Hodgkin lymphoma-related vanishing bile duct syndrome and idiopathic cholestasis: Statistical analysis of all published cases and literature review

Figures & data

Figure 1.  Axial CT scan of the chest with IV contrast showing a large anterior mediastinal soft-tissue mass measuring approximately 6.5 x 4.5 cm (depicted by white arrow).

Figure 2.  Liver biopsy, photographs taken of Masson trichrome-stained slides at 100× original magnification. 2a) Bile duct injury: this photograph shows a complete portal triad demonstrating bile duct injury. The bile duct (arrow) shows distortion of the duct with loss of nuclei. In this injured duct, only two nuclei remain. The hepatic artery branch is just above the duct cross section. 2b) Bile duct loss: this photograph shows an artery that is similar in appearance to the artery in Figure 2a (it is the structure in the middle of the portal tract in both cases). But, in contrast to the other photo, there is no bile duct cross-section in this portal tract, representing destruction of the bile duct.

Table I.  Summary of Reported Literature.

Author	Year	Age	Sex	Stage	Stage	Liver Biopsy	Chemo	XRT	Steroids	Residual HL	F/U (mo)	Outcome
Bouroncle [7]	1962	44	M	relapse	relapse	IC	y	y	n	nr	7	d: liver failure
Bouroncle [7]	1962	13	F	nr	nr	IC	n	n	y	nr	8	d: liver failure
Juniper [8]	1963	23	M	IIBS	IIBS	IC	n	n	y	y	19	d: liver failure
Groth [9]	1972	70	M	relapse	relapse	IC	y	n	n	y	5	d: liver failure
Perera [10]	1974	31	F	IIIA	IIIA	IC	n	y	y	y	19	d: liver failure
Perera [10]	1974	21	F	IA	IA	IC	n	y	y	n	nr	a
Perera [10]	1974	36	F	IIA	IIA	IC	n	y	y	n	nr	a
Piken [11]	1979	54	M	IVB	IVB	IC	y	n	y	y	4	d: nr
Trewby [12]	1979	41	M	II	II	PI	n	n	y	y	1	d:liver failure
Trewby [12]	1979	34	M	III	III	IC	y	n	nr	y	1	d: liver failure
Lieberman [13]	1986	53	M	IVB	IVB	IC	n	n	n	y	1	d: respiratory arrest
Birrer [14]	1987	54	F	IIIB	IIIB	IC	y	n	y	n	nr	d: sepsis
Hubscher [1]	1993	44	M	IA	IA	VBDS	y	y	y	y	22	d: liver failure
Hubscher [1]	1993	37	F	IIBE	IIBE	VBDS	y	n	y	n	1	d: liver failure/PNA
Hubscher [1]	1993	26	M	nr	nr	VBDS	y	n	y	n	6	d: liver failure
Warner [27]	1994	nr	nr	IB	IB	IC	n	y	nr	n	36	a
Jansen [28]	1994	29	M	IA	IA	IC	n	y	n	n	24	d: variceal bleed
Crosbie [17]	1997	21	F	IIIB	IIIB	VBDS	y	n	y	n	13	a
Gottrand [3]	1997	3.5	M	IIA	IIA	VBDS	y	y	y	n	12	d: liver failure
de Medieros [18]	1998	27	F	IIIB	IIIB	VBDS	y	n	y	n	5	a: increasing bilirubin
de Medieros [18]	1998	50	F	relapse	relapse	VBDS	y	n	y	n	9	d: sepsis
Yalcin [29]	1999	53	F	IIIBS	IIIBS	IC	n	n	y	y	1	d: bacteremia
Yalcin [29]	1999	47	F	IIB	IIB	IC	y	y	y	n	26	a
Yusuf [16]	2000	5	M	IB	IB	VBDS	y	n	y	nr	2.5	d: liver failure
Rossini [2]	2000	38	M	IA	IA	VBDS	y	n	y	y	7	d: liver failure
Allory [19]	2000	nr	M	nr	nr	VBDS	nr	nr	nr	n	24	a
Ozkan [20]	2001	3.5	M	IIIB	IIIB	VBDS	y	n	y	nr	3	d: liver failure
Komurcu [21]	2002	23	M	relapse	relapse	VBDS	n	n	n	nr	1	d: liver failure
Liangpunsakul [30]	2002	72	M	IB	IB	CH	y	n	n	n	18	a
Ripoll [22]	2002	28	F	IIAX	IIAX	VBDS	y	y	y	n	6	d: HL
Ripoll [22]	2002	23	M	IIAE	IIAE	VBDS	y	y	y	n	48	A
Guliter [23]	2004	46	M	IIIB	IIIB	VBDS	y	n	y	nr	6	d: sepsis/DIC
Cordoba [15]	2005	17	M	nr	nr	VBDS	nr	nr	nr	n	nr	A
Han [24]	2005	45	M	relapse	relapse	VBDS	nr	nr	nr	n	2	a: recurrent HL
Schmitt [25]	2006	46	M	IIIA	IIIA	VBDS	n	n	n	y	2	D: sepsis
Barta [26]	2006	41	M	IIA	IIA	IC	n	y	n	n	21	A
Our Case	2007	22	M	IIA	IIA	VBDS	y	y	y	n	29	A

*Abbreviations: nr = not reported, HG = Hodgkin's granuloma, NS = nodular sclerosing, MC = mixed cellularity, LD = lymphocyte depleted, LP = lymphocyte predominant, VBDS = vanishing bile duct syndrome, IC = idiopathic cholestasis, PI = portal inflammation, CH = cholestatic hepatitis, PNA = pneumonia, a = alive, d = dead.

Figure 3.  Kaplan-Meier survival curves for overall survival (OS) and liver failure-free survival (LFFS).

Figure 4.  Kaplan-Meier liver failure-free survival curves correlated to stage of Hodgkin lymphoma (4a), radiation treatment (4b), and HL response (4c). Abbreviations: LFFS = liver failure-free survival, HL = Hodgkin lymphoma, CR = complete response. P-values calculated using the log-rank test.

Table II.  Univariate Analysis for Liver Failure–Free Survival.

Variable	1-Year LFFS (%)	Hazard Ratio*	95% CI	p-value
Sex
Female	48	0.71	0.30–1.67	0.43
Male	37
Age
≤ 35	40	1.03	0.45–2.39	0.94
> 35	37
Stage
I/II	63	0.40	0.15–0.87	0.02
III/IV/Relapse	21
B Symptoms
No B Sx's	59	0.59	0.21–1.49	0.24
B Sx's	36
HL Histology
LP/NS	53	0.51	0.14–1.32	0.14
MC/LD/HG	20
Liver Biopsy
IC/CH/PI	52	0.81	0.35–1.83	0.59
VBDS	30
Radiation
Radiation	75	0.21	0.06–0.37	<0.0001
No Radiation	15
Chemotherapy
Chemo	30	1.10	0.47–2.61	0.82
No Chemo	53
Steroids
Steroids	37	0.85	0.31–2.30	0.73
No Steroids	38
HL Response
CR	63	0.22	0.04–0.38	0.0002
No CR	25

*Hazard Ratio <1 favors first variable.

Abbreviations: HL = Hodgkin lymphoma, LP = lymphocyte predominant, NS = nodular sclerosing, MC = mixed cellularity, LD = lymphocyte depleted, HG = Hodgkin's granuloma, IC = idiopathic cholestasis, CH = cholestatic hepatitis, PI = portal inflammation, VBDS = vanishing bile duct syndrome, CR = complete response, LFFS = liver failure–free survival, CI = confidence interval.

p-values calculated using log-rank analysis.

Bouroncle B, Old J, Vazques A. Pathogenesis of jaundice in Hodgkin's disease. Arch Intern Med 1962; 110: 872–83

 PubMedGoogle Scholar

Juniper K. Prolonged severe obstructive jaundice in Hodgkin's disease. Gastroenterology 1963; 44: 199–204

 PubMedGoogle Scholar

Groth C, Hellstrom K, Hofvendahl S, Nordenstam H, Wengle B. Diagnosis of malignant lymphoma at laparotomy disclosing intrahepatic cholestasis. Acta Chir Scand 1972; 138: 186–9

 PubMedGoogle Scholar

Perera D, Greene M, Fenster L. Cholestasis associated with extrabiliary Hodgkin's disease. Gastroenterology 1974; 67: 680–5

 PubMed Web of Science ®Google Scholar

Piken E, Abraham G, Hepner G. Investigation of a patient with Hodgkin's disease and cholestasis. Gastroenterology 1979; 77: 145–7

 PubMedGoogle Scholar

Trewby PN, Portmann B, Brinkley DM, Williams R. Liver disease as presenting manifestation of Hodgkin's disease. Quart J Med 1979; 189: 137–50

 Google Scholar

Lieberman D. Intrahepatic cholestasis due to Hodgkin's disease. J Clin Gastroenterol 1986; 8: 304–7

 PubMed Web of Science ®Google Scholar

Birrer M, Young R. Differential diagnosis of jaundice in lymphoma patients. Sem Liver Disease 1987; 7: 269–77

 PubMedGoogle Scholar

Hubscher SC, Lumley MA, Elias E. Vanishing bile duct syndrome: A possible mechanism for intrahepatic cholestasis in Hodgkin's lymphoma. Hepatology 1993; 17: 70–7

 PubMed Web of Science ®Google Scholar

Warner AS, Whitcomb FF. Extrahepatic Hodgkin's disease and cholestasis. Am J Gastroenterol 1986; 8: 304–7

 Google Scholar

Jansen PL, van der Lelie H. Intrahepatic cholestasis and biliary cirrhosis associated with extrahepatic Hodgkin's disease. Neth J Med 1994; 44: 99–102

 PubMedGoogle Scholar

Crosbie OM, Crown JP, Nolan NP, Murray R, Hegarty JE. Resolution of paraneoplastic bile duct paucity following successful treatment of Hodgkin's disease. Hepatology 1997; 26: 5–8

 PubMed Web of Science ®Google Scholar

Gottrand F, Cullu F, Mazingue F, Nelken B, Lecomte-Houcke M, Farriaux JP. Intrahepatic cholestasis related to vanishing bile duct syndrome in Hodgkin's disease. J Pediatr Gastroenterol Nutr 1997; 24: 430–3

 PubMedGoogle Scholar

de Medieros BC, Lacerda MA, Telles JE, da Silva JA, de Medieros CR. Cholestasis secondary to Hodgkin's disease: Report of 2 cases of vanishing bile duct syndrome. Haematologica 1998; 83: 1038–40

 PubMedGoogle Scholar

Yalcin S, Kars A, Sokmensuer C, Atahan L. Extrahepatic Hodgkin's disease with intrahepatic cholestasis: Report of two cases. Oncology 1999; 57: 83–5

 PubMed Web of Science ®Google Scholar

Yusuf MA, Elias E, Hubscher SG. Jaundice caused by the vanishing bile duct syndrome in a child with hodgkin lymphoma. J Pediatr Hematol Oncol 2000; 22: 154–7

 PubMedGoogle Scholar

Rossini M, Lorand-Metze I, Oliveira G, De Souza C. Vanishing bile duct syndrome in Hodgkin's disease: Case report. Sao Paulo Med J 2000; 118: 154–7

 PubMedGoogle Scholar

Allory Y, Metreau J, Zafrani E. Paraneoplastic vanishing bile duct syndrome in a case of Hodgkin's disease. Ann Pathol 2000; 20: 52–5

 PubMedGoogle Scholar

Ozkan A, Yoruk A, Celkan T, Apak J, Yildiz I, Ozbay G. The vanishing bile duct syndrome in a child with Hodgkin disease. Med Pediatr Oncol 2001; 36: 398–9

 PubMedGoogle Scholar

Kormurcu S, Ozet A, Altundag MK, Arpaci F, Ozturk B, Celasun B, et al. Vanishing bile duct syndrome occurring after high-dose chemotherapy and autologous peripheral stem cell transplantation in a patient with Hodgkin's disease. Ann Hematol 2002; 81: 57–8

 PubMedGoogle Scholar

Liangpunsakul S, Kwo P, Koukoulis GK. Hodgkin's disease presenting as cholestatic hepatitis with prominent ductal injury. Eur J Gastroenterol Hepatol 2002; 14: 323–7

 PubMed Web of Science ®Google Scholar

Ripoll C, Carretero L, Sabin P, Alvarez E, Marrupe D, Banares R. Idiopathic cholestasis associated with progressive ductopenia in two patients with Hodgkin's disease. Gastroenterol Hepatol 2002; 25: 313–5

 PubMedGoogle Scholar

Guliter S, Erdem O, Isik M, Yamac K, Uluoglu O. Cholestatic liver disease with ductopenia (vanishing bile duct syndrome) in Hodgkin's disease: Report of a case. Tumori 2004; 90: 517–20

 PubMedGoogle Scholar

Cordoba Iturriagagoitia A, Inarrairaegui Bastarrica M, Perez de Equiza E, Zosaya Urmeneta JM, Marinez-Penuela JM, Beloqui Perez R. Ductal regeneration in vanishing bile duct syndrome in Hodgkin's lymphoma. Gastroenterol Hepatol 2005; 28: 275–8

 PubMedGoogle Scholar

Han WS, Jung ES, Kim YH, et al. Spontaneous resolution of vanishing bile duct syndrome in Hodgkin's lymphoma. Korean J Hepatol 2005; 11: 164–8

 PubMedGoogle Scholar

Schmitt A, Gilden DJ, Saint S, Moseley R. Empirically incorrect. N Engl J Med 2006; 354: 509–14

 PubMedGoogle Scholar

Barta SK, Yahalom J, Shia J, Hamlin P. Idiopathic cholestasis as a paraneoplastic phenomenon in Hodgkin's lymphoma. Clin Lymphoma Myeloma 2006; 7: 77–82

 PubMedGoogle Scholar