohn's disease in 75-80% of cases. It has a male predominance and although patients may have other autoimmune disease or have positive serology, PSC is not considered to be a classic autoimmune disease and it does not respond to immunosuppression. One important consideration is that there are a variety of other diseases and conditions that may be associated with PSC-like pathology. These include the sclerosing cholangitis of HIV [10], drug-induced injury from hepatic artery floxuridine infusions [11], rupture of echinococcal cysts into the biliary tree and infiltration of the biliary tree by Langerhans' cell histiocytosis [12]. PSC-like changes have been seen in other primary immunodeficiency syndromes such as hyper-IgM immunodeficiency [13]. One model of the pathogenesis of PSC involves the presentation of a foreign antigen, presumably an infectious agent, in the biliary tract. The presence of this antigen in a susceptible host sets off a cascade of immune events that culminates in chronic damage to bile ducts [14, 15, 16] . This model would bring together both patients with PSC and inflammatory bowel disease and secondary sclerosing cholangitis associated with immunodeficiency. All of these patients would have immune dysregulation combined with increased opportunity for pathogens to reach the biliary tree.

So in summary, careful consideration of the pathologic features of this complex case permits the construction of a pathology-based differential diagnosis that can then be evaluated in light of the patient's systemic disease. Patients with unusual manifestations of their primary disease may require different management than patients with a new second disease. In this case, the initial attention of the pathologist was focused entirely on the evaluation of the hepatic abscesses, because abscesses are the known pathologic manifestation of CGD in the liver. A more objective, open-minded approach allows all of the pathologic findings to be noted prior to interpretation in light of the patient's medical history.

References

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