Histologic Lesions of Porto-Sinusoidal Vascular Disease Following Phlebotomy in Hemochromatosis

Abstract

Background: Phlebotomy induces regression of liver fibrosis in genetic hemochromatosis. We assessed the histologic changes in prephlebotomy and post-phlebotomy liver biopsies from patients with HFE mutation as a model to study regression of fibrosis. We aimed to show that phlebotomy-induced histologic lesions overlap with portosinusoidal vascular disease (PSVD, also known as idiopathic noncirrhotic portal hypertension), histologically. Methods: A total of 51 biopsies (22 pre-phlebotomy and 29 postphlebotomy) were reviewed, and three variables were studied: iron index indicative of the amount of accumulated iron (range 0 to 18), the combined score of vascular changes reflecting the presence of histological lesions that are described in PSVD (range 0 to 9) and the high-grade shunt vessel by calculating the proportion of portal tracts with shunt vessels, with a cutoff of 50%. Two-tailed Student's t-test and Fisher's exact test were performed to compare the means of two variables and frequencies of the histologic lesions in two groups, respectively. A P-value < 0.05 was considered statistically significant. Results: The iron index was higher in the pre-phlebotomy compared to post-phlebotomy group (P = 0.01). Compared to the pre-phlebotomy group, the combined score was higher in the post-phlebotomy group when the cases of advanced fibrosis were excluded (P = 0.023) and remained higher when patients with risk factors for PSVD were further excluded (P = 0.034). The high-grade shunt vessel tended to be more common in the post-phlebotomy group when advanced fibrosis was excluded; however, the statistical significance was marginal (P = 0.056). Conclusions: Phlebotomy reduces hepatic iron load and induces histologic lesions of PSVD in patients with HFE mutation. Our data support a postulation that some of the histologic lesions of PSVD represent vascular remodeling following a regression of fibrosis and may not be reflective of risk factors or etiopathogenesis of PSVD. Regressed fibrosis and PSVD may not be reliably distinguished in a limited sample, therefore warranting cautious interpretation in the right clinical context.

Idiopathic Non-Cirrhotic Portal Hypertension and Porto-Sinusoidal Vascular Disease: Review of Current Data

“…For example, portal vascular aberrancies that have been described in INCPH were seen in “normal” aging livers [ 15 ] and liver samples from trauma patients [ 16 ]. Similarly, portal and lobular vascular changes that can be seen in INCPH were present in liver biopsies taken during gastric bypass surgery or cholecystectomy [ 13 ], in patients with hemochromatosis with or without history of phlebotomy [ 14 ] and in nine (69%) of 13 patients on dialysis [ 17 ], all in the absence of PH. Likewise, in a recent interobserver variability study, the control group patients without PH who showed some features of INCPH in their liver biopsies did not develop PH after a mean follow-up of 38 months [ 18 ].…”

“…Regardless, the authors speculated that the findings of histologic features of INCPH were reflective of the presence of known INCPH/PSVD risk factors that are commonly encountered in this patient population. PSVD without PH was also reported as a form of vascular remodeling in regressed fibrosis following phlebotomy in hemochromatosis patients [ 14 ]. On the other hand, some PSVD patients without PH at presentation may develop overt PH on follow-up studies [ 40 , 79 ].…”

“…These include portal tract abnormalities such as aberrant vessels (i.e., periportal shunting vessels, herniated portal veins branches, multiplicity of portal vessels within a single portal tract, dilatation of arteries), irregular distribution of the portal tracts and central veins, non-zonal sinusoidal dilatation and mild perisinusoidal fibrosis [ 2 ] ( Table 2 ). Additionally, portal tract remnants (defined as portal tract smaller than twice the size of a bile duct) are frequently seen in INCPH/PSVD [ 9 , 13 , 14 , 18 , 79 ].…”

Interobserver study on histologic features of idiopathic non-cirrhotic portal hypertension

“…One needle biopsy from group A and three wedge biopsies from group B were subcapsular sampling, histologically. Ten of 19 group B cases had been used for previous studies [ 8 , 9 , 12 ]. The principal investigator (HL) selected additional 9 cases after assessing histologic features.…”

“…However, it has been increasingly recognized that INCPH-like histologic features can be seen in liver samples without evidence of portal hypertension, including in liver biopsies obtained during cholecystectomy or gastric bypass, fatty liver disease [ 8 ], regressed fibrosis [ 9 ], and normal “control” liver [ 10 ]. As such, the clinical significance of individual or any combination of histologic features that can be seen in INCPH remains speculative in daily liver pathology practice.…”