Non-cirrhotic Intrahepatic Portal Hypertension Research Articles

Focused panel sequencing points to genetic predisposition in non-cirrhotic intrahepatic portal hypertension patients in India.

Non-cirrhotic intrahepatic portal hypertension (NCIPH), a portal microangiopathy affecting small portal vein radicles, is a disease of Indian sub-continent. NCIPH appears to be a complex disease with interactions between inherited and acquired factors, though the exact pathophysiological mechanism is unknown. We aimed at investigating the genetic variants that might contribute to susceptibility to NCIPH. In this case-control study, we analyzed genes associated with microangiopathy-VWF-ADAMTS13 (von Willebrand factor and its cleavase enzyme-a disintegrin and matrix metalloprotease with thrombospondin type-1 motifs member 13) and alternative complement system vitamin B12 metabolismand withfamilial NCIPH. Eighty-four Indian patients with liver biopsy-proven NCIPH (cases) and 103 healthy controls (matched for residential region of India) were included in the study. Targeted next-generation sequencing (NGS) panel, comprising 11 genes of interest, was done on 54 cases. Genotyping of selected variants was performed in 84 cases and 103 healthy controls. We identified variants in MBL2, CD46 and VWF genes either associated or predisposing to NCIPH. We also identified a single case with a novel compound heterozygous mutation in MBL2 gene, possibly contributing to development of NCIPH. In this first of a kind comprehensive gene panel study, multiple variants of significance have been noted, especially in ADAMTS13-VWF and complement pathways in NCIPH patients in India. Functional significance of these variants needs to be further studied.

Fatty liver and celiac disease: Why worry?

Celiac disease (CD) is a chronic inflammatory intestinal disorder mediated by the ingestion of gluten in genetically susceptible individuals. Liver involvement in CD has been widely described, and active screening for CD is recommended in patients with liver diseases, particularly in those with autoimmune disorders, fatty liver in the absence of metabolic syndrome, noncirrhotic intrahepatic portal hypertension, cryptogenic cirrhosis, and in the context of liver transplantation. Non-alcoholic fatty liver disease is estimated to affect approximately 25% of the world's adult population and is the world's leading cause of chronic liver disease. In view of both diseases' global significance, and to their correlation, this study reviews the available literature on fatty liver and CD and verifies particularities of the clinical setting.

NON-CIRRHOTIC PORTAL FIBROSIS CAUSING PORTAL HYPERTENSION

Portal hypertension is more prevalent in patients with liver cirrhosis and occurs infrequently in those without liver cirrhosis. Non-cirrhotic portal brosis (NCPF) and extrahepatic portal venous obstruction (EHPVO) are the two most common causes of non-cirrhotic portal hypertension. Unlike EHPVO, NCPF does not cause thrombosis of the extrahepatic portal vein. Sclerosis of the portal vein's medium and small branches occurs in NCPF. In NCPF, the hepatic venous pressure gradient (HVPG) is normal, in contrast to cirrhosis, where it is increased. Additionally, NCPF is referred to as non-cirrhotic intrahepatic portal hypertension (NCIPH), idiopathic portal hypertension, hepatoportal sclerosis, and benign intrahepatic portal hypertension. It is a disease with an unknown etiology that primarily affects middle-aged males and females and manifests as hematemesis and massive splenomegaly

Non-Cirrhotic Intrahepatic Portal Hypertension Induced Pulmonary Arterial Hypertension: Is it More Prevalent than we Think?

Introduction Porto-Pulmonary Hypertension (PoPH) belongs to WHO group I, Pulmonary Arterial Hypertension (PAH). It has a prevalence of 0.5-5% and is potentially curable with liver transplant. Non-cirrhotic intrahepatic portal hypertension (NCIPH) is a rare cause of PoPH that shares clinical features of advanced right heart failure. Based on review of the literature and Pulmonary Hypertension (PH) registries, most studies report the prevalence of patients with the liver cirrhosis with little to no data on the incidence of PoPH amongst the non-cirrhotic patient population. In this report, we describe the two cases of “missed” NCIPH and PoPH who were diagnosed in our institution within the span of six months. Case Reports The first patient was a 36 year old African American female who carried an initial diagnosis of SLE and ITP. She was on combination therapy with prostacyclin and endothelin receptor antagonist for the treatment of PAH. Her recurrent epistaxis from thrombocytopenia was refractory to therapy with prednisone, Rituximab, Romiplostim requiring multiple PRBC transfusions. Abdominal imaging revealed splenomegaly while liver biopsy demonstrated Nodular Regenerative Hyperplasia (NRH) without cirrhosis. The second patient, a 44 year old Chinese female, was initially diagnosed with idiopathic PAH. She was also identified to have ITP and showed no significant response to dexamethasone. On hospital admission, both patients presented with large volume ascites, splenomegaly and dependent edema. While in the ICU, they underwent RHC with assessment of Hepatic Venous Pressure Gradient (HVPG) demonstrating severely elevated pressures at 14 mmHg (Normally ≤ 5 mmHg) (Table 1). Liver biopsy was performed during the same procedure without complications. The pathology was consistent with NCIPH. Summary Our report illustrates the importance of considering the diagnosis of NCIPH in patients with PH and refractory ITP, particularly in the setting of splenomegaly and lack of overt cirrhosis. Due to an estimated 50% of patients with NCIPH that go on to develop portal hypertension, it is important to consider this diagnosis when evaluating patients with PH as the treatment strategy differs from idiopathic and connective tissue disease-associated PAH. Given the limited risk of HVPG measurement as part of the evaluation of patients with PAH, our single center experience would suggest screening for NCIPH in select patients and embracing this etiology in the differential.

What makes non-cirrhotic portal hypertension a common disease in India? Analysis for environmental factors.

In India, an unexplained enteropathy is present in a majority of non-cirrhotic intrahepatic portal hypertension (NCIPH) patients. Small intestinal bacterial contamination and tropical enteropathy could trigger inflammatory stimuli and activate the endothelium in the portal venous system. Groundwater contaminated with arsenic is an environmental factor of epidemic proportions in large areas of India which has similar consequences. Von Willebrand factor (a sticky protein) expressed by activated endothelium may promote formation of platelet microthrombi and occlusion of intrahepatic portal vein branches leading to NCIPH. Environmental factors linked to suboptimal hygiene and sanitation, which enter through the gastrointestinal (GI) tract, predispose to platelet plugging onto activated endothelium in portal microcirculation. Thus, NCIPH, an example of poverty linked thrombophilia, is a disease mainly affecting the lower socio-economic strata of Indian population. Public health measures to improve sanitation, provide clean drinking water and eliminate arsenic contamination of drinking water are urgently needed. Till such time as these environmental factors are addressed, NCIPH is likely to remain 'an Indian disease'.

ADAMTS13 missense variants associated with defective activity and secretion of ADAMTS13 in a patient with non-cirrhotic portal hypertension.

Non-cirrhotic intrahepatic portal hypertension (NCIPH) is characterized by thrombotic microangiopathy of the portal venous system, low ADAMTS13 (a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs-13), and high vWF (von Willebrand factor) levels. This study aimed to screen for ADAMTS13 mutations, focusing on the CUB domain, in these patients. Prospectively recruited NCIPH patients and healthy volunteers underwent tests for plasma vWF-ADAMTS13 balance. Sanger sequencing of the CUB domain of ADAMTS13 was done in a subset of the NCIPH patients, and the detected mutation was screened for in all the study participants. Next-generation sequencing of clinically relevant exome and liver immunostaining for ADAMTS13 was done in patients with detected ADAMTS13 mutation. Plasma vWF-ADAMTS13 balance was significantly altered in 24 NCIPH patients (Child's class A:23, B:1) as compared to 22 controls. On initial sequencing of the CUB domain (17 cases and 3 controls), one NCIPH patient showed a rare missense variant (SNV) at position c.3829C>T resulting in p.R1277W (rs14045669). Subsequent RFLP analysis targeted to the R1277W variant did not detect this in any other NCIPH patient, nor in any of the 22 controls. The NCIPH patient with the R1277W variant had severe ADAMTS13 deficiency, consistently high vWF, other missense SNVs in ADAMTS13, vWF, and complement genes. Immunostaining of his liver biopsy revealed globules of ADAMTS13 within stellate cells. We report missense variants in ADAMTS13, vWF, and complement genes in a patient with NCIPH who had decreased secretion and activity of ADAMTS13 protein. Further studies are needed in NCIPH patients in this regard.

To screen or not to screen? Celiac antibodies in liver diseases.

Celiac disease (CD) is a systemic immune-mediated disorder triggered by dietary gluten in genetically predisposed individuals. The typical symptoms are anemia, diarrhea, fatigue, weight loss, and abdominal pain. CD has been reported in patients with primary sclerosing cholangitis, primary biliary cholangitis, autoimmune hepatitis, aminotransferase elevations, nonalcoholic fatty liver disease, hepatitis B, hepatitis C, portal hypertension and liver cirrhosis. We evaluate recommendations for active screening for CD in patients with liver diseases, and the effect of a gluten-free diet in these different settings. Active screening for CD is recommended in patients with liver diseases, particularly in those with autoimmune disorders, steatosis in the absence of metabolic syndrome, noncirrhotic intrahepatic portal hypertension, cryptogenic cirrhosis, and in the context of liver transplantation. In hepatitis C, diagnosis of CD can be important as a relative contraindication to interferon use. Gluten-free diet ameliorates the symptoms associated with CD; however, the associated liver disease may improve, remain the same, or progress.

Arsenicosis, possibly from contaminated groundwater, associated with noncirrhotic intrahepatic portal hypertension.

Idiopathic noncirrhotic intrahepatic portal hypertension (NCIPH), a chronic microangiopathy of the liver caused by arsenicosis from use of contaminated groundwater, was reported from Asia. This study aimed to see, if in the twenty-first century, arsenicosis was present in NCIPH patients at our hospital and, if present, to look for groundwater contamination by arsenic in their residential locality. Twenty-seven liver biopsy proven NCIPH patients, 25 portal hypertensive controls with hepatitis B or C related cirrhosis and 25 healthy controls, matched for residential locality, were studied. Eighty-four percent to 96% of study subjects belonged to middle or lower socioeconomic category. Arsenicosis was looked for by estimation of arsenic levels in finger/toe nails and by skin examination. Arsenic levels in nails and in ground water (in NCIPH patients with arsenicosis) was estimated by mass spectrometry. Nail arsenic levels were raised in five (10%) portal hypertensive study subjects [two NCIPH patients (both had skin arsenicosis) and three portal hypertensive controls]. All of these five patients were residents of West Bengal or Bangladesh. Skin arsenicosis was noted in three NCIPH patients (11%) compared to none of disease/healthy controls. Ground water from residential locality of one NCIPH patient with arsenicosis (from Bangladesh) showed extremely high level of arsenic (79.5μg/L). Arsenicosis and microangiopathy of liver, possibly caused by environmental contamination continues in parts of Asia. Further studies are needed to understand the mechanisms of such 'poverty-linked thrombophilia'.

Orthotopic liver transplantation (OLTx) in non-cirrhotic portal hypertension secondary to ADAMTS13 deficiency.

Non-cirrhotic intrahepatic portal hypertension (NCIPH), also called idiopathic or benign, may lead to life-threatening complications. It is a rare indication for orthotopic liver transplantation (OLTx), although it may remain underdiagnosed. Overt symptoms of portal hypertension, predominantly variceal bleedings, misleadingly suggest that these patients are cirrhotic. Non-cirrhotic intrahepatic portal hypertension can be related to obliteration of portal venous microcirculation as a consequence of ADAMTS13 deficiency, a metalloproteinase which cleaves the ultra-large molecular weight forms of von Willebrand factor (VWF). The physiological role of VWF, secreted from endothelium, is to facilitate platelet adhesion at sites of endothelial damage. Decreased ADAMTS13 activity and persistence of ultra-large VWF at the endothelial surface predisposes to platelet clumping, causing microvascular occlusion. We describe the first OLTx for ADAMTS13 deficiency-related NCIPH in Poland. A 20-year-old, previously healthy male student presented with upper gastrointestinal bleeding. Gastroduodenoscopy revealed active bleeding from oesophageal varices, which was successfully treated with endoscopic banding ligation. Physical examination showed splenomegaly, but was otherwise normal with no signs suggesting chronic liver disease. Laboratory investigations were all normal except thrombocytopenia of 40,000/ml. Viral, metabolic, and autoimmunological markers of liver disease as well as bone marrow examination were normal. Transjugular liver biopsy was performed and was essentially normal. However, the tissue sample size was rather slight and we were not able to measure hepatic venous pressure gradient (HVPG). Percutaneous liver biopsy performed later confirmed these findings. Contrast enhanced magnetic resonance imaging scan excluded portal vein thrombosis and Budd-Chiari syndrome. Laboratory investigations showed undetectable levels of ADAMTS13. The patient has been followed up over a period of 5 years, showing constant progression of his portal hypertension with continuous enlargement of his spleen (Figures 1 and ​and2)2) and frequent oesophageal/gastric variceal treatments. Follow-up liver biopsy showed progression to F2 fibrosis. He underwent OLTx with rapid recovery and remains extremely well 6 months after surgery. The histological changes in the explanted liver are shown in Figures 3 A–C. Figure 1 Magnetic resonance imaging of portal hypertension Figure 2 Computed tomography images of the liver hypotrophy and spleen enlargement Figure 3 Histopathology of the explanted liver: A – Liver fibrosis with inflammatory infiltrates. Neocholangioles, small venules, and lack of correct arterioles. Haematoxylin and eosin stain (H + E). Objective magnification 10×. B – Thick ... Non-cirrhotic intrahepatic portal hypertension secondary to ADAMTS13 deficiency is a progressive condition and in case of uncontrolled symptoms of portal hypertension may require liver transplantation. Non-cirrhotic intrahepatic portal hypertension is also called idiopathic or benign portal hypertension. The latter term is misleading as it was shown that more than half of these patients develop liver failure when observed over a median period of 88 months [1]. Thus NCIPH is considered a rare but clinically important cause of portal hypertension. The underlying problem is related to the obliteration of portal venous microcirculation, secondary to the deficiency of ADAMTS13, a metalloproteinase that cleaves the ultra-large molecular weight forms of VWF to smaller ones [2]. The physiological role of VWF, secreted from endothelium, is to facilitate platelet adhesion at sites of endothelial damage. Mutations of ADAMTS13 are seen in congenital TTP, while antibodies to ADAMTS13 are found in the majority of adult acquired cases. Decreased ADAMTS13 activity and persistence of ultra-large VWF at the endothelial surface is thought to predispose to platelet clumping, causing microvascular occlusion. The imbalance in VWF and ADAMTS13 levels in portal microcirculation, where hepatic arterial blood pressures are superimposed, with upstream relation to hepatic stellate cells, would provide a mechanism for obliteration of terminal portal venules, which is characteristic of NCIPH. In our patient plasma activity of ADAMTS13 was below 1%, and its inhibitor was within the normal ranges. He has been treated with β-blockers and remains clinically stable with appropriate endoscopic surveillance. However, in sequential MRI and computed tomography imagines, atrophy of the right lobe of the liver has been observed, with enlargement of the left lobe, periportal fibrosis, varices, and dilatation of the portal tract veins. Chronic NCIPH leads to hepatic atrophy, although the progression of the disease is usually slow. The disorder can be associated with celiac disease and ulcerative colitis, and sustained deficiency of ADAMTS13 appears characteristic of NCIPH despite preserved liver function [1]. Older age at first presentation, hepatic encephalopathy, and portal vein thrombosis were found to be significant predictors of reduced transplant-free survival with, as already mentioned, progression to decompensated liver disease and the need for liver transplantation in a significant proportion of patients [1].

Analysis of Single Nucleotide Polymorphism at rs6677604 in Patients With Non-Cirrhotic Intrahepatic Portal Hypertension

month, 2 within six months and the rest after 3 years following TIPS. Median duration from clinical presentation to TIPS was 6 weeks andmedian survival till follow-up was 55.3 months (0–130 months). 33/42 patients underwent TIPS prior to 2013, their median survival till follow-up was 64.2 months. Conclusion: Our results validate the role of TIPS in the management of patients with BCS. With the accessibility of TIPS, requirement for liver transplantation has become rare.

Investigation into celiac disease in Indian patients with portal hypertension.

There is limited data on celiac disease in patients with cryptogenic cirrhosis or idiopathic noncirrhotic intrahepatic portal hypertension (NCIPH). Our objective was to evaluate for celiac disease in patients with portal hypertension in India. Consecutive patients with portal hypertension having cryptogenic chronic liver disease (cases) and hepatitis B- or C-related cirrhosis (controls) were prospectively enrolled. We studied tissue transglutaminase (tTG) antibody and duodenal histology in study patients. Sixty-one cases (including 14 NCIPH patients) and 59 controls were enrolled. Celiac disease was noted in six cases (including two NCIPH patients) as compared to none in controls. In a significant proportion of the remaining study subjects, duodenal biopsy showed villous atrophy, crypt hyperplasia, and lamina propria inflammation, not accompanied by raised intraepithelial lymphocytes (IELs); this was seen more commonly in cases as compared to controls. An unexpectedly high rate of tTG antibody positivity was seen in study subjects (66%) of cases as compared to 29% in controls (p-value < 0.001), which could indicate false-positive test result. In this study, 10% of patients with unexplained portal hypertension (cryptogenic chronic liver disease) had associated celiac disease. In addition, an unexplained enteropathy was seen in a significant proportion of study patients, more so in patients with cryptogenic chronic liver disease. This finding warrants further investigation.

A Rare Cause of Noncirrhotic Intrahepatic Portal Hypertension

Question: A 38-year-old woman with history of splenomegaly and thrombocytopenia was referred to the outpatient hepatology office after an extensive negative hematologic and infectious workup. On physical examination, the patient seemed to be comfortable with a blood pressure of 110/65 mm Hg and heart rate of 72 bpm. Her abdominal examination showed an enlarged spleen. A rectal examination revealed brown stool without melena. Laboratory evaluation revealed a white blood cell count of 4,800/mL, hemoglobin of 11.3 g/dL (baseline, 12.2 g/dL), platelets 53 10/mL (baseline, 70 10/mL), creatinine of 0.6 mg/dL, prothrombin time of 12 seconds, and International Normalized Ratio of 1.1. Electrolytes, amylase, lipase, liver chemistry tests, ceruloplasmin, and immunoglobulin levels were normal. Anti-smooth muscle antibody and antimitochondrial antibody were negative. Pertinent review of systems revealed that the patient is a current tobacco user with a 10-year pack history and a former user of intravenous heroine. Abdominal ultrasonography with Doppler revealed a diffusely heterogeneous liver parenchyma and enlarged spleen measuring 20.2 cm with a patent splenic vein (Figure A). Esophagogastroduodenoscopy demonstrated multiple columns of large esophageal varices in the lower third of the esophagus (Figure B). A colonoscopy demonstrated small to medium sized, nonbleeding rectal varices. Both studies were consistent with portal hypertension. A transjugular core liver biopsy was performed and the slides demonstrated liver cell plate atrophy alternating with hepatocellular regeneration (hematoxylin and eosin, and reticulin stains), and focal portal and pericellular fibrosis (trichrome stain). A minimal to mild inflammatory infiltrate composed of lymphocytes and clutters of macrophages containing brown granular refractive material was noted in the portal tracts without evidence of cirrhosis (Figure C, D). No significant bile duct injury, steatosis, granulomas, siderosis, or alpha1-antitrypsin globule was identified on histology. These findings were consistent with nodular regenerative hyperplasia, a condition of noncirrhotic intrahepatic portal hypertension (NCIPH). However, further inquisition of the same region under polarized light revealed multiple scattered, white, birefringent, irregular or needle-shaped material within some of the portal tracts (Figures E [arrow head], F [arrow head]).

Noncirrhotic intrahepatic portal hypertension.

Noncirrhotic intrahepatic portal hypertension.

ADAMTS13 deficiency, despite well-compensated liver functions in patients with noncirrhotic portal hypertension.

We have reported A disintegrin and metalloprotease with thrombospondin type 1 motif, member 13 (ADAMTS13) deficiency in noncirrhotic intrahepatic portal hypertension (NCIPH) patients of European origin with preserved liver function. We aimed to study ADAMTS13-von Willebrand factor (vWF) imbalance in Indian patients with NCIPH. Twenty-nine cases with NCIPH [22 males; 29years (13-58); Child's A, 23; B, 6], 22 disease controls with cryptogenic chronic liver disease [15 males; 46years (18-74); Child's A, 9; B, 9; C, 4] and 17 healthy controls [14 males; 32years (27-45)] were enrolled in the study. We measured ADAMTS13 antigen and activity (by collagen binding assay (CBA) and by fluorescence resonance energy transfer [FRET] assay), and vWF antigen levels in plasma of study patients. ADAMTS13 activity by CBA in NCIPH patients (32 %, 5 % to 100 %; median, range; p-value <0.001) and disease controls (36 %, 5 % to 144 %; p = 0.001) was significantly lower than in healthy controls (87 %; 60 % to 148 %). ADAMTS13 antigen and activity by FRET assay were also lower in cases and disease controls. ADAMTS13 activity (by CBA) to antigen ratio was lower in NCIPH and disease controls than in healthy controls. Of 29 NCIPH patients, 3 (all in Child's A) had severe ADAMTS13 deficiency (<10% ADAMTS13 activity), and 8 (Child's A, 7; B, 1) had moderate ADAMTS13 deficiency (10 % to 25% activity). Conversely, vWF antigen and vWF:ADAMTS13 ratio were higher in patients with NCIPH and in disease controls than in healthy controls. This study validates the finding of ADAMTS13 deficiency in NCIPH despite preserved liver functions in an Indian population suggesting its involvement in pathogenesis of NCIPH.

Non-cirrhotic portal fibrosis

Portal hypertension occurs commonly in patients with cirrhosis and rarely in those without cirrhosis of liver. The two most important causes of non-cirrhotic portal hypertension are non-cirrhotic portal fibrosis (NCPF) and extrahepatic portal venous obstruction (EHPVO). Unlike EHPVO, there is no thrombosis of the extrahepatic portal vein in NCPF. In NCPF, there occurs sclerosis of medium and small branches of the portal vein. The hepatic venous pressure gradient (HVPG) is normal in NCPF, when compared with cirrhosis where it is elevated. NCPF is also known as non-cirrhotic intrahepatic portal hypertension (NCIPH), idiopathic portal hypertension, hepatoportal sclerosis, and benign intrahepatic portal hypertension. It is a disease of obscure etiology, predominantly affecting the middle-aged males and females who present with hematemesis and massive splenomegaly.

Obliterative Portal Venopathy: A Rare Cause of Pre-sinusoidal Portal Hypertension

Introduction: Making an etiologic diagnosis in patients with noncirrhotic portal hypertension can often be a formidable challenge for clinicians. We describe a rare case of pre-sinusoidal intrahepatic portal hypertension. Case: A 54-year-old man presented with an upper GI bleed. He had a longstanding history of fibrostenotic Crohn's disease s/p surgical resections and therapy with various immunomodulating agents. He had a history of massive splenomegaly and thrombocytopenia (platelets ˜40,000), for which he'd been followed by a hematologist without a definitive diagnosis, despite numerous tests including a bone marrow biopsy. An EGD revealed large, grade four esophageal varices, for which he underwent several variceal band ligation sessions. Initial CT imaging demonstrated a non-cirrhotic liver with a 25-cm spleen, patent portal, hepatic and splenic veins, and no ascites. LFT's were normal, and an MRCP showed no evidence of PSC. Viral, autoimmune, and genetic etiologies of chronic liver disease were unrevealing. A transjugular liver biopsy revealed a borderline elevated hepatic venous pressure gradient of 8 mmHg. Histology showed moderate macrovesicular steatosis (30%) and a NAFLD activity score (NAS) of 3/8. In addition, there were prominent periportal shunt vessels with muscularization of small portal vein branches and nodular regenerative hyperplasia changes; all consistent with a diagnosis of “obliterative portal venopathy (OPV).” There was mild periportal fibrosis (2/4), but no cirrhosis. A full hypercoaguable work-up failed to reveal an underlying clotting disorder. A partial splenic artery embolization was performed to reduce the spleen volume, prevent recurrent portal hypertensive bleeding, and improve the patient's thrombocytopenia. Several weeks post-procedure, his platelet count rose to the 200,000 range, and there was complete resolution of varices on follow-up EGD. He has since developed evidence of some thrombosis in the splenic and portal veins, requiring anti-coagulation. Discussion: OPV has also been termed “hepatoportal sclerosis,” “noncirrhotic intrahepatic portal hypertension,” and “idiopathic presinusoidal portal hypertension,” a rare etiology of portal hypertension diagnosed by the astute pathologist, based on specific histologic features. There is usually minimal-to-moderate portal fibrosis, but no cirrhosis and a patent splenoportal venous axis. The mechanism of disease pathogenesis is unclear, but in our patient, an autoimmune/inflammatory disease of the gut may predispose to portal bacteremia/pylephlebitis, which may result in thrombosis, sclerosis, and obstruction of small- and medium-sized portal vein radicals. His long-term exposure to 6 MP/imuran is another putative precipitating factor.

Porto-pulmonary hypertension exacerbated by platelet transfusion in a patient with ADAMTS13 deficiency

We propose that porto-pulmonary hypertension (PPH) may arise as a consequence of deficiency of ADAMTS13 (a plasma metalloprotease that regulates von Willebrand factor size and reduces its platelet adhesive activity) and provide a clinical case history to support our hypothesis.A patient with non-cirrhotic intrahepatic portal hypertension (NCIPH), ulcerative colitis and celiac disease developed symptoms of PPH, which had advanced beyond levels which would have made her an eligible candidate for liver transplantation (mean pulmonary artery pressure (PAP) 49mmHg). She was known to have severe ADAMTS13 deficiency, which we considered to be causative of, or contributory to her NCIPH. We postulated that increasing porto-systemic shunting associated with advancing portal hypertension would make the next encountered vascular bed, the lung, susceptible to the pathogenic process that was previously confined to the portal system, with pulmonary hypertension as its consequence. Her pulmonary artery pressures fell significantly during the next year on weekly replacement of plasma ADAMTS13 by infusions of fresh frozen plasma and conventional drug treatment of her pulmonary hypertension. Her pulmonary artery pressures had fallen to acceptable levels when, in response to platelet infusion, it rose precipitously and dangerously.The sequence strongly supports our hypothesis that PPH is a consequence of ADAMTS13 deficiency and is caused by platelet deposition in afferent pulmonary vessels.

Use of Serum Vitamin B12 Level as a Marker to Differentiate Idiopathic Noncirrhotic Intrahepatic Portal Hypertension from Cryptogenic Cirrhosis

Idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH) is often mis-diagnosed as cryptogenic cirrhosis. Serum vitamin B12 levels can be raised in cirrhosis, probably because of excess release or reduced clearance. Because NCIPH is characterised by long periods of preserved liver function, we examined whether serum B12 level could be used as a marker to differentiate NCIPH from cryptogenic cirrhosis. We analysed serum B12 levels in 45 NCIPH and 43 cryptogenic cirrhosis patients from January 2009 to September 2011. Serum B12 levels were significantly lower in NCIPH patients than in cryptogenic cirrhosis patients (p < 0.001) and were useful in differentiating the two disorders (area under ROC: 0.84; 95% C.I: 0.76-0.93). Low serum B12 level (≤250 pg/ml) was noted in 25/72 (35%) healthy controls, 14/42 (33%) NCIPH patients, and 1/38 (3 %) cryptogenic cirrhosis patients. In patients with intrahepatic portal hypertension of unknown cause, serum B12 level ≤ 250 pg/ml was useful for diagnosing NCIPH (positive predictive value: 93 %, positive likelihood ratio 12.7), and serum B12 level >1,000 pg/ml was useful in ruling out NCIPH (negative predictive value: 86 %, negative likelihood ratio: 6.67). Low serum B12 levels (≤250 pg/ml) correlated with diagnosis of NCIPH after adjusting for possible confounders (O.R: 13.6; 95% C.I:1.5-126.2). Among patients in Child's class A, serum B12 level was ≤250 pg/ml in 14/35 NCIPH patients compared with 1/21 cryptogenic cirrhosis patients (O.R: 13.3; 95% C.I: 1.6-111). Serum vitamin B12 level seems to be a useful non-invasive marker for differentiation of NCIPH from cryptogenic cirrhosis.

Clinical Analysis of 15 Cases of Liver Nodular Regenerative Hyperplasia

Nodular regenerative hyperplasia (NRH) of liver may be one of the leading causes of non-cirrhotic intrahepatic portal hypertension (NCIPH), although the exact relationship is currently unknown. Diagnosis of NRH is relatively difficult and involves surgical pathology, and thus it is necessary to improve the preoperative recognition of NRH. Here, we analyze 15 cases of NRH to better understand this disease. All the liver specimens were microscopically examined by hematoxylin-eosin staining and reticulin and Masson trichrome staining. Diagnoses of NRH were confirmed by pathological examination. Clinically, NRH presents as diffused liver lesions with mildly increased liver enzymes. Portal hypertension is the most common clinical manifestation presenting prominently as splenomegaly, hypersplenism, and esophageal varices bleeding. NRH is often associated with autoimmune or collagen vascular diseases, and such patients often present with a variety of positive autoantibodies and increased erythrocyte sedimentation rate (ESR), Ig and γ %. Pathological examination of the liver showed diffuse small regenerative nodules without fibrous septa and obstructive portal venopathy. For those patients with portal hypertension of unknown cause and preserved liver function, especially, those combined with autoimmune diseases, NRH should be considered.

Noncirrhotic Portal Hypertension due to Nodular Regenerative Hyperplasia Treated with Surgical Portacaval Shunt

Nodular regenerative hyperplasia (NRH) is an uncommon condition, but an important cause of noncirrhotic intrahepatic portal hypertension (NCIPH), characterized by micronodules of regenerative hepatocytes throughout the liver without intervening fibrous septae. Herein, we present a case of a thirty-seven-year-old female with systemic lupus erythematosus (SLE) who was discovered to have significant esophageal varices on endoscopy for dyspepsia. Her labs revealed a slight elevation in the alkaline phosphatase and mild thrombocytopenia. Abdominal MRI revealed seven focal hepatic masses, splenomegaly, no ascites, and a patent portal vein. Ultrasound-guided core biopsy was reported as focal nodular hyperplasia. However, her varices persisted despite treatment with beta-blockers and four additional upper endoscopies with banding. She was subsequently referred for a surgical opinion. At that time, given her history of SLE, azathioprine use, and portal hypertension, suspicion for NRH was raised. Given her normal synthetic function and lack of parenchymal liver disease, the patient was offered surgical shunting. During shunt surgery, a liver wedge biopsy was also performed and this confirmed NRH. An upper endoscopy six weeks after shunting verified complete resolution of varices. Currently, fifteen months after surgery duplex ultrasonography demonstrates shunt patency and the patient is without recurrence of her portal hypertension.