Chronic Cholestatic Disease With Associated Tubulointerstitial Nephropathy in Early Childhood

ABSTRACT. We report the clinical and morphological the age of 19 months, blood biochemistry was performed be- features of an unusual hepatorenal disorder in 2 patients. cause of the mother’s positivity for hepatitis B surface antigen, The main clinical features were early onset of cholestatic and it showed a mild anemia and increased values of aspartate and progressive tubulointerstitial nephritis, aminotransferase (AST), alanine aminotransferase (ALT), and gamma glutamyl transferase (GGT) (Table 1); plasma urea and leading to renal death in early childhood. Renal histol- creatinine concentrations were 30 and 0.6 mg/dL (10.7 mmol/L ogy showed interstitial fibrosis, tubular atrophy and di- and 53 ␮mol/L), respectively. At the age of 2.5 years, he was latation, glomerular cysts in the cortex and periglomeru- referred to our hospital because of the biochemical features of lar fibrosis; liver histology was characterized by portal advanced renal failure, with severe edema and circulatory over- fibrosis and duct abnormalities. Evaluating the 12 load, marked anemia, hypertension, oligoanuria, and metabolic patients published in the literature, the long-term prog- acidosis. The patient had been apparently well and active until nosis of the liver function appears bad, suggesting the 2 weeks earlier, when he experienced a flu-like symptomatol- possibility of a combined liver and transplanta- ogy and a few days before admission his breathing became tion. Pediatrics 1997;100(3). URL: http://www.pediatrics. labored. Laboratory studies, performed on the day of admis- e sion, confirmed severe renal failure and showed moderate org/cgi/content/full/100/3/ 10; cholestasis, tubulointersti- hepatocytolysis (AST and ALT were twice the normal values), tial nephritis, end-stage renal disease, liver and kidney and cholestasis (high plasma values of GGT and alkaline phos- transplantation, childhood. phatase (ALP), mild hypercholesterolemia without hyperbiliru- binemia), [Table 1]. Coagulative tests have always been normal. Serologic markers for hepatitis viruses (A, B, and C) were ABBREVIATIONS. AR-PKD, autosomal recessive polycystic kid- negative. Normal values of ␣-1 antitrypsin, alphafetoprotein, ney disease; NPH, ; AST, aspartate aminotrans- cupremia, ceruloplasmin, and plasma ammonium, excluded the ferase; ALT, alanine aminotransferase; GGT, gamma glutamyl coexistence of the most common liver diseases. Ocular evalua- transferase; ALP, alkaline phosphatase; ESRF, end-stage renal tion excluded retinal involvement. Renal ultrasound showed failure. small kidneys with homogeneous echogenicity and loss of cor- ticomedullary differentiation. Renal biopsy (Fig 1), performed during initial admission, showed interstitial fibrosis and diffuse he association between congenital hepatic and inflammatory infiltrate, tubular atrophy and dilatations, some renal disease is intriguing and sometimes glomeruli with cystic dilatation and others jalinized with peri- poses a difficult interpretation for the physi- glomerular fibrosis. Immunofluorescence was negative. T Chronic peritoneal dialysis was started on the day of admis- cian. Autosomal recessive polycystic kidney disease sion. On ultrasound, liver was increased in volume with regular (AR-PKD) and nephronophthisis (NPH) are the renal echostructure. showed severe portal fibrosis with problems known to be associated with liver dis- small proliferation and without inflammatory cell ease.1,2 There are instead situations in which the clin- infiltration (Fig 2). At the age of 3.5 years, severe itching de- ical picture poses numerous nosologic problems, and veloped and was associated with an increased concentration of serum total bile acids. Cholestyramine treatment was not ben- even the pathologic features are lacking the typical eficial, whereas ursodesossicholic acid markedly reduced the elements for a specific diagnosis. Furthermore, as symptomatology. A hepatobiliary scintigraphy (with TC 99M kidney transplantation is necessary for these pa- Disida) was performed and confirmed mild intrahepatic cho- tients, the physician also has to face the long-term lestasis. This examination showed a worsening of cholestasis 3 prognosis of the liver function, especially if a precise years later. The patient is now 6 years old and is maintained by chronic peritoneal dialysis. He has hepatomegaly (5 cm below knowledge of the underlying disease is lacking. right costal margin) without clinical signs of portal hyperten- We describe 2 children with an unusual hepatore- sion. Liver tests are reported in Table 1. nal disease and early end-stage renal insufficiency. We also review the data of 12 children from the Case 2 literature3–9 with an associated early renal death and The patient is the product of a full-term uncomplicated preg- cholestatic liver disease and discuss the role of a nancy. He has no family history of renal or liver disease. The child had been apparently well until the age of 4.5 years, when polyuria, combined liver and kidney transplant in these pa- polydipsia, and ingravescent pallor developed. He was first hos- tients. pitalized in another hospital where laboratory data were consis- tent with severe renal failure and cholestatic liver disease (high CASE REPORTS plasma values of GGT and ALP and moderate increase of serum total bile acids and ), with hepatocytolysis (Table 1). Case 1 After 1 month of conservative treatment, he was started on chronic The patient is the product of a full-term, uncomplicated peritoneal dialysis. When he was referred to our hospital at the pregnancy and delivery. He is the second child of unrelated, age of 5.5 years, he was in poor general condition, had severe and healthy parents; there is no family history of renal or liver diffuse itching, and hypertension was not controlled by the usual disease. His weight has always been below the third centile. At treatment. Liver tests are reported in Table 1. Blood tests of coag- ulation, ammoniemia, ceruloplasmin, cupremia, and ␣-1 antitryp- sin were within normal ranges. Serologic markers for hepatitis Received for publication Aug 20, 1996; accepted Mar 6, 1997. viruses were negative. Ultrasound images showed two kidneys at Reprint requests to (G.M.) Dipartimento di Pediatria, Universita`degli studi, the inferior limit of normal range, with loss of corticomedullary Via Giustiniani 3, 35128 Padova, Italy. differentiation and diffuse hyperechogenic structure; the liver had PEDIATRICS (ISSN 0031 4005). Copyright © 1997 by the American Acad- a normal size, morphology, and echo structure. emy of Pediatrics. Needle biopsy of kidney, represented only by cortical tissue, http://www.pediatrics.org/cgi/content/full/100/3/Downloaded from www.aappublications.org/newse10 by PEDIATRICS guest on September Vol. 28, 100 2021 No. 3 September 1997 1of4 TABLE 1. Summary of Laboratory Data Age (Years) 1.5 2 2.5 3 3.5 4 4.5 5 5.5 6 Case 1 AST (10–55 U/L) 77 129 94 101 116 137 143 102 79 89 ALT (5–55 U/L) 156 215 80 258 100 289 266 195 138 148 Serum bilirubin total (0.1–1 mg/dL) 0.4 0.8 1 1.5 1.4 1.3 1.1 0.6 [1.7–17 mmol/L] 7.3 15 17 26.9 24.4 22.8 20 11 Serum cholesterol (Յ200 mg/dL) 280 450 385 550 515 505 410 490 [Ͻ5.18 mmol/L] 5.6 9 7.7 11 10.3 10.1 8.2 9.8 ALP (40–141 U/L) 464 495 234 213 502 522 552 357 250 GGT (30–65 U/L) 388 571 600 790 975 641 607 Serum bile acids (0–3.5 umol/L) 14.6 100 50 20 26 Age (Years) 5.5 6 6.5 7 Case 2 AST (10–55 U/L) 175 295 294 149 ALT (5–55 U/L) 186 530 351 179 Serum bilirubin total (0.1–1 mg/dL) 0.8 0.8 1 [1.7–17 mmol/L] 14 14 19 Serum cholesterol (Ͻ200 mg/dL) 300 335 250 [Ͻ5.18 mmol/L] 6 6.7 5 ALP (40–141 U/L) 1215 1133 498 GGT (30–65 U/L) 606 1070 662 261 Serum bile acids (0–3.5 umol/L) 26 36 Normal values are in brackets.

Fig 1. Renal biopsy of case 1. Mild diffuse inflammatory infil- trate; cystically dilated proximal tubules, three glomerular cysts, some glomeruli almost com- pletely fibrotic, mild diffuse in- terstitial fibrosis. (Masson trichrome ϫ 120.)

showed tubular atrophy, severe interstitial fibrosis, mild inflam- DISCUSSION matory infiltrate, thrombosis of some arterioles, cystic aspect of some glomeruli, and sclerojalinization of others. Liver biopsy The 2 patients reported in this article have clinical showed moderate portal fibrosis and paucity of interlobular bile and pathologic features that do not conform to the ducts (ratio of ducts to portal areas ϭ 0.6). childhood nephropathies known to be associated At the age of 7 years he underwent renal transplantation, which with hepatic involvement: AR-PKD and NPH with failed a few months later because of serious cyclosporine toxicity, probably caused by the presence of cholestasis. Our patient congenital hepatic fibrosis. More recently a tubulo- showed cyclosporine levels in the low range for the drug mea- interstitial nephritis has been described associated sured by a monoclonal antibody-based radioimmunoassay (range with arteriohepatic dysplasia (Alagille syndrome).7 73 to 198 ng/mL) and very high for the polyclonal antibody-based radioimmunoassay (range 901 to 2400 ng/mL), with a ratio of In fact our children showed: 1) early onset of tubu- nonspecific-to-specific cyclosporine levels ranging from 9 to more lointerstitial nephritis, leading to renal death within than 20 (normal value around 2.0). The dosage of the drug was the first years of life; 2) renal histology characterized around 13 to 14 mg/kg/day. Furthermore, a fine needle aspiration by tubular atrophy and dilatation, interstitial and biopsy, performed 16 days after transplantation, showed changes secondary to cyclosporine A toxicity together with rejection. periglomerular fibrosis, and even by glomerular We have since lost the child to follow-up. cysts in the cortex; 3) clinical and laboratory signs of

2of4 CHRONIC CHOLESTASISDownloaded from AND www.aappublications.org/news INTERSTITIAL NEPHROPATHY by guest on September 28, 2021 Fig 2. Liver biopsy of case 1. Severe portal fibrosis without inflammatory infiltration and mild proliferation of interlobu- lar bile ducts. (Masson trichro- mic ϫ 120.)

cholestasis; and 4) hepatic histology characterized by hepatic involvement of these nephropathies is typically portal fibrosis with bile duct proliferation in 1 patient represented by congenital hepatic fibrosis, clinically and paucity in the other. characterized by minimal disturbances of the liver We ruled out the diagnosis of AR-PKD and of NPH, function without cholestasis.2,10,11 because AR-PKD manifests with renal enlargement,1,2 Alagille syndrome was excluded in the patient whereas our patients’ kidneys were both small, with- with bile duct paucity, because of the absence of the out the typical collecting duct ectasia,1,2 and because in typical clinical features. the NPH complex the first symptoms occur between 3 We have reviewed 12 children (Table 2) from the and 7 years of age and end-stage renal failure (ESRF) is literature,3–9 with a renal histologic pattern character- usually reached during the second decade of life. The ized by chronic tubulointerstitial lesions and cortical

TABLE 2. Clinical and Laboratory Data on Patients From the Literature and on Our Two Patients No. of Age of Age of AST, ALT* GGT* Clinical Outcome Patients Onset ESRF U/L U/L Features Popovic ’93 4 0–2 2–9 ALT:283 1284 Itching, Two died during hemodialysis, years years , 1 received combined RT and hepatomegaly LT, 1 RT and worsening of liver disease Hernot ’90 1 birth 10 AST:176 1054 Jaundice, Died at the age of 10 months months ALT:289 hepatomegaly Gagnadoux ’89 1 1 month 11–12 Increased Jaundice, Died at the age of 1 year (portal months hepatomegaly, hypertension with splenomegaly gastrointestinal bleeding) Harris ’86 2 4–12 14 AST:156 Both received RT and 1 months months developed portal hypertension Hyams ’83 1 2 weeks 10 AST:162 Itching Died at 10 months for renal months ALT:112 failure Proesman ’79 2 1 month Increased Jaundice, Died at 10 months for renal hepatomegaly, failure splenomegaly Tolia ’87 1 birth 25 AST:43 Jaundice Died at the age of two months days ALT:24 Total 12 Case 1 2 years 2 AST:143 975 Itching, years ALT:289 hepatomegaly

Case 2 4.5 5 AST:295 1070 Itching, Received RT, lost because of years years ALT:530 hepatomegaly severe nephrotoxicity RT, renal transplantation; LT, ; GGT, gammaglutamyltransferase; ESRF, end-stage renal failure. * Highest recorded value.

Downloaded from www.aappublications.org/newshttp://www.pediatrics.org/cgi/content/full/100/3/ by guest on September 28, 2021 e10 3of4 microcysts, with rapid progression to ESRF, and asso- similar to NPH and a liver disease with intrahepatic ciated marked hepatic damage and cholestasis. Liver cholestasis. The clinical distinguishing features of the histology was represented by bile duct proliferation 2 children reported in this study are: early onset of and portal fibrosis in all the cases, apart from the 2 renal impairment, particularly in the first case, with patients described by Hyams7 and Tolia8 in which pau- necessity of dialytic treatment at the age of 2 years, city of bile ducts was present. For these 12 patients, and the presence of marked cholestasis. The natural especially for the cases with onset in the first 2 years of history of this pathologic entity in unknown. After life, it has been suggested that a NPH-like nephropathy restoration of renal function with renal transplanta- associated with an unusual form of liver disease could tion, the long-term survival of these patients may represent a new syndrome.4 Our 2 patients are very depend on the progression of the liver disease and, similar, from the clinical and histologic point of view, therefore, combined liver and kidney transplantation to the 4 described by Popovic et al4, in whom the liver could be considered for these children. disease was progressive. In the other 9 patients described,3,5–9 the age of Giovanni Montini, MD onset of the disease and of ESRF is earlier (first year Carla Carasi, MD Lucia Zancan, MD of life) than in our patients but the overall prognosis Roberto Dall’Amico, MD was poor as for the 4 children above. Luisa Murer, MD It seems, therefore, that the 12 patients reported by Graziella Zacchello, MD the literature have a poor overall prognosis and the Department of Pediatrics liver function contributes to a relevant part of it. It is University of Padova tempting to speculate that, at some stage, these pa- Padova, Italy tients with cholestasis and portal fibrosis will also Palma Sorino, MD need a liver transplant. Giovanni XXIII Hospital Furthermore, 1 of our patients who underwent kid- Bari, Italy ney transplantation, lost his graft after 2 months and we believe that a relevant part was played by cyclospo- REFERENCES rine toxicity. In fact, the liver is the major site of the 1. Gardner KD Jr, Bernstein J. Familial juvenile nephronophthisis: medul- metabolism of this drug, through several cytochrome lary cystic disease complex. In: Edelmann CM Jr, ed. Pediatric Kidney P450 isoenzymes, and also the primary excretion site Disease, II. 2nd ed. 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Downloaded from www.aappublications.org/news by guest on September 28, 2021 Chronic Cholestatic Liver Disease With Associated Tubulointerstitial Nephropathy in Early Childhood Giovanni Montini, Carla Carasi, Lucia Zancan, Roberto Dall'Amico, Luisa Murer, Graziella Zacchello and Palma Sorino Pediatrics 1997;100;e10 DOI: 10.1542/peds.100.3.e10

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