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liver in FHL

Tuesday 10 May 2011

The familial hemophagocytic lymphohistiocytosis (FHL) is a rare, rapidly progressive disorder characterized by an activation of the immune system resulting in a systemic proliferation of lymphocytes and histiocytes. Hepatic dysfunction often occurs early in the clinical course, but the pathology of the liver is not well characterized.

The disease is genetically heterogeneous and maps to at least 4 loci including the gene encoding perforin, a protein critical for the cytotoxic and regulatory functions of T lymphocytes and natural killer (NK) cells.


- hepatic failure
- hepatosplenomegaly
- hepatorenal failure
- portal infiltrates of T lymphocytes
- portal infiltrates of histiocytes
- periportal infiltrates of T lymphocytes
- periportal infiltrates of histiocytes
- activation of the hepatic mononuclear phagocytic system
- focal hemophagocytosis
- loss of interlobular bile ducts (biliary ductopenia)
- paucity of bile ducts (biliary ductopenia)
- portal and sinusoidal infiltrate of CD3+, CD8+, granzyme B+ lymphocytes admixed with CD68+, CD1a- histiocytes that exhibited hemophagocytosis.
- endothelialitis of portal and central veins
- lymphocyte-mediated bile duct injury
- portal lymphohistiocytic infiltration
- extensive periportal necrosis
- erthrophagocytosis
- hemophagocytosis
- lymphophagocytosis

As hepatomegaly and hepatic dysfunction occur early in the disease, the liver is frequently biopsied for diagnosis.

Hepatomegaly and hepatic dysfunction, including elevated serum transaminases and bilirubin, cholestasis, and coagulopathy typically occur early in the disease and are associated with marked hematologic and/or neurological abnormalities.

In rare instances acute hepatic failure may dominate the clinical picture, which in combination with hyperferritinemia, may mimic neonatal hemochromatosis.

The degree of portal and sinusoidal lymphohistiocytic infiltrate and endothelialitis varied from mild to marked and correlated with clinical severity.

In some cases, histiocytic cells predominated and in others, there is extensive hepatocellular giant cell transformation.

Accordingly, 4 histopathologic patterns were observed:
- (1) chronic hepatitis-like
- (2) leukemia-like
- (3) histiocytic storage disorder-like
- (4) neonatal giant cell hepatitis-like (giant cell transformation of hepatocytes - GCTH)

The majority of specimens show a relatively well-preserved hepatic parenchyma with a portal and sinusoidal lymphohistiocytic, T cell-rich infiltrate that, when mild or moderate, mimicked chronic hepatitis and when extensive, expanded the portal tracts encroaching upon the periphery of the lobules and mimicked leukemia.

The lymphocyte population is rich in CD8-positive cytotoxic/suppressor cells. B lymphocytes, plasma cells, NK cells, neutrophils, and eosinophils, if present, were rare.

In some cases, the infiltrate is predominantly histiocytic, and the accumulation of histiocytes within distended sinusoids and veins mimicked a histiocytic storage disorder.

In others, the lymphohistiocytic infiltrate is associated with an extensive multinucleated giant cell transformation of hepatocytes and architectural disarray resulting in a neonatal giant cell hepatitis-like injury.

Accordingly, 4 histopathologic patterns of liver injury are observed:
- (1) chronic hepatitis-like
- (2) leukemia-like
- (3) histiocytic storage disease-like
- (4) neonatal giant cell hepatitis-like.

Common to all specimens and helpful in diagnosing FHL was a constellation of additional features that included lymphocyte-mediated bile duct injury, significant endothelialitis and hemophagocytosis. Steatosis and cholestasis were also usually present.

The lymphocyte-mediated bile duct injury, which has been earlier described, is often somewhat distinctive. Nests or circumferential sheaths of mononuclear cells, usually undergoing apoptosis, are interposed between the epithelium and the basal lamina eliciting little damage to the epithelium.

The portal inflammation with cholangitis observed in FHL is reminiscent of primary sclerosing cholangitis, primary biliary cirrhosis, and vanishing bile duct syndrome; in contrast to these disorders, neutrophils, plasma cells, granulomatous inflammation, periductal sclerosis, or ductopenia are not observed. Lymphocyte-mediated cholangitis with endothelialitis is also observed in graft-versus-host disease and allograft rejection; in these disorders, however, the epithelial damage is proportional to the degree of inflammation and nests or circumferential sheaths of inflammatory cells are usually not observed.

Endothelialitis of terminal hepatic and portal veins, present in all specimens, is usually significant, occasionally resulting in transmural phlebitis and in a few cases, hemorrhage and extensive apoptosis of perivenular hepatocytes.

The degree of inflammation, bile duct damage, endothelialitis, cholestasis, and steatosis seem to reflect the clinical stage of the disease.

The portal fibrosis with dystrophic changes of bile ducts and the intimal proliferation of terminal hepatic veins seen in postmortem specimens were attributed to complications related to the stem cell transplantation including graft-versus-host disease and veno-occlusive disease; however, the possibility that these changes were the result of FHL could not be excluded.33 Ductopenia was not observed.


Cytotoxic T lymphocytes and NK cells play a critical role in the surveillance against infections and transformed cells, prevention of autoimmune diseases, graft rejection, and maintenance of immune homeostasis.

Multiple effector mechanisms contribute to their cytolytic function. In the granule-exocytosis pathway, cytotoxic proteins within activated T lymphocytes and NK cells are released and bind to the plasma membrane of target cells. These cytotoxic proteins include perforin, a membrane-disrupting molecule and granzyme B, a serine protease that synergistically induce apoptosis of target cells by caspase-dependent and independent mechanisms.

The cytotoxic lymphocytes in the majority of the hepatic specimens coexpressed perforin and granzyme B. That perforin expression is largely unaffected in most specimens partly reflects the genetic heterogeneity of the disease.

Mutations in at least 4 genetic loci are associated with FHL and perforin gene mutations account for 13% to 58% of cases, their prevalence varying in part by region and ethnicity.

Over 60 disease-associated perforin mutations have been described to date, and the spectrum of perforin alterations includes missense, nonsense, deletion, and insertion mutations. A nonsense or deletion/insertion mutation that introduces a premature stop codon is predicted to give rise to a truncated, misfolded, and nonfunctional protein leading to its intracellular retention and degradation. By contrast, missense perforin mutations, which can be inherited as homozygous or compound heterozygous alleles, have more varied effects on perforin expression and/or function.

Differential diagnosis

The hepatic histopathology of FHL may mimic other disorders, particularly chronic hepatitis, leukemia, histiocytic storage disorder, or neonatal giant cell hepatitis.

However, a constellation of features that includes bile duct injury, significant endothelialitis/phlebitis, and hemophagocytosis occurs in all cases and in conjunction with the immunophenotype of the infiltrating cells and the appropriate clinical setting, permits an early diagnosis and treatment.


- Pathology of the liver in familial hemophagocytic lymphohistiocytosis. Chen JH, Fleming MD, Pinkus GS, Pinkus JL, Nichols KE, Mo JQ, Perez-Atayde AR. Am J Surg Pathol. 2010 Jun;34(6):852-67. PMID: 20442642

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- Kapelari K, Fruehwirth M, Heitger A, et al. Loss of intrahepatic bile ducts: an important feature of familial hemophagocytic lymphohistiocytosis. Virchows Arch. 2005;446:619–625. PMID: 15906086

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- Shneider B, Selsky C, Komp D. Idiopathic neonatal iron-storage disease: clinical similarity to hemophagocytic lymphohistiocytosis. Gastroenterology. 1992;102:1826–1827. PMID: 1568600