A 14-year-old boy presenting with gradual abdominal distension and occasional abdominal pain for 2 years

Dr. Md. Nazmul Hassan (Resident): A 14-yearold boy, 4th issue of his non-consanguineous parents got admitted in the Department with the complaints of gradual abdominal distension and occasional abdominal pain since two years of his age. There was no history of jaundice, upper gastrointestinal bleeding, fever, contact with a known case of tuberculosis patient or family history of such type of illness. On examination, he was alert, anicteric, no facial dysmorphism, vitally stable, no stigmata of chronic liver disease and anthropometrically well thrived. On alimentary system examination, the abdomen was hugely distended, visible engorged vein (Figure 1), hepatomegaly (10 cm), spleen just palpable and huge ascites was present. Other systemic examination revealed no abnormality. Routine laboratory investigations showed hemoglobin was 11.4 g/dL; a total leucocyte count was 6,500 cells/mm3 and among, neutrophils were 44% and lymphocytes 49%. The erythrocyte sedimentation rate was 40 mm in 1st hour and platelet count was 136 × 109/mm3. The liver function tests showed serum albumin (41 g/L), prothrombin time (14.8 sec), international normalized ratio 1.25 and normal alanine aminotransferase level (9 U/L). Serum electrolyte and creatinine levels were also normal. The ascitic fluid examination showed total cell count of 160 cells/mm3 with 10% polymorph nuclear neutrophils and 90% lymphocytes. The biochemical examination showed the protein level was 5.5 g/dL and the sugar level was 5.3 g/dL. The adenosine deaminase level was normal. The serum ascites albumin gradient was high of 1.5 (>1.1). Endoscopy of the upper gastrointestinal tract revealed a developing varix (Figure 2A). Ultrasonography of the abdomen showed hepatosplenomegaly with huge ascites. Color doppler study showed a compressed middle hepatic vein due to enlarged caudate lobe (8.5 x 3.9 cm), loss of normal flow characteristics, hepato-fugal flow direction and features of mild portal hypertension but no thrombosis was found. Computer tomography venogram of the liver revealed portal vein was dilated, tortuous and produced varices along with the spleno-portal circulation (Figure 2B). Mantoux test and Chest X-ray were normal. Blood for inherited deficiency revealed a deficiency of protein S and antithrombin III but protein C was normal (Table I).

(14.8 sec), international normalized ratio 1. 25 and normal alanine aminotransferase level (9 U/L). Serum electrolyte and creatinine levels were also normal. The ascitic fluid examination showed total cell count of 160 cells/mm 3 with 10% polymorph nuclear neutrophils and 90% lymphocytes. The biochemical examination showed the protein level was 5.5 g/dL and the sugar level was 5.3 g/dL. The adenosine deaminase level was normal. The serum ascites albumin gradient was high of 1.5 (>1.1). Endoscopy of the upper gastrointestinal tract revealed a developing varix ( Figure 2A). Ultrasonography of the abdomen showed hepatosplenomegaly with huge ascites. Color doppler study showed a compressed middle hepatic vein due to enlarged caudate lobe (8.5 x 3.9 cm), loss of normal flow characteristics, hepato-fugal flow direction and features of mild portal hypertension but no thrombosis was found. Computer tomography venogram of the liver revealed portal vein was dilated, tortuous and produced varices along with the spleno-portal circulation ( Figure 2B). Mantoux test and Chest X-ray were normal. Blood for inherited deficiency revealed a deficiency of protein S and antithrombin III but protein C was normal (Table I).

Provisional Diagnosis
Budd-Chiari syndrome most probably due to inherited thrombophilia (deficiency of protein C, protein S and antithrombin III)

Differential Diagnosis
Dr. Mahmudul Hasan (Resident): As the patient was having a history of gradual abdominal distension and occasionally abdominal pain and on examination hepatosplenomegaly and ascites present, we differentially thought about chronic liver disease.
Dr. Kaniz Fathema (Resident): As Bangladesh is a highly endemic zone for tuberculosis and patient having gradual abdominal distension, occasional abdominal pain along with hepato-splenomegaly and ascites, so after evaluating the other features, it could be a case of abdominal tuberculosis.

Budd-Chiari syndrome
Dr. Hassan: Budd-Chiari syndrome is a rare heterogeneous disease characterized by obstruction of the hepatic venous outflow tract in the absence of constrictive pericarditis or right heart failure. It may be thrombotic or non-thrombotic anywhere along the venous course from the hepatic venules to the junction of the inferior vena cava with the right atrium. Hepatic veno-occlusive disease and cardiac disorders are not included in the definition. The classical Budd-Chiari syndrome is characterized clinically by a triad of ascites, hepatomegaly and right upper quadrant pain. It is an uncommon but important syndrome because of many disorders. It may be associated with several hematologic or malignant diseases. 1-3 In the late 1800s, the term Budd-Chiari was first named after a British inter-nist, George Budd, described three cases of hepatic vein thrombosis due to abscess-induced phlebitis and in 1899 Austrian pathologist Hans Chiari, added the first pathologic description of a liver with obliterating endophlebitis of the hepatic veins. 4 The prevalence of Budd-Chiari syndrome is 1/100,000 among the general population worldwide. 5 Compared to adults, it is very uncommon in children.
Most of the cases of classic Budd-Chiari syndrome occur between the ages of 20 and 39 years and only 5% were found be below 12 years of age. 6-8 The syndrome can be classified as: a) Primary (intraluminal obstruction by a thrombus or web) or b) secondary (extrinsic compression by an abscess, tumor, cyst, or hyperplastic nodules). 5, 8 Clinically, it can be presented as a) Acute-develops usually within 1 month or symptomatic for less than 6 months and characterized by intractable ascites, abdominal pain, liver enlargement, renal failure, elevation of hepatic enzymes and coagulopathy; 9 b) subacute-which is insidious onset. It may take as long as 3 months to become asymptomatic, usually having minimal/trace or no ascites but do not have esophageal bleeding; 10 c) chronic-disease duration of 6 or more months or signs of portal hypertension present. 11 For diagnostic evaluation of Budd-Chiari syndrome, the first step is the doppler ultrasonography of the hepatic vessels and inferior vena cava, which in 95% cases establish the diagnosis. In doppler ultrasonography, highly specific findings for Budd-Chiari syndrome are stenosis, thrombosis, fibrotic cord, or insufficient recanalization of the vessel in the hepatic or caval veins, along with caudate lobe hypertrophy. 12

Chronic liver disease
Dr. Mahmud: Chronic liver disease comprises both chronic hepatitis and cirrhosis. Cirrhosis is defined as a diffuse liver process where fibrosis has resulted in a conversion of the liver architecture into structurally abnormal nodules. 13 In children, a wide range of causes of hepatocellular injury present that include causes of cholestasis, infection, toxin, metabolic, vascular, and nutritional disorders that may result in cirrhosis of the liver. Irrespective of the cause of chronic injury, and in the absence of removal of the cause of injury, the cirrhotic state and many complications persist. 14 The diagnosis is based on the combination of clinical (stigmata of chronic liver disease), biochemical (liver function tests) and imaging findings. Unfortunately, available therapies for many chronic liver diseases causing cirrhosis in children are ineffective. The treatment is limited to the management of these secondary pathophysiological complications and liver transplantation is the only available definitive option when the liver failure established. 15

Abdominal tuberculosis
Dr. Fathema: Disseminated abdominal tuberculosis involves the gastrointestinal tract, peritoneum, lymph nodes and solid viscera. 16 In children, the number of extra-pulmonary tuberculosis cases is higher compared to pulmonary tuberculosis. 17 It is difficult to diagnose childhood tuberculosis because of non-specific clinical findings as well as low-quality of sampling, paucibacillary and lack of Mycobacterium culture facilities. 18 Tuberculous bacilli can spread into the abdomen and gastro-intestinal tract by the following route: a) hematogenous spread from the lung focus, b) ingestion of bacilli from the infected sputum, c) unpasturized cow's milk ingestion, and d) direct spread from adjacent infected structures. 19 Anorexia, malaise, low grade fever, weight loss and abdominal distension due to ascites are the non-specific symptoms of abdominal tuberculosis. Physical examinations may reveal cachexia, fever, lymphadenopathy, absent BCG mark, hepatomegaly, splenomegaly, ascites and features of intestinal obstruction.

Dr. Khondaker Mobasher (Resident):
After evaluating the patient's presenting features, physical findings as patient having no stigmata of chronic liver disease and the liver function tests showed serum albumin (41 g/L), prothrombin time (14.8 sec), normal alanine aminotransferase level (9 U/L) and ultrasonography of the abdomen showed hepatosplenomegaly and huge ascites but hepatic architecture was normal. So, chronic liver disease was excluded.
Our patient was presented with ascites and hepatosplenomgaly which are suggestive but no history of cow's milk ingestion, no contact history with tuberculosis patient, absence of growth failure and no lymphadenopathy go against the diagnosis of disse-minated abdominal tuberculosis. To reach the other differential (abdominal tuberculosis), we did complete blood count, ascitic fluid study, serum ascites albumin gradient, Monteux test and chest X-ray which were normal. So, abdominal tuberculosis was also excluded.

Prof. A. K. M. Fazlul Bari:
To establish our provisional diagnosis, we do the color doppler study of portal vein, hepatic veins and inferior vena cava which showed middle hepatic vein was compressed due to enlarged caudate lobe, loss of normal flow characteristics, hepatofugal flow direction along with caudate lobe hypertrophy and features of mild portal hypertension but no thrombosis was found.
Dr. Hassan: According to the color doppler study, we finally diagnosed it as a case of Budd-Chiari syndrome. To find out the cause as well as site of thrombosis, we do the computer tomography venogram of the liver revealed portal vein was dilated, tortuous and produces varices along with the splenoportal circulation. Blood for inherited deficiency revealed deficiency of protein S (60%) and antithrombin III (72%) but protein C (83%) was normal. We also did the endoscopy of upper gastrointestinal tract which revealed developing esophageal varices.

Dr. Hasan's Diagnosis
Chronic Budd-Chiari syndrome due to inherited thrombophilia (deficiency of protein S and antithrombin III)

Discussion
The child was treated with diuretics and therapeutic paracentesis. Presence of some condition like: a) Abrupt onset of ascites and painful hepatomegaly; b) massive ascites with relatively preserved liver functions; c) sinusoidal dilation in liver biopsy without heart disease; d) fulminant hepatic failure associated with hepatomegaly and ascites; e) unexplained chronic liver disease; and f) liver disease with thrombogenic disorder when present, Budd-Chiari syndrome should be suspected. 24 Our patient had massive ascites with preserved hepatic function.
The highly specific investigation for Budd-Chiari syndrome is doppler ultrasonography of hepatic vessels and inferior vena cava and it is the first step in evaluation to find out hepatic venous outflow obstruction. Stenosis, thrombosis, fibrotic cord or insufficient recanalization of the hepatic or caval vessel along with caudate lobe hypertrophy in doppler ultrasonography are highly specific for Budd-Chiari syndrome. 12 Caudate lobe hypertrophy usually causes extrinsic compression of the inferior vena cava but this finding is less common in children than the adult. 25 Other imaging findings include no flow signal and with spider-web appearance in hepatic veins, hepatic venous collateral circulation and stagnant, reversed or turbulent flow.
No visualization of hepatic veins or tortuosity is non-specific but most common sonographic findings of Budd-Chiari syndrome. 3 In our case color doppler study showed middle hepatic vein compressed due to enlarged caudate lobe, loss of normal flow characteristics, hepatofugal flow direction and features of mild portal hypertension indicating Budd-Chiari syndrome but no thrombosis in hepatic outflow was found.
Magnetic resonance imaging, computer tomography scan, magnetic resonance angiography, hepatic venography are other second-line imaging modalities which are required to find out any thrombosis and its exact location. Spider-web pattern on hepatic venography or presence of obstacle or its consequences, the collaterals to hepatic veins or inferior vena cava is diagnostic of Budd-Chiari syndrome. 3 In our patient, computer tomography scan of hepatic vessels revealed portal vein is dilated, tortuous and produces varices along with the spleno-portal circulation but no thrombosis was found. When these investigations failed to demonstrate the site of obstruction or any thrombosis then these patients need hepatic/inferior vena caval angiography for confirmation of hepatic venous/ inferior vena caval obstruction site or presence of thrombus. 26 In our case, we could not do hepatic/ inferior vena caval angiogram due to refusal of the patient party for financial constraint.
Serum bilirubin, aminotransferase levels, alkaline phosphatase and albumin should be done to see hepatic function. Histological findings by liver biopsy of Budd-Chiari syndrome are congestion, liver cell loss and fibrosis predominantly located in the centrilobular area. Liver biopsy is important in the differentiation of Budd-Chiari syndrome from veno-occlusive disease but not for a diagnosis. 27 Our patient had a normal liver function and thus we didn't do a liver biopsy.
For differentiation between Budd-Chiari syndrome and cardiac disorders like tricuspid regurgitation and constrictive pericarditis echocardiography is helpful. To find out the etiology of Budd-Chiari syndrome hemogram, evaluation of peripheral blood, determination of coagulation factors and inhibitors, genetic tests for factor Ⅴ and prothrombin mutation, determination of anti-phospholipid antibody, lupus anticoagulant and flow cytometry for paroxysmal nocturnal hemoglobinuria should be performed. For the diagnosis of primary myeloproliferative disorder and determination of total red cell mass bone marrow biopsy may be helpful. 27 Our patient had normal hemogram, echocardiography and we found a deficiency of protein S and antithrombin III. So, the patient is on hypercoagulable state due to inherited thrombophilia.
Dr. Hassan: The therapeutic algorithm for Budd-Chiari syndrome is supportive, medical management of complications, surgical management and liver transplantation. It depends on the chronicity and site of the obstruction, the degree of liver dysfunction in children. Medical, surgical and endovascular therapeutic are options for the treatment of this condition. Initial medical therapy is conservative emphasizing diuretics, therapeutic paracentesis, treatment of predisposing factors, control of portal hypertension and prophylactic anticoagulation to decrease the risk of additional thrombosis. 10,24 Inferior vena caval reconstruction with a pericardial patch, portosystemic shunts, mesoatrial shunts, portoatrial shunts, membrane resection and liver transplantation are the surgical options. Liver transplantation is an appropriate option in patients with long-standing obstruction, having evidence of severe portal hypertension or synthetic dysfunction. 1,28 Endovascular management options are stent placement, balloon angioplasty, catheter-directed thrombolysis, thrombus maceration and transjugular intrahepatic portosystemic shunt for of Budd-Chiari syndrome. 29 In our patient, we managed by giving diuretics and therapeutic paracentesis.
Dr. Mobasher: Important negative prognostic indicators include ascites, encephalopathy, elevated prothrombin time, and altered serum levels of sodium, creatinine, albumin, and bilirubin, cirrhosis and the presence of portal hypertension. 30 In our case, features of portal hypertension is developing so, the prognosis is guarded.
Dr. Ayesha Siddiqua (Resident): Why the prophylaxis of anticoagulant is not given?
Dr. Mazumder: As we don't find any thrombosis and as well as the patient had developing varices. 1 And the patient refuses to take warfarin prophylaxis due to its regular monitoring schedule. Dr. Sharmistha Ghosal (Resident): How will you differentiate acute from chronic Budd-Chiari syndrome clinically?
Dr. Md. Saidul Islam Sumon (Resident): Acute Budd-Chiari syndrome develops usually within 1 month or symptomatic for less than 6 months and chronic with disease duration of 6 or more months or signs of PHT present. 9 Dr. Rafiqul Islam (Resident): What are the common causes of Budd-Chiari syndrome?
Dr. Ahmadur Rahman (Resident): Common causes are inherited or acquired hypercoagulable state due to factor V Leiden and prothrombin mutation, deficiency of protein C, protein S and antithrombin-III. 1,
Dr. Nahid-E-Subha (Resident): It may help in the differentiation of Budd-Chiari syndrome from veno -occlusive disease but not for a diagnosis. Congestion, liver cell loss and fibrosis predominantly located in the centrilobular area are findings in liver biopsy. 27 Dr. Nazmul Ahmed (Resident): What are the prognostic factors in Budd-Chiari syndrome?
Dr. Ruhina Tasmeen (Resident): Bad prognostic indicators include ascites, encephalopathy, elevated prothrombin time, and altered serum levels of sodium, creatinine, albumin, and bilirubin, cirrhosis and the presence of portal hypertension. 30

Follow-up
The patient was improved clinically and biochemically after 3 months of treatment and then further treatment continues accordingly.

Final Diagnosis
Chronic Budd-Chiari syndrome due to inherited thrombophilia (deficiency of protein S and antithrombin III)