Hyperreactive malarial syndrome with noncirrhotic portal hypertension

Patients from tropical areas where malaria is endemic sometimes present with massive splenomagaly, that is usually known as tropical splenomegaly syndrome after ruling out other possible causes of splenomegaly. At present this condition is defined as hyperreactive malarial syndrome (HMS). One of the rarest and unique complication of HMS is prehepatic type of portal hypertension/ noncirrhotic portal hypertension. We report a case of HMS with prehepatic portal hypertension.

Keywords: Hyperreactive malarial Syndrome, malaria, noncirrhotic portal hypertension, splenomegaly

Several reports have been published over the last century describing patients from tropical areas with massive splenomegaly. This condition is a well-known entity of tropical splenomegaly syndrome, ^[1],[2] which later was defined as a separate entity called hyperreactive malarial syndrome (HMS) using clear diagnostic criteria. ^[3],[4] Although the exact mechanism is uncertain, evidence suggests that exposure to malaria elicits exaggerated stimulation of polyclonal B lymphocytes, leading to excessive and partially uncontrolled production of immunoglobulin M (IgM) as the initiating event. ^[5] IgM is polyclonal and is not specific for any particular malarial species.

Defective immunoregulatory control of B lymphocytes by suppressor or cytotoxic T lymphocytes causes the increase in B lymphocytes, although the mechanism by which malarial parasitemia drives these changes is unclear. ^[6] T-cell infiltration of the hepatic and splenic sinusoids accompanies this process. Serum cryoglobulin and autoantibody levels increase, as does the presence of high molecular weight immune complexes. The result is anaemia, deposition of large immune complexes in Kupffer cells in the liver and spleen, reticuloendothelial cell hyperplasia, and hepatosplenomegaly. Genetic factors, pregnancy, and malnutrition may play a role in the etiology of HMS.

A 32 year old female presented to us with chief complaints of distension of abdomen since the last 4 years. There was no history of pain in the abdomen, hematemesis, malena, hematochezia, constipation or vomiting. She had a positive history of intermittent fever episode lasting for 6 to 7 days two to four times a year, weakness and fatigue. General examination was otherwise insignificant apart from pallor. Vital signs were normal. Abdominal examination revealed a massive splenomegaly, which was grade 3 crossing the umbilicus measuring around 13 cms below the left costal margin. It was soft- to- firm in consistency and non tender. Liver was also palpable 4 cms below right the costal margin. It was firm and non tender. There was no free fluid. Other system examinations were normal.

On investigation, we observed Hb-5gm%, Total Leucocyte Count, -1,700/mm ³ , Differential Leucocyte Count, -polymorphs 66%, lymphocytes 30%, eosinophils 3%, monocytes 1%. Absolute platelet count was 90,000/mm ³ . On peripheral smear, Red Bloood Cell’s were normocytic and normochromic, there were few target cells. Peripheral Smear was negative for malaria parasites. Coagulation profile was normal. Reticulocyte count was 1.8%. Direct Coombs test was negative. Bone marrow was hypercellular with a normal myeloid to erythroid ratio. Serum LDH was slightly raised. Haemoglobin electrophoresis showed “AA pattern”. Ultrasonography of the abdomen was done which revealed a slightly enlarged liver with normal echo texture, portal vein dilated measuring 18mm, splenic vein was dilated and tortuous measuring 14cms. There was a massive spleen measuring 22.5cms. Splenorenal collaterals were noted and there was no free fluid in the abdomen. There was no evidence of any thrombus or compression of any intra-abdominal vessel. All of these features were suggestive of noncirrhotic portal hypertension. Upper GI endoscopy revealed grade 1 oesophageal varices. There was no evidence of rectal varices on proctoscopy. Computed Tomography scan of abdomen revealed dilated splenic and portal veins with massive splenomegaly [Figure 1] and [Figure 2]. After ruling out all other causes of a massive splenomegaly,a possibility of hyperreactive malarial splenomegaly was suspected because this area is malaria endemic. A quantitative assay of serum Ig M was done which was very high (398 mg/dl) in our patient (normal reference range 52-156 mg/dl). Malarial antibodies could not be detected.

Figure 2: CT scan of abdomen showing massive splenomegaly with a dilated splenic vein. Click here to view

Treatment was started with tablet chloroquine 150mg base two tablets per week with an advice to continue the regimen for at least for 1 year. Tablet propranolol 40mg was started as a prophylactic for portal hypertension. The patient was called for follow up after 2 months and was advised for a repeat upper gastrointestinal endoscopy after 6 months.

HMS occurs only in people who have resided in or who have visited areas where malaria is endemic. Accurate assessment of the incidence of HMS is difficult because many conditions that cause splenomegaly are prevalent in areas where malaria is endemic. These conditions include hemoglobinopathies, leukemias, lymphomas, hepatic cirrhosis, leishmaniasis, typhoid, and tuberculosis. The most common presenting symptoms of HMS, or tropical splenomegaly syndrome, are chronic abdominal swelling (64%) and pain (52%) that usually waxes and wanes. Most patients report weight loss but rarely patients report intermittent fever. Anemia, leucopenia and thrombocytopenia usually are associated because of hypersplenism like in this case. Decreased immunity causes susceptibility to infections which predominantly affects the respiratory system. Splenomegaly is the hallmark. Hepatomegaly is also a common accompaniment. In a study of 69 Nigerian patients, 93% had accompanying hepatomegaly. ^[2]

Portal hypertension is one of the rare complications of HMS. It occurs with the absence of cirrhosis. Classically two factors are chiefly responsible for portal hypertension. Firstly, there is a considerable increase in liver blood flow which in turn leads to increase intrasplenic pressure and wedged hepatic venous pressures (WHVP). Secondly, there is an increase in presinusoidal resistance in addition to increase hepatic blood flow. The increase in liver blood flow is because of increase in intrasplenic blood flow. But as the spleen size goes on increasing, there is a compensatory slowing of flow in the spleen. Pathologically the splenic sinusoids and pulp are infiltrated with lymphocytes. ^[7] Another factor that increases the liver blood flow is anaemia in these patients. Liver blood flow has been shown to be increase when haemoglobin level falls below 7 gm%.

The portal hypertension is usually prehepatic type but there is no evidence of any thrombosis or fibrosis as usually seen in conditions like schistosomiasis, Hodgkins disease, myeloproliferative disorders. Splenic venography reveals a widely dilated portal vein and its primary branches without any obstruction, but the peripheral branches are usually narrow suggesting that probably this is the site of increase resistance. The cause of this narrowing is postulated to be because of reflex vasoconstriction due to increased hepatic and portal blood flow. ^[7]

Our case presented with massive splenomegaly and hypersplenism. Investigations suggested portal hypertension with a normal liver echotexture. Post hepatic causes of portal hypertension has been ruled out as there were no cardiac abnormalities and clinical examination and USG abdomen/CT abdomen did not show features of IVC obstruction/thrombosis or possibility of  Budd-Chiari syndrome ^{More Details} (massive ascites and large, tender hepatomegaly). As far as intrahepatic causes are concerned, USG ruled out the most common cause that is cirrhosis of liver or congenital hepatic fibrosis. Schistosomiasis is not common in our country. It typically causes periportal fibrosis which was not documented. Myeloproliferative and lymphoproliferative disorders should always be considered in such cases as a cause of prehepatic portal hypertension. Hemogram in our patient suggested pancytopenia which could be explained by a massive spleen causing increase destruction of all cell lines, peripheral smear examination did not reveal any malignant blasts or any features of myelodysplasia, all the more bone marrow examination in this case did not suggest a possibility of haematological malignancy or a lymphoid malignancy. A normal haemoglobin electrophoresis ruled out hemoglobinopathy. Conditions causing non cirrhotic portal fibrosis (idiopathic phlebosclerosis,splenic vein sclerosis/thrombosis, portal vein sclerosis/thrombosis) is ruled out by USG and CT scan of abdomen which only shows dilatation of the veins without any obstruction. HMS was a diagnosis of exclusion in our case and there were some points which supported the same. The case satisfied some important criteria like, she belonged to malaria endemic zone, she had a history of episodes of intermittent fever over two to three years,she had massive splenomegaly with hypersplenism, serum Ig M was increased which is one of the important criteria of HMS. Although malarial antibodies could not be detected, it is not a mandatory criteria for the diagnosis. ^[8] Thus HMS was probably the cause of portal hypertension in our case. Classically, the spleen regresses to more than 40% of its initial size within 6 months of malaria chemotherapy and the anaemia also improves along with physical well being of the patient. The specific drug of choice is based on the pattern and prevalence of drug resistance in the patient’s geographic area. In endemic areas, treatment should be prolonged and continued regularly. Months may pass before a response is observed, and relapses may occur when therapy is discontinued. Chloroquine and proguanil appear to be equally effective. Eradication of parasitemia is the common pathway for therapeutic responses. Pyrimethamine may be an alternative. Data regarding the usefulness of other antimalarial drugs in HMS are limited.

Proguanil 200 mg daily or chloroquine 300mg base once a week are usually given for a prolong period, at least for 1-year and rarely may be required to give lifelong in some cases with frequent relapses after a good response. Splenectomy always carries a risk of serious infections and is usually best avoided. The only indication being incapacitating abdominal pain or discomfort. Presence of oesophageal varices always suggest high presinusoidal and intrasplenic resistance and should be treated appropriately.

HMS should be suspected in any patient presenting with massive splenomegaly in an area endemic for malaria. After ruling out other common causes, specific tests to diagnose the condition should be sent. Although rare, portal hypertension should be sought for and prophylaxis to prevent variceal bleeding should be initiated along with malarial chemotherapy. Splenectomy has least role in management of HMS in modern medicine.

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1755-6783.77194

[Figure 1], [Figure 2]