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Topographic distribution pattern in hepatic amyloidosis presenting with portal hypertension

Published:November 07, 2022DOI:https://doi.org/10.1016/j.jceh.2022.10.011

      Abstract

      Introduction

      The liver is often involved in both primary and secondary forms of amyloidosis. Significant clinical evidence of portal hypertension is relatively uncommon and seems to be related to the reduced sinusoidal lumen and increased resistance to blood flow due to massive perisinusoidal amyloid deposits. The relationships between the pattern and extent of amyloid deposition in patients presenting with portal hypertension have not yet been clearly demonstrated. This study is focusing on the topographic distribution of amyloidosis in patients presenting with portal hypertension.

      Materials and Methods

      The study included biopsy-proven cases of hepatic amyloidosis. The clinical, biochemical, and serological data, involvement of the extrahepatic organs, and HVPG values were recorded. Tissue sections were re-evaluated for the distribution patterns of amyloid deposits.

      Results

      We had 41 patients with hepatic amyloidosis, of which, 32 were male. A mixed pattern (sinusoidal and vascular) was the most common (32/41;78%). Hepatic venous pressure gradient was available in 21 cases. Portal hypertension was found in 14 patients (14/21; 67%). Cases of portal hypertension were found to have a sinusoidal pattern (3/14; 21.4%), vascular pattern (1/14; 7.1%) or a mixed sinusoidal and vascular pattern (10/14; 71.4 %). Those not having portal hypertension showed hepatic artery involvement in 6/7 (85.7 %) cases. A comparative analysis between PTH and non-PTH group showed that hepatic artery amyloid deposition was dominant in the non-PTH group (6/7; 85.7%) and sinusoidal deposition in the PTH group (13/14; 92.8%). The difference was found to be significant (p<0.05)

      Conclusion

      We found that portal hypertension noted in cases with diffuse sinusoidal deposition or mixed sinusoidal with portal vein deposition. In the non-PHT group, the deposition was in the mainly in hepatic artery alone.
      IntroductionAmyloidosis is a protein metabolism disorder involving the extracellular matrix of various organ systems. The liver is the major site of amyloid deposition and could be involved in both primary and secondary forms of the disease. A series of autopsies suggest that hepatic amyloidosis may be present in 96% of cases of AL amyloidosis.(
      • Ebert E.C.
      • Nagar M.
      Gastrointestinal manifestations of amyloidosis.
      • Girnius S.
      • Seldin D.C.
      • Skinner M.
      • Finn K.T.
      • Quillen K.
      • Doros G.
      • et al.
      Hepatic response after high-dose melphalan and stem cell transplantation in patients with AL amyloidosis associated liver disease.
      • Park M.A.
      • Mueller P.S.
      • Kyle R.A.
      • Larson D.R.
      • Plevak M.F.
      • Gertz M.A.
      Primary (AL) hepatic amyloidosis: clinical features and natural history in 98 patients.
      ) although the liver is often involved, the clinically apparent disease is relatively rare and usually only manifests as mild hepatomegaly and an elevation in serum alkaline phosphatase. Jaundice is reported in less than 5% of the literature.(
      • Bujanda L.
      • Beguiristain A.
      • Alberdi F.
      • Cosme A.
      • Ruiz de la Hermosa J.
      • Gutierrez S.
      • et al.
      Spontaneous rupture of the liver in amyloidosis.
      ) Portal hypertension is a rare complication and appears to be related to the reduced sinusoidal lumen and increased resistance to blood flow due to massive perisinusoidal amyloid deposits.
      • Norero B.
      • Perez-Ayuso R.M.
      • Duarte I.
      • Ramirez P.
      • Soza A.
      • Arrese M.
      • et al.
      Portal hypertension and acute liver failure as uncommon manifestations of primary amyloidosis.
      ,
      • Takayasu V.
      • Laborda L.S.
      • Bernardelli R.
      • Pinesi H.T.
      • Silva M.P.
      • Chiavelli V.
      • et al.
      Amyloidosis: an unusual cause of portal hypertension.
      A definite diagnosis of amyloidosis requires histological confirmation and immunohistochemistry.
      • Wang Y.D.
      • Zhao C.Y.
      • Yin H.Z.
      Primary hepatic amyloidosis: a mini literature review and five cases report.
      ,
      • Lee S.S.
      • Hadengue A.
      • Girod C.
      • Braillon A.
      • Lebrec D.
      Reduction of intrahepatic vascular space in the pathogenesis of portal hypertension. In vitro and in vivo studies in the rat.
      A relationship between pattern and extent of amyloid deposition in patients presenting with portal hypertension needs to be understood. In this study, we aimed to describe the topographic distribution of hepatic amyloidosis in patients presenting with portal hypertension (Figs. 1 and 2).
      Figure 1
      Figure 1Pure sinusoidal pattern displaying extensive amyloid deposition in the space of Disse with associated hepatic cord atrophy and compressed portal tract. (a; H&E stain; 200x)
      Pure vascular pattern showing thickening of the vessel walls such as hepatic arteriole and portal vein in the portal areas due to amyloid deposition (b, c; H&E stain; 200x). Polarizing microscopy showing amyloid deposition (green birefringence) in the sinusoidal spaces or limited to the walls of hepatic arteries. (d & e; Congo red; 100x and 200x). Positive immunohistochemical staining for amyloid light chain associated protein, highlighting the sinusoidal linear deposition of amyloid (f; kappa, g; lambda, 400x).
      Figure 2
      Figure 2Liver tissue with massive deposition of extracellular pale eosinophilic amyloid material predominantly a sinusoidal pattern as well as along the hepatic arterioles (a; H&E stain; 200x). The amyloid material is stained orange-red by Congo Red stain. Focal deposition of amyloid was identified in the arterioles in the portal tracts (arrows) (× 400). Amyloid deposition in the vessel walls and in the stroma of the portal tracts (b; portal vascular and stromal; H&E stain; 400x). Numerous round eosinophilic globules seen in the hepatic parenchyma and also seen within and around a portal tract. Note the prominence of these globules around the portal vein branch (arrows). Deposits are Congo-red positive (d; Congo-Red; 200x) and gives an apple-green birefringence under a polarized microscopy (Inset).

      Materials And Methods

      It was a retrospective analysis conducted at the Institute of liver and biliary sciences from July 2010 to July 2021. All patients diagnosed with amyloidosis with biopsy-proven liver involvement had their medical records searched by computer. Forty-one cases of hepatic amyloidosis were retrieved from the pathology department archives. For each patient, biochemical and serological data as well as the involvement of the liver and extrahepatic organs were recorded. Tissue sections stained with hematoxylin and eosin (H&E), Masson’s trichrome, orcein, Gomori’s reticulin, and Congo red were re-evaluated, including polarized light microscopy, for the distribution patterns of amyloid deposits as well as for the presence of any significant histological features, including fibrosis. We used an antibody against AA protein and AL protein to immunostain for amyloid A, lambda, and kappa using the peroxidase–anti peroxidase method. According to the immunohistochemical staining patterns and clinical findings, the type of amyloid protein was classified as Amyloid Associated (AA), Amyloid Light Chain (AL), and those who showed inconsistent IHC staining named as Amyloidosis Indeterminate (AI).(
      • Nasr S.H.
      • Dasari S.
      • Hasadsri L.
      • Theis J.D.
      • Vrana J.A.
      • Gertz M.A.
      • et al.
      Novel Type of Renal Amyloidosis Derived from Apolipoprotein-CII.
      ) The deposition of amyloid protein in the liver could be linear or globular.
      • Gioeva Z.
      • Kieninger B.
      • Rocken C.
      [Amyloidosis in liver biopsies].
      ,
      • Makhlouf H.R.
      • Goodman Z.D.
      Globular hepatic amyloid: an early stage in the pathway of amyloid formation: a study of 20 new cases.
      The linear form has two major topographic distribution patterns. The first is along the space of Disse or sinusoidal linear pattern, and the second, is a vascular pattern, along the wall of the portal vein or hepatic artery and arterioles. The sinusoidal pattern is semi-quantitatively classified into grades 1, 2, and 3 based on the extent of hepatic acinus zone involvement. The globular form is rare and may be found in the space of Disse and/or portal tract stroma. Hepatic vein pressure gradient (HVPG) was available in 21 patients, calculated as the difference between wedged and free hepatic vein pressures. HVPG of 10 mm Hg or greater was considered to be increased, as described.(
      • Kumar A.
      • Sharma P.
      • Sarin S.K.
      Hepatic venous pressure gradient measurement: time to learn.
      )

      Statistical Analysis

      Statistical analysis was done with the help of SPSS software22.0 (SPSS, Chicago IL). Quantitative variables are indicated as mean± standard deviation and median. Categorical variables are represented as frequency (%). Intergroup comparison of categorical variables was done using the Chi-Square test and non-parametric Wilcoxon Mann Whitney test was used to compare the groups having a smaller number of cases. A p-value of <0.05 was considered statistically significant.

      Results

      Basic attributes

      There were 41 patients with hepatic amyloidosis in this series (38 ante mortem and 3 post-mortem), 32 of whom were males and 9 were females. Patient age ranged from 15 to 77 years (mean 53.5 years). The immunohistochemistry staining patterns, and clinical results indicated that 32 patients (78.5%) had AL amyloidosis, and 6 patients (14.2%) had AA amyloidosis. A total of three patients (7.1%) did not fall into either category and classified as indeterminate amyloidosis cases. There were liver biopsies in all cases, and 25 (61%) patients underwent multi-organ biopsies, including bone marrow, kidney, rectum, gastric, spleen, lymph nodes, and fat pad aspiration.

      Histological Pattern of Amyloid

      A pure pattern of hepatic amyloid deposition was found in nine patients (9/41;22%), including five (12.2%) with a pure vascular pattern and four (9.8%) with a pure sinusoidal pattern. The predominant distribution pattern was mixed (sinusoidal and vascular), observed in 32 of 41 patients (78%). AL (26/32; 81.3%), AA (3/6; 50%), and AI (3/3; 100%) showed mixed pattern distributions of amyloid deposits. As shown in Table 1, various types of deposited amyloid protein in liver biopsies have different topographic distributions.
      Table 1Distribution pattern of amyloid proteins.
      Pattern of amyloid distributionAL (n=32)AA (n=6)AI (n=3)Total (n=41)
      PureS4 (12.5%)--4 (9.8%)
      Vs (HA/PV)2 (6.2%)3 (50%)-5 (12.2%)
      MixedS+Vs26 (81.3%)3 (50%)3 (100%)32 (78%)

      Biochemical parameters

      Most patients (28/41;68.3%) had normal or mildly elevated bilirubin levels (1.2-2.5mg/dl), while 13/41 (31.7%) had significantly elevated levels (>2.5mg/dl). The incidence of cholestatic jaundice was observed in 10 (24.4%) patients with moderate to severe elevations of alkaline phosphatases (>500mg/dl). Patients with cholestatic jaundice have either a pure or mixed, diffuse (grade 3) sinusoidal pattern involving all three zones of the liver and causing pressure atrophy. Amyloid topographic distributions in patients with cholestasis are shown in Table 2.
      Table 2Patients presenting with Cholestasis.
      S No.Amyloidosis Type (AL, AA, AI)Topographic distribution of amyloid depositionAlkaline Phosphatase (ALP)
      Sinusoidal (S)Portal Stromal (PS)Hepatic Artery (HA)Portal Vein (PV)
      1AL31011223
      2AI2101848
      3AL3111610
      4AL30001375
      5AL3010674
      6AL3111882
      7AL2101641
      8AL31111478
      9AL3101628
      10AL31011490

      Amyloidosis with Portal Hypertension

      HVPG value of >10 mmHg considered portal hypertension, which was available in 21 cases. A total of 14 patients (14/21;67%) had portal hypertension, whereas seven (7/21;33%) did not. Table 3 describes laboratory findings in patients with portal hypertension. Among the cases of portal hypertension, the observed pattern of amyloid deposition was sinusoidal; 3/14; 21.4% or a vascular (PV); 1/14; 7.1%. Mixed pattern was noted in 10/14 (71.4%). Patients without portal hypertension had a pure vascular distribution in 4/7 (57.1%) and pure sinusoidal distribution was not observed. Table 4 gives the details. According to the above results, the non-PTH group had predominant hepatic artery involvement, whereas the PTH group had predominant sinusoidal compartment involvement. The distribution pattern of sinusoids or hepatic arteries was compared between PTH and Non-PHT groups. As shown by the results, HA amyloid deposits were found in 6/7 (85.7%) of the non-PTH groups compared to 6/14 (42.8%) of the PTH groups. There was a sinusoidal predominance in the PTH group with 13/14 (92.8%) patients versus 4/7 (57.1%) patients in the non-PTH group. The difference was found to be significant (p<0.05) and shown in Table 5.
      Table 3Laboratory details of patients having hepatic amyloidosis and presenting with hypertension.
      S NoAge (years)SexType of Amy.HVPG (mmHg)T Bil. (mg/dL)D Bil. (mg/dL)AST (U/L)ALT (U/L)ALP (U/L)GGT (U/L)TP (g/dL)ALB (g/dL)CAL (mg/dL)HB (g/dL)PLT

      103/μL
      INR
      161FAL161.170.253118106247.83.20.6911.91111.3
      274MAL181.10.354293421437.62.70.5510.61101.1
      335MAL20126.827061018203334.52.61.39.21101.7
      437MAL202820.7856138210883.92.11.16.7202.57
      543MAL1431.420.12489613752344.62.31.313.81881.51
      661MAL1840.930.911240422816.73.30.915.52873.33
      742FAA140.50.32714152344.91.30.3610.43271.41
      849MAL110.50.262348827764.10.90.2313.93571.26
      947MAL2224.514.8109404921376.92.10.78.34051.31
      1059MAA100.90.3304064545.230.811.21991.2
      1158MAL260.90.41137014785705.71.20.2614.81701.49
      1264MAL120.90.469552522157.23.81.112.41251.02
      1349FAL201.61.138144071734.92.30.711.23271.76
      1470MAL187.024.11146514904806.82.630.6311.31711.06
      HVPG: Hepatic vein pressure gradient, T Bil.: Total bilirubin, D Bil.: Direct bilirubin, AST: Aspartate transaminase, ALT: Alanine transferase, ALP: Alkaline phosphatase, GGT: Gamma glutamine transferase, TP: Total protein, ALB: Albumin, CAL: Calcium, HB: Hemoglobin, PLT: Platelet, INR: International normalized ratio.
      Table 4Distribution pattern in patients of PTH and Non-PTH group.
      A pattern of amyloid depositionNo PHT (n=7)PHT (n=14)Total (n=21)
      S033
      HA202
      PV011
      HA+PV202
      S+VsS+PV145
      S+HA202
      S+PV+HA066
      Table 5Association of sinusoidal and vascular deposition in PTH and Non-PTH groups.
      Amyloid deposition patternPatients without PHT (n=7)Patients with PHT (n=14)p-value
      HA6/7 (85.7%)6/14 (42.8%)<0.001
      S3/7 (57.1%)13/14 (92.8%)<0.001

      Discussion

      Liver involvement is a well-recognized feature of both primary AL and secondary AA types of systemic amyloidosis. In this study, 78.5% of cases are associated with AL amyloidosis, and various studies have found it to be involved in 62-90% of cases.
      Amyloid deposition occurs in three different ways, including the vascular pattern involving hepatic artery/arterioles and portal veins, the sinusoidal pattern involving Disse space, and the portal stromal pattern involving the loose connective tissue of the portal tract. Mixed patterns (sinusoidal and vascular) are the most prevalent, while pure sinusoidal or vascular patterns are quite rare.
      The most common clinical presentation of hepatic amyloidosis is hepatomegaly (57-83%).(
      • Syed U.
      • Ching Companioni R.A.
      • Alkhawam H.
      • Walfish A.
      Amyloidosis of the gastrointestinal tract and the liver: clinical context, diagnosis and management.
      ) Significant clinical evidence of hepatic dysfunction is uncommon, and the patients rarely exhibit cholestatic jaundice and portal hypertension.(
      • Ebert E.C.
      • Nagar M.
      Gastrointestinal manifestations of amyloidosis.
      ) We found a fair number of patients presented with cholestatic jaundice, with diffuse sinusoidal (pure or mixed grade 3 pattern in 8/10; 80%) amyloid deposition and atrophic hepatocytic cords on histology.(
      • Norero B.
      • Perez-Ayuso R.M.
      • Duarte I.
      • Ramirez P.
      • Soza A.
      • Arrese M.
      • et al.
      Portal hypertension and acute liver failure as uncommon manifestations of primary amyloidosis.
      ) The pathogenesis of cholestasis in hepatic amyloidosis occurs as a result of amyloid deposits in the sinusoidal space and portal stroma that compress the canalicular system and intrahepatic bile ducts respectively. Raised transaminases in a few patients seem to be related to hepatocytic injury. The compression effect of amyloid deposition leads to hepatocytic atrophy and damage.
      • Rubinow A.
      • Koff R.S.
      • Cohen A.S.
      Severe intrahepatic cholestasis in primary amyloidosis: a report of four cases and a review of the literature.
      ,
      • Ford M.
      • Disney B.
      • Shinde V.
      • Ishaq S.
      Hepatic amyloidosis: a cause of rapidly progressive jaundice.
      Chopra et al. reported sinusoidal amyloid deposition and hepatic cord atrophy in their AL amyloid patients (100% and 92%, respectively).(
      • Chopra S.
      • Rubinow A.
      • Koff R.S.
      • Cohen A.S.
      Hepatic amyloidosis. A histopathologic analysis of primary (AL) and secondary (AA) forms.
      ) According to Banu Sarsik et al, parenchymal (sinusoidal) involvement is a consistent feature of AL amyloidosis, while vascular involvement is a uniform feature of AA amyloidosis.(
      • Sarsik B.
      • Sen S.
      • Kirdok F.S.
      • Akarca U.S.
      • Toz H.
      • Yilmaz F.
      Hepatic amyloidosis: morphologic spectrum of histopathological changes in AA and nonAA amyloidosis.
      ) However, the two patterns can coexist in both types of amyloidosis. A sinusoidal deposition is found in 30 of 32 AL cases; 93.7% (4 are pure sinusoidal and 26 are mixed sinusoidal and vascular). A pure vascular pattern was seen in 3/6; 50% of AA amyloid cases. There have also been reports of globular deposits of amyloid in the space of Disse and the portal triads of some patients with systemic amyloidosis in addition to sinusoidal and portal vascular deposits. Three cases of globular amyloid bodies were found in the current study. Amyloid globules may be formed due to a defect in the secretion of amyloid by hepatocytes, according to Agaram et al. Other postulations are, that it may represent the initial stage of the sinusoidal linear type or could be associated with leukocyte chemotactic factor 2-associated amyloid (ALect2) amyloidosis.(
      • Picken M.M.
      The Pathology of Amyloidosis in Classification: A Review.
      )
      There are few case reports of portal hypertension associated with hepatic amyloidosis in the literature, and the pathogenesis is also not well known. The degree of PHT is dependent primarily on intrahepatic blood flow and intrahepatic resistance. In amyloidosis, sinusoidal and portal vein involvement leads to an increased sinusoidal and presinusoidal resistance, respectively. The obstruction of intrahepatic portal flow caused by perisinusoidal/portal vein amyloid deposits causes arterio-portal shunts (APS) between the portal vein and hepatic arterioles. The abnormal transmission of HA pressure to the PV will contribute to the increase in portal vein pressure. Based on our study, diffuse sinusoidal deposits and mixed sinusoidal and portal vein deposits showed portal hypertension.(

      Sim Wanjou, 2019, Fig. 1: Anatomy of the portal venous system.

      )
      Another possible theory could be that both the afferent systems (PV, HA) merge at the sinusoidal bed and contribute to the tendency for local blood flow to remain constant. Besides the intrinsic regulation of the HA, there is a secondary form of intrinsic regulation known as the Hepatic Artery Buffer Response (HABR). According to this mechanism, the HA can modify its flow in response to changes in PV flow. If the portal flow is reduced caused by increased intrahepatic resistance or after temporary occlusion of PV, the HA dilates and a significant increase in HA flow was noted. The occlusion of HA had no significant effect on PV circulation.(
      • Burton-Opitz R.
      • Lucas D.R.
      The Blood Supply of the Kidney. V. The Influence of the Vagus Nerve Upon the Vascularity of the Left Organ.
      )
      We found that in the non-PHT group, the predominant pattern of deposition is in the hepatic artery, which does not contribute to sinusoidal or presinusoidal intrahepatic portal hypertension. Increased intrahepatic resistance and PV involvement leads to a progressive decrease in blood flow. In compensation, the hepatic artery dilated to maintain the intrahepatic blood flow as well as the increased intrahepatic pressure. However, due to HA amyloid deposition, the stiff arterial walls fail to maintain the HABR and lead to lower down blood flow, thus resulting in a decrease in intrahepatic blood flow and pressure.(
      • Eipel C.
      • Abshagen K.
      • Vollmar B.
      Regulation of hepatic blood flow: the hepatic arterial buffer response revisited.
      ) A similar observation was noted that hepatic artery involvement along with sinusoidal (Grade1/2) or portal vein deposition will not increase the portal pressure or mildly increase HVPG, likely because of decreased intrahepatic blood flow.
      The pattern of deposition in hepatic amyloidosis has imperative value as the clinician may take better care of portal hypertension related complications, patient counselling and management related to specific type of amyloid deposition. The number of patients in portal hypertensive and non-portal hypertensive groups are very less and is a limitation of our study. Larger studies are requested to validate our observations.

      Conclusion

      The possible association can be drawn between the pattern of amyloid deposition and development of portal hypertension. It is mainly sinusoidal and portal vein amyloid deposition that results in portal hypertension in cases of hepatic amyloidosis. The deposition of amyloid in hepatic arteries does not contribute to sinusoidal or presinusoidal intrahepatic portal hypertension. A hepatic artery involvement combined with sinusoidal (Grade1/2) or portal vein deposition will not increase portal pressure or HVPG, likely due to decreased intrahepatic blood flow.

      Statement of Ethics

      The paper is exempt from ethical committee approval. It is a retrospective study and done by the archival smears only.

      Funding Sources

      The study has not been funded by any agency/Institution.

      Author's Contribution

      Dr. Neha Nigam and Dr. Chhagan Bihari: Conception, design, analysis of data, and writing of the manuscript. Dr. Archana Rastogi and Dr. Pavni Bhatt: Analyse the data and review the draft of the paper.

      Data Availability

      All data generated or analyzed during this study are included in this article. The article contains no supplementary material files. Further inquiries can be directed to the corresponding author.

      Declaration of Competing Interest

      The authors have no conflict of interest to declare.

      Acknowledgment

      None.

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