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Portal hypertension in infants and children with histiocytosis X
Portal Hypertension in Infants and Children with Histiocytosis X Jay L. Grosfeld, MD, Indianapolis, Indiana Joseph F. Fitzgerald, MD, Indianapolis, Indiana Virginia M. Wagner, MD, Indianapolis, Indiana William A. Newton, MD, Columbus, Ohio Robert L. Baehner, MD, Indianapolis, Indiana
Histiocytosis acterized
X describes
by histiocytic
loendothelial gland.
system,
The
duced
term,
skin,
syndromes:
are
granuloma.
disseminated
granuloma fecting mon
in nature
presents
bone.
and
and young
reticu-
pituitary
was
syndrome, former
intro-
three
often
disease, and (3) eo-
two syndromes
whereas
as a solitary
Disseminated
in infants
bones,
(1) Letterer-Siwe The
char-
of the
[I] and includes
(2) Hand-Schiiller-Christian sinophilic
spectrum
“histiocytosis-X,”
by Lichtenstein
overlapping
a disease infiltration
eosinophilic
lesion
usually
af-
disease
is more
com-
children
whereas
soli-
occurs more often in older children and adolescents. Newton and Hamoudi [3] divided the disseminated forms into two histopathologic types that have either a malignant or benign behavior and an acute or chronic course that cannot be differentiated clinically. The malignant form is characterized by a hemorrhagic eczematous rash, anemia, and hepatosplenomegaly due to diffuse histiocytic infiltration of the skin, bone marrow, lungs, lymph nodes, liver, spleen, intestinal submucosa, and rarely bone. It is usually refractory to therapy and often ends in early death. The benign form is always associated with lytic bone lesions and often with otitis, gingival involvement, skin rash, lymphadenopathy, hepatosplenomegaly, exophthalmos, and diabetes insipidus. This form often responds to chemotherapy, although a long protracted course is still the rule. Recent data suggest that modern chemotherapy has improved the prognosis in patients with histiotary
eosinophilic
granuloma
From the Section of Pediatric Surgery, Department of Surgery, and the Sections of Pediatric Gastroenterology and Pediatric Hematology-Oncology, lndttna University School of Medicine and The James Whitcomb Riley Hospftal for Children, Indianapolis, Indiana. Reprint requests should be addressed to Jay L. Grosfeld. MD, Surgaonin-Chief, James Whitcomb Riley Hospital for Children, 1100 West Michigan Street, Indianapolis, Indiana 46202. Presented at the Sixteenth Annual Meeting of the Society for Surgery of the Alimentary Tract, San Antonio, Texas, May 20-21. 1975.
108
cytosis X, since 71 per cent of affected infants and children now survive [3]. Sixty-three per cent of survivors, however, demonstrate some residual disability related to fibrosis of tissues previously infiltrated by histiocytes. In cases of liver involvement, healing by fibrosis may result in cirrhosis, leading to portal hypertension and bleeding of esophageal or gastric varices or both. Little attention has been given to this complication or its management in the literature. This report describes three children with histiocytosis X in whom cirrhosis, portal hypertension, and bleeding varices developed despite a good response to chemotherapy. These cases suggest that long-term survival is possible after portosystemic shunt procedures. Case Reports Case I. A thirteen month old boy was admitted to the James Whitcomb Riley Hospital for Children on February 2,1972 because of skin rash, cervical lymphadenopathy, hepatosplenomegaly, and gingival lesions. Skin and gingival biopsies both showed histiocytic infiltration. An x-ray film of the mandible demonstrated a lytic lesion. The liver was palpable, and percutaneous biopsy showed periportal histiocytic infiltration. The diagnosis of disseminated histiocytosis was made. Monthly cycles of chemotherapy including Velban@, prednisone, methotrexate, and Cytoxane were started. The mandible and involved gingival areas received 1,000 r of x-ray therapy. Persistent hepatosplenomegaly led to his readmission at the age of twenty-five months. Repeated liver biopsy showed cirrhosis with wide interportal fibrous bands and fine septa dividing the parenchyma into pseudolobules of various size. There was no evidence of active histiocytosis. Liver function studies gave normal results with the exception of a 45 minute Bromsulphaleine retention of 9.5 per cent. Chemotherapy was discontinued in August 1974. Ascites developed in the ensuing month which was treated with salt restriction, infusion of saltpoor albumin, and diuretics.
The American Journal of Surgery
Portal Hypertension
1. Cm I. Views of am&gram esopbagsal varlces.
F&we
auggsative
of
The onset of gastrointestinal. hemorrhage (hematemesis and hematochezia) led to his third hospital admission on October 15, 1974. The liver was palpable 5.0 cm below the right costal margin in the midclavicular line, and the spleen was palpable 7.0 cm below the left costal margin. Ascites was noted. Laboratory data showed an admission hemoglobin of 6.9 gm/lOO ml and a hematocrit of 21 per cent. The total bilirubin was elevated at 3.0 mg/lOO ml, serum glutamic oxalacetic transaminase was minimally elevated at 58 international units, and the alkaline phosphatase, prothrombin activity, and serum ammonia levels were within normal limits. Total serum proteins were.within the normal range, and the serum albumin was 3.3 gm/lOO ml. The platelet count was reduced at 70,000 per mm3 whereas the fibrinogen level and partial thromboplastin time were normal. An esophogram was suggestive of esophageal varices (Figure 1); esophagoscopy confirmed this finding. After blood transfusion, the hemoglobin was 10.1 gm/lOO ml and the hematocrit 32 per cent. The bleeding stopped, and diuretic therapy relieved the ascites. A second episode of hematemesis occurred during this hospitalization. On November 1, 1974, a splenoportogram was obtained; the splenic pulp pressure was 475 mm of water. Tortuous collateral veins, a large coronary vein, and multiple esophageal varices were demonstrated. (Figure 2.) The portal vein was 11 mm in diameter and significant hepatopetal flow was noted. Laparotomy demonstrated that the liver was enlarged, hard, and fibrotic. A 1.2 cm side-to-side portacaval shunt was performed because of ascites and significant hepatopetal flow. Postshunt manometry demonstrated a decrease in the portal pressure to 275 mm of water. The postoperative course
Vohma 131, January 1976
F&u 2. Case I. Anteroposterlor vlew of sptenoporiogram showlng collateral venous trffndades and esoghapal varkes. Spknk pulp peswfe was 475 mm of water.
Flpue 3. Case I. Mlcroscopfc appeararm, (ori@nal megnlftcathm X3) of open liver blqwy showed d&se macronoddar ckrhodo wHh dense bands of ffbrous connectlve tlssue per@orial ln spaces. was uncomplicated; the spleen decreased dramatically in size, and the ascites resolved. No further episodes of bleeding have occurred. Liver biopsy obtained at the time of the operation demonstrated diffuse macronodular cirrhosis with dense bands of collagenized connective tissue connecting portal spaces and prominent proliferation of bile ducts. (Figure 3.) This pattern was thought to be consistent with cirrhosis due to healed histiocytosis X. The child is now five years of age, asymptomatic, and shows no evidence of further bleeding or postoperative encephalopathy.
109
et Grosfeld
al
Figure 4. Case II. Selective celiac angiogram shows a large superior mesenteric vein and esophageal varlces. Case II. A fourteen month old girl had an eczematous rash on the scalp and upper part of the chest. Hepatosplenomegaly and cervical lymphadenopathy were noted at the age of twenty months when the family sought medical advice. A poor growth and developmental pattern coincided with these findings. The patient was seen for evaluation at the James Whitcomh Riley Hospital for Children on the Indiana University Medical Center campus in December 1966. A skin biopsy was obtained and demonstrated histiocytic infiltration of the dermis with invasion of the epidermis consistent with a diagnosis of histiocytosis X. The administration of prednisone and 6-mercaptopurine was begun. In October 1967 she had gastrointestinal bleeding in the form of hematemesis and melena. Hepatosplenomegaly had persisted. The bleeding ceased spontaneously. An esophogram obtained during that admission was noncontributory. A second hemorrhage occurred in February 1968. The hemoglobin fell to 6.6 gm/lOO ml and the hematocrit to 20 per cent; the bilirubin was 1.0 mg/lOO ml, albumin 2.6 gm/lOO ml, total protein 5.5 gm/lOO ml, and prothrombin activity 15 per cent of control. Appropriate transfusion and vitamin K therapy were employed. The patient was receiving methotrexate, prednisone, and Ci-mercaptopurine therapy. An additional episode of upper gastrointestinal bleeding occurred in 1970. The patient was referred to the Pediatric Surgical Service in October 1972. By this time, she had had six episodes of gastrointestinal bleeding and was seven years of age. An esophogram demonstrated large esophageal varices which were confirmed endoscopically. The platelet count was 66,000 per mms, alkaline phosphatase 202 units, white blood cell count 3,200 per mm3, and serum glutamic oxalacetic transaminase 214 units; prothrombin time was 50 per cent of normal, and serum albumin 2.9 gm/lOO ml. The liver edge extended 4 cm below the right costal margin, and the spleen 8 cm below
110
Figure 5. Case II. Splenoportogram demonstrates coronary and superb mesenteric vein with large esophageal varlces. the left costal margin. In this instance, hematemesis and melena followed an upper respiratory tract infection associated with an elevated temperature of 103’F for which she received aspirin. After appropriate stabilization and transfusion, a selective celiac and superior mesenteric angiogram demonstrated a large superior mesenteric vein and esophageal varices. (Figure 4.) Splenoportography was performed, and the pulp pressure measured 330 mm of water. A large coronary vein and esophageal and gastric varices were noted along with the large superior mesenteric vein. There ,was some flow through the portal systern. (Figure 5.) A mesocaval shunt was performed. The postshunt pressure was 160 mm of water: At the time of the procedure, minimal ascites was present and the liver was multinodular, fibrous, and shrunken in appearance. (Figure 6A.) A liver biopsy demonstrated islands of liver parenchyma surrounded by dense concentric layers of fibrous tissue. (Figure 6B.) Her postoperative course was uncomplicated. The child has been asymptomatic for two and a half years with neither recurrence of bleeding nor evidence of encephalopathy. The spleen continues to be enlarged, and evidence of hypersplenism persists with a platelet count of 66,000 per mm3. Case III. A two and a half year old white boy was admitted to the Columbus Children’s Hospital, Columbus, Ohio, in October 1955 because of an eczematous skin rash and a fracture of the right humerus which, on x-ray film, was noted to contain a lytic lesion. Polyuria and polydypsia were present. Physical examination showed hepatosplenomegaly with the liver edge palpated 4 cm below the right costal margin and the spleen 5 cm below the left costal margin. X-ray films demonstrated lytic lesions in many bones, including the skull, mastoid process, right humerus, and thoracic vertebral column. Biopsy of the humeral lesion at the fracture site showed “benign” histiocytosis. The administration of Pitressine
The
American Journal of Surgery
Portal Hypertension
Figure 6A. Case Il. Gross appearance of shrunken, flbrotk liver at the tlme of mesocaval shunt.
and Aminopterin was started, and radiation in a dose of 600 r was administered to the pituitary area. Audiometric testing revealed severe bilateral conductive hearing loss. Growth failure was noted over the ensuing three year period. The liver remained enlarged, and mild elevation of the bilirubin level was observed. The boy was then treated with oral methotrexate, 1.25 mg daily. Sixteen months later, at the age of seven years, clinical jaundice was noted and the liver was palpated 3 cm below the right midcostal margin; the spleen was greatly enlarged and palpable near the left iliac crest. Laboratory data showed a prolonged prothrombin time (less than 50 per cent of normal), serum glutamic oxalacetic/pyruvic transaminase levels of 190/110 units, total bilirubin of 18 mg/lOO ml (10.4 mg/lOO ml direct), total protein of 4.7 gm/lOO ml (2.9 gm/lOO ml of albumin). Liver biopsy showed diffusely nodular periportal fibrosis consistent with cirrhosis. The jaundice subsided, the patient’s condition gradually improved, and he was discharged. The patient was readmitted at the age of eight years because of hematemesis and melena. The liver and spleen were still palpable. The hemoglobin was 4.2 gm/lOO ml and total bilirubin was 2.3 mg/lOO ml (1 mg/lOO ml direct). Bromsulphalein retention was 28 per cent. Splenoportography revealed esophageal varices; -the splenic pulp pressure was 360 mm of water. At operation, the liver was green and diffusely nodular with nodules up to l/8 of an inch in diameter. A central splenorenal shunt was performed. No further episodes of gastrointestinal hemorrhage occurred. Aside from occasional episodes of mastoiditis, the clinical course was uneventful over a fourteen year period. In June 1973, at the age of twenty years, a hard mass became palpable in the left lobe of the liver. Chest x-ray film suggested multiple pulmonary metastases, and ar-
teriography, a tumor. A percutaneous liver biopsy was consistent with a diagnosis of hepatoma. The patient
Vohma 131, January 1978
Fl@ure 66. Case II. Mkroscopk appearance of open liver bkpsy (or@lnal magnMlcatkn X 10) shows nodutar islands of liver parenchyma surrownted by dense concentric layers of fibrous tissue.
died shortly thereafter at home, and permission for necropsy was not obtained.
Chemotherapy has significantly improved the survival in infants and children with disseminated histiocytosis. Vinblastine, vincrktine, Cytoxan, 6mercaptopurine, prednisone, chlorambucil, and methotrexate have all been beneficial in the management of these patients [3+]. Response is often slow and improvement gradual so that long-term therapy (six to twelve months after there is no evidence of disease activity) is advised. The response to therapy is influenced considerably by the age of the patient, the histologic appearance of tissues, and evidence of organ dysfunction. A decreased response to therapy and increased mortality are observed in the youngest patients with a “malignant” histologic pattern and multiple organ system involvement. Lahey et al [3] noted a response to chemotherapy with survival in fifty-nine of eighty-three children (71 per cent) with disseminated histiocytosis (Children’s Cancer Study Group, [CCSG]). Twenty-two of fifty-nine survivors (37 per cent) in this study were completely well after successful treatment with chemotherapy. The thirty-seven additional children who survived (63 per cent) are living with some residual disability after similar therapy. Clinical sequelae result from the scarring effect of fibrous healing in areas of previously active disease; these include short stature, diabetes insipidus, exophthalmos, ear disorders, pulmonary
111
Grosfeld et al
TABLE I
Composite Data in Three Patients with Histiocytosis X with Portal Hypertension and Bleeding. Age at
Age at
Shunt
Portal Pressure (mm H,O)
Sex
Onset
Procedure
1
M
13 mo
4 yr
475
2 3
F M
14 mo 30 mo
7 yr 6 yr
360 335
Patient
insufficiency, and cirrhosis of the liver. Small stature results from vertebral collapse and scoliosis. There is some evidence this may also be related to growth hormone deficiency [ 71. Diabetes insipidus is seen in up to 20 per cent of survivors and is related to previous hypothalamic and pituitary involvement. Pitressin therapy is usually effective. Lung involvement may lead to chronic pulmonary fibrosis, emphysema, pneumothorax, and bronchiectasis. Mastoid involvement is often associated with mastoiditis, chronic otitis, cholesteatoma formation, and hearing loss. Liver involvement is usually present at the onset of the disease or shortly thereafter. Hepatosplenomegaly, jaundice, ascites, hypoalbuminemia, prolonged prothrombin time, elevated alkaline phosphatase levels, and Bromsulphalein retention are frequently observed. Histiocytes infiltrate periportal areas when active disease is present. As the patient gradually responds to chemotherapy, the affected areas apparently heal by fibrosis, and this results in cirrhosis. Histologic examination shows a characteristic dense “macronodular” cirrhotic pattern. These changes may result in portal venous hypertension and gastrointestinal bleeding from esophageal and gastric varices. The initial presentation may vary from mild episodes of bleeding to massive gastrointestinal hemorrhage. Lahey et al [3] described two children and Newton and Hamoudi [2] three such children who died of gastrointestinal hemorrhage and liver failure, documenting the potentially fatal sequeleae of liver involvement. The three patients in the present report demonstrate that portosystemic shunt procedures prevent further episodes of bleeding and can provide long-term survival in children with portal hypertension related to healed histiocytosis X. (Table I.) Portacaval, central splenorenal, and mesocaval shunts were equally successful in decompressing the portal venous bed in those cases. Despite evidence of some organ dysfunction in each of these children, general anesthesia and the shunt procedure were well tolerated. The three patients who received shunts had neither recurrence
112
Type
of Shunt
Side-to-side portacaval Mesocaval Central splenorenal
Rebleeding or Encephalopathy
Status
No
Well
7 mo
No No
Well 2.5 yr Died of hepatoma 14 yr later
of bleeding nor evidence of encephalopathy. In one patient (case III) a hepatoma developed in the cirrhotic liver fourteen years after the shunt procedure (at the age of twenty years) and he died of pulmonary metastases. This documents that a primary malignant lesion may develop in the cirrhotic liver associated with healed histiocytosis X.as has previously been well documented in cirrhosis from other causes. Even though hypersplenism with pancytopenia may be associated with histiocytosis X, splenectomy should be avoided. Early in the course of the disease, splenectomy should be withheld to avoid fatal or life-threatening infection in these young patients receiving immunosuppressive chemotherapy. Recent reports describing immunologic deficiency syndromes associated with Letterer-Siwe disease support this statement [8,9]. Splenectomy was unsuccessful in achieving remission in patients with pancytopenia in the Children’s Cancer Study Group. Pancytopenia and gastrointestinal bleeding occurring in children with a history of histiocytosis X demand thorough investigation for evidence of cirrhosis and portal hypertension. Portosystemic shunt procedures effectively relieve the threat of potentially fatal gastrointestinal hemorrhage and improve the opportunity for long-term survival in children with cirrhosis and portal hypertension due to healed histiocytosis X. Summary Histiocytosis X describes a disease characterized by histiocytic infiltration of the reticuloendothelial system, skin, bones, and pituitary gland. The disseminated form frequently occurs in infants and children. Chemotherapy has significantly improved the prognosis in this disorder. Sixtythree per cent of survivors, however, have some residual disability related to fibrosis of tissues previously infiltrated by histiocytes. In instances of liver involvement, healing by fibrosis may result in cirrhosis with portal hypertension and bleeding esophageal varices. Clinical findings include hepa-
The American Journal of Surgery
Portal Hypertension
tosplenomegaly, jaundice, ascites, hypoalbuminemia, prolonged prothrombin time, and Bromsulphalein retention. Histologic examination of the liver shows a characteristic dense “macronodular” periportal cirrhotic pattern. Three children with portal hypertension and bleeding varices due to healed histiocytosis X were successfully managed by portosystemic shunt procedures. Portacaval, mesocaval, and central splenorenal shunts were equally effective in relieving portal hypertension. These children had neither recurrence of bleeding nor evidence of encephalopathy. Two children remain well whereas in one patient a primary hepatoma developed fourteen years postshunt and he died of pulmonary metastases. Portosystemic shunt procedures effectively relieve the threat of potentially fatal variceal hemorrhage and improve the opportunity for long-term survival in children with cirrhosis and portal hypertension due to healed histiocytosis X.
References 1. Lichtenstein L: Histiocytosis-X. Arch Pathol56: 84. 1953. 2. Newton WA, Hamoudi AB: Histiocytosis: a histologic classification with clinical correlation, p 251. Perspectives in Pediatric Pathology, vol 1. Chicago, Year Book Medical, 1973. 3. Lahey ME, Borges W. Evans AE. Heyn R. Newton WA: Histiocytosis-X: comparison of three treatment regimens in chitdren. Proceedings of the Xth International Cancer Congress. 1970. (Children’s Cancer Study Group data). 4. Lahey ME: Prognosis in reticuloendotheliosis in children. J Ped&r 60: 644. 1962. 5. Starling KA. Fernbach DJ: Histiocytosis. p 337. Clinical Pediatric Oncology (Sutow WW et al, ed). St Louis, CV Mosby, 1973. 6. Jones B: Chemotherapy of reticuloendotheliosis. Can Chemother Rep 57: 110. 1973.
Volume 131, January 1976
7. Braunstein GD. Kohler PO: Pltultary function in Hand-SchiMar-
Christian disease. N.&g/J A.&d 286: 1225. 1972. 8. Cederbaum SD, Niwayama, G. Stiahm ER, Neemout RC. Ammann AJ. Berman W Jr: Comb&red immunodefictency manifested by Letterer-Siwe syndrome. Lancet 1: 958. 1972. 9. Barth RF, Khurana SK. Vergara GG, Lowman JT, Beckwtth JB: Rapidly fatal familial histlocytosis associated with eosinophilia and primary immunologic deficiency. Lsncet 2: 503. 1972.
Discussion Rajiv R. Varma (Milwaukee, WI): As you know, immunosuppressed patients are more likely to acquire Australia antigenemia and possibly chronic forms of liver disease. Jay L. Grosfeld (closing): First, a remark concerning the cirrhotic effect of methotrexate. As we know, methotrexate and a number of other drugs (including isoniazid and methyldopa) affect the liver. Among patients who demonstrated cirrhotic patterns, two of three children who underwent shunt procedures as well as a number of other children in the group study who died, had treatment with methotrexate. Two of the patients in this report received early methotrexate therapy and one did not; one of the two patients received methotrexate after a liver biopsy had already documented the presence of cirrhosis. Cirrhosis also occurred, however, in a patient who did not recieve methotrexate. Methotrexate is the drug of choice for long-term chemotherapy in patients with histiocytosis. The use of long-term courses of chemotherapy rather than just a single course has improved the prognosis for this disorder. I imagine the use of methotrexate will be continued in these patients, and its role as a possible cause of cirrhosis must be carefully evaluated in the future. These cases were presented to suggest that this form of cirrhosis may be a complication of healing. These afflicted children respond well to portesystemic shunts which may indeed be lifesaving procedures.
113
Histiocytosis acterized
X describes
by histiocytic
loendothelial gland.
system,
The
duced
term,
skin,
syndromes:
are
granuloma.
disseminated
granuloma fecting mon
in nature
presents
bone.
and
and young
reticu-
pituitary
was
syndrome, former
intro-
three
often
disease, and (3) eo-
two syndromes
whereas
as a solitary
Disseminated
in infants
bones,
(1) Letterer-Siwe The
char-
of the
[I] and includes
(2) Hand-Schiiller-Christian sinophilic
spectrum
“histiocytosis-X,”
by Lichtenstein
overlapping
a disease infiltration
eosinophilic
lesion
usually
af-
disease
is more
com-
children
whereas
soli-
occurs more often in older children and adolescents. Newton and Hamoudi [3] divided the disseminated forms into two histopathologic types that have either a malignant or benign behavior and an acute or chronic course that cannot be differentiated clinically. The malignant form is characterized by a hemorrhagic eczematous rash, anemia, and hepatosplenomegaly due to diffuse histiocytic infiltration of the skin, bone marrow, lungs, lymph nodes, liver, spleen, intestinal submucosa, and rarely bone. It is usually refractory to therapy and often ends in early death. The benign form is always associated with lytic bone lesions and often with otitis, gingival involvement, skin rash, lymphadenopathy, hepatosplenomegaly, exophthalmos, and diabetes insipidus. This form often responds to chemotherapy, although a long protracted course is still the rule. Recent data suggest that modern chemotherapy has improved the prognosis in patients with histiotary
eosinophilic
granuloma
From the Section of Pediatric Surgery, Department of Surgery, and the Sections of Pediatric Gastroenterology and Pediatric Hematology-Oncology, lndttna University School of Medicine and The James Whitcomb Riley Hospftal for Children, Indianapolis, Indiana. Reprint requests should be addressed to Jay L. Grosfeld. MD, Surgaonin-Chief, James Whitcomb Riley Hospital for Children, 1100 West Michigan Street, Indianapolis, Indiana 46202. Presented at the Sixteenth Annual Meeting of the Society for Surgery of the Alimentary Tract, San Antonio, Texas, May 20-21. 1975.
108
cytosis X, since 71 per cent of affected infants and children now survive [3]. Sixty-three per cent of survivors, however, demonstrate some residual disability related to fibrosis of tissues previously infiltrated by histiocytes. In cases of liver involvement, healing by fibrosis may result in cirrhosis, leading to portal hypertension and bleeding of esophageal or gastric varices or both. Little attention has been given to this complication or its management in the literature. This report describes three children with histiocytosis X in whom cirrhosis, portal hypertension, and bleeding varices developed despite a good response to chemotherapy. These cases suggest that long-term survival is possible after portosystemic shunt procedures. Case Reports Case I. A thirteen month old boy was admitted to the James Whitcomb Riley Hospital for Children on February 2,1972 because of skin rash, cervical lymphadenopathy, hepatosplenomegaly, and gingival lesions. Skin and gingival biopsies both showed histiocytic infiltration. An x-ray film of the mandible demonstrated a lytic lesion. The liver was palpable, and percutaneous biopsy showed periportal histiocytic infiltration. The diagnosis of disseminated histiocytosis was made. Monthly cycles of chemotherapy including Velban@, prednisone, methotrexate, and Cytoxane were started. The mandible and involved gingival areas received 1,000 r of x-ray therapy. Persistent hepatosplenomegaly led to his readmission at the age of twenty-five months. Repeated liver biopsy showed cirrhosis with wide interportal fibrous bands and fine septa dividing the parenchyma into pseudolobules of various size. There was no evidence of active histiocytosis. Liver function studies gave normal results with the exception of a 45 minute Bromsulphaleine retention of 9.5 per cent. Chemotherapy was discontinued in August 1974. Ascites developed in the ensuing month which was treated with salt restriction, infusion of saltpoor albumin, and diuretics.
The American Journal of Surgery
Portal Hypertension
1. Cm I. Views of am&gram esopbagsal varlces.
F&we
auggsative
of
The onset of gastrointestinal. hemorrhage (hematemesis and hematochezia) led to his third hospital admission on October 15, 1974. The liver was palpable 5.0 cm below the right costal margin in the midclavicular line, and the spleen was palpable 7.0 cm below the left costal margin. Ascites was noted. Laboratory data showed an admission hemoglobin of 6.9 gm/lOO ml and a hematocrit of 21 per cent. The total bilirubin was elevated at 3.0 mg/lOO ml, serum glutamic oxalacetic transaminase was minimally elevated at 58 international units, and the alkaline phosphatase, prothrombin activity, and serum ammonia levels were within normal limits. Total serum proteins were.within the normal range, and the serum albumin was 3.3 gm/lOO ml. The platelet count was reduced at 70,000 per mm3 whereas the fibrinogen level and partial thromboplastin time were normal. An esophogram was suggestive of esophageal varices (Figure 1); esophagoscopy confirmed this finding. After blood transfusion, the hemoglobin was 10.1 gm/lOO ml and the hematocrit 32 per cent. The bleeding stopped, and diuretic therapy relieved the ascites. A second episode of hematemesis occurred during this hospitalization. On November 1, 1974, a splenoportogram was obtained; the splenic pulp pressure was 475 mm of water. Tortuous collateral veins, a large coronary vein, and multiple esophageal varices were demonstrated. (Figure 2.) The portal vein was 11 mm in diameter and significant hepatopetal flow was noted. Laparotomy demonstrated that the liver was enlarged, hard, and fibrotic. A 1.2 cm side-to-side portacaval shunt was performed because of ascites and significant hepatopetal flow. Postshunt manometry demonstrated a decrease in the portal pressure to 275 mm of water. The postoperative course
Vohma 131, January 1976
F&u 2. Case I. Anteroposterlor vlew of sptenoporiogram showlng collateral venous trffndades and esoghapal varkes. Spknk pulp peswfe was 475 mm of water.
Flpue 3. Case I. Mlcroscopfc appeararm, (ori@nal megnlftcathm X3) of open liver blqwy showed d&se macronoddar ckrhodo wHh dense bands of ffbrous connectlve tlssue per@orial ln spaces. was uncomplicated; the spleen decreased dramatically in size, and the ascites resolved. No further episodes of bleeding have occurred. Liver biopsy obtained at the time of the operation demonstrated diffuse macronodular cirrhosis with dense bands of collagenized connective tissue connecting portal spaces and prominent proliferation of bile ducts. (Figure 3.) This pattern was thought to be consistent with cirrhosis due to healed histiocytosis X. The child is now five years of age, asymptomatic, and shows no evidence of further bleeding or postoperative encephalopathy.
109
et Grosfeld
al
Figure 4. Case II. Selective celiac angiogram shows a large superior mesenteric vein and esophageal varlces. Case II. A fourteen month old girl had an eczematous rash on the scalp and upper part of the chest. Hepatosplenomegaly and cervical lymphadenopathy were noted at the age of twenty months when the family sought medical advice. A poor growth and developmental pattern coincided with these findings. The patient was seen for evaluation at the James Whitcomh Riley Hospital for Children on the Indiana University Medical Center campus in December 1966. A skin biopsy was obtained and demonstrated histiocytic infiltration of the dermis with invasion of the epidermis consistent with a diagnosis of histiocytosis X. The administration of prednisone and 6-mercaptopurine was begun. In October 1967 she had gastrointestinal bleeding in the form of hematemesis and melena. Hepatosplenomegaly had persisted. The bleeding ceased spontaneously. An esophogram obtained during that admission was noncontributory. A second hemorrhage occurred in February 1968. The hemoglobin fell to 6.6 gm/lOO ml and the hematocrit to 20 per cent; the bilirubin was 1.0 mg/lOO ml, albumin 2.6 gm/lOO ml, total protein 5.5 gm/lOO ml, and prothrombin activity 15 per cent of control. Appropriate transfusion and vitamin K therapy were employed. The patient was receiving methotrexate, prednisone, and Ci-mercaptopurine therapy. An additional episode of upper gastrointestinal bleeding occurred in 1970. The patient was referred to the Pediatric Surgical Service in October 1972. By this time, she had had six episodes of gastrointestinal bleeding and was seven years of age. An esophogram demonstrated large esophageal varices which were confirmed endoscopically. The platelet count was 66,000 per mms, alkaline phosphatase 202 units, white blood cell count 3,200 per mm3, and serum glutamic oxalacetic transaminase 214 units; prothrombin time was 50 per cent of normal, and serum albumin 2.9 gm/lOO ml. The liver edge extended 4 cm below the right costal margin, and the spleen 8 cm below
110
Figure 5. Case II. Splenoportogram demonstrates coronary and superb mesenteric vein with large esophageal varlces. the left costal margin. In this instance, hematemesis and melena followed an upper respiratory tract infection associated with an elevated temperature of 103’F for which she received aspirin. After appropriate stabilization and transfusion, a selective celiac and superior mesenteric angiogram demonstrated a large superior mesenteric vein and esophageal varices. (Figure 4.) Splenoportography was performed, and the pulp pressure measured 330 mm of water. A large coronary vein and esophageal and gastric varices were noted along with the large superior mesenteric vein. There ,was some flow through the portal systern. (Figure 5.) A mesocaval shunt was performed. The postshunt pressure was 160 mm of water: At the time of the procedure, minimal ascites was present and the liver was multinodular, fibrous, and shrunken in appearance. (Figure 6A.) A liver biopsy demonstrated islands of liver parenchyma surrounded by dense concentric layers of fibrous tissue. (Figure 6B.) Her postoperative course was uncomplicated. The child has been asymptomatic for two and a half years with neither recurrence of bleeding nor evidence of encephalopathy. The spleen continues to be enlarged, and evidence of hypersplenism persists with a platelet count of 66,000 per mm3. Case III. A two and a half year old white boy was admitted to the Columbus Children’s Hospital, Columbus, Ohio, in October 1955 because of an eczematous skin rash and a fracture of the right humerus which, on x-ray film, was noted to contain a lytic lesion. Polyuria and polydypsia were present. Physical examination showed hepatosplenomegaly with the liver edge palpated 4 cm below the right costal margin and the spleen 5 cm below the left costal margin. X-ray films demonstrated lytic lesions in many bones, including the skull, mastoid process, right humerus, and thoracic vertebral column. Biopsy of the humeral lesion at the fracture site showed “benign” histiocytosis. The administration of Pitressine
The
American Journal of Surgery
Portal Hypertension
Figure 6A. Case Il. Gross appearance of shrunken, flbrotk liver at the tlme of mesocaval shunt.
and Aminopterin was started, and radiation in a dose of 600 r was administered to the pituitary area. Audiometric testing revealed severe bilateral conductive hearing loss. Growth failure was noted over the ensuing three year period. The liver remained enlarged, and mild elevation of the bilirubin level was observed. The boy was then treated with oral methotrexate, 1.25 mg daily. Sixteen months later, at the age of seven years, clinical jaundice was noted and the liver was palpated 3 cm below the right midcostal margin; the spleen was greatly enlarged and palpable near the left iliac crest. Laboratory data showed a prolonged prothrombin time (less than 50 per cent of normal), serum glutamic oxalacetic/pyruvic transaminase levels of 190/110 units, total bilirubin of 18 mg/lOO ml (10.4 mg/lOO ml direct), total protein of 4.7 gm/lOO ml (2.9 gm/lOO ml of albumin). Liver biopsy showed diffusely nodular periportal fibrosis consistent with cirrhosis. The jaundice subsided, the patient’s condition gradually improved, and he was discharged. The patient was readmitted at the age of eight years because of hematemesis and melena. The liver and spleen were still palpable. The hemoglobin was 4.2 gm/lOO ml and total bilirubin was 2.3 mg/lOO ml (1 mg/lOO ml direct). Bromsulphalein retention was 28 per cent. Splenoportography revealed esophageal varices; -the splenic pulp pressure was 360 mm of water. At operation, the liver was green and diffusely nodular with nodules up to l/8 of an inch in diameter. A central splenorenal shunt was performed. No further episodes of gastrointestinal hemorrhage occurred. Aside from occasional episodes of mastoiditis, the clinical course was uneventful over a fourteen year period. In June 1973, at the age of twenty years, a hard mass became palpable in the left lobe of the liver. Chest x-ray film suggested multiple pulmonary metastases, and ar-
teriography, a tumor. A percutaneous liver biopsy was consistent with a diagnosis of hepatoma. The patient
Vohma 131, January 1978
Fl@ure 66. Case II. Mkroscopk appearance of open liver bkpsy (or@lnal magnMlcatkn X 10) shows nodutar islands of liver parenchyma surrownted by dense concentric layers of fibrous tissue.
died shortly thereafter at home, and permission for necropsy was not obtained.
Chemotherapy has significantly improved the survival in infants and children with disseminated histiocytosis. Vinblastine, vincrktine, Cytoxan, 6mercaptopurine, prednisone, chlorambucil, and methotrexate have all been beneficial in the management of these patients [3+]. Response is often slow and improvement gradual so that long-term therapy (six to twelve months after there is no evidence of disease activity) is advised. The response to therapy is influenced considerably by the age of the patient, the histologic appearance of tissues, and evidence of organ dysfunction. A decreased response to therapy and increased mortality are observed in the youngest patients with a “malignant” histologic pattern and multiple organ system involvement. Lahey et al [3] noted a response to chemotherapy with survival in fifty-nine of eighty-three children (71 per cent) with disseminated histiocytosis (Children’s Cancer Study Group, [CCSG]). Twenty-two of fifty-nine survivors (37 per cent) in this study were completely well after successful treatment with chemotherapy. The thirty-seven additional children who survived (63 per cent) are living with some residual disability after similar therapy. Clinical sequelae result from the scarring effect of fibrous healing in areas of previously active disease; these include short stature, diabetes insipidus, exophthalmos, ear disorders, pulmonary
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Grosfeld et al
TABLE I
Composite Data in Three Patients with Histiocytosis X with Portal Hypertension and Bleeding. Age at
Age at
Shunt
Portal Pressure (mm H,O)
Sex
Onset
Procedure
1
M
13 mo
4 yr
475
2 3
F M
14 mo 30 mo
7 yr 6 yr
360 335
Patient
insufficiency, and cirrhosis of the liver. Small stature results from vertebral collapse and scoliosis. There is some evidence this may also be related to growth hormone deficiency [ 71. Diabetes insipidus is seen in up to 20 per cent of survivors and is related to previous hypothalamic and pituitary involvement. Pitressin therapy is usually effective. Lung involvement may lead to chronic pulmonary fibrosis, emphysema, pneumothorax, and bronchiectasis. Mastoid involvement is often associated with mastoiditis, chronic otitis, cholesteatoma formation, and hearing loss. Liver involvement is usually present at the onset of the disease or shortly thereafter. Hepatosplenomegaly, jaundice, ascites, hypoalbuminemia, prolonged prothrombin time, elevated alkaline phosphatase levels, and Bromsulphalein retention are frequently observed. Histiocytes infiltrate periportal areas when active disease is present. As the patient gradually responds to chemotherapy, the affected areas apparently heal by fibrosis, and this results in cirrhosis. Histologic examination shows a characteristic dense “macronodular” cirrhotic pattern. These changes may result in portal venous hypertension and gastrointestinal bleeding from esophageal and gastric varices. The initial presentation may vary from mild episodes of bleeding to massive gastrointestinal hemorrhage. Lahey et al [3] described two children and Newton and Hamoudi [2] three such children who died of gastrointestinal hemorrhage and liver failure, documenting the potentially fatal sequeleae of liver involvement. The three patients in the present report demonstrate that portosystemic shunt procedures prevent further episodes of bleeding and can provide long-term survival in children with portal hypertension related to healed histiocytosis X. (Table I.) Portacaval, central splenorenal, and mesocaval shunts were equally successful in decompressing the portal venous bed in those cases. Despite evidence of some organ dysfunction in each of these children, general anesthesia and the shunt procedure were well tolerated. The three patients who received shunts had neither recurrence
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Type
of Shunt
Side-to-side portacaval Mesocaval Central splenorenal
Rebleeding or Encephalopathy
Status
No
Well
7 mo
No No
Well 2.5 yr Died of hepatoma 14 yr later
of bleeding nor evidence of encephalopathy. In one patient (case III) a hepatoma developed in the cirrhotic liver fourteen years after the shunt procedure (at the age of twenty years) and he died of pulmonary metastases. This documents that a primary malignant lesion may develop in the cirrhotic liver associated with healed histiocytosis X.as has previously been well documented in cirrhosis from other causes. Even though hypersplenism with pancytopenia may be associated with histiocytosis X, splenectomy should be avoided. Early in the course of the disease, splenectomy should be withheld to avoid fatal or life-threatening infection in these young patients receiving immunosuppressive chemotherapy. Recent reports describing immunologic deficiency syndromes associated with Letterer-Siwe disease support this statement [8,9]. Splenectomy was unsuccessful in achieving remission in patients with pancytopenia in the Children’s Cancer Study Group. Pancytopenia and gastrointestinal bleeding occurring in children with a history of histiocytosis X demand thorough investigation for evidence of cirrhosis and portal hypertension. Portosystemic shunt procedures effectively relieve the threat of potentially fatal gastrointestinal hemorrhage and improve the opportunity for long-term survival in children with cirrhosis and portal hypertension due to healed histiocytosis X. Summary Histiocytosis X describes a disease characterized by histiocytic infiltration of the reticuloendothelial system, skin, bones, and pituitary gland. The disseminated form frequently occurs in infants and children. Chemotherapy has significantly improved the prognosis in this disorder. Sixtythree per cent of survivors, however, have some residual disability related to fibrosis of tissues previously infiltrated by histiocytes. In instances of liver involvement, healing by fibrosis may result in cirrhosis with portal hypertension and bleeding esophageal varices. Clinical findings include hepa-
The American Journal of Surgery
Portal Hypertension
tosplenomegaly, jaundice, ascites, hypoalbuminemia, prolonged prothrombin time, and Bromsulphalein retention. Histologic examination of the liver shows a characteristic dense “macronodular” periportal cirrhotic pattern. Three children with portal hypertension and bleeding varices due to healed histiocytosis X were successfully managed by portosystemic shunt procedures. Portacaval, mesocaval, and central splenorenal shunts were equally effective in relieving portal hypertension. These children had neither recurrence of bleeding nor evidence of encephalopathy. Two children remain well whereas in one patient a primary hepatoma developed fourteen years postshunt and he died of pulmonary metastases. Portosystemic shunt procedures effectively relieve the threat of potentially fatal variceal hemorrhage and improve the opportunity for long-term survival in children with cirrhosis and portal hypertension due to healed histiocytosis X.
References 1. Lichtenstein L: Histiocytosis-X. Arch Pathol56: 84. 1953. 2. Newton WA, Hamoudi AB: Histiocytosis: a histologic classification with clinical correlation, p 251. Perspectives in Pediatric Pathology, vol 1. Chicago, Year Book Medical, 1973. 3. Lahey ME, Borges W. Evans AE. Heyn R. Newton WA: Histiocytosis-X: comparison of three treatment regimens in chitdren. Proceedings of the Xth International Cancer Congress. 1970. (Children’s Cancer Study Group data). 4. Lahey ME: Prognosis in reticuloendotheliosis in children. J Ped&r 60: 644. 1962. 5. Starling KA. Fernbach DJ: Histiocytosis. p 337. Clinical Pediatric Oncology (Sutow WW et al, ed). St Louis, CV Mosby, 1973. 6. Jones B: Chemotherapy of reticuloendotheliosis. Can Chemother Rep 57: 110. 1973.
Volume 131, January 1976
7. Braunstein GD. Kohler PO: Pltultary function in Hand-SchiMar-
Christian disease. N.&g/J A.&d 286: 1225. 1972. 8. Cederbaum SD, Niwayama, G. Stiahm ER, Neemout RC. Ammann AJ. Berman W Jr: Comb&red immunodefictency manifested by Letterer-Siwe syndrome. Lancet 1: 958. 1972. 9. Barth RF, Khurana SK. Vergara GG, Lowman JT, Beckwtth JB: Rapidly fatal familial histlocytosis associated with eosinophilia and primary immunologic deficiency. Lsncet 2: 503. 1972.
Discussion Rajiv R. Varma (Milwaukee, WI): As you know, immunosuppressed patients are more likely to acquire Australia antigenemia and possibly chronic forms of liver disease. Jay L. Grosfeld (closing): First, a remark concerning the cirrhotic effect of methotrexate. As we know, methotrexate and a number of other drugs (including isoniazid and methyldopa) affect the liver. Among patients who demonstrated cirrhotic patterns, two of three children who underwent shunt procedures as well as a number of other children in the group study who died, had treatment with methotrexate. Two of the patients in this report received early methotrexate therapy and one did not; one of the two patients received methotrexate after a liver biopsy had already documented the presence of cirrhosis. Cirrhosis also occurred, however, in a patient who did not recieve methotrexate. Methotrexate is the drug of choice for long-term chemotherapy in patients with histiocytosis. The use of long-term courses of chemotherapy rather than just a single course has improved the prognosis for this disorder. I imagine the use of methotrexate will be continued in these patients, and its role as a possible cause of cirrhosis must be carefully evaluated in the future. These cases were presented to suggest that this form of cirrhosis may be a complication of healing. These afflicted children respond well to portesystemic shunts which may indeed be lifesaving procedures.
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