Case Reports

Indian Pediatrics 2002; 39:491-494

Veno-Occlusive Disease of Liver:A Case Series from Eastern Rajasthan

From the Department of Pediatric Medicine, Sir Padampat Mother and Child Health Institute, S.M.S. Medical College, Jaipur, India.

Correspondence to: Dr. S.P. Choudhary, C-62, Lal Kothi Scheme, Tonk Road, Jaipur, Rajasthan 302 015, India.

E-mail: [email protected]

Manuscript received: May 17, 2001;

Initial review completed: June 21, 2001;

Revision accepted: October 12, 2001.

Veno-occlusive disease of the liver (VOD) is a well-recognized form of toxic liver injury, produced by pyrrolizidine alkaloid and other toxic substances. Cases have been reported from Jamaica, where consumption of Crotolaria and Senecio plants in the form of "bush tea" was found to be responsible(1,2). A large epidemic of the disease in Afghanistan was caused due to consumption of seeds of Heliotropium plants(3). It has been reported from other parts of the world(4,5). In India, epidemics of VOD of liver have been reported from Sarguja district in Madhya Pradesh in 1973 and 1975(6). We are reporting five cases of this disease in a family from a village of Rajasthan, India.

Five children from a single family were admitted in Pediatric Ward of S.M.S. Medical College Hospital, with complaints of pain abdomen, vomiting, poor appetite and gradually increasing distension of abdomen for two to three weeks. Three children were male (aged 4,7 and 10 years) and two were female (aged 12 and 17 years). The ten years-old male child also had decreased urinary output, low-grade pyrexia, irrelevant talk and drowsiness for four days. There was no history of jaundice or transfusion of blood or blood products in the past in all patients. The family was eating Bajra and wheat grown in their farmland. There was no history of similar disease pattern in other residents of village or nearby area.

Clinical features of all cases are summarized in Table I. Pain abdomen, poor appetite and vomiting were present in all the five cases. Hepatomegaly was also present in all the five cases. Liver was non-tender, firm in consistency, with smooth surface and sharp margins. Two other siblings (one 6 month old male and another 19 year old female) and the parents were normal.

Investigations revealed severe anemia, (Hb 6.4 g/dl) in Case 1 and moderate anemia (Hb 9-10.9 g/dl) in other cases. Serum transaminase (60-574 unit/dl), prothrombin time (16-21 sec) and serum alkaline phosphatase (98.5-488 KA unit/dl) were raised in all cases. Bilirubin levels were increased in Cases 3 and 4 (3.4 and 4.4 mg/dl, respectively). Hypoalbuminemia and abnormal albumin: globulin ratio (1 : 1 to 1.2 : 1) was observed in all cases. Abdominal ultrasonography showed hepatomegaly, splenomegaly, patent hepatic veins without any sign of obstruction, bright echotexture of liver in all cases and right pleural effusion in Case 3. Total leukocyte count, differential leukocyte count, ESR, blood level of urea and creatinine, sugar and electrolytes were within normal limits. Australia antigen and anti-HCV antibody were negative in all five cases. Ascitic fluid from case 3 was transudate (protein 104 mg/dl with less than 5 cells/mm3) and was sterile on culture. Liver biopsy in Case 1 showed ballooning degeneration of hepatocytes with congestion of sinusoids and focal hemorrhagic areas. There was peri-sinusiodal condensation of reticulin. Portal areas were normal. In other cases. liver biopsy was refused by the parents.

After 20 days of hospitalization, all cases except Case 3, were stable, showing signs of improvement and discharged. Case 3 showed progressive increase in abdominal distension, jaundice, decreased urinary output and was taken away from the hospital against medical advice.

Cases did not turn up for follow-up. After about 12 months, follow up was done by one of the authors. On follow up visit, all cases except Case 3 and Case 4 were found to be alive and healthy, without any clinical sign of liver cell failure. The father also suffered from similar illness about one month after and remained ill for about 20 days. He recovered after conservative treatment at a local hospital. Case 3 had expired after 5 days of leaving the hospital. Case 4 had expired after about one month due to progression of illness. The father and all surving cases refused further investigations.

Hepatic VOD is a progressive and concentric, non-thrombotic obliteration of small intra-hepatic veins by loose connective tissue with necrosis of hepatocytes in centri-lobular areas(7). False negative results of liver biopsy are found in large number of patients, in whom the diagnosis of VOD of liver is considered; therefore, clinical diagnosis is more important(8).

Clinical features of VOD of liver have been subdivided into three clinical stages: (i) Acute stage: Hepatomegaly developing suddenly in five to ten days with ascites; (ii) Sub-acute stage: Firm hepatomegaly with or without ascites may occur spontaneously or after acute stage. It may subside clinically or may pass into the chronic stage; and (iii) Chronic stage: This is the stage of cirrhosis(2,4,9).

Clinical diagnosis of VOD of liver may be established if two or more of the following are present within 2-5 months of exposure to the offending agent(7): (i) Jaundice; (ii) Hepatomegaly and/or right upper quadrant pain; and (iii) Ascites or unexplained weight gain.

In all five cases, hepatomegaly and ascites were present. In two cases, jaundice was also present. Liver function tests were deranged in all, showing hepatocellular damage. Liver biopsy report was also in favour of VOD of liver.

Hepatotoxic pyrrolizidine alkaloids have been found in plants belonging to unrelated botanical families including Crotolaria (San-hemp) family, Leguminacae family, Heliotropium (Hatisura - Family Boragi-nacae), Senecio (family Compositae). San-hemp is a tall, stiff herb of rainy season with strong fibres and is used for forming ropes. Its seeds are small, dark colored and may be confused with bajra. San-hemp is grown in the village for it’s subsequent use. The unsaturated pyrrolizidine alkaloids are toxic because they are dehydrogenated by the liver micro- somes. The pyrollic derivates are reactive compounds that damage hepatocyte DNA and proteins(10).

Clinical features and investigations of all five children suggest subacute or chronic liver disease. Similar disease pattern in all five cases and involvement of five out of seven children of one family, simultaneously strongly suggests toxic liver injury. Common causes of subacute or chronic liver disease such as Budd Chiari Syndrome, infective hepatitis, chronic hepatitis B and C, extra-hepatic biliary atresia (EHBA), atuoimmune hepatitis, Wilson’s disease and other metabolic diseases were not suggested by history, examination or relevant investigation. Budd Chiari Syndrome was ruled out by visualization of patent hepatic veins and absence of any evidence of obstruction in hepatic veins in all five cases on abdominal Ultrasonography(11). There was no history of exposure to blood or blood products in any of these cases and viral markers were also absent. Absence of jaundice in neonatal age was against the possibility of EHBA. Absence of Kayser-Fleishcher ring and neurological features in older children was against Wilson’s disease. Normal neurological development, absence of splenomegaly, cataract and cherry red macula along with absence of history of recurrent vomiting and convulsions were against the possibility of other metabolic liver diseases. There was no history of ingestion of allopathic, Ayurvedic or other forms of drugs.

Clinical features of our patients, that is, epigastric pain, followed by tender hepatomegaly and rapidly developing ascites with mild icterus and simultaneous occurrence in a group of subjects of a locality are characteristic of VOD of the liver. One should have a high index of suspicion for VOD of liver in cases of rapidly developing ascites with tender hepatomegaly.

Contributors: RKG and SPC worked up cases, conceived and designed the paper; SPC critically revised the manuscript for important intellectual content; she will act as guarantor for the paper. RKG and NKS contributed to literature search and drafting.

Funding: None.

Competing interests: None stated.

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