Letter to the Editor
Histological changes of the intestinal mucosa in complications following a living donor liver
transplantation for progressive familial intrahepatic cholestasis type 1
To the Editor
Progressive familial intrahepatic cholestasis-1 (PFIC-1) is a rare autosomal disorder presenting intrahepatic cholesta- sis in infancy and progressing rapidly to liver cirrhosis.
PFIC-1 is caused by the absence of FIC1 encoded by ATP8B1 on 18q21-22. Liver transplantation is the treatment for PFIC-1 patients who develop end-stage liver disease.
However, patients with PFIC-1 also present extrahepatic manifestations such as recurrent diarrhea. These manifes- tations, as well as fatty liver, can persist or even become exacerbated after liver transplantation (LT).1 We report a case of a 2-year-3-month old female with PFIC-1 in whom recurrent diarrhea and fatty liver developed after LT. An intestinal and liver biopsy were done. This is the first histopathological assessment of an intestinal biopsy in a post-transplant PFIC-1 patient.
A 2-year-3-month old female patient born after a normal pregnancy and delivery presented jaundice and white stool three weeks after birth. Diarrhea developed at 9 months old, and PFIC-1 was diagnosed by genetic analysis demon- strating the presence of an ATP8B1 defect (exon10 c916T>C: pCys306Arg mother-derived; exon23 c2854C>T:
pArg952x father-derived). She underwent LDLT due to icterus, pruritus, liver dysfunction, and growth retardation.
Her father was the donor; his liver showed 10% macro- vesicular steatosis without significant inflammation or fibro- sis. Post-transplant liver biopsies were done at 135 days, 9 months, 11 months, and 21 months. At the time of the first biopsy (135 days), the patient had mild diarrhea, and fatty liver was not recognized on ultrasonography. At 11 months, the patient was experiencing recurrent diarrhea and vomit- ing several times a day. Fatty liver was seen on ultrasonog- raphy. A post-operative liver biopsy at 135 days, and 9, 11, and 21 months showed progressive steatosis of 5%, 30%, 35%, and 80%, respectively. At 11 months, the steatosis progressed to steatohepatitis with ballooning hepatocytes, moderate lobular inflammation mainly comprised of lympho- cytes, and thick pericellular fibrosis. Biopsies of the ileum, colon, and rectum were also done simultaneously at 11 months and 21 months after LDLT to investigate the cause of her diarrhea and malnutrition. The biopsy of the ileum showed mild chronic inflammation, and the biopsy of the
colon and rectum showed mild to moderately acute and chronic inflammation accompanied by an abundance of foamy macrophages (Fig. 1a,b). At 21 months, the biopsy of the ileum and colon showed a morphology similar to that seen in the previous biopsy. The foamy macrophages were negative for Periodic acid-Schiff (PAS) staining and were identified as lipid-laden macrophages. (Fig. 1c).
Verhulstet al. investigated the impact of ATP8B1 deple- tion in a culture of human intestinal epithelial Caco-2 cells, which showed a disorganized apical actin cytoskeleton and a loss of microvilli.2According to Shillingford et al., CD10 can highlight the brush border or microvilli in normal intestine; thus the negative result may suggest damage to, or absence of, the intestinal brush border.3An immunohis- tochemical examination of the CD10 to investigate the brush border in the ileum and a colon biopsy showed positive and negative staining, respectively (Fig. 1d,e). The staining results showed no evidence of brush border damage in the ileum of our patient. The normal control (colon biopsy taken from 3-year-old boy) was also negative for CD10 (Fig. 1f), so the lack of CD10 in the colonic biopsy of this patient was not abnormal. From these results, we could not prove that damage of the intestinal brush border was the cause of diarrhea morphologically.
FIC1 is more highly expressed in the small intestine than in the liver and plays a role in enterohepatic circulation of the bile acids.1 An FIC-1 defect reduces Farnesoid X receptor (FXR) activity and leads to impairment of bile salt transport in the liver and intestines. FXR is a nuclear receptor involved in bile acid homeostasis, which binds to the bile acids and regulates the expression of genes encoding enzymes involved in bile acid synthesis and conjugation. In the intestine, FXR upregulates the expres- sion of ileal bile acid binding protein (I-BABP), which is instrumental in transporting bile acid from the intestines to the liver and in downregulating apical sodium-dependent bile salt transporter (ASBT), which is involved in the intestinal absorption of bile salts. Even after bile salt secretion is restored following an LT, an FIC1 deficiency in the intestines and FXR downregulation lead to an enhance- ment of bile salt presentation to the ileum.4,5 It is possible that the increase in bile salt presentation to the small intestine may also have affected the large intestine and contributed to the aggregation of foamy macrophages observed in the colon and rectal biopsy of our patient.
We recommend an intestinal biopsy to identify and evaluate the pathology of PFIC-1 patients after LT. A follow- up biopsy of the intestines and liver is important for
Pathology International2018;68:536–537 doi:10.1111/pin.12686
evaluating the state of the disease and for preventing more adverse outcomes or extrahepatic manifestations after an LT. To the best of our knowledge this is the first report describing the histopathology of an intestinal biopsy in a post-transplant PFIC-1 patient.
ACKNOWLEDGMENTS
The authors would like to thank Mr. James R. Valera for his assistance with editing the manuscript.
DISCLOSURE STATEMENT
None declared.
Marini Stephanie,1,2,Rie Irie,1Kengo Sasaki,3 Yoshihiro Hirata,3Soichi Narumoto,3Akinari Fukuda,3 Seisuke Sakamoto,3Katsuhiro Arai,4Takako Yoshioka1 and Mureo Kasahara3
1Department of Pathology, National Center for Child Health and Development, Tokyo, Japan,2Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia/Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia,3Organ Transplantation Center, National Center for Child Health and Development Tokyo, Japan, and
4Division of Gastroenterology, National Center for Child Health and Development Tokyo, Japan
Present address: Department of Anatomical Pathology, Faculty of Medicine Universitas Indonesia/Dr. Cipto Mangunkusumo Hospital, Jakarta, Indonesia. Jl. Salemba Raya no:6, Jakarta, Indonesia.
REFERENCES
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2 Verhulst PM, van der Velden LM, Oorschot Vet al. Aflippase- independent function of ATP8B1, the protein affected in familial intrahepatic cholestasis type 1, is required for apical protein expression and microvillus formation in polarized epithelial cells.
Hepatology2010;51: 2049–60.
3 Shillingford NM, Calicchio ML, Teot LAet al.Villin immunohis- tochemistry is a reliable method for diagnosing microvillus inclusion disease.Am J Surg Pathol2015;39: 245–50.
4 Alvarez L, Jara P, Sanchez-Sabate E et al. Reduced hepatic expression of farnesoid X receptor in hereditary cholestasis associated to mutation in ATP8B1.Hum Mol Genet 2004; 13:
2451–60.
5 Demeilliers C, Jacquemin E, Barbu Vet al. Altered hepatobili- ary gene expressions in PFIC1: ATP8B1 gene defect is associated with CFTR downregulation. Hepatology 2006; 43:
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Figure 1 (a) Biopsy of the ileum showing mild chronic inflammation. (b) Biopsy of the colon showing an abundance of foamy macrophages. (c) The foamy macrophages were negative for periodic acid-Schiff staining. (d) Immunohistochemistry of the CD10 in the ileum biopsy showed positive staining on the brush border. (e) Immunohistochemistry of the CD10 in the colon biopsy showed negative staining. (f) Immunohistochemistry of the CD10 in the normal control (colon biopsy taken from 3-year-old boy) showed negative staining (a, b, Hematoxylin and eosin stain, 200; c, Periodic acid-Schiff staining, 200; d, Immunohistochemistry of CD10, 200; e, Immunohis- tochemistry of CD10, 400;f, Immunohistochemistry of CD10, 200).
© 2018 Japanese Society of Pathology and John Wiley & Sons Australia, Ltd
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