li-11-7        GRAFT-VERSUS-HOST DISEASE        by Dr. E. Orfei


 

 

DEFINITION

Clinical syndrome following allograft bone marrow transplantation or following blood transfusion with non-irradiated blood in an immunosuppressed patient.

 

The reaction may develop in two forms: as an acute reaction within 6 weeks from marrow transplantation or as a chronic reaction developing between100 and 400 days after transplantation. The chronic form may affect individuals who survived the acute form or can attack de novo. The difference between the two forms is not only in the different time of onset but also in the difference of the organs affected. The acute form involves mainly skin, gastro-intestinal tract and liver. The chronic form produces a disease similar to an autoimmune syndrome involving multiple organs: liver, skin, intestine, lachrymal glands, salivary glands and other organs.

 

The acute form is probably caused by immunocompetent cytotoxic lymphocytes attacking the tissues of the recipient thus it does not responding cyclosporin treatment.

The chronic form seems to be caused by an immune disorder and responds to cyclosporin.

The acute form carries a 50% mortality. The chronic form, especially when develops after the acute phase is also equally fatal. The patients donít die of liver failure but because of superimposed infections.

 

The diagnosis is made mostly on clinical manifestations . Only in doubtful cases liver biopsy is required in order to recognize DVHD from other liver injuries such as radiation, immunosuppressant drugs and opportunistic infections .

 


ACUTE FORM

 

CLINICAL MANIFESTATIONS

Skin rash diarrhea and jaundice is the complete clinical manifestation of the disease, appearing altogether or isolated in variable intensity. There are no signs of liver failure such as ascites and encephalopathy. Abnormal liver function tests usually precede the onset of jaundice. Cases of normal alkaline phosphatase but with positive biopsy have occurred. 

 PATHOLOGY

 

Laboratory Tests:

-serum alkaline phosphatase: usually increased, but may be normal.

-bilirubin, increased.

-transaminases moderately elevated

-anti-mitochondria antibodies, present in a minority of cases.

Liver biopsy:

-lobular inflammation: focal with liver cell necrosis with lymphocitic infiltration and eosinophilic bodies. Seen in 50% of cases

-cholestasis: canalicular and prominent, present in about all cases

-Kupffer cells: proliferated with erythrophagocytosis and hemosiderosis.

-Portal inflammation: is minimal with sparse cytotoxic lynphocytes.

-Interlobular bile ducts: damage consisting of epithelial swelling, picknosis and necrosis, rupture of the wall and lymphocytes attacking ductal cells. Ductal damage is the most consistent damage.

-Periportal area: clean.

-Fibrosis: none.

-Endothelialitis consisting of attachment of lymphocytes to the endothelium o f central a portal veins. This change is considered specific for GVHD by some authors.

 

CHRONIC FORM

The chronic form is a multiorgan autoimmune-like disease and is treated like an autoimmune disease.

In most cases it is preceded by the acute form. About 30% are de novo onset. It appears between 100 and 400 days after the bone marrow transplantation. The organs affected are skin, intestine lachrymal glands , salivary glands, mouth and other organs. The liver is involved in about 90% of cases. In this form , cholestasis may be more severe than in the acute form. Alkaline phosphatase my reach levels of 30 times normal. Jaundice may affect 50% of cases and may sometimes severe. There is moderate increase of serum transaminases. Anti mitochondrial and anti liver/kidney may be found.

The liver biopsy will show severe bile duct damage with disappearance of their lumen. Portal and lobular inflammation may be slight or very severe. There may be seen periportal fibrosis. Cirhhosis is a rare complication.

 

ILLUSTRATIONS

Click on the pictures to enlarge

11-7-1.jpg (108965 bytes)

Fig, 11-7-1. Organs involved.

Organs affected by

GVHD after bone marrow transplant and after  non-irradiated blood transfusion

in a immunosuppressed patient.

where also the bone marrow is affected with severe aplasia.

11-7-2.jpg (125811 bytes)

Fig.11-7-2. Bile duct damage.

The epithelium and wall are damaged and infiltrated by lymphocytes which are relatively few and T type.

11-7-3.jpg (195021 bytes) Fig.11-7-3.Disappearingduct.

The nuclei are picknotic . The

lumen has disappeared. Notice the scarcity of inflammatory cells.

 

 

11-7-4b.jpg (200421 bytes) Fig11-7-4.Cytotoxic damage. Interlobular bile duct attacked by a lymohocyte in acute form of GVHD

 

 

11-7-5.jpg (43996 bytes)

Fig. 11-7-5. Kupffer cell reaction. Marked proliferation of Kupffer cells with siderosis 

and erythrophagia. Notice also canalicular cholestasis

11-7-6.jpg (55920 bytes)

 

 

Fig. Fig.11-7-6.Ductal atrophy. Remnants of bile ducts in a portal area. Keratin immuno- stain for bile ducts

 

 

11-7-7.jpg (45807 bytes)

 

 

Fig.11-7-7. Fig. 11-7-7. Normal control. Portal area with normal bile ducts satained with  same compound as previous slide.

11-7-8.jpg (86541 bytes) Fig.11-7-8. Skin Changes.

Notice the infiltration of lynphocytes of the basal layer of the epidermis in early skin damage which can proceed to complete sloughing of the epidermis.

 


 

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