|Year : 2019 | Volume
| Issue : 4 | Page : 468-478
What makes non-cirrhotic portal hypertension a common disease in India? Analysis for environmental factors
Ashish Goel1, Banumathi Ramakrishna2, Uday Zachariah1, KG Sajith1, Deepak K Burad2, Thomas A Kodiatte2, Shyamkumar N Keshava3, KA Balasubramanian4, Elwyn Elias5, CE Eapen1
1 Department of Hepatology, Division of GI Sciences, Christian Medical College, Vellore, India
2 Department of Pathology, Division of GI Sciences, Christian Medical College, Vellore, India
3 Department of Radio-diagnosis, Division of GI Sciences, Christian Medical College, Vellore, India
4 Department of Wellcome Research Laboratory, Division of GI Sciences, Christian Medical College, Vellore, India
5 Department of Hepatology, Division of GI Sciences, Christian Medical College, Vellore, India; Liver Unit, University Hospitals, Birmingham, UK
|Date of Submission||27-Aug-2017|
|Date of Web Publication||16-Jul-2019|
Dr C E Eapen
Department of Hepatology, Christian Medical College, Vellore 632 004, Tamil Nadu
Source of Support: None, Conflict of Interest: None
| Abstract|| |
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'.
Keywords: Endothelial dysfunction - non-cirrhotic portal fibrosis - obliterative portal venopathy - poverty linked thrombophilia
|How to cite this article:|
Goel A, Ramakrishna B, Zachariah U, Sajith K G, Burad DK, Kodiatte TA, Keshava SN, Balasubramanian K A, Elias E, Eapen C E. What makes non-cirrhotic portal hypertension a common disease in India? Analysis for environmental factors. Indian J Med Res 2019;149:468-78
|How to cite this URL:|
Goel A, Ramakrishna B, Zachariah U, Sajith K G, Burad DK, Kodiatte TA, Keshava SN, Balasubramanian K A, Elias E, Eapen C E. What makes non-cirrhotic portal hypertension a common disease in India? Analysis for environmental factors. Indian J Med Res [serial online] 2019 [cited 2019 Dec 12];149:468-78. Available from: http://www.ijmr.org.in/text.asp?2019/149/4/468/262874
| Introduction|| |
A two-part series published in 1967 described a new syndrome of non-cirrhotic portal fibrosis (NCPF) with portal hypertension ,. The nomenclature of unexplained portal hypertension without cirrhosis of liver including NCPF, hepatoportal sclerosis, nodular regenerative hyperplasia, idiopathic portal hypertension, incomplete septal cirrhosis and partial nodular transformation of the liver (mostly histology based nomenclature), is now regarded as representing aspects of a single clinical entity of non-cirrhotic intrahepatic portal hypertension (NCIPH),. NCIPH is a vascular disorder of the liver, a consequence of chronic microangiopathy of portal vein branches, leading to intrahepatic portal vein occlusion. In addition to the original description of this disease from India, publication of other seminal research work from India ,,,,,,,, led to the question as to why this disease was so common in India .
Multifactorial diseases maybe caused by an interplay of multiple acquired and/ or genetic factors. The incidence of NCIPH has been linked to poor sanitation and hygiene, a reflection of living standards in the strata of society affected. As Indian economic development translates into better living standards for its citizens, one can predict that the incidence of NCIPH in India will come down.
An imbalance of low ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) and high von Willebrand factor (vWF) levels has been documented as example of a mechanistic pathway that would permit poverty-linked environmental triggers to promote obliteration of portal vein radicles in the liver in NCIPH patients ,. ADAMTS13 is an enzyme which cleaves vWF multimers. Uncleaved ultralarge vWF multimers are extremely adhesive and favour platelets to stick onto the activated endothelium. It has been postulated that endothelial activation (vWF is an endothelial protein) leads to platelet plugs in the microcirculation in the liver in NCIPH ,.
This review describes some environmental factors which may explain the predilection of NCIPH for India, and how NCIPH is diagnosed and how NCIPH masquerades (and is often mislabelled) as cryptogenic cirrhosis in India.
| Diagnosis of Non-Cirrhotic Intrahepatic Portal Hypertension (Nciph)|| |
As the disease process is limited to small intrahepatic portal vein radicles not visualized by currently available imaging techniques, the diagnosis of NCIPH is based on the presence of colour Doppler documenting patent inflow into (portal vein) and outflow out of (hepatic venous outflow tract) the liver, negative aetiological workup for any aetiology of liver disease (e.g. hepatitis B or C virus, iron or copper overload, autoimmune liver disease), liver biopsy documenting absence of bridging fibrosis/cirrhosis and excluding other causes that can closely mimic NCIPH on histology (e.g. schistosomiasis, primary biliary cirrhosis and sarcoidosis). History of significant alcohol intake (>20 g/day), risk factors for non-alcoholic fatty liver disease (metabolic syndrome), portal vein thrombosis and hepatic malignancy are exclusion criteria for making a diagnosis of NCIPH.
Role of liver biopsy
Cryptogenic cirrhosis tends to mimic NCIPH and adequate liver biopsy (i.e. containing at least 10 portal tracts with multiple cores) is central to this differentiation. The telltale signs of microangiopathy (portal venule sclerosis/ectasia, sinusoidal dilation, nodular regenerative hyperplasia etc.) are present in a proportion of these patients. For diagnosis of NCIPH, absence of significant fibrosis, i.e. bridging fibrosis/ cirrhosis, is mandatory. Liver biopsy also excludes alternative aetiology (e.g. steatosis, steatohepatitis and significant inflammation) and mimickers of NCIPH (e.g. schistosomiasis and congenital hepatic fibrosis).
Hepatic venous pressure studies
Hepatic venous pressure measurements (balloon or catheter wedge technique ) can help differentiate cirrhosis from NCIPH. As the disease process (and the gradient) in NCIPH is presinusoidal, hepatic venous pressure gradient (HVPG) is expected to be normal in these patients. However, this is true only in one-third of the patients with NCIPH, and the rest tend to have higher than normal HVPG .
| Is NCIPH Still Present in India?|| |
Initial detailed reports from India described and established NCPF as a disease entity ,. Multiple reports corroborate the fact that NCIPH remains prevalent in India ,,,. [Table 1] presents some of the recent studies from India reporting the prevalence of NCIPH ,,,,,,. The prevalence greatly varies depending on the group of patients studied and modalities used for diagnosis.
|Table 1: Prevalence of non-cirrhotic intrahepatic portal hypertension (NCIPH) among patients with portal hypertension in India|
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Several new patients with NCIPH have been diagnosed and reported  from a tertiary centre, catering predominantly to middle/ lower socio-economic class patients from southern and eastern parts of India every year [Figure 1].
|Figure 1: Number of new non-cirrhotic intrahepatic portal hypertension (NCIPH) patients (liver biopsy proven) diagnosed in a single tertiary centre in southern India from 2000 to 2016 (unpublished data).|
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| Are We Underdiagnosing NCIPH?|| |
NCIPH mimics cryptogenic cirrhosis in every aspect, and as mentioned previously, diagnosis of NCIPH requires extensive evaluation. Diagnosis of NCIPH is confirmed only with liver biopsy , and often, the diagnosis is made with explant biopsy after transplant for presumed cryptogenic cirrhosis ,. Sampling the liver for biopsy is often difficult to achieve in a patient with, often severe, thrombocytopenia. In a prospective study spanning one year from our tertiary centre, although cryptogenic chronic liver disease was the most common aetiologic label noted in 203 of 583 (35%) portal hypertensive patients, only 39 (19%) patients were subjected to liver biopsy evaluation .
Most centres in India have limited access to transjugular liver biopsy and hepatic venous pressure measurement. In addition, pathogenesis of NCIPH remains poorly understood and consequently has limited treatment options available. As oesophageal and gastric variceal bleeds are now almost exclusively managed by endotherapy, shunt surgeries are rarely performed for portal hypertension. As a consequence, peroperative liver biopsy (common method of liver sampling for histology previously for NCIPH) is hardly ever done now in India ,,.
Madhu et al, in a retrospective analysis of liver biopsy in patients with previously labelled as cryptogenic cirrhosis, noted that 48 per cent had NCIPH. Another prospective study  noted 41 per cent prevalence of NCIPH in patients undergoing liver biopsy for cryptogenic cirrhosis. Although there may be a selection bias, yet it is more than likely that NCIPH forms a significant subset of Indian portal hypertensive patients who are currently labelled as cryptogenic cirrhosis. It has been estimated that in India, 10-30 per cent patients with portal hypertensive bleeds may have underlying NCIPH .
| Role of Potential Environmental Factors in NCIPH Patients|| |
‘Poverty-linked thrombophilia’ is probably secondary to environmental factors, especially related to gut inflammation . In a prospective study it was noted that most patients with NCIPH belonged to low and middle socio-economic status . Limited access to clean drinking water, inadequate sewage facilities and continued close existence with animals contribute to a state of mild gut inflammation (environmental enteropathy) in India . This chronic low-grade gut inflammation creates a pro-thrombotic milieu in portal circulation and can drive NCIPH .
Microangiopathy restricted to intrahepatic small portal vein radicles suggests the active involvement of gut in the pathogenesis of NCIPH. An animal model of NCIPH has been created by repeatedly injecting Escherichia More Details coli into portal circulation . Often silent gut disorders (celiac disease and ulcerative colitis) accompany NCIPH . The presence of these disorders was also associated with worse outcome. Higher plasma titres of IgA anti-cardiolipin antibodies  and deposition of IgA2-complement complexes in the kidneys of NCIPH patients who developed nephrotic syndrome after splenorenal shunt  also suggest the dominant role of gut in pathogenesis of NCIPH.
Tropical sprue was initially reported in residents of India, as well as visitors to India as a cause of malabsorption . The epidemiology of tropical sprue in India has changed over the past several decades. Epidemics of tropical sprue are no longer reported in India. Sporadic cases of tropical sprue still constitute the main cause of malabsorption in many centres in India ,,,. Tropical enteropathy (subclinical malabsorption) is common in India. Xylose malabsorption was documented in 50 per cent of the apparently healthy population in southern India . Despite elaborate investigations and researching putative causes , the definitive cause of tropical sprue has never been identified. It has been postulated that tropical enteropathy may be an adaptive response to recurrent intestinal infections .
It is possible that with improving sanitation, the causative environmental factor(s) may have got attenuated. However, the sporadic cases of tropical sprue suggests that the environmental causative factors are still present in India. Small intestinal bacterial overgrowth occurs in patients with tropical sprue . Low-grade small intestinal bacterial growth is common in patients with non-alcoholic fatty liver disease in India . Celiac disease is now increasingly recognized in India. Its prevalence varies with the wheat-consuming habits of the population . The association of (asymptomatic) celiac disease and NCIPH has been reported ,,.
Systematic studies looking for enteropathy in NCIPH patients unearthed an unexplained enteropathy, significantly higher in NCIPH patients compared to patients with hepatitis B or C causing portal hypertension (disease controls) as well as in healthy controls . Further research is needed to explore this as yet unexplained enteropathy in NCIPH patients. Of the different types of gut disorders discussed above, it is likely that some disorders - tropical sprue, tropical enteropathy, small bowel bacterial overgrowth – affect individuals in lower socio-economic strata of society who are more exposed to the consequences of suboptimal sanitation .
The link between therapeutic arsenic use (Fowler's solution - arsenic trioxide - used to treat psoriasis) and non-cirrhotic portal hypertension was initially reported from Europe . Chronic arsenicosis is a multisystem disorder and skin is most commonly involved (melanosis and keratosis); other organs involved include peripheral nerves, liver, lungs, etc. NCIPH is the typical hepatic manifestation ,. In long-standing cases, cancer (of skin, lungs, liver, kidney and urinary bladder) can develop ,. In affected locations, children in addition to adults are affected ,.
In 1970s, Datta et al reported the link between chronic arsenicosis and NCIPH in India. These patients had consumed arsenic from three sources: consumption of groundwater contaminated with arsenic; use of arsenic mixed with opium (illegal recreational drug) and Ayurvedic medicines (bhasams prepared by repeated oxidation of ores) containing arsenic.
Ground water contamination by arsenic
The entire Ganga River basin covering large areas of land in India, Bangladesh, Nepal and Tibet, has high levels of arsenic in groundwater, water used for irrigation and in food materials. The arsenic levels here are in excess of World Health Organization standards for drinking water and United Nations Food and Agricultural Organization's standard for irrigation water (100 μg/l). Arsenic contamination of groundwater and water used for drinking continues to be documented on a significant scale in Bihar , Uttar Pradesh  and West Bengal . In Kolkata Municipal Corporation, the southern parts of the Corporation face a higher degree of groundwater arsenic contamination .
The population affected by arsenic in India in 2018 was estimated to be 1.48 crores . The States maximally affected are West Bengal (1.04 crore affected persons), Bihar (16.88 lakh affected) and Assam (14.48 lakh affected). In West Bengal, the ground water contamination by arsenic is recognized in 83 blocks in eight districts (Bardhaman, Malda, Hooghly, Howrah, Murshidabad, Nadia, North 24 Parganas and South 24 Parganas). Subclinical arsenicosis (higher level of arsenic in hair, nail or urine samples, with no overt clinical manifestations) was seen in >90 per cent of adults and children studied, residing in the affected localities . Typical skin lesions of arsenicosis (hyperpigmentation and keratosis) were seen in 10 per cent of adults and six per cent of children from these localities (Uttar Pradesh, Bihar and West Bengal) who were examined ,,. Individuals residing in these localities and consuming arsenic-laden drinking water continue to be diagnosed with NCIPH .
Prevention of arsenic poisoning in India
The technology needed to remove arsenic from groundwater is expensive. Attempts to treat NCIPH with arsenic chelating agents have shown limited success . The urgent need is to educate the public about the arsenic contamination of groundwater. Adequate infrastructure is needed to treat and provide arsenic free drinking water. The water supply needs to be continuously monitored for arsenic contamination. Rainwater harvesting (thus avoiding use of contaminated groundwater) is another suggested option. Cost-effective arsenic mitigation programmes which can be sustained with public participation for implementation are urgently needed ,.
Use of arsenic mixed in recreational drugs and Ayurvedic/alternative medicines
A survey from Chandigarh showed highly prevalent use of substances including that of opioids . Dependence rates on opioids, cannabinoids and sedative hypnotics were 1.5 per cent. The association between use of arsenic containing Ayurvedic medicines, arsenicosis and NCIPH has been reported in India . In patients who develop drug-induced liver injury due to these drugs, the presence of arsenic or mercury is found to be associated with a higher risk of death .
Animal models of liver damage in arsenicosis
Chronic ingestion of arsenic (over 15 months duration of arsenic exposure) leads to hepatic fibrosis in mice. Oxidative stress in the liver has been demonstrated in murine model of arsenicosis causing hepatic fibrosis . The lack of progression to portal hypertension in mice exposed to arsenic for prolonged periods suggests that arsenic exposure alone is not sufficient to produce NCIPH in mice .
Vitamin B12 deficiency is common in general population of India . Low serum vitamin B12 may be due to subclinical malabsorption (like tropical enteropathy), genetic variations or low intake (vegetarianism),,,. Low serum vitamin B12 level in patients with unexplained portal hypertension is a marker of NCIPH . Low serum vitamin B12 predicts lack of advanced hepatic fibrosis in patients with intrahepatic portal hypertension . Whether vitamin B12 deficiency (and consequent hyperhomocysteinemia) has a pathogenic role in causing portal venous obliteration in NCIPH is unclear at present. In a study from West Bengal, the degree of arsenic contamination of drinking water correlated with low serum vitamin B12 levels in the population consuming this water . Whether B12 deficiency predisposes to NCIPH in areas with endemic arsenicosis in India needs further study.
[Table 2] summarizes the findings of various case-control and observational studies regarding the prevalence of potential environmental factors in patients with NCIPH in India.
|Table 2: Analysis of potential environmental factors causing non-cirrhotic intrahepatic portal hypertension (NCIPH) in case-control (where the control was cirrhosis)/observation studies from India|
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| Mechanistic Pathway|| |
Platelet sequestration occurs in spleen and liver in healthy individuals as well as in syndromes of splenomegaly ,. Platelet sequestration onto endothelium is one mechanism of thrombocytopenia in patients with portal hypertension. Marked, at times symptomatic, thrombocytopenia is a characteristic feature of NCIPH. Platelet sequestration onto the activated endothelium in portal vein branches in the liver is postulated as a pathogenic mechanism of NCIPH .
Plasma vWF levels are raised (reflecting endothelial activation) in NCIPH patients. Release of pro-inflammatory cytokines in response to the chronic inflammatory stimulus from the intestine can activate the endothelium to release vWF into portal circulation ,. It is likely that chronic low-grade inflammatory stimuli released from the gut trigger vWF expression on portal venous endothelium, with potential to promote platelet sequestration and occlusion of portal vein radicles causing NCIPH. ADAMTS13 is a vWF-cleaving protease synthesized almost exclusively by hepatic stellate cells. In advancing cirrhosis, as liver synthetic functions decrease, the plasma levels of ADAMTS13 also decrease. In a study of 142 hepatitis C-infected patients, mean plasma ADAMTS13 levels were 87, 79, 63 and 31 per cent in chronic hepatitis, cirrhosis in Child's A, B and C classes, respectively. Severe ADAMTS13 deficiency was seen in five patients in Child's C cirrhosis . In contrast, two studies of NCIPH patients from Birmingham, UK  and at Vellore, India have documentedsevere ADAMTS13 deficiency in 10 to 28 per cent despite most patients having well-preserved liver functions. This suggests that ADAMTS13 deficiency may be a primary event and involved in pathogenesis of NCIPH; in contrast to being a secondary phenomenon due to reduced liver synthetic function in advanced cirrhosis because of hepatitis C. The association of ADAMTS13 deficiency in NCIPH patients is being increasingly recognized .
| Genetic Predisposition to NCIPH|| |
Prevalence of familial NCIPH
There have been isolated reports of NCIPH occurring in childhood and families suggesting a possible role of genetic predisposition ,,,,,,. In a retrospective analysis of prospectively collected database of 174 NCIPH patients (age at presentation: 32±12 yr) at our centre, only three patients had another 1st degree family member having a chronic liver disease . In a large Western study on natural history of NCIPH, none of the 69 patients reportedly had a family history of liver disease . Thus, familial NCIPH appears to be uncommon.
Genetic alterations in NCIPH
Multiple studies have attempted to explore the role of genetic influence in pathogenesis of NCIPH. Whole exome sequencing in familial NCIPH revealed potential pathogenic mutations needing further studies ,. Studies have attempted to analyze possible genetic influences such as immunogenetic (major histocompatibility complex), thrombophilic and metabolic (especially drug susceptibility) in pathogenesis of NCIPH ,,,,,. Except for in isolated families affected by NCIPH, there are not enough data at present to suggest a monogenic cause in majority of these patients.
Genetic predisposition to microangiopathy
NCIPH may be considered as a localized form of thrombotic microangiopathy affecting the small portal vein radicles as there is evidence of low ADAMTS13,,, and alternative complement system activation ,, being involved in its pathogenesis. In addition, low ADAMTS13 is associated with enhanced complement activation, especially in alternative pathway . Both mutations in ADAMTS13 and the complement regulators are known to predispose to thrombotic microangiopathy ,,,.
A rare non-synonymous variant in ADAMTS13 gene (CUB domain, rs2301612) was detected in a single patient with NCIPH (absent in 20 healthy controls) in a study at our centre, which was associated with ADAMTS13 protein trapping inside the hepatic stellate cells and also decrease in functional activity . East Asians have been shown to harbour polymorphisms that lead to decrease in ADAMTS13 activity, which can make the population vulnerable to develop thrombotic microangiopathy in the presence of a second insult .
There is evidence to suggest complement activation (primary or secondary), especially alternative complement pathway may play a role in pathogenesis of NCIPH . Thrombotic microangiopathy is known to be associated with mutations in alternative complement pathway . These mutations render the alternative complement system hyperactive with loss of natural suppression. In a recent case-control study on 21 patients with NCIPH (compared with healthy controls), we found no significant association with a single nucleotide polymorphism at rs6677604 (polymorphism associated with decrease in complement factor H and known to predispose to thrombotic microangiopathy).
| Is the Epidemiology of Nciph Changing in India?|| |
Decline in incidence of NCIPH has been reported from some centres in India ,. However, multiple reports in the past decade corroborate the fact that NCIPH remains prevalent in India ,,,,,. NCIPH mimics cryptogenic cirrhosis . As discussed earlier, NCIPH is currently underdiagnosed in India.
| Causes of NCIPH in Different Parts of the World|| |
The factors triggering NCIPH are diverse . In the West, haematological and malignant thrombophilic disorders are often associated with NCIPH ,. Association of NCIPH with certain drugs (most commonly azathioprine and some anti-retroviral drugs) have often been reported ,,,. Such association have not been reported from India, but widespread use of herbal products needs to be considered . In India, gut derived environmental factors are probably the predominant triggers of NCIPH at present.
| Future Directions|| |
The available evidence showed that deleterious environmental factors, entering the portal venous system through the gut, could promote endothelial-platelet interaction leading to occlusion of intrahepatic portal vein radicles in NCIPH. While it is likely that all socio-economic categories in India are exposed to these environmental factors, the impact may be more prominent in the lower socio-economic categories. Urgent public health measures to improve hygiene and sanitation are needed to reduce incidence of NCIPH. Governmental initiatives such as Swatch Bharat Mission or Clean India Mission , National Mission for Clean Ganga , Task Force to reduce Arsenicosis  as well as community-led initiatives  in this regard are likely to contribute to reduction of NCIPH in India, in the days to come.
Financial support & sponsorship: Authors acknowledge funds received from the Science and Engineering Research Board, Government of India (EMR/2015/000570) and Fluid research funds, Christian Medical College, Vellore, India, towards conduct of these studies into non-cirrhotic portal hypertension.
Conflicts of Interest: None.
| References|| |
Basu AK, Boyer J, Bhattacharya R, Mallik KC, Sen Gupta KP. Non-cirrhotic portal fibrosis with portal hypertension: A new syndrome. I. Clinical and function studies and results of operations. Indian J Med Res
Mallik KC, Sen Gupta KP, Basu AK, Biswas SK, Pal NC, Boyer J, et al.
Non-cirrhotic portal fibrosis with portal hypertension: A new syndrome. II. Histopathological studies. Indian J Med Res
Nakanuma Y, Hoso M, Sasaki M, Terada T, Katayanagi K, Nonomura A, et al.
Histopathology of the liver in non-cirrhotic portal hypertension of unknown aetiology. Histopathology
Sherlock S, Feldman CA, Moran B, Scheuer PJ. Partial nodular transformation of the liver with portal hypertension. Am J Med
Goel A, Elias JE, Eapen CE, Ramakrishna B, Elias E. Idiopathic non-cirrhotic intrahepatic portal hypertension (NCIPH)-newer insights into pathogenesis and emerging newer treatment options. J Clin Exp Hepatol
Ramakrishna BS. Noncirrhotic intrahepatic portal hypertension: Towards a unifying definition and etiology. Indian J Gastroenterol
Nayak NC, Ramalingaswami V. Obliterative portal venopathy of the liver. Associated with so-called idiopathic portal hypertension or tropical splenomegaly. Arch Pathol
Tandon BN, Lakshminarayanan R, Bhargava S, Nayak NC, Sama SK. Ultrastructure of the liver in non-cirrhotic portal fibrosis with portal hypertension. Gut
Sama SK, Bhargava S, Nath NG, Talwar JR, Nayak NC, Tandon BN, et al.
Noncirrhotic portal fibrosis. Am J Med
Datta DV, Mitra SK, Chhuttani PN, Chakravarti RN. Chronic oral arsenic intoxication as a possible aetiological factor in idiopathic portal hypertension (non-cirrhotic portal fibrosis) in India. Gut
Sarin SK, Sethi KK, Nanda R. Measurement and correlation of wedged hepatic, intrahepatic, intrasplenic and intravariceal pressures in patients with cirrhosis of liver and non-cirrhotic portal fibrosis. Gut
Sharma BC, Singh RP, Chawla YK, Narasimhan KL, Rao KL, Mitra SK, et al.
Effect of shunt surgery on spleen size, portal pressure and oesophageal varices in patients with non-cirrhotic portal hypertension. J Gastroenterol Hepatol
Ganguly S, Dasgupta J, Das AS, Biswas K, Mazumder DN. Study of portal hypertension in children with special reference to sclerotherapy. Trop Gastroenterol
Poddar U, Thapa BR, Puri P, Girish CS, Vaiphei K, Vasishta RK, et al.
Non-cirrhotic portal fibrosis in children. Indian J Gastroenterol
Dhiman RK, Chawla Y, Vasishta RK, Kakkar N, Dilawari JB, Trehan MS, et al.
Non-cirrhotic portal fibrosis (idiopathic portal hypertension): Experience with 151 patients and a review of the literature. J Gastroenterol Hepatol
Okuda K. Non-cirrhotic portal hypertension: Why is it so common in India? J Gastroenterol Hepatol
Mackie I, Eapen CE, Neil D, Lawrie AS, Chitolie A, Shaw JC, et al.
Idiopathic noncirrhotic intrahepatic portal hypertension is associated with sustained ADAMTS13 deficiency. Dig Dis Sci
Goel A, Alagammai PL, Nair SC, Mackie I, Ramakrishna B, Muliyil J, et al.
ADAMTS13 deficiency, despite well-compensated liver functions in patients with noncirrhotic portal hypertension. Indian J Gastroenterol
Chelliah ST, Keshava SN, Moses V, Surendrababu NR, Zachariah UG, Eapen C, et al.
Measurement of hepatic venous pressure gradient revisited: Catheter wedge vs. balloon wedge techniques. Indian J Radiol Imaging
Goel A, Madhu K, Zachariah U, Sajith KG, Ramachandran J, Ramakrishna B, et al.
A study of aetiology of portal hypertension in adults (including the elderly) at a tertiary centre in Southern India. Indian J Med Res
Sood V, Lal BB, Khanna R, Rawat D, Bihari C, Alam S, et al.
Noncirrhotic portal fibrosis in pediatric population. J Pediatr Gastroenterol Nutr
Rajalingam R, Javed A, Sharma D, Sakhuja P, Singh S, Nag HH, et al.
Management of hypersplenism in non-cirrhotic portal hypertension: A surgical series. Hepatobiliary Pancreat Dis Int
Sinha A, Samanta T, Mallik S, Pal D, Ganguly S. Non-cirrhotic portal fibrosis among children admitted in a tertiary care hospital of Kolkata: A search for possible aetiologies. J Indian Med Assoc
Bhargava DK, Dasarathy S, Sundaram KR, Ahuja RK. Efficacy of endoscopic sclerotherapy on long-term management of oesophageal varices: A comparative study of results in patients with cirrhosis of the liver, non-cirrhotic portal fibrosis (NCPF) and extrahepatic portal venous obstruction (EHO). J Gastroenterol Hepatol
Poddar U, Thapa BR, Rao KL, Singh K. Etiological spectrum of esophageal varices due to portal hypertension in Indian children: Is it different from the west? J Gastroenterol Hepatol
Simon EG, Joseph AJ, George B, Zachariah UG, Jeyamani R, Eapen CE, et al.
Aetiology of paediatric portal hypertension - experience of a tertiary care centre in South India. Trop Doct
Madhu K, Avinash B, Ramakrishna B, Eapen CE, Shyamkumar NK, Zachariah U, et al.
Idiopathic non-cirrhotic intrahepatic portal hypertension: Common cause of cryptogenic intrahepatic portal hypertension in a Southern Indian tertiary hospital. Indian J Gastroenterol
Nayak NC, Jain D, Vasdev N, Gulwani H, Saigal S, Soin A, et al.
Etiologic types of end-stage chronic liver disease in adults: Analysis of prevalence and their temporal changes from a study on native liver explants. Eur J Gastroenterol Hepatol
Goel A, Ramakrishna B, Zacharaiah U, Sajith KG, Chandy G, Kurian G, et al
. Prognosticating after variceal bleed in cryptogenic cirrhosis: Non cirrhotic portal hypertension can be a confounder. J Hepatol
Levison DA, Kingham JG, Dawson AM, Stansfeld AG. Slow cirrhosis – Or no cirrhosis? A lesion causing benign intrahepatic portal hypertension. J Pathol
Saigal S, Nayak NC, Jain D, Kumaran V, Mohanka R, Saraf N, et al.
Non-cirrhotic portal fibrosis related end stage liver disease in adults: Evaluation from a study on living donor liver transplant recipients. Hepatol Int
Sarin SK, Khanna R. Non-cirrhotic portal hypertension. Clin Liver Dis
Kosek M, Guerrant RL, Kang G, Bhutta Z, Yori PP, Gratz J, et al.
Assessment of environmental enteropathy in the MAL-ED cohort study: Theoretical and analytic framework. Clin Infect Dis
(Suppl 4) : S239-47.
Omanwar S, Rizvi MR, Kathayat R, Sharma BK, Pandey GK, Alam MA, et al.
A rabbit model of non-cirrhotic portal hypertension by repeated injections of E. coli
through indwelling cannulation of the gastrosplenic vein. Hepatobiliary Pancreat Dis Int
Eapen CE, Nightingale P, Hubscher SG, Lane PJ, Plant T, Velissaris D, et al.
Non-cirrhotic intrahepatic portal hypertension: Associated gut diseases and prognostic factors. Dig Dis Sci
Austin A, Campbell E, Lane P, Elias E. Nodular regenerative hyperplasia of the liver and coeliac disease: Potential role of IgA anticardiolipin antibody. Gut
Dash SC, Bhuyan UN, Dinda AK, Saxena S, Agarwal SK, Tiwari SC, et al.
Increased incidence of glomerulonephritis following spleno-renal shunt surgery in non-cirrhotic portal fibrosis. Kidney Int
Mathan VI. Tropical sprue in Southern India. Trans R Soc Trop Med Hyg
Ramakrishna BS, Venkataraman S, Mukhopadhya A. Tropical malabsorption. Postgrad Med J
Dutta AK, Balekuduru A, Chacko A. Spectrum of malabsorption in India – Tropical sprue is still the leader. J Assoc Physicians India
Ghoshal UC, Srivastava D, Verma A, Ghoshal U. Tropical sprue in 2014: The new face of an old disease. Curr Gastroenterol Rep
Pipaliya N, Ingle M, Rathi C, Poddar P, Pandav N, Sawant P, et al.
Spectrum of chronic small bowel diarrhea with malabsorption in Indian subcontinent: Is the trend really changing? Intest Res
Baker SJ, Mathan VI. Tropical enteropathy and tropical sprue. Am J Clin Nutr
Baker SJ, Mathan M, Mathan VI, Jesudoss S, Swaminathan SP. Chronic enterocyte infection with coronavirus. One possible cause of the syndrome of tropical sprue? Dig Dis Sci
Mathan VI, Ponniah J, Mathan M. Tropical enteropathy: An adaptation of the small intestine to accelerated cell loss in “contaminated” environments. In: Robinson JWL, Dowling RH, Riecken EO, editors. Mechanisms of intestinal adaptation
. Lancaster: MTP Press; 1982. p. 609-10.
Ghoshal UC, Ghoshal U, Ayyagari A, Ranjan P, Krishnani N, Misra A, et al.
Tropical sprue is associated with contamination of small bowel with aerobic bacteria and reversible prolongation of orocecal transit time. J Gastroenterol Hepatol
Ghoshal UC, Baba CS, Ghoshal U, Alexander G, Misra A, Saraswat VA, et al.
Low-grade small intestinal bacterial overgrowth is common in patients with non-alcoholic steatohepatitis on quantitative jejunal aspirate culture. Indian J Gastroenterol
Ramakrishna BS, Makharia GK, Chetri K, Dutta S, Mathur P, Ahuja V, et al.
Prevalence of adult celiac disease in India: Regional variations and associations. Am J Gastroenterol
Sharma BC, Bhasin DK, Nada R. Association of celiac disease with non-cirrhotic portal fibrosis. J Gastroenterol Hepatol
Maiwall R, Goel A, Pulimood AB, Babji S, Sophia J, Prasad C, et al.
Investigation into celiac disease in Indian patients with portal hypertension. Indian J Gastroenterol
Berendes D, Leon J, Kirby A, Clennon J, Raj S, Yakubu H, et al.
Household sanitation is associated with lower risk of bacterial and protozoal enteric infections, but not viral infections and diarrhoea, in a cohort study in a low-income urban neighbourhood in Vellore, India. Trop Med Int Health
Morris JS, Schmid M, Newman S, Scheuer PJ, Sherlock S. Arsenic and noncirrhotic portal hypertension. Gastroenterology
Santra A, Das Gupta J, De BK, Roy B, Guha Mazumder DN. Hepatic manifestations in chronic arsenic toxicity. Indian J Gastroenterol
Mazumder DN, Das Gupta J, Santra A, Pal A, Ghose A, Sarkar S, et al.
Chronic arsenic toxicity in West Bengal – The worst calamity in the world. J Indian Med Assoc
: 4-7, 18.
Guha Mazumder D, Dasgupta UB. Chronic arsenic toxicity: Studies in West Bengal, India. Kaohsiung J Med Sci
Rahman MM, Chowdhury UK, Mukherjee SC, Mondal BK, Paul K, Lodh D, et al.
Chronic arsenic toxicity in Bangladesh and West Bengal, India – A review and commentary. J Toxicol Clin Toxicol
Mazumder DN. Effect of drinking arsenic contaminated water in children. Indian Pediatr
Chakraborti D, Singh SK, Rahman MM, Dutta RN, Mukherjee SC, Pati S, et al.
Groundwater arsenic contamination in the Ganga river basin: A future health danger. Int J Environ Res Public Health
. pii: E180.
Chakraborti D, Rahman MM, Ahamed S, Dutta RN, Pati S, Mukherjee SC, et al.
Arsenic groundwater contamination and its health effects in Patna district (capital of Bihar) in the Middle Ganga plain, India. Chemosphere
Ahamed S, Kumar Sengupta M, Mukherjee A, Amir Hossain M, Das B, Nayak B, et al.
Arsenic groundwater contamination and its health effects in the state of Uttar Pradesh (UP) in upper and middle Ganga plain, India: A severe danger. Sci Total Environ
Chakraborti D, Das B, Rahman MM, Nayak B, Pal A, Sengupta MK, et al.
Arsenic in groundwater of the Kolkata municipal corporation (KMC), India: Critical review and modes of mitigation. Chemosphere
Goel A, Christudoss P, George R, Ramakrishna B, Amirtharaj GJ, Keshava SN, et al.
Arsenicosis, possibly from contaminated groundwater, associated with noncirrhotic intrahepatic portal hypertension. Indian J Gastroenterol
Guha Mazumder DN, De BK, Santra A, Ghosh N, Das S, Lahiri S, et al.
Randomized placebo-controlled trial of 2,3-dimercapto-1-propanesulfonate (DMPS) in therapy of chronic arsenicosis due to drinking arsenic-contaminated water. J Toxicol Clin Toxicol
Lalwani S, Dogra TD, Bhardwaj DN, Sharma RK, Murty OP. Study on arsenic level in public water supply of Delhi using hydride generator accessory coupled with atomic absorption spectrophotometer. Indian J Clin Biochem
Avasthi A, Basu D, Subodh BN, Gupta PK, Malhotra N, Rani P, et al.
Pattern and prevalence of substance use and dependence in the union territory of Chandigarh: Results of a rapid assessment survey. Indian J Psychiatry
Khandpur S, Malhotra AK, Bhatia V, Gupta S, Sharma VK, Mishra R, et al.
Chronic arsenic toxicity from ayurvedic medicines. Int J Dermatol
Philips CA, Paramaguru R, Joy AK, Antony KL, Augustine P. Clinical outcomes, histopathological patterns, and chemical analysis of ayurveda and herbal medicine associated with severe liver injury-A single-center experience from Southern India. Indian J Gastroenterol
Santra A, Maiti A, Das S, Lahiri S, Charkaborty SK, Mazumder DN, et al.
Hepatic damage caused by chronic arsenic toxicity in experimental animals. J Toxicol Clin Toxicol
Sarin SK, Sharma G, Banerjee S, Kathayat R, Malhotra V. Hepatic fibrogenesis using chronic arsenic ingestion: Studies in a murine model. Indian J Exp Biol
Gupta Bansal P, Singh Toteja G, Bhatia N, Kishore Vikram N, Siddhu A, Kumar Garg A, et al.
Deficiencies of serum ferritin and Vitamin B12, but not folate, are common in adolescent girls residing in a slum in Delhi. Int J Vitam Nutr Res
Nongmaithem SS, Joglekar CV, Krishnaveni GV, Sahariah SA, Ahmad M, Ramachandran S, et al.
GWAS identifies population-specific new regulatory variants in FUT6 associated with plasma B12 concentrations in Indians. Hum Mol Genet
Sivaprasad M, Shalini T, Balakrishna N, Sudarshan M, Lopamudra P, Suryanarayana P, et al.
Status of Vitamin B12 and folate among the urban adult population in South India. Ann Nutr Metab
Goel A, Ramakrishna B, Muliyil J, Madhu K, Sajith KG, Zachariah U, et al.
Use of serum Vitamin B12 level as a marker to differentiate idiopathic noncirrhotic intrahepatic portal hypertension from cryptogenic cirrhosis. Dig Dis Sci
Goel A, Ramakrishna B, Job V, Zachariah U, Eapen CE. Vitamin B12 deficiency in patients with unexplained portal hypertension indicates absence of severe liver fibrosis. J Clin Gastroenterol
Mukherjee AK, Manna SK, Roy SK, Chakraborty M, Das S, Naskar JP, et al.
Plasma-aminothiols status and inverse correlation of total homocysteine with B-vitamins in arsenic exposed population of West Bengal, India. J Environ Sci Health A Tox Hazard Subst Environ Eng
Heyns AD, Lötter MG, Badenhorst PN, van Reenen OR, Pieters H, Minnaar PC, et al.
Kinetics, distribution and sites of destruction of 111indium-labelled human platelets. Br J Haematol
Hill-Zobel RL, McCandless B, Kang SA, Chikkappa G, Tsan MF. Organ distribution and fate of human platelets: Studies of asplenic and splenomegalic patients. Am J Hematol
Manavalan JS, Hernandez L, Shah JG, Konikkara J, Naiyer AJ, Lee AR, et al.
Serum cytokine elevations in celiac disease: Association with disease presentation. Hum Immunol
Bernardo A, Ball C, Nolasco L, Moake JF, Dong JF. Effects of inflammatory cytokines on the release and cleavage of the endothelial cell-derived ultralarge von willebrand factor multimers under flow. Blood
Uemura M, Fujimura Y, Matsumoto M, Ishizashi H, Kato S, Matsuyama T, et al.
Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis. Thromb Haemost
Raszeja-Wyszomirska J, Wasilewicz M, Andrzejewska A, Dudek K, Figiel W, Urasińska E, et al.
Orthotopic liver transplantation (OLTx) in non-cirrhotic portal hypertension secondary to ADAMTS13 deficiency. Prz Gastroenterol
Yilmaz G, Sari S, Egritas O, Dalgic B, Akyol G. Hepatoportal sclerosis in childhood: Some presenting with cholestatic features (a re-evaluation of 12 children). Pediatr Dev Pathol
Albuquerque A, Cardoso H, Lopes J, Cipriano A, Carneiro F, Macedo G, et al.
Familial occurrence of nodular regenerative hyperplasia of the liver. Am J Gastroenterol
Barnett JL, Appelman HD, Moseley RH. A familial form of incomplete septal cirrhosis. Gastroenterology
Sarin SK, Mehra NK, Agarwal A, Malhotra V, Anand BS, Taneja V, et al.
Familial aggregation in noncirrhotic portal fibrosis: A report of four families. Am J Gastroenterol
Dumortier J, Boillot O, Chevallier M, Berger F, Potier P, Valette PJ, et al.
Familial occurrence of nodular regenerative hyperplasia of the liver: A report on three families. Gut
Majumdar A, Delatycki MB, Crowley P, Lokan J, Tharian B, Angus PW, et al.
An autosomal dominant form of non-cirrhotic portal hypertension. J Hepatol
Franchi-Abella S, Fabre M, Mselati E, De Marsillac ME, Bayari M, Pariente D, et al.
Obliterative portal venopathy: A study of 48 children. J Pediatr
Schouten JN, Nevens F, Hansen B, Laleman W, van den Born M, Komuta M, et al.
Idiopathic noncirrhotic portal hypertension is associated with poor survival: Results of a long-term cohort study. Aliment Pharmacol Ther
Vilarinho S, Sari S, Yilmaz G, Stiegler AL, Boggon TJ, Jain D, et al.
Recurrent recessive mutation in deoxyguanosine kinase causes idiopathic noncirrhotic portal hypertension. Hepatology
Koot BG, Alders M, Verheij J, Beuers U, Cobben JM. A de novo
mutation in KCNN3 associated with autosomal dominant idiopathic non-cirrhotic portal hypertension. J Hepatol
Vispo E, Cevik M, Rockstroh JK, Barreiro P, Nelson M, Scourfield A, et al.
Genetic determinants of idiopathic noncirrhotic portal hypertension in HIV-infected patients. Clin Infect Dis
Błogowski W, Marlicz W, Smereczyński A, Lawniczak M, Lewosiuk A, Starzyńska T, et al.
Nodular regenerative liver hyperplasia as a complication of azathioprine-containing immunosuppressive treatment for Crohn's disease. Immunopharmacol Immunotoxicol
Bayan K, Tüzün Y, Yilmaz S, Canoruc N, Dursun M. Analysis of inherited thrombophilic mutations and natural anticoagulant deficiency in patients with idiopathic portal hypertension. J Thromb Thrombolysis
Buchel O, Roskams T, Van Damme B, Nevens F, Pirenne J, Fevery J, et al.
Nodular regenerative hyperplasia, portal vein thrombosis, and avascular hip necrosis due to hyperhomocysteinaemia. Gut
Ishii M, Katada Y. Idiopathic portal hypertension in a systemic sclerosis patient heterozygous for factor V Leiden mutation. Rheumatol Int
Taneja V, Mehra NK, Sarin SK, Sharma BK, Vaidya MC. Possible HLA influence in governing susceptibility to non-cirrhotic portal fibrosis. Tissue Antigens
Potter BJ, Elias E, Fayers PM, Jones EA. Profiles of serum complement in patients with hepatobiliary diseases. Digestion
Sarin SK, Nayyar AK, Malhotra P, Sharma BK, Kumar R, Broor SL, et al.
Immunological profile of patients with non-cirrhotic portal fibrosis. J Gastroenterol Hepatol
Bettoni S, Galbusera M, Gastoldi S, Donadelli R, Tentori C, Spartà G, et al.
Interaction between multimeric von Willebrand factor and complement: A fresh look to the pathophysiology of microvascular thrombosis. J Immunol
Levy GG, Nichols WC, Lian EC, Foroud T, McClintick JN, McGee BM, et al.
Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature
Vieira-Martins P, El Sissy C, Bordereau P, Gruber A, Rosain J, Fremeaux-Bacchi V, et al.
Defining the genetics of thrombotic microangiopathies. Transfus Apher Sci
Phillips EH, Westwood JP, Brocklebank V, Wong EK, Tellez JO, Marchbank KJ, et al.
The role of ADAMTS-13 activity and complement mutational analysis in differentiating acute thrombotic microangiopathies. J Thromb Haemost
Tseng SC, Kimchi-Sarfaty C. SNPs in ADAMTS13. Pharmacogenomics
Goel A, Raghupathy V, Amirtharaj GJ, Chapla A, Venkatraman A, Ramakrishna B, et al.
ADAMTS13 missense variants associated with defective activity and secretion of ADAMTS13 in a patient with non-cirrhotic portal hypertension. Indian J Gastroenterol
Akiyama M, Nakayama D, Takeda S, Kokame K, Takagi J, Miyata T, et al.
Crystal structure and enzymatic activity of an ADAMTS-13 mutant with the East Asian-specific P475S polymorphism. J Thromb Haemost
Noris M, Bucchioni S, Galbusera M, Donadelli R, Bresin E, Castelletti F, et al.
Complement factor H mutation in familial thrombotic thrombocytopenic purpura with ADAMTS13 deficiency and renal involvement. J Am Soc Nephrol
Saravanan S, Bharadwaj T, Goel A, Balasubramanian AL, Ramachandran A, Jude J, et al
. Analysis of single nucleotide polymorphism at rs6677604 in patients with non-cirrhotic intrahepatic portal hypertension. J Clin Exp Hepatol
Sarin SK, Kumar A, Chawla YK, Baijal SS, Dhiman RK, Jafri W, et al.
Noncirrhotic portal fibrosis/idiopathic portal hypertension: APASL recommendations for diagnosis and treatment. Hepatol Int
Chawla Y, Duseja A. Non-cirrhotic portal fibrosis (NCPF) is a vanishing disease in India. Trop Gastroenterol
Goel A, Ramakrishna B, Madhu K, Zachariah U, Ramachandran J, Keshava SN, et al.
Idiopathic noncirrhotic intrahepatic portal hypertension is an ongoing problem in India. Hepatology
Madhu K, Ramakrishna B, Zachariah U, Eapen CE, Kurian G. Non-cirrhotic intrahepatic portal hypertension. Gut
Khanna R, Sarin SK. Non-cirrhotic portal hypertension - diagnosis and management. J Hepatol
Hillaire S, Bonte E, Denninger MH, Casadevall N, Cadranel JF, Lebrec D, et al.
Idiopathic non-cirrhotic intrahepatic portal hypertension in the west: A re-evaluation in 28 patients. Gut
Ghabril M, Vuppalanchi R. Drug-induced nodular regenerative hyperplasia. Semin Liver Dis
Logan S, Rodger A, Maynard-Smith L, O'Beirne J, Fernandez T, Ferro F, et al.
Prevalence of significant liver disease in human immunodeficiency virus-infected patients exposed to didanosine: A cross sectional study. World J Hepatol
Rios FF, Rodrigues de Freitas LA, Codes L, Santos Junior GO, Schinoni MI, Paraná R, et al.
Hepatoportal sclerosis related to the use of herbals and nutritional supplements. Causality or coincidence? Ann Hepatol
Mission or Clean India Mission, Ministry of Drinking water and sanitation, Government of India. Available from: http://www.sbm.gov.in/sbm/
, accessed on June 10, 2017.
National Mission for Clean Ganga, Ministry of Water Resources, River Development and Ganga Rejuvenation, Government of India. Available from: http://www.nmcg.nic.in/
, accessed on June 10, 2017.
[Table 1], [Table 2]