Some non-infective diseases endemic in the West Indies

The West Indies is one of the most diverse archipelagos in the world. Into the numerous islands, with varying features of geography and natural history, have poured Europeans, Africans, Indians and small numbers of other ethnic groups, almost completely displacing the original Amerindian inhabitants. They have brought with them characteristic cultures and customs which, although to some extent blended and modified have, however, retained their identity. Such diversity affords exceptional opportunities for studies of disease in relation to geography and to racial origins, studies which can throw light on many aetiological problems (AU)

The effects of fulvine on human and rat mitotic chromosomes

With increasing interest in mutagenicity an array of agents such as chemicals and drugs are being defined as chromosome damaging agents. The activities of these agents were reviewed. An intensive investigation of the mutagenic potential of fulvine was undertaken for three reasons. 1. Fulvine is still widely consumed in Jamaica as a herbal remedy which causes a well defined pathological condition - veno - occlusive disease of the liver (VOD). 2. Fulvine was found to cause chromosome damage in previous screening experiments. 3. Fulvine is a member of the pyrrolizidine group of alkaloids which are known to have mutagenic effects. The mutagenic activities were investigated by in vivo studies in children who have recovered from VOD and experimentally in rats. Serial examination of 3 members of a family recently recovered showed a decline of the percentage of cells with damage to normal over a five month period. No abnormalities were detected in 7 recovered children. Fulvine was administered to rats at varying dosages of 0.08 mg/gm, 0.04 mg/gm, 0.02 mg/gm, 0.01 mg/gm, and repeated administrations of 0.04 mg/gm body weight. Chromosomal abnormalities were produced which included gaps, breaks, bivalent and quadriradial configurations, ring chromosomes, dicentrics, abnormal metacentrics and submetacentrics, chromatic exchanges. Tetraploidy was rarely detected. The abnormalities were comparable in type to those seen in human VOD. At all dosages exchanges predominated over other types of abnormalities. Abnormalities were induced within 48 hours after fulvine administration at a threshold dosage of 0.02 mg/gm. Mitotic inhibition and liver damage were more marked in 12 weanling rats treated with doses of 0.08 mg/gm body weight of fulvine. The model for investigation of fulvine as a mutagenic agent was evaluated (AU)

An ultrastructural study of the liver in experimental veno-occlusive disease - abstract

Fulvine, a toxic constituent of the herb Crotolaria fulva, has been incriminated as the causative factor of veno-occlusive disease of the liver (V.O.D.), which is endemic in Jamaica. In an attempt to elucidate further the pathogenesis of the disease, hepatic veno-occlusive lesions were induced in Wistar rats following treatment with fulvine (5-20 mg/kg body weight). The livers of these animals were examined with an electron-microscope 24, 48 or 72 hours later, using standard techniques. Rough endoplasmic reticulum was reduced 24 hours following treatment and the channel system disrupted into a system of vesticles. After 48 hours, smooth endoplasmic reticulum showed considerable increase and displayed progressive dilation and balooning. Mitochondrial changes (swelling, decrease of the internal matrix density and loss of cristae) were detected. Liver cells revealed degenerative cytoplasm and damaged cell membranes. Sinusoidal walls appeared intermittently naked, and swollen microvilli projected into dilated perisinusoidal spaces. The alterations became pronounced 72 hours after treatment. Fulvine caused a decrease in the number of mitochondria, further disorganization of mitochondrial structure, and conspicuous nuclear changes. The sinusoids, lined by swollen endothelial cells and necrotic hepatocytes, appeared distended with erythrocytes. Following breakdown of the space of Disse, the hepatocytes were usually obsreved to be in direct contact with blood. These early ultrastructural findings in the pathogenesis of V.O.D. support our previously reported histo-chemical observations of differences in hepatic enzymatic activities and is indicative of primary hepatocellular damages. The venovascular damage. The venovascular changes represent, in our opinion, a more advanced stage in the pathogenesis of the disease, and as such there is no primary veno-occlussive process (AU)

Early sequential hepatic changes in fulvine treated rats

The purpose of this experiment was to study the early structural and functional hepatic changes occurring in rats treated with a standardized dose of fulvine by gastric intubation. Histologic observationas and biochemical determinants were done at 1, 3, 6, 9, 18 and 32 hours after treatment. The results indicated that fulvine induced a wide spectrum of hepatic lesions that were detected as early as one hour after its administration. Some of the earliest lesions, such as the deterioration of hepatocytic endoplasmic reticulum and of the nuclei, progressed with time and suggested that the hepatocytes, rather than the vascular structures were the primary site of attack. Although single hepatocytic necrosis was detected at 3 hours and was only observed at the latest period (32 hours). This zonal necrosis was preceded by a prominent and progressive hepatocytic swelling in periportal and centrolobular areas and by increasing accumulation of cell debris and blood elements in the sinusoids. While fulvine or its metabolities appears to exert a direct necrotizing effect on the hepatocytes, the microcirculatory changes observed in our previous studies and suggested by the ultrastructural findings in the present one, may offer an explanation for the preferential location of the lesions that precede the occlusion of the terminal hepatic venules. (AU)

Histochemistry of the liver in experimentally induced veno-occlusive disease - abstract

Ingestion of the herb Crotolaria fulva in the form of a bush tea is believe to cause veno-occlusive disease of the liver. The mechanism by which the herb exerts its deleterious effects is poorly understood. The present histochemical investigation was undertaken inorder to correlate biochemical distrubances with liver lesions. Extensive haemorrhagic necrosis and veno-vascular changes were induced in rat liver after intragastric administration of fulvine, the toxic alkaloidal constituent of Crotolaria fulva. Glycogen loss was marked in all regions of the liver lobule. Lipid droplets were seen widely distributed in the parenchymal cells. The activity of cytochrome oxidase and succinate dehydrogenase was decreased: The activity of glutamate dehydrogenase was increased. The activity of glucose-6-phosphatase was moderately increased in the peripheral zone of the lobule, but comparatively weaker in the central region. The activity of acid phosphatase and non-specific esterase showed a moderate increase in all experiments. Alkaline phosphatase gave a comparatively stronger reaction. The activity of ATP'ase was moderately reduced. These differences in hepatic enzyme activities suggest functional impairment of the cell membrane, mitochondria, lysosomes and endoplasmatic reticulum of the liver cells. It might be postulated that the cells of the liver parenchyma are primarily damaged in veno-occlusive disease of the liver (AU)

A clinical follow-up and further observations on veno-occlusive disease of the liver - abstract

A study has been made of 82 Jamaican patients suffering from veno-occlusive disease of the liver (V.O.D.). Seventy-three have been followed up for periods from 6 months to 5 years. The clinical picture is described and an attempt is made to outline the clinical natural history. In addition to previous reports of the syndrome from Jamaica, three cases have been reported recently from Barbados. The prognosis, incidence, morbidity and mortality of the condition have been considered. The aetiology is unknown; but it does not appear to be primarily or entirely nutritional. The possibility that V.O.D. is produced by the action of plant toxins with special reference to "bush teas" which are widely used in Jamaica is considered. The three cases from Barbados were all associated with the use of Crotalaria retusa, a known hepato-toxin in animals; and Senecio, another outstanding herbal hepato-toxin, is commonly used in Jamaica. The histological features will be presented by Dr. Bras (AU)

Familial and recurrent veno-occlusive disease of liver in Jamaican children (abstract only)

The case histories of four children in a family of seven are presented. The eldest of the four, a girl, presented in 1961 at age 4 1/2 years with evidence of liver disease and portal hypertension. A liver biopsy was not performed. This child died in 1964 of hepatorenal failure and unfortunately permission for autopsy was refused. The second affected child, a boy, presented at age 2 years with hepatosplenomegaly and jaundice and a needle biopsy of his liver revealed a histological picture consistent with post V.O.D. cirrhosis. He has remained fairly well since, although signs of cirrhosis persist. In June 1966 two female siblings age 1 year and 2 years respectively, presented at the same time with acute abdominal swelling. Liver biopsies confirmed the clinical diagnosis of acute V.O.D. and their subsequent progress is briefly reviewed. The case history of a boy who has had two proven episodes of acute V.O.D. is presented. This child was first admitted in January 1958 at age 1 year and five months, with acute abdominal swelling. A liver biopsy revealed histological evidence of acute V.O.D. His clinical condition settled and repeat biopsy in March 1958 showed no residual liver disease. He remained well after this until he had an episode of obstructive jaundice in 1960 which subsided spontaneously. In 1965 he was readmitted with a history of acute abdominal swelling and after two months during which time his ascites gradually subsided, a liver biopsy was performed and this showed subacute V.O.D. A final biopsy was done in September 1966 and this showed only minimal increase of fibrous tissue. A brief note on the aetiology of V.O.D. is submitted(AU)

Portal hypertension in veno-occlusive disease of the liver (abstract only)

Veno-occlusive disease of the liver is the commonest cause of cirrhosis of the liver in Jamaican children and accounts for 30 per cent of all cirrhosis at all ages. The first 100 documented cases of veno-occlusive disease at the University College of the West Indies, Jamaica, have been studied. Sixteen per cent died in the acute phase, 23 per cent made a complete clinical recovery, 17 per cent passed into the chronic phase and then died of their disease. 17 per cent defaulted to follow up, 27 per cent passed into the chronic phase with cirrhosis of the liver and are being followed, in some instances for over five years. Seventeen patients have died of oesophageal haemorrhage, 5 during the acute phase of veno-occlusive disease and 12 during the chronic phase. The majority succumbed during the first bleeding episode. In an attempt to salvage patients who develop portal hypertension, portal-caval shunts have been created during the past three years. There have been 6 such patients, all children. There was no operative mortality and all of these patients have done very well clinically since operation and have been followed regularly. Certain unusual details of the clinical picture and of the pathology as noted at operation are presented. The disease has now been produced in dogs and details of experimentral work using Crotalaria extract are presented. It is suggested that with better public health education this disease will become a rarity but that it has provided us with a valuable research tool for experimental production of cirrhosis in laboratory animals (AU)

Veno-occlusive disease of the liver: surgical aspects

Veno-occlusive disease of the liver is a recently established disease entity. Its etiology, pathology, and symptomatology, and natural history are discussed on the basis of 99 cases of this disease so far authenticated at the University College of the West Indies. In the surgical literature the disease is added to the list of causes of intra-hepatic portal hypertension, and the cases of 4 patients are presented in detail in whom portacaval anastomoses were performed for the decompression of esophageal varices. The surgical implications of this disease have been stated and some of the difficulties enountered in the treatment of portal hypertension in infants and children outlined (Summary)

Some disease associated with protein malnutrition, as seen in Jamaica

Three diseases which occur in Jamaica, akee poisoning, veno-occlusive disease, and kwashiorkor are described. It is thought that previous protein malnutrition is necessary for these disease to appear (AU)

Experimental crotalaria in calves (abstract only)

During the past years experiments have been conducted in order to reproduce in animals Veno-Occlusive disease of the liver. Toxic damage to the liver has been observed when infusions of various plants were given to a variety of experimental animals. However, feeding of Crotalaria fulva to cows produced changes in the liver with occlusion of the hepatic veins closely similar to human Veno-Occlusive (AU)

Further clinical and investigative uses of liver biopsy: an analysis of five hundred and twenty-seven biopsies

Five hundred twenty-seven biopsies have been performed on 330 patients. The conditions studied included kwashiorkor, marasmus, veno-occlusive disease of the liver, vomiting sickness, diabetes mellitus, various neuropathies, nephrosis, sickle-cell anemia, and unexplained hepatomegaly, splenomegaly, jaundice, pyrexia, and anemia. A clinical outline has been given of veno-occlusive disease, kwashiorkor, marasmus, and the vomiting sickness of Jamaica. The tissue obtained at biopsy was examined histologically in all cases. In a number of cases chemical examination of the liver tissue was also performed. The chemical studies included nucleic acids and protein, water and fat content, and glycogen estimations. In them malnutrition group it is shown (a) that the degree of fatty infiltration is no indication of the severity or probable outcome of the disease, (b) that hepatic protein depletion is severe in these infants but that its degree cannot be quantitatively correlated with the clinical picture or prognosis, (c) that fatty infiltration does not apparently interfere with the ability of the liver to store glycogen. Occlusion of the smaller and medium-sized branches of the hepatic veins is responsible for the hepatomegaly and ascites found clinically in veno-occlusive disease. The prognosis of veno-occlusive disease is linked with the severity of the associated hepatocellular damage. Serial biopsies have made it possible to define more accurately the clinical natural history of this disease. In cases that recover the histological appearances of the liver return to normal. When the disease advances to the chronic stage, a progressive nonportal cirrhosis is found to develop in biopsy specimens. The histological changes in liver in diabetes are minimal and cannot be correlated with the response to treatment, clinical hepatomegaly, or alteration of liver-function tests. The hypoglycemia of vomiting sickness is associated with severe depletion of hepatic glycogen, which is rapidly restored by successful glucose therapy. There is a high incidence of fibrosis of the liver in patients with sickle-cell anemia, and a possible etiological relationship is suggested. Because of the frequently mixed nature of hepatic cirrhosis in the tropics and the variability of the clinical syndromes presented, liver biopsy is a useful and often essential tool for establishing a correct diagnosis. Its uses in unexplained hepatomegaly, jaundice, and splenomegaly have also been demonstrated. It is also pointed out that liver biopsy often makes it necessary to alter an apparently firmly established clinical diagnosis. The advantages of simultaneous histopathological and chemical examination of portions of the tissue obtained at biopsy have been stressed (SUMMARY)

Veno-occlusive disease of the liver and Indian childhood cirrhosis

Cirrhosis of the liver is common in children in parts of India, especially in West Bengal and Madras, and in the West Indian island of Jamaica, where it usually occurs as a late result of 'veno-occlusive disease of the liver'. The literature concerning veno-occlusive disease is reviewed, with especial reference to its possible relation to the ingestion of plant toxins of certain 'bush teas', particularly species of Crotalaria and Senecio. The clinical and pathological features of 15 cases of Indian childhood cirrhosis (I.C.C) seen in Calcutta, West Bengal, are presented, analysed and compared with accounts in the literature. A two-stage clinical classification is suggested: (1) stage of hapatomegaly, (2) stage of clinical cirrhosis. The socio-economic background of the present cases is compared with reports by previous workers. The clinical picture and morbid anatomy of veno-occlusive disease and I.C.C., as judged by the literature and the present cases, are compared and contrasted. While some cases are clinically similar, the absence in I.C.C. of the acute episode that occurs in some children with veno-occlusive disease is stressed. Hepatic venous occlusion was found in all six of the 15 children who were liver biopsied or who came to necropsy. This histological feature has been noted by some other investigators, although more workers have stressed the presence of parenchymal damage. It is noted that, in both experimental animals and in veterinary medicine, it has been shown that certain plant toxins may sometimes act on liver cells and sometimes on the hepatic veins. The possibility of a similarly varied response in children is suggested (Summary)

Plants as aetiological factor in veno-occlusive disease of the liver

It is postulated, on the evidence of experiments with Carotalaria fulva on cattle in Jamaica, that herbal infusions made from carotalaria and taken by the Jamaican population for medicinal and other purposes constitute (one of) the aetiological factor(s) in veno-occlusive disease of the liver. It appears that a similar role is played by senecio (Summary)