•
Liver Imaging in the Diagnosis of Hepatic Venous Thrombosis in Paroxysmal Nocturnal Hemoglobinuria 1
•
Nuclear Medicine
Edward V. Staab, M.D.,2 Robert C. Hartman, M.D.,3 and James A. Parrott, M.D. 4
Eleven patients with paroxysmal nocturnal hemoglobinuria were studied by serial liver imaging. Thisdisease has a generalized thrombotic tendency, and progressive diffusehepatic venous thrombosis has been emphasized in recent studies. Radionuclide imaging proved to be of great help in establishing the diagnosis of hepatic venous thrombosis and following the progress of the disease process. Abnormal patterns in hepatic venous occlusion include (a) enlargement of the liver (especially the right lobe), (b) extrahepatic localization of radionuclide, and (c) areas of decreased uptake in the distribution of the involved veins. These findings develop rapidly and are very characteristic in the clinical setting. TERMS: Hemoglobinuria • Liver, blood supply. Liver, diseases. Liver, radionuclide studies. Veins, hepatic
INDEX
•
Radiology 117:341-348, November 1975
•
AROXYSMAL nocturnal hemoglobinuria (PNH) is a rare acquired hemolytic anemia characterized by chronic intravascular hemolysis with frequent bouts of gross hemoglobinuria. Despite a high frequency of thrombocytopenia, spontaneous bleeding is unusual; rather, a generalized thrombotic tendency has been clearly recognized as a major complication and cause of death in PNH (1, 2). Although isolated cases of progressive, diffuse hepatic venous thrombosis (HVT) have long been reported in PNH, only recently have attempts been made to define this entity at a clinical level (3). With improvement in the management of PNH in general, HVT may represent the most common cause of death (3, 4). In 1967, Clain et al. reported abnormal liver images showing diminished or no uptake in the right hepatic lobe in 5 patients with hepatic vein occlusion in conditions other than PNH (5). There have also been brief comments on abnormal images in HVT (6,7). During the past 5 years we have performed liver studies on 11 PNH patients, of whom HVT developed in 4.
duced red blood cell acetylcholinesterase and leukocyte alkaline phosphatase, hemoglobinemia, and hemosiderinuria. Most patients showed persistent or at least transient pancytopenia. Five patients died prior to 1967; since they were not studied by radionuclide imaging, they were eliminated from the present study. These included 1 patient (CASE 1) with "liver failure," 2 (CASES 6 and 11) with hepatic venous thrombosis, 1 (CASE 9) with acute leukemia, and 1 (CASE 7) with basilar artery thrombosis and HVT. Serial views of the liver were obtained from all survivors at approximately 6-month intervals beginning in 1967, following the finding of striking changes in one patient with HVT (CASE 4) which correlated well with subsequent autopsy findings. Five of these 11 patients died, and autopsy was performed on 4. In 3, HVT was the cause of death, while in the fourth (CASE 8) sagittal sinus thrombosis was the primary cause of death, though HVT was pronounced. Three patients (CASES 4, 8, and 13) showed HVT clinically as well as at autopsy; one (CASE 16) had HVT on clinical examination, but autopsy was not performed. The patient in CASE 3 died of cerebral hemorrhage secondary to anticoagulant therapy and did not have HVT. Method: Sulfur colloid labeled with 1.5-3.0 mCi of technetium (99mTc) was used in all studies (10). Images were obtained with either an Ohio Nuclear Model 84 rectilinear scanner with a D collimator or a Searle Pho Gamma III Anger camera with a low-energy straightbore collimator. Roentgenologic and hematologic studies were carried out using standard methods.
P
MATERIALS AND METHODS
PNH Clinical Material: Sixteen patients with PNH have undergone long-term intensive study at the Vanderbilt MedicaJ Center during the past 16 years (3, 4, 8, 9); the case numbers used here correspond to those in the previous publications. The diagnosis of PNH was firmly established in all cases by serologic tests (acid and sucrose hemolysis, thrombin, and "heat" tests), re-
1 Fromthe Department of Radiology (Division of Nuclear Medicine) andthe Department of Medicine (Division of Hematology), Vanderbilt University Medical School and Hospital, Nashville, Tenn. Accepted for publication in February 1975. Supported in part by research grantsHL03509, AM 05129, RR-95, and FR 05424 from the USPHS. 2 Present address: Department of Radiology, Division of Nuclear Medicine, University of NorthCarolina Schoolof Medicine, Chapel Hill, N. C. 27514. 3 Present address: Sectionof Hematology/Oncology, Veterans Administration Hospital (111), 13000N. 30th st., Tampa, Fla. 33620. 4 Present address: Jenny Stewart Hospital, Hopkinsville, Ky. sjh
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Abdominal pain, headaches, peculiar skin lesions Ankle ulcer, inferior vena cava occlusion, papilledema, diplopia, right sixth nerve palsy, abdominal pain, peculiar skin lesions, terminal pulmonary embolism
Abdominal pain, thrombophlebitis of the legs Headaches, abdorninal pain Thrombophlebitis of the legs; suspected pulmonary, splenic, and intestinal infarction, episodic headaches, suspected HVT, peptic ulcer Abdominal pain, headaches
Headaches, abdominal pain, thrombophlebitis, suspected pulmonary infarction
Abdominal pain Abdominal pain, cramps and thrombophlebitis of the legs, possible infarct on EKG "Hemorrhagic bullae!" on the leg, duodenal deformity, pulmonary infarction, abdominal pain Headaches, thrornbophlebitis, abdominal pain
Clinical Features Compatible with Thrombosis
6
3
5
10
6
2
3
5
1
8 5
Abnormal
Normal
Normal
Abnormal
Normal
Abnormal
Normal
Normal
Abnormal
Abnormal Normal
rRadionuciide Images, "No. of Studies Result
Venous angiogram showed an obstructed inferior vena cava; CO 2 study showed HVT; excretory urography showed cortica I defects; marked renal siderosis, small bowel edema, gallstones
Cortical detects on excretory urography; gallstones
Venous angiogram showed HVT; colonic edema on barium enema study
.. .
Gallstones (?)
Duodenal ulcer; cortical defects on excretory urography Sagittal sinus thrombosis
/enous angiogram showed HVT; esophageal varices, nonvisualized gall bladder
Bilateral subdural hematomas
Roentgenography
No autopsy
Hemachromatosis on liver biopsy
Liver weighed 3,300 g; old and recent thrombi in the hepatic veins; diffuse necrosis of the liver; laminated white thrombus of the inferior vena cava; old myocardial infarct; fresh pulmonary embolus
.. .
...
Liver weighed 2,200 g; thrornbosis of small and medium hepatic veins; old and recent hemorrhagic necrosis; diffuse cortical and sagittal sinus venous thrombosis; cerebral infarction
Liver weighed 1,600 g; old and recent hepatic venous thrombosis; hemorrhagic necrosis and fibrosis; focal areas of regeneration
Bilateral subdural hematomas with pressure effect: liver weighed 1,750 g; no thrombosls: peculiar heart lesions
Major Findings at Autopsy
Liver Scan Data Correlated with Pertinent Clinical, Pathological, and Roentgenographic Findings in Patients with PNH
*These patients also had hepatic vein thrombosis. __ _ _ __ __ _ __ _ _ tNo gross hemoglobinuria; blood dyscrasia compatible with PNH diagnosed at age 37; positive serologic tests for PNH 2 years later.
Sex
PNH Case No.
Age at Onset of Hemoglobinuria* (yr.)
Table I:
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HVT
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HVT
Intracranial hemorrhage
Major Cause of Death
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HEPATIC VENOUS THROMBOSIS IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
343
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Fig . 1. Normal anterior views of the liver (upper row) and spleen (lower row). A. CASE 12 . B. CASE 15. C. D.
CASE 14. CASE 5 .
Fig . 2. Abnormal anterior views of the liver. A. CASE 2. The liver is enlarged and the left lobe is larger than the right lobe. The spleen is at the upper limit of normal in size. B. CASE 10. The contours of the liver are rounded and the spleen is absent. C. The left lobe is minimally rounded in contour and colloid uptake in the bone marrow is increased.
RESULTS
TABLE I shows the results of liver images correlated with pertinent clinical, roentgenographic, and pathological findings in the 11 PNH patients studied. Clinical features diagnostic of or compatible with thrombotic events involving multiple organ systems are listed. Six patients are living, of whom 5 are for the most part nonanemic, on androgen therapy in 4 (CASES 2, 5, 10, and 12) and adrenocorticosteroids in 1 (CASE 15). Four of those who died had evidence of multiple thromboses at autopsy.
Postmortem examination was not obtained in one patient (CASE 16). Normal Liver Images: Four patients (CASES 5, 12, 14, and 15) have had consistently normal liver images (Fig. 1). One of them (CASE 12) had previously undergone splenectomy. The duration of PNH to date in these 4 cases has been 8 to 16 years, indicating that the disease can be present for a long time without the development of abnormal liver images. Three patients Stable, Abnormal Liver Images: (CASES 2, 3, and 10) have had consistently abnormal
344
EDWARD V. STAAB AND OTHERS
November 1975
Fig. 3. CASE 4. Gamma camera image of the liver demonstrates an enlarged left lobe and increased bone marrow uptake. A. Lower anterior view. B. Left lobe of the liver and spleen. C. Right lateral view.
Fig. 4. CASE 4. Selective hepatic venogram reveals a clot in the smaller radicles of the hepatic veins (arrows); this was confirmed at autopsy. A similar pattern may be present in severe cirrhosis. . liver images during the past 5 to 6 years (Fig. 2). The duration of disease was also long, ranging from 16 to 28 years. The patient in CASE 2 demonstrated hepatic enlargement, especially of the left lobe (Fig. 2, A), which was actually suggested on routine abdominal films in 1964. The increased bone marrow uptake in CASES 3 and 10 is of particular interest. The patient in CASE 3 (Fig. 2, C) had the most severe anemia and the greatest number of transfusions (300). At autopsy in 1972, marked hepatic hemosiderosis was detected but not HVT. The severe anemia may account for increased . bone marrow uptake in the absence of HVT (11). The other patient with increased bone marrow uptake (CASE 10, Fig. 2, B) was not anemic during the 6-year radionuclide study.
Liver Images in Patients with Progressive HVT and PNH The 4 patients whose liver images showed evidence of progressive HVT will be considered in more detail. CASE 4: Episodic gross hemoglobinuria developed in this 54year-old white man in 1955, and a diagnosis of PNH was established 2 years later. His clinical course from 1955 to 1964 was characterized by bouts of gross hemoglobinuria, severe anemia requiring many transfusions, multiple thrombotic episodes, and infections (8, 9). He responded well to fluoxymesterone therapy and was free of gross hemoglobinuria, nonanemic, and required no transfusions from 1964 to February 1969 ; however, there was a slow but steady rise in the conjugated bilirubin level during this 5.year span, not accounted for by any obvious liver disease or biliary obstruction (3).
Fig. 5. CASE 8. A. Anterior scan of the liver demonstrates that the left lobe is normal in size, with decreased activity compared to the right lobe. The spleen is probably enlarged. . B. Anterior gamma camera image of the liver taken with a diverging collimator shows increased activity in the left lobe . The contours are more rounded, and there is marked splenomegaly. Activity is also present in the colon from a brain scan performed on the previous day. In February 1960, pain developed in the right upper quadrant, accompanied by malaise, nausea, and mild ascites. A gamma camera image of the liver showed hepatomegaly, especially of the left lobe (Fig. 3). The spleen was enlarged, and there was increased activity in the bone marrow. Selective celiac arteriography demonstrated a normal arterial pattern, with a patent portal vein of normal size on the late phase . Selective study of the hepatic veins demonstrated a patent confluens with marked attenuation. of the smaller veins (Fig. 4), characteristic of hepatic vein thrombosis (5). Heparin therapy was begun but had to be discontinued because of hemorrhage into the rectus sheath. The patient's condition became progressively worse , leading to death. At autopsy, the left lobe of the liver was grossly nodular but the right lobe was smooth. Features characteristic of hepatic venous thrombosis were present. CASE 8: This 44-year-old white man first noted gross hemoglobinuria in 1960 , and PNH was diagnosed 2 years later. The course was characterized by relatively mild anemia, only occasional gross hemoglobinuria, recurrent thrombophlebitis of the legs, episodic abdominal pain, headaches, and finally death from sagittal sinus thrombosls ln January 1970 (3, 9). Major autopsy findings included sagittal sinus thrombosis and an unexpected degree of HVT. The initial liver scan, taken in March 1969, was normal; however, a repeat study 10 months later, shortly before his death, showed definite changes. The contours of the liver were rounder, the spleen was larger, and the left lobe of the fiver was also larger and had relatively increased uptake in comparison to the 1969 study (Fig. 5). CASE 13: This 20-year-old white man presented in November 1968 with marked pancytopenia and hypocellular bone marrow 2 months after spray-painting his car in an enclosed area. His in~ial
Vol. 117
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Fig . 6. CASE 13. A. Scan obta ined before the onset of HVT is normal (August 1969). B-D. Sequential studies in January, March, and April 1970 demonstrate progressive hepatomegaly with "mottled" decreased uptake in the right lobe and progressive compensatory increased uptake in the left lobe, as well as progressive evidence of increased extrahepatic uptake as the liver damage increases. Note the increased uptake in the bone marrow. course was characterized by an episode of thrombophlebitis and repeated attacks of gastrointestinal bleeding. A diagnosis of aplastic anemia was made, and the patient was treated with fluoxymesterone (40 mg daily). Several months later. gross hemoglobinuria developed and laboratory tests were positive for PNH. Fluoxymesterone was discontinued after 6 months, but the hema tocrit remained at about 38 % . A liver scan taken in August 1969 was normal (Fig. 6, A). In January 1970, fever and crampy abdominal pain developed: these were originally diagnosed as gastroenteritis but were followed by severe right-upper-quadrant pain and ascites. Scans demonstrated a remarkable change in the contour and radiocolloid distribution of the liver: the left lobe was nearly as large as the right lobe and contained more colloid (Fig. 6. B). Heparin therapy produced initial improvement, but attempts to switch from heparin to Coumadin were unsuccessful. During the ensuing months, repeated episodes occurred, and follow-up scans demonstrated a progressive and changing liver pattern consisting largely of progressive hepatomegaly with decreased uptake in the right lobe and increased uptake in the left lobe as well as visible extrahepatic uptake as the liver damage progressed (Fig. 6, C and D). A double-contrast study using CO 2 failed to demonstrate patent hepatic veins. Laboratory studies revealed increased conjugated bilirubin and LDH and striking elevations in SGOT and SGPT, unaccounted for by any significant accentuation in hemolysis (3). The patient was discharged in May 1970 on maintenance subcutaneous heparin therapy. In July he was hospitalized elsewhere for persistent headaches and heparin was discontinued, following which a pulmonary embolus was thought to have developed. Shortly thereafter, evidence of recurrent, severe hepatic venous thrombosis and hepatic coma again developed and the patient died shortly after readmission to Vanderbilt University Hospital on August 31 . Autopsy revealed massive hepatic venous thrombosis with only a single left hepatic vein remaining patent, as confirmed by postmortem injection of barium into the inferior vena cava (Fig. 7): this single patent vein drained the region wh ich had shown the most colloid uptake on the liver scans. CASE 16: Gross hemoglobinuria, jaundice, and anemia first developed in 1960 in this 13-year-old white girl following a booster tetanus toxoid injection. Her subsequent course was characterized by
Fig . 7. CASE 13. Postmortem barium injection into the inferior vena cava (ive) . The straight arrow indicates the only patent hepatic vein. The IVC was tied above the diaphragm and below the liver. Clot is present throughout the IVC . r. = right lobe ; I. = left lobe.
mild to moderate pancytopenia, multiple transfusions, and episodic gross hemoglobinuria. Four years later, bilateral swelling of the legs developed, accompanied by ascites and persistent dilatation of the veins on the abdominal wall , probably due to thrombosis of the inferior vena cava . In 1969 PNH was diagnosed elsewhere following another ep isode of gross hemoglobinur ia . In January 1973 she was admitted to Vanderbilt University Hospital. The width of the liver , measured vertically, was 10 em on clinical examination and the splenic tip was palpable. Gamma camera images of the liver showed hepatosplenomegaly, and colloid concentration was greater in the spleen than in the liver (Fig. 8, A and B). The patient was discharged on March 7, 1973. Late that same month, malaise, slight fever, nausea, and right-upper-quadrant pain and tenderness developed. followed by overt jaundice. Clinically the width of the liver had increased from 10 to 22 em , but the spleen was not palpable. On April 7 and 13, repeat studies showed a marked increase in the size of the liv er. along with increased visualization of the vertebral bone marrow. Because of the uniform involvement, we considered primary hepatocellular disease rather than HVT (Fig. 8. C): however, within 2 weeks persistent and increasing ascites developed, as well as further hepatic enlargement, more accentuated dilatation of the abdominal wall veins . and swelling of the legs . On April 20 , unequal distribution of colloid in the lobes of the liver was first appreciated in addition to massive hepatic enlargement (Fig. 8, D), though in retrospect differences in distribution may have been present on the earlier studies. Colloid was distributed pr imarily in the left lobe and the medial portion of the right lobe, making HVT a much more likely diagnosis and prompting further studies. The enlarged, " m ott led" liver seen on April 7 is shown in Figure 9, A, while the altered colloid pattern seen on June 4 is shown in Figure 9, B. There was a wedge-shaped defect in the spleen, probably secondary to an infarction. Injection of dye into the right iliac vein confirmed complete occlusion of the inferior vena cava with marked collateral circulation. A CO 2 study showed an air pattern in the right ventricle ; however, it stopped at the hepatic confluens and did not extend into the hepatic venous system. The condition of the patient precluded further vascular catheterization. Heparin therapy was begun, but the patient continued to show progression of signs and symptoms. Because of the ominous outlook, Win-Kinase (urokinase) treatment was instituted;
EDWARD
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STAAB AND OTHERS
November 1975
Fig. 8. Serial anterior images of the liver in CASE 16. A. The liver is enlarged, with " mott led" uptake. The double cross is a lead marker with bars 5 em apart (1/5/73). B. There is no change from the earlier appearance (2/20/73). Note the enlarged spleen with increased uptake. C. On 4/13/73, there is marked hepatic enlargement with mildly unequal colloid distribution favoring the left lobe . D. Increased uptake of colloid in the upper part of the liver, spleen, and bone marrow (4/20/73). E. The area of liver uptake is more prominent, with the remainder of the liver decreased in size (6/4/73).
however, fever, hepatic precoma, and acute renal tubular necrosis developed, followed by a slight but distinct improvement in liver and renal function and general status on adrenocorticoid and diuretic therapy. Studies performed on May 17 and June 4 (Fig. 8, E) showed a progressive decrease in size and colloidal uptake in the right lobe. An area corresponding to a hypertrophied caudate lobe or a medial portion of the right lobe became enlarged and trapped more colloid. There was also increased activity in the iung and thoracic cage bone marrow. When the patient was discharged on June 7, the width of the liver was 10 cm on Clinical examination. Two days later, pain developed in both lower legs and in the right lower chest, accompanied by severe respiratory dtstress , and she died despite emergency measures. Autopsy was not performed; however, the immed iate cause of death was judged to be pulmonary embolism.
DISCUSSION
Occlusion of the hepatic veins is a relatively rare condition; usually of unknown etiology. It is commonly designated as the Budd-Chiari syndrome, which like so many other eponyms in medicine is imprecise: Budd's description in 1845 omitted the clinical features (12), while Chiari, more than 50 years later, was neither the first to report the cliilical picture nor the first to conceive its importance (13). Parker presented the single most exhaustive review of the literature in 1959, recording 149 instances of symptomatic hepatic vein occlusion (14). In 1968, Ramsay and Britton stated that more than 500 cases had been reported (15) . Asymptomatic cases consisting of incidental findings at autopsy have
been documented (14) but are not the subject of this report. Major causes of symptomatic hepatic vein occlusion have been reviewed by Parker (14). The etiology was unknown in two-thirds of cases. Polycythemia was the most common associated condition in cases of known etiology, accounting for about 30 %; this is congruent with the known generalized thrombotic tendency in polycythemia as cited in an autopsy series of 250 patients, in which thrombotic complications occurred in 63 % and death was attributed to thrombosis in 40% (16). Hypernephroma and tumors of the vena cava were second and third in incidence, while other etiologies accounted for only one or a small number of cases each. PNH should be added to this list, as should the use of oral contraceptives, which has been cited in 8 cases (16, 17). Poisoning by pyrrolidine (senecio) alkaloids, such as those found in Jamaican bush teas and related plants, appear to be associated primarily with hepatic endophlebitis (18) and will not be considered here. The major clinical features of HVT are ascites, hepatomegaly, and abdominal pain (14). Less prominent or terminal features have included jaundice, nausea and vomiting, hernaternesis, and melena. Edema of the lower legs suggests associated thrombosis of the inferior vena cava (14), which has been noted in about 30% of cases; portal vein thrombosis has been seen in about 20% (14, 19). The precise pathophysiology of the
Vol. 117
Table II:
HEPATIC VENouS THROMBOSIS IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
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Nuclear Medicine
Postulated Pathophysiology of HVT Hepatic vein thrombos is
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Cessation of blood flow in area dra ined by vein
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Attempted conversion of portal ve in in t o efferent channel
~. S inuso idal congestion
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Atrophy o r' destruction of centrilobular pa renchyma .
Regenerat ion of periportal areas
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Chronic centrtlobular f ibrosis
Acute in f ar ct ion with death
Cirrhosis
changes seen in association with HVT has not been established. TABLE " presents a tentative schema as derived from the observations of Parker (14) and from our pathological studies. Although the roles of hepatography, hepatic venography, and arteriography In the diagnosis of HVT have been amply described (15, 20, 21), very little has been said about the findings on radionuclide images of the liver. Claln et al. (5) reported 6 patients with Budd-Chiari syndrome, 5 of whom were studied with colloidal gold. Four showed reduced uptake in the right lobe, 1 had decreased activity in the left lobe, and 3 demonstrated excess splenic uptake. Chaudhuri et al. reported a single case and commented that the liver image "appeared almost the same as that in advanced cirrhosis of liver" (6). Our experience with HVT in PNH suggests that while an individual image cannot differentiate HVT from advanced cirrhosis, the rapidity of changes in the hepatic pattern is quite different from the slower progression seen in cirrhosis. Carulli et al. commented on liver images obtained in 3 patients in "the early stage of Budd-Chiari syndrome" (7). Increased splenic uptake and uneven distribution in the liver were noted. They suggested that the area of increased uptake between the right and left hepatic lobes may actually represent the caudate (Spiegel's) lobe . This lobe may remain uninvolved and capable of hypertrophy in HVT, since its venous drainage may be directly into the inferior vena cava. Hepatic venous thrombosis in paroxysmal nocturnal hemoglobinuria is probably just one of the manifestations of a generalized thrombotic tendency in this disorder (3), but it was the most common cause of death In our series. The clinical symptomatology and altered liver function have been detailed by Peytremann et al. (3). For the most part, these changes seem to be manifestations of late, irreversible disease; thus it was hoped that serial liver images might make diagnosis possible at an earlier stage. Thrombotic obstruction of the hepatic venous confluens might initially be expected to present only as an
Fig. 9. Gamma camera images of the liver in CASE 16. A. Study done on 4/13/73 demonstrates a large liver and "mottled" appearance. The spleen is enlarged but has uniform uptake. B. Study on 6/4/73 shows activity primarily in the upper middle region of the liver (?quadrate lobe). There is also a defect in the lower spleen and increased activity In the bone marrow. The view. ln the : upperleft corner shows the anterior liver, followed clockwise by the anterior spleen, posterior spleen , and right lateralliver.
enlarged, so-called " mottl ed" liver pattern. The progressive changes noted in our patients may represent involvement of smaller venous channels as well as destruction and regeneration of hepatic cells and attempts at recanalization. A case in point is that of the patient with PNH in CASE 16, who initially presented with clinical and laboratory findings suggesting HVT but showed only a massively enlarged, "mottled" liver on the radionuelide image. Within 2 weeks, changes typical of HVT developed, demonstrating clearly that the earliest manifestation of progressive, fulminating HVT may be only striking enlargement of the liver. This finding should be regarded as evidence of HVT in PNH unless it can easily be explained on another basis. Autopsy was not obtained in this patient, so that it was impossible to determine whether or not the predominant initial event might have been thrombosis in the hepatic venous confluens; nevertheless, the common denominator at autopsy in our cases of PNH with HVT was diffuse thrombosis in secondary and tertiary venous radicles (3). We now recommend that heparin therapy be promptly instituted for any unexplained and striking hepatic enlargement in a patient with PNH. If the clinical and
EDWARD V . STAAB AND OTHERS
348
laboratory features and liver pattern are not sufficiently diagnostic of HVT in the setting of PNH, further studies should be carried out. Clain et al. reported on the use of extensive invasive diagnostic procedures in the search for HVT in non-PNH patients (5); however, we urge that caution be exerted in PNH patients, who are generally prone to numerous complications. For example, thrombocytopenia is frequently present and may make needle biopsy of the liver risky, while infusions of platelets prior to biopsy may precipitate gross hemoglobinuria analogous to reactions to whole blood transfusions (4). The small amount of tissue obtained by liver biopsy may fail to reveal venous thrombosis but may show centrolobular congestion and necrosis, which is likely to be seen only in HVT or acute, severe right-sided congestive cardiac failure. While open liver biopsy has demonstrated thrombosis, the presence of severe liver damage makes the operative procedure far too great a risk (3). Likewise, one is naturally hesitant to carry out extensive venous catheterization studies in view' of the generalized thrombotic tendency in PNH. However, we have done so without seemingly untoward effects using preliminary heparinization. Radiologists are generally reluctant to carry out vascular catheterization if the patient has been on prolonged heparin therapy. We now suggest that if other, less invasive procedures are not diagnostic, a CO 2 study and hepatic venography be performed reasonably soon after heparinization is started. It is probably best to initially carry out hepatic venography via the right femoral vein in order to determine whether the inferior vena cava is patent or thrombosed; if thrombosis is discovered, hepatic venography should be carried out via the right jugular or brachial vein. There are other urgent reasons for making the decision whether to carry out such studies promptly. Delay produces further deterioration and complications such as progressively severe thrombocytopenia, making management and study even more difficult. Valuable time may also be lost in instituting heparin therapy, which is currently the best hope for at least temporary improvement.
SUMMARY Serial liver images and selected roentgenographic studies were carried out in 11 patients with paroxysmal nocturnal hemoglobinuria (PNH) during a 6-year period. Four patients had normal liver images and 3 had stable abnormalities without development of clinical hepatic venous thrombosis. Hepatic venous thrombosis (HVT) developed in 5 patients and was confirmed at autopsy in 4. Serial liver images of the 4 with HVT revealed changes which were helpful in the diagnosis of HVT in PNH when considered in the clinical setting: these included hepatic and splenic enlargement, unequal distribution of colloid in the various lobes of the liver, rapid changes in pattern, and extrahepatic uptake.
November 1975
ACKNOWLEDGMENTS: Without the facilities of the Clinical Research Center at Vanderbilt University Hospital, our observations and studies would have been impossible to conduct. We also wish to thank Miss Diane G. Grammer, Mrs. Frances R. Beaver, and Mrs. De Lois Popp for their expert secretarial assistance.
Department of Radiology Division of Nuclear Medicine University of North Carolina School of Medicine Chap~Hm,N.C. 27514
REFERENCES 1. Crosby WH: Paroxysmal nocturnal hemoglobinuria. A classic description by Paul Strubinq in 1882, and a bibliography of the disease. Blood 6:270-284, Mar 1951 2. Dacie JV: The Haemolytic Anaemias-Congenital and Acquired. Part 4: Drug-Induced Haemolytic Anaemias. New York, Grune & Stratton, 2d Ed, 1967 3. Peytremann R, Rhodes RS, Hartmann RC: Thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) with particular reference to progressive, diffuse hepatic venous thrombosis. Ser Haematol 5:115-136, 1972 4. Hartmann RC, Kolhouse JF: Viewpoints on the management of paroxysmal nocturnal hemoglobinuria (PNH). Ser Haematol 5:42-60,1972 5. Clain D, Freston J, Kreel L, et al: Clinical diagnosis of the Budd-Chiari syndrome. A report of six cases. Am J Mad 43:544554, Oct 1967 6. Chaudhuri TK, Chaudhuri TK, Suzuki Y, et al: Liver scan in the Budd-Chiari syndrome. JAMA 221:506-507, 31 Jul1972 7. Carulli N, Boraldi F, Roncaia R, et al: Liver scans in the Budd-Chiari syndrome. JAMA 223:1161, 5 Mar 1973 8. Hartmann RC, Auditore JV: Paroxysmal nocturnal hemoglobinuria. I. Clinical studies. Am J Med 27:389-400, Sep 1959 9. Hartmann RC, Jenkins DE Jr, McKee LC, et al: Paroxysmal nocturnal hemoglobinuria: clinical and laboratory studies relating to iron metabolism and therapy with androgen and iron. Medicine 45: 331-363, Sep 1966 10. Patton DD, Garcia EN, Webber MM: Simplified preparation of technetium 99m sulfide colloid for liver scanning. Am J RoentgenoI97:880-885, Aug 1966 11. Bekerman C, Gottschalk A: Diagnostic significance of the relative uptake of liver compared with spleen in 99"'T c-sulfur colloid scintiphotography. J Nucl Med 12:237-240, May 1971 12. Budd G: On Diseases of the Liver. London, Churchill, 1845, p 146 13. Chiari H: Ueber der sejbstandlqe Phlebitis obliterans der Hauptstarnrne der Vena hepaticae als Todesursache. Beitr Pathol Anat 26:1-18, 1899 14. Parker RGF: Occlusion of the hepatic veins in man. Medicine 38:369-402, Dec 1959 15. Ramsay GC, Britton RC: Intraparenchymal angiography in the diagnosis of hepatic veno-occlusive diseases. Radiology 90: 716-726, Apr 1968 16. Chievitz E, Thiede T: Complications and causes of death in polycythaemia vera. Acta Med Scand 172:513-523, Nov 1962 17. Hoyumpa AM Jr, Schiff L, Helfman EL: Budd-Chiari syndrome in women taking oral contraceptives. Am J Med 50:137-140, Jan 1971 18. Sherlock S: Diseases of the Liver and Biliary System. Oxford, Blackwell; Philadelphia, Davis, 4th Ed, 1968, pp 245-250 19. Schreiber JT, Gonzalez LL: Thrombosis of hepatic veins and inferior vena cava. Relief by thoracic transposition of spleen. Am J Surg 113:807-811, Jun 1967 20. Pollard JJ, Nebesar RA: Altered hemodynamics in the Budd-Chiari syndrome demonstrated by selective hepatic and selective splenic angiography. Radiology 89:236-243, Aug 1967 21. Reuter SR, Redman HC: Gastrointestinal Angiography. Philadelphia, Saunders, 1972, p 233
Liver Imaging in the Diagnosis of Hepatic Venous Thrombosis in Paroxysmal Nocturnal Hemoglobinuria 1
•
Nuclear Medicine
Edward V. Staab, M.D.,2 Robert C. Hartman, M.D.,3 and James A. Parrott, M.D. 4
Eleven patients with paroxysmal nocturnal hemoglobinuria were studied by serial liver imaging. Thisdisease has a generalized thrombotic tendency, and progressive diffusehepatic venous thrombosis has been emphasized in recent studies. Radionuclide imaging proved to be of great help in establishing the diagnosis of hepatic venous thrombosis and following the progress of the disease process. Abnormal patterns in hepatic venous occlusion include (a) enlargement of the liver (especially the right lobe), (b) extrahepatic localization of radionuclide, and (c) areas of decreased uptake in the distribution of the involved veins. These findings develop rapidly and are very characteristic in the clinical setting. TERMS: Hemoglobinuria • Liver, blood supply. Liver, diseases. Liver, radionuclide studies. Veins, hepatic
INDEX
•
Radiology 117:341-348, November 1975
•
AROXYSMAL nocturnal hemoglobinuria (PNH) is a rare acquired hemolytic anemia characterized by chronic intravascular hemolysis with frequent bouts of gross hemoglobinuria. Despite a high frequency of thrombocytopenia, spontaneous bleeding is unusual; rather, a generalized thrombotic tendency has been clearly recognized as a major complication and cause of death in PNH (1, 2). Although isolated cases of progressive, diffuse hepatic venous thrombosis (HVT) have long been reported in PNH, only recently have attempts been made to define this entity at a clinical level (3). With improvement in the management of PNH in general, HVT may represent the most common cause of death (3, 4). In 1967, Clain et al. reported abnormal liver images showing diminished or no uptake in the right hepatic lobe in 5 patients with hepatic vein occlusion in conditions other than PNH (5). There have also been brief comments on abnormal images in HVT (6,7). During the past 5 years we have performed liver studies on 11 PNH patients, of whom HVT developed in 4.
duced red blood cell acetylcholinesterase and leukocyte alkaline phosphatase, hemoglobinemia, and hemosiderinuria. Most patients showed persistent or at least transient pancytopenia. Five patients died prior to 1967; since they were not studied by radionuclide imaging, they were eliminated from the present study. These included 1 patient (CASE 1) with "liver failure," 2 (CASES 6 and 11) with hepatic venous thrombosis, 1 (CASE 9) with acute leukemia, and 1 (CASE 7) with basilar artery thrombosis and HVT. Serial views of the liver were obtained from all survivors at approximately 6-month intervals beginning in 1967, following the finding of striking changes in one patient with HVT (CASE 4) which correlated well with subsequent autopsy findings. Five of these 11 patients died, and autopsy was performed on 4. In 3, HVT was the cause of death, while in the fourth (CASE 8) sagittal sinus thrombosis was the primary cause of death, though HVT was pronounced. Three patients (CASES 4, 8, and 13) showed HVT clinically as well as at autopsy; one (CASE 16) had HVT on clinical examination, but autopsy was not performed. The patient in CASE 3 died of cerebral hemorrhage secondary to anticoagulant therapy and did not have HVT. Method: Sulfur colloid labeled with 1.5-3.0 mCi of technetium (99mTc) was used in all studies (10). Images were obtained with either an Ohio Nuclear Model 84 rectilinear scanner with a D collimator or a Searle Pho Gamma III Anger camera with a low-energy straightbore collimator. Roentgenologic and hematologic studies were carried out using standard methods.
P
MATERIALS AND METHODS
PNH Clinical Material: Sixteen patients with PNH have undergone long-term intensive study at the Vanderbilt MedicaJ Center during the past 16 years (3, 4, 8, 9); the case numbers used here correspond to those in the previous publications. The diagnosis of PNH was firmly established in all cases by serologic tests (acid and sucrose hemolysis, thrombin, and "heat" tests), re-
1 Fromthe Department of Radiology (Division of Nuclear Medicine) andthe Department of Medicine (Division of Hematology), Vanderbilt University Medical School and Hospital, Nashville, Tenn. Accepted for publication in February 1975. Supported in part by research grantsHL03509, AM 05129, RR-95, and FR 05424 from the USPHS. 2 Present address: Department of Radiology, Division of Nuclear Medicine, University of NorthCarolina Schoolof Medicine, Chapel Hill, N. C. 27514. 3 Present address: Sectionof Hematology/Oncology, Veterans Administration Hospital (111), 13000N. 30th st., Tampa, Fla. 33620. 4 Present address: Jenny Stewart Hospital, Hopkinsville, Ky. sjh
341
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Abdominal pain, headaches, peculiar skin lesions Ankle ulcer, inferior vena cava occlusion, papilledema, diplopia, right sixth nerve palsy, abdominal pain, peculiar skin lesions, terminal pulmonary embolism
Abdominal pain, thrombophlebitis of the legs Headaches, abdorninal pain Thrombophlebitis of the legs; suspected pulmonary, splenic, and intestinal infarction, episodic headaches, suspected HVT, peptic ulcer Abdominal pain, headaches
Headaches, abdominal pain, thrombophlebitis, suspected pulmonary infarction
Abdominal pain Abdominal pain, cramps and thrombophlebitis of the legs, possible infarct on EKG "Hemorrhagic bullae!" on the leg, duodenal deformity, pulmonary infarction, abdominal pain Headaches, thrornbophlebitis, abdominal pain
Clinical Features Compatible with Thrombosis
6
3
5
10
6
2
3
5
1
8 5
Abnormal
Normal
Normal
Abnormal
Normal
Abnormal
Normal
Normal
Abnormal
Abnormal Normal
rRadionuciide Images, "No. of Studies Result
Venous angiogram showed an obstructed inferior vena cava; CO 2 study showed HVT; excretory urography showed cortica I defects; marked renal siderosis, small bowel edema, gallstones
Cortical detects on excretory urography; gallstones
Venous angiogram showed HVT; colonic edema on barium enema study
.. .
Gallstones (?)
Duodenal ulcer; cortical defects on excretory urography Sagittal sinus thrombosis
/enous angiogram showed HVT; esophageal varices, nonvisualized gall bladder
Bilateral subdural hematomas
Roentgenography
No autopsy
Hemachromatosis on liver biopsy
Liver weighed 3,300 g; old and recent thrombi in the hepatic veins; diffuse necrosis of the liver; laminated white thrombus of the inferior vena cava; old myocardial infarct; fresh pulmonary embolus
.. .
...
Liver weighed 2,200 g; thrornbosis of small and medium hepatic veins; old and recent hemorrhagic necrosis; diffuse cortical and sagittal sinus venous thrombosis; cerebral infarction
Liver weighed 1,600 g; old and recent hepatic venous thrombosis; hemorrhagic necrosis and fibrosis; focal areas of regeneration
Bilateral subdural hematomas with pressure effect: liver weighed 1,750 g; no thrombosls: peculiar heart lesions
Major Findings at Autopsy
Liver Scan Data Correlated with Pertinent Clinical, Pathological, and Roentgenographic Findings in Patients with PNH
*These patients also had hepatic vein thrombosis. __ _ _ __ __ _ __ _ _ tNo gross hemoglobinuria; blood dyscrasia compatible with PNH diagnosed at age 37; positive serologic tests for PNH 2 years later.
Sex
PNH Case No.
Age at Onset of Hemoglobinuria* (yr.)
Table I:
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HVT
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HVT
Intracranial hemorrhage
Major Cause of Death
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HEPATIC VENOUS THROMBOSIS IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
343
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Fig . 1. Normal anterior views of the liver (upper row) and spleen (lower row). A. CASE 12 . B. CASE 15. C. D.
CASE 14. CASE 5 .
Fig . 2. Abnormal anterior views of the liver. A. CASE 2. The liver is enlarged and the left lobe is larger than the right lobe. The spleen is at the upper limit of normal in size. B. CASE 10. The contours of the liver are rounded and the spleen is absent. C. The left lobe is minimally rounded in contour and colloid uptake in the bone marrow is increased.
RESULTS
TABLE I shows the results of liver images correlated with pertinent clinical, roentgenographic, and pathological findings in the 11 PNH patients studied. Clinical features diagnostic of or compatible with thrombotic events involving multiple organ systems are listed. Six patients are living, of whom 5 are for the most part nonanemic, on androgen therapy in 4 (CASES 2, 5, 10, and 12) and adrenocorticosteroids in 1 (CASE 15). Four of those who died had evidence of multiple thromboses at autopsy.
Postmortem examination was not obtained in one patient (CASE 16). Normal Liver Images: Four patients (CASES 5, 12, 14, and 15) have had consistently normal liver images (Fig. 1). One of them (CASE 12) had previously undergone splenectomy. The duration of PNH to date in these 4 cases has been 8 to 16 years, indicating that the disease can be present for a long time without the development of abnormal liver images. Three patients Stable, Abnormal Liver Images: (CASES 2, 3, and 10) have had consistently abnormal
344
EDWARD V. STAAB AND OTHERS
November 1975
Fig. 3. CASE 4. Gamma camera image of the liver demonstrates an enlarged left lobe and increased bone marrow uptake. A. Lower anterior view. B. Left lobe of the liver and spleen. C. Right lateral view.
Fig. 4. CASE 4. Selective hepatic venogram reveals a clot in the smaller radicles of the hepatic veins (arrows); this was confirmed at autopsy. A similar pattern may be present in severe cirrhosis. . liver images during the past 5 to 6 years (Fig. 2). The duration of disease was also long, ranging from 16 to 28 years. The patient in CASE 2 demonstrated hepatic enlargement, especially of the left lobe (Fig. 2, A), which was actually suggested on routine abdominal films in 1964. The increased bone marrow uptake in CASES 3 and 10 is of particular interest. The patient in CASE 3 (Fig. 2, C) had the most severe anemia and the greatest number of transfusions (300). At autopsy in 1972, marked hepatic hemosiderosis was detected but not HVT. The severe anemia may account for increased . bone marrow uptake in the absence of HVT (11). The other patient with increased bone marrow uptake (CASE 10, Fig. 2, B) was not anemic during the 6-year radionuclide study.
Liver Images in Patients with Progressive HVT and PNH The 4 patients whose liver images showed evidence of progressive HVT will be considered in more detail. CASE 4: Episodic gross hemoglobinuria developed in this 54year-old white man in 1955, and a diagnosis of PNH was established 2 years later. His clinical course from 1955 to 1964 was characterized by bouts of gross hemoglobinuria, severe anemia requiring many transfusions, multiple thrombotic episodes, and infections (8, 9). He responded well to fluoxymesterone therapy and was free of gross hemoglobinuria, nonanemic, and required no transfusions from 1964 to February 1969 ; however, there was a slow but steady rise in the conjugated bilirubin level during this 5.year span, not accounted for by any obvious liver disease or biliary obstruction (3).
Fig. 5. CASE 8. A. Anterior scan of the liver demonstrates that the left lobe is normal in size, with decreased activity compared to the right lobe. The spleen is probably enlarged. . B. Anterior gamma camera image of the liver taken with a diverging collimator shows increased activity in the left lobe . The contours are more rounded, and there is marked splenomegaly. Activity is also present in the colon from a brain scan performed on the previous day. In February 1960, pain developed in the right upper quadrant, accompanied by malaise, nausea, and mild ascites. A gamma camera image of the liver showed hepatomegaly, especially of the left lobe (Fig. 3). The spleen was enlarged, and there was increased activity in the bone marrow. Selective celiac arteriography demonstrated a normal arterial pattern, with a patent portal vein of normal size on the late phase . Selective study of the hepatic veins demonstrated a patent confluens with marked attenuation. of the smaller veins (Fig. 4), characteristic of hepatic vein thrombosis (5). Heparin therapy was begun but had to be discontinued because of hemorrhage into the rectus sheath. The patient's condition became progressively worse , leading to death. At autopsy, the left lobe of the liver was grossly nodular but the right lobe was smooth. Features characteristic of hepatic venous thrombosis were present. CASE 8: This 44-year-old white man first noted gross hemoglobinuria in 1960 , and PNH was diagnosed 2 years later. The course was characterized by relatively mild anemia, only occasional gross hemoglobinuria, recurrent thrombophlebitis of the legs, episodic abdominal pain, headaches, and finally death from sagittal sinus thrombosls ln January 1970 (3, 9). Major autopsy findings included sagittal sinus thrombosis and an unexpected degree of HVT. The initial liver scan, taken in March 1969, was normal; however, a repeat study 10 months later, shortly before his death, showed definite changes. The contours of the liver were rounder, the spleen was larger, and the left lobe of the fiver was also larger and had relatively increased uptake in comparison to the 1969 study (Fig. 5). CASE 13: This 20-year-old white man presented in November 1968 with marked pancytopenia and hypocellular bone marrow 2 months after spray-painting his car in an enclosed area. His in~ial
Vol. 117
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Fig . 6. CASE 13. A. Scan obta ined before the onset of HVT is normal (August 1969). B-D. Sequential studies in January, March, and April 1970 demonstrate progressive hepatomegaly with "mottled" decreased uptake in the right lobe and progressive compensatory increased uptake in the left lobe, as well as progressive evidence of increased extrahepatic uptake as the liver damage increases. Note the increased uptake in the bone marrow. course was characterized by an episode of thrombophlebitis and repeated attacks of gastrointestinal bleeding. A diagnosis of aplastic anemia was made, and the patient was treated with fluoxymesterone (40 mg daily). Several months later. gross hemoglobinuria developed and laboratory tests were positive for PNH. Fluoxymesterone was discontinued after 6 months, but the hema tocrit remained at about 38 % . A liver scan taken in August 1969 was normal (Fig. 6, A). In January 1970, fever and crampy abdominal pain developed: these were originally diagnosed as gastroenteritis but were followed by severe right-upper-quadrant pain and ascites. Scans demonstrated a remarkable change in the contour and radiocolloid distribution of the liver: the left lobe was nearly as large as the right lobe and contained more colloid (Fig. 6. B). Heparin therapy produced initial improvement, but attempts to switch from heparin to Coumadin were unsuccessful. During the ensuing months, repeated episodes occurred, and follow-up scans demonstrated a progressive and changing liver pattern consisting largely of progressive hepatomegaly with decreased uptake in the right lobe and increased uptake in the left lobe as well as visible extrahepatic uptake as the liver damage progressed (Fig. 6, C and D). A double-contrast study using CO 2 failed to demonstrate patent hepatic veins. Laboratory studies revealed increased conjugated bilirubin and LDH and striking elevations in SGOT and SGPT, unaccounted for by any significant accentuation in hemolysis (3). The patient was discharged in May 1970 on maintenance subcutaneous heparin therapy. In July he was hospitalized elsewhere for persistent headaches and heparin was discontinued, following which a pulmonary embolus was thought to have developed. Shortly thereafter, evidence of recurrent, severe hepatic venous thrombosis and hepatic coma again developed and the patient died shortly after readmission to Vanderbilt University Hospital on August 31 . Autopsy revealed massive hepatic venous thrombosis with only a single left hepatic vein remaining patent, as confirmed by postmortem injection of barium into the inferior vena cava (Fig. 7): this single patent vein drained the region wh ich had shown the most colloid uptake on the liver scans. CASE 16: Gross hemoglobinuria, jaundice, and anemia first developed in 1960 in this 13-year-old white girl following a booster tetanus toxoid injection. Her subsequent course was characterized by
Fig . 7. CASE 13. Postmortem barium injection into the inferior vena cava (ive) . The straight arrow indicates the only patent hepatic vein. The IVC was tied above the diaphragm and below the liver. Clot is present throughout the IVC . r. = right lobe ; I. = left lobe.
mild to moderate pancytopenia, multiple transfusions, and episodic gross hemoglobinuria. Four years later, bilateral swelling of the legs developed, accompanied by ascites and persistent dilatation of the veins on the abdominal wall , probably due to thrombosis of the inferior vena cava . In 1969 PNH was diagnosed elsewhere following another ep isode of gross hemoglobinur ia . In January 1973 she was admitted to Vanderbilt University Hospital. The width of the liver , measured vertically, was 10 em on clinical examination and the splenic tip was palpable. Gamma camera images of the liver showed hepatosplenomegaly, and colloid concentration was greater in the spleen than in the liver (Fig. 8, A and B). The patient was discharged on March 7, 1973. Late that same month, malaise, slight fever, nausea, and right-upper-quadrant pain and tenderness developed. followed by overt jaundice. Clinically the width of the liver had increased from 10 to 22 em , but the spleen was not palpable. On April 7 and 13, repeat studies showed a marked increase in the size of the liv er. along with increased visualization of the vertebral bone marrow. Because of the uniform involvement, we considered primary hepatocellular disease rather than HVT (Fig. 8. C): however, within 2 weeks persistent and increasing ascites developed, as well as further hepatic enlargement, more accentuated dilatation of the abdominal wall veins . and swelling of the legs . On April 20 , unequal distribution of colloid in the lobes of the liver was first appreciated in addition to massive hepatic enlargement (Fig. 8, D), though in retrospect differences in distribution may have been present on the earlier studies. Colloid was distributed pr imarily in the left lobe and the medial portion of the right lobe, making HVT a much more likely diagnosis and prompting further studies. The enlarged, " m ott led" liver seen on April 7 is shown in Figure 9, A, while the altered colloid pattern seen on June 4 is shown in Figure 9, B. There was a wedge-shaped defect in the spleen, probably secondary to an infarction. Injection of dye into the right iliac vein confirmed complete occlusion of the inferior vena cava with marked collateral circulation. A CO 2 study showed an air pattern in the right ventricle ; however, it stopped at the hepatic confluens and did not extend into the hepatic venous system. The condition of the patient precluded further vascular catheterization. Heparin therapy was begun, but the patient continued to show progression of signs and symptoms. Because of the ominous outlook, Win-Kinase (urokinase) treatment was instituted;
EDWARD
346
V.
STAAB AND OTHERS
November 1975
Fig. 8. Serial anterior images of the liver in CASE 16. A. The liver is enlarged, with " mott led" uptake. The double cross is a lead marker with bars 5 em apart (1/5/73). B. There is no change from the earlier appearance (2/20/73). Note the enlarged spleen with increased uptake. C. On 4/13/73, there is marked hepatic enlargement with mildly unequal colloid distribution favoring the left lobe . D. Increased uptake of colloid in the upper part of the liver, spleen, and bone marrow (4/20/73). E. The area of liver uptake is more prominent, with the remainder of the liver decreased in size (6/4/73).
however, fever, hepatic precoma, and acute renal tubular necrosis developed, followed by a slight but distinct improvement in liver and renal function and general status on adrenocorticoid and diuretic therapy. Studies performed on May 17 and June 4 (Fig. 8, E) showed a progressive decrease in size and colloidal uptake in the right lobe. An area corresponding to a hypertrophied caudate lobe or a medial portion of the right lobe became enlarged and trapped more colloid. There was also increased activity in the iung and thoracic cage bone marrow. When the patient was discharged on June 7, the width of the liver was 10 cm on Clinical examination. Two days later, pain developed in both lower legs and in the right lower chest, accompanied by severe respiratory dtstress , and she died despite emergency measures. Autopsy was not performed; however, the immed iate cause of death was judged to be pulmonary embolism.
DISCUSSION
Occlusion of the hepatic veins is a relatively rare condition; usually of unknown etiology. It is commonly designated as the Budd-Chiari syndrome, which like so many other eponyms in medicine is imprecise: Budd's description in 1845 omitted the clinical features (12), while Chiari, more than 50 years later, was neither the first to report the cliilical picture nor the first to conceive its importance (13). Parker presented the single most exhaustive review of the literature in 1959, recording 149 instances of symptomatic hepatic vein occlusion (14). In 1968, Ramsay and Britton stated that more than 500 cases had been reported (15) . Asymptomatic cases consisting of incidental findings at autopsy have
been documented (14) but are not the subject of this report. Major causes of symptomatic hepatic vein occlusion have been reviewed by Parker (14). The etiology was unknown in two-thirds of cases. Polycythemia was the most common associated condition in cases of known etiology, accounting for about 30 %; this is congruent with the known generalized thrombotic tendency in polycythemia as cited in an autopsy series of 250 patients, in which thrombotic complications occurred in 63 % and death was attributed to thrombosis in 40% (16). Hypernephroma and tumors of the vena cava were second and third in incidence, while other etiologies accounted for only one or a small number of cases each. PNH should be added to this list, as should the use of oral contraceptives, which has been cited in 8 cases (16, 17). Poisoning by pyrrolidine (senecio) alkaloids, such as those found in Jamaican bush teas and related plants, appear to be associated primarily with hepatic endophlebitis (18) and will not be considered here. The major clinical features of HVT are ascites, hepatomegaly, and abdominal pain (14). Less prominent or terminal features have included jaundice, nausea and vomiting, hernaternesis, and melena. Edema of the lower legs suggests associated thrombosis of the inferior vena cava (14), which has been noted in about 30% of cases; portal vein thrombosis has been seen in about 20% (14, 19). The precise pathophysiology of the
Vol. 117
Table II:
HEPATIC VENouS THROMBOSIS IN PAROXYSMAL NOCTURNAL HEMOGLOBINURIA
347
Nuclear Medicine
Postulated Pathophysiology of HVT Hepatic vein thrombos is
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Regenerat ion of periportal areas
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Acute in f ar ct ion with death
Cirrhosis
changes seen in association with HVT has not been established. TABLE " presents a tentative schema as derived from the observations of Parker (14) and from our pathological studies. Although the roles of hepatography, hepatic venography, and arteriography In the diagnosis of HVT have been amply described (15, 20, 21), very little has been said about the findings on radionuclide images of the liver. Claln et al. (5) reported 6 patients with Budd-Chiari syndrome, 5 of whom were studied with colloidal gold. Four showed reduced uptake in the right lobe, 1 had decreased activity in the left lobe, and 3 demonstrated excess splenic uptake. Chaudhuri et al. reported a single case and commented that the liver image "appeared almost the same as that in advanced cirrhosis of liver" (6). Our experience with HVT in PNH suggests that while an individual image cannot differentiate HVT from advanced cirrhosis, the rapidity of changes in the hepatic pattern is quite different from the slower progression seen in cirrhosis. Carulli et al. commented on liver images obtained in 3 patients in "the early stage of Budd-Chiari syndrome" (7). Increased splenic uptake and uneven distribution in the liver were noted. They suggested that the area of increased uptake between the right and left hepatic lobes may actually represent the caudate (Spiegel's) lobe . This lobe may remain uninvolved and capable of hypertrophy in HVT, since its venous drainage may be directly into the inferior vena cava. Hepatic venous thrombosis in paroxysmal nocturnal hemoglobinuria is probably just one of the manifestations of a generalized thrombotic tendency in this disorder (3), but it was the most common cause of death In our series. The clinical symptomatology and altered liver function have been detailed by Peytremann et al. (3). For the most part, these changes seem to be manifestations of late, irreversible disease; thus it was hoped that serial liver images might make diagnosis possible at an earlier stage. Thrombotic obstruction of the hepatic venous confluens might initially be expected to present only as an
Fig. 9. Gamma camera images of the liver in CASE 16. A. Study done on 4/13/73 demonstrates a large liver and "mottled" appearance. The spleen is enlarged but has uniform uptake. B. Study on 6/4/73 shows activity primarily in the upper middle region of the liver (?quadrate lobe). There is also a defect in the lower spleen and increased activity In the bone marrow. The view. ln the : upperleft corner shows the anterior liver, followed clockwise by the anterior spleen, posterior spleen , and right lateralliver.
enlarged, so-called " mottl ed" liver pattern. The progressive changes noted in our patients may represent involvement of smaller venous channels as well as destruction and regeneration of hepatic cells and attempts at recanalization. A case in point is that of the patient with PNH in CASE 16, who initially presented with clinical and laboratory findings suggesting HVT but showed only a massively enlarged, "mottled" liver on the radionuelide image. Within 2 weeks, changes typical of HVT developed, demonstrating clearly that the earliest manifestation of progressive, fulminating HVT may be only striking enlargement of the liver. This finding should be regarded as evidence of HVT in PNH unless it can easily be explained on another basis. Autopsy was not obtained in this patient, so that it was impossible to determine whether or not the predominant initial event might have been thrombosis in the hepatic venous confluens; nevertheless, the common denominator at autopsy in our cases of PNH with HVT was diffuse thrombosis in secondary and tertiary venous radicles (3). We now recommend that heparin therapy be promptly instituted for any unexplained and striking hepatic enlargement in a patient with PNH. If the clinical and
EDWARD V . STAAB AND OTHERS
348
laboratory features and liver pattern are not sufficiently diagnostic of HVT in the setting of PNH, further studies should be carried out. Clain et al. reported on the use of extensive invasive diagnostic procedures in the search for HVT in non-PNH patients (5); however, we urge that caution be exerted in PNH patients, who are generally prone to numerous complications. For example, thrombocytopenia is frequently present and may make needle biopsy of the liver risky, while infusions of platelets prior to biopsy may precipitate gross hemoglobinuria analogous to reactions to whole blood transfusions (4). The small amount of tissue obtained by liver biopsy may fail to reveal venous thrombosis but may show centrolobular congestion and necrosis, which is likely to be seen only in HVT or acute, severe right-sided congestive cardiac failure. While open liver biopsy has demonstrated thrombosis, the presence of severe liver damage makes the operative procedure far too great a risk (3). Likewise, one is naturally hesitant to carry out extensive venous catheterization studies in view' of the generalized thrombotic tendency in PNH. However, we have done so without seemingly untoward effects using preliminary heparinization. Radiologists are generally reluctant to carry out vascular catheterization if the patient has been on prolonged heparin therapy. We now suggest that if other, less invasive procedures are not diagnostic, a CO 2 study and hepatic venography be performed reasonably soon after heparinization is started. It is probably best to initially carry out hepatic venography via the right femoral vein in order to determine whether the inferior vena cava is patent or thrombosed; if thrombosis is discovered, hepatic venography should be carried out via the right jugular or brachial vein. There are other urgent reasons for making the decision whether to carry out such studies promptly. Delay produces further deterioration and complications such as progressively severe thrombocytopenia, making management and study even more difficult. Valuable time may also be lost in instituting heparin therapy, which is currently the best hope for at least temporary improvement.
SUMMARY Serial liver images and selected roentgenographic studies were carried out in 11 patients with paroxysmal nocturnal hemoglobinuria (PNH) during a 6-year period. Four patients had normal liver images and 3 had stable abnormalities without development of clinical hepatic venous thrombosis. Hepatic venous thrombosis (HVT) developed in 5 patients and was confirmed at autopsy in 4. Serial liver images of the 4 with HVT revealed changes which were helpful in the diagnosis of HVT in PNH when considered in the clinical setting: these included hepatic and splenic enlargement, unequal distribution of colloid in the various lobes of the liver, rapid changes in pattern, and extrahepatic uptake.
November 1975
ACKNOWLEDGMENTS: Without the facilities of the Clinical Research Center at Vanderbilt University Hospital, our observations and studies would have been impossible to conduct. We also wish to thank Miss Diane G. Grammer, Mrs. Frances R. Beaver, and Mrs. De Lois Popp for their expert secretarial assistance.
Department of Radiology Division of Nuclear Medicine University of North Carolina School of Medicine Chap~Hm,N.C. 27514
REFERENCES 1. Crosby WH: Paroxysmal nocturnal hemoglobinuria. A classic description by Paul Strubinq in 1882, and a bibliography of the disease. Blood 6:270-284, Mar 1951 2. Dacie JV: The Haemolytic Anaemias-Congenital and Acquired. Part 4: Drug-Induced Haemolytic Anaemias. New York, Grune & Stratton, 2d Ed, 1967 3. Peytremann R, Rhodes RS, Hartmann RC: Thrombosis in paroxysmal nocturnal hemoglobinuria (PNH) with particular reference to progressive, diffuse hepatic venous thrombosis. Ser Haematol 5:115-136, 1972 4. Hartmann RC, Kolhouse JF: Viewpoints on the management of paroxysmal nocturnal hemoglobinuria (PNH). Ser Haematol 5:42-60,1972 5. Clain D, Freston J, Kreel L, et al: Clinical diagnosis of the Budd-Chiari syndrome. A report of six cases. Am J Mad 43:544554, Oct 1967 6. Chaudhuri TK, Chaudhuri TK, Suzuki Y, et al: Liver scan in the Budd-Chiari syndrome. JAMA 221:506-507, 31 Jul1972 7. Carulli N, Boraldi F, Roncaia R, et al: Liver scans in the Budd-Chiari syndrome. JAMA 223:1161, 5 Mar 1973 8. Hartmann RC, Auditore JV: Paroxysmal nocturnal hemoglobinuria. I. Clinical studies. Am J Med 27:389-400, Sep 1959 9. Hartmann RC, Jenkins DE Jr, McKee LC, et al: Paroxysmal nocturnal hemoglobinuria: clinical and laboratory studies relating to iron metabolism and therapy with androgen and iron. Medicine 45: 331-363, Sep 1966 10. Patton DD, Garcia EN, Webber MM: Simplified preparation of technetium 99m sulfide colloid for liver scanning. Am J RoentgenoI97:880-885, Aug 1966 11. Bekerman C, Gottschalk A: Diagnostic significance of the relative uptake of liver compared with spleen in 99"'T c-sulfur colloid scintiphotography. J Nucl Med 12:237-240, May 1971 12. Budd G: On Diseases of the Liver. London, Churchill, 1845, p 146 13. Chiari H: Ueber der sejbstandlqe Phlebitis obliterans der Hauptstarnrne der Vena hepaticae als Todesursache. Beitr Pathol Anat 26:1-18, 1899 14. Parker RGF: Occlusion of the hepatic veins in man. Medicine 38:369-402, Dec 1959 15. Ramsay GC, Britton RC: Intraparenchymal angiography in the diagnosis of hepatic veno-occlusive diseases. Radiology 90: 716-726, Apr 1968 16. Chievitz E, Thiede T: Complications and causes of death in polycythaemia vera. Acta Med Scand 172:513-523, Nov 1962 17. Hoyumpa AM Jr, Schiff L, Helfman EL: Budd-Chiari syndrome in women taking oral contraceptives. Am J Med 50:137-140, Jan 1971 18. Sherlock S: Diseases of the Liver and Biliary System. Oxford, Blackwell; Philadelphia, Davis, 4th Ed, 1968, pp 245-250 19. Schreiber JT, Gonzalez LL: Thrombosis of hepatic veins and inferior vena cava. Relief by thoracic transposition of spleen. Am J Surg 113:807-811, Jun 1967 20. Pollard JJ, Nebesar RA: Altered hemodynamics in the Budd-Chiari syndrome demonstrated by selective hepatic and selective splenic angiography. Radiology 89:236-243, Aug 1967 21. Reuter SR, Redman HC: Gastrointestinal Angiography. Philadelphia, Saunders, 1972, p 233
