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Toxicity to Para-aminosalicylic Acid and Isoniazid
Toxicity to Para-aminosalicylic Acid and Isoniazid JOSEPH ADRIANY, M.D., F.C .C.P.· Mount Vernon, Missouri
PRIMUM NON NOCERE: this advice of the ancients to physicians is still with us today. We have to remember it whenever we treat patients with drugs. A case of toxicity developing after administration of para-aminosalicylic acid (PAS) and isoniazid (INH) is described. This 62 year-old white woman who was admitted for treatment of pulmonary tuberculosis November I, 1957, had Mycobacterium tuberculosis in her sputum and x-ray film showing extensive 1n1lltration in the whole left lung field . A complete blood count done shortly before admission showed normal red blood count and hemoglobin, also normal white count and ditJerential count. On adm1ss1on, slight anemia was present with 11 grams of hemoglobin, white count and ditJerent1al was within normal limits. Before adm1ss1on, she was treated daily with streptomycin injections for a period of one month. She was started on para-aminosalicylic acid 15 grams daily and isonicotinic acid hydrazid 200 mlligrams daily on November 5, 1957. Her fever soon subsided and in January, 1958 her temperature became normal. Her blood study in December, 1957 showed slight anemia and granulocytopenia of 30 per cent and lymphocytosis of 66 per cent of a total count of 6,800 white cells. In December, she complained of gastrointestinal upsets and on January 31 she developed an erythematous rash all over her body. Pruritus was also present. The rash subsided, but reappeared on February 13. PAS was then discontinued for a week and she was discharged to home treatment on a regimen of PAS and INH in the usual dosage to be continued indefinitely. She continued to take these drugs at home, had gastrointestinal upsets and noticed a slowly increasing numbness in her lower limbs which became "stiff." Numbness appeared first in her toes, continued to feet, then appeared in her hands, these becoming increasingly clumsy. Due to this numbness and a lack of feeling in her feet, she became unable to walk in January, 1959. She was readmitted in February with symptoms of numbness and feeling of formication in all extremities and inability to walk even with help. Her blood study revealed slight anemia with 10 grams of hemoglobin granulocytopenia of 24 per cent, lymphocytosis of 76 per cent and 4,000 white blood cells. Peripheral blood smear showed anisocytosis, hypochromia, increase of lymphocytes with some prolymphocytic type of cells and an occasional lymphoblast, reduction in the number of platelets, and an occasional nucleated red blood cell. Morphologic appearance was suggestive of aleukemic lymphatic leukemia. Bone marrow biopsy showed no abnormality of maturation of the red blood cells and of the white cells, with a mild shift to the left, no increase of lymphocytes. There was no indication of leukemia. Another bone marrow biopsy done in April, 1959 showed only an overall decrease of cells of the erythroid series. Blood study repeated at weekly intervals showed further increase in lymphocytes up to 81 per cent, granulocytopenia 15 per cent and a decrease of hemoglobin to 7.9 grams. After a single blood transfusion her hemoglobin increased to 12.1 grams. However, lymphocytosis and granulocytopenia persisted. She was treated with pyridoxine, vitamin B complex and trtnsicon and showed clinical improvement. The numbness gradually disappeared, feeling in hands and feet returned, so she is now able to walk again without help.
In contrast to the damage to the hematopoetic system, the following case report illustrates another aspect of PAS and INH toxicity. W.B.: This 50 year-old white man was admitted March 9, 1954 with far advanced pulmonary tuberculosis. PAS, 12 grams dally, and INH, 300 m1l1grams daily, were started March 18, 1954 and continued regularly until April 19 when he developed fever. Until then, he was losing weight, having lost 12 pounds in two weks. However, x-ray films showed clearing of the 1n1lltration. On April 24, 1954, he had high fever and a generalized rash appeared. All medication was stopped and his temperature returned to normal May 4, 1954, but jaundice appeared. Isoniazid was tried again and his temperature increased to 103 0 • He became irrational, highly jaundiced requiring sedation and restraint. Later he ceased to respond, was moaning loudly, became more Jaundiced on May 8, 1954 and expired in hepatic coma May 9, 1954. Autopsy showed deep icterus, deeply bUe stained free fluid in the abdomen. The lungs
"Missouri state Sanatorium.
107
108
JOSEPH ADRIANY
July. 1960
showed tuberculosis and hemorrhagic infarction. Extensive degeneration necrosis was found in the liver parenchyma, with cords of regenerating tissue and proliferation of bUe ducts. <>ccas1onally there were seen solitary multinucleated giant cell formations which appeared to be fused regenerating epithelial tissue. The histological features were of acute yellow atrophy. Dr. D. Gorelick, pathologist, reported: "Findings reveal an acute yellow atrophy of the liver which, in view of the patient's history, was probably a toxic manifestation secondary to a reaction to para-aminosalicylic acid or isonicotinic acid hydrazide."
The following case of a fatal liver necrosis after treatment with PAS and INH is of a patient who underwent pneumonectomy for pulmonary tuberculosis successfully. This 61 year-old white woman was admitted in January, 1956. Her sputum contained acid-fast bacUli and her x-ray films revealed evidence of extensive tuberculosis in the left lung. PAS and INH were begun in January and left pleuropneumonectomy was performed in March, 1956. She was discharged in July, 1956 to continue PAS and INH at home. Symptoms of indigestion, swel11ng of abdomen, bulky stools, fatigue and malaise developed and she was readmitted in January, 1957. No active tuberculosis was found and PAS was discontinued. Jaundice appeared in March, 1957, when liver function tests showed bromsufalein retention of 61 per cent. There was slight increase in serum alkaline phosphatase to 10 Bodansky units. The findings were typical of hepatocellular jaundice. The jaundice increased gradually and she died in hepatic coma in AprU, 1957. Autopsy by Dr. Fred Coller revealed acute yellow atrophy of the liver on macroscopic and microscopic examination. Since the incubation period exceeded 10 months, viral hepatitis due to homologous serum hepatitis was considered unlikely.
Comment Symptoms of severe toxic reactions to PAS and INH appear only in a minority of patients and therefore are thought to be due to sensitization, possibly to a protein drug combination acting as antigen, the toxin then possibly developing from a combination of the antibody with the antigen acting on the liver interfering with the metabolism of the liver cells probably by injury to the enzymes. Investigation using PAS or INH combinations with proteins as antigens to produce allergy might possibly shed some light on this mystery.
PRIMUM NON NOCERE: this advice of the ancients to physicians is still with us today. We have to remember it whenever we treat patients with drugs. A case of toxicity developing after administration of para-aminosalicylic acid (PAS) and isoniazid (INH) is described. This 62 year-old white woman who was admitted for treatment of pulmonary tuberculosis November I, 1957, had Mycobacterium tuberculosis in her sputum and x-ray film showing extensive 1n1lltration in the whole left lung field . A complete blood count done shortly before admission showed normal red blood count and hemoglobin, also normal white count and ditJerential count. On adm1ss1on, slight anemia was present with 11 grams of hemoglobin, white count and ditJerent1al was within normal limits. Before adm1ss1on, she was treated daily with streptomycin injections for a period of one month. She was started on para-aminosalicylic acid 15 grams daily and isonicotinic acid hydrazid 200 mlligrams daily on November 5, 1957. Her fever soon subsided and in January, 1958 her temperature became normal. Her blood study in December, 1957 showed slight anemia and granulocytopenia of 30 per cent and lymphocytosis of 66 per cent of a total count of 6,800 white cells. In December, she complained of gastrointestinal upsets and on January 31 she developed an erythematous rash all over her body. Pruritus was also present. The rash subsided, but reappeared on February 13. PAS was then discontinued for a week and she was discharged to home treatment on a regimen of PAS and INH in the usual dosage to be continued indefinitely. She continued to take these drugs at home, had gastrointestinal upsets and noticed a slowly increasing numbness in her lower limbs which became "stiff." Numbness appeared first in her toes, continued to feet, then appeared in her hands, these becoming increasingly clumsy. Due to this numbness and a lack of feeling in her feet, she became unable to walk in January, 1959. She was readmitted in February with symptoms of numbness and feeling of formication in all extremities and inability to walk even with help. Her blood study revealed slight anemia with 10 grams of hemoglobin granulocytopenia of 24 per cent, lymphocytosis of 76 per cent and 4,000 white blood cells. Peripheral blood smear showed anisocytosis, hypochromia, increase of lymphocytes with some prolymphocytic type of cells and an occasional lymphoblast, reduction in the number of platelets, and an occasional nucleated red blood cell. Morphologic appearance was suggestive of aleukemic lymphatic leukemia. Bone marrow biopsy showed no abnormality of maturation of the red blood cells and of the white cells, with a mild shift to the left, no increase of lymphocytes. There was no indication of leukemia. Another bone marrow biopsy done in April, 1959 showed only an overall decrease of cells of the erythroid series. Blood study repeated at weekly intervals showed further increase in lymphocytes up to 81 per cent, granulocytopenia 15 per cent and a decrease of hemoglobin to 7.9 grams. After a single blood transfusion her hemoglobin increased to 12.1 grams. However, lymphocytosis and granulocytopenia persisted. She was treated with pyridoxine, vitamin B complex and trtnsicon and showed clinical improvement. The numbness gradually disappeared, feeling in hands and feet returned, so she is now able to walk again without help.
In contrast to the damage to the hematopoetic system, the following case report illustrates another aspect of PAS and INH toxicity. W.B.: This 50 year-old white man was admitted March 9, 1954 with far advanced pulmonary tuberculosis. PAS, 12 grams dally, and INH, 300 m1l1grams daily, were started March 18, 1954 and continued regularly until April 19 when he developed fever. Until then, he was losing weight, having lost 12 pounds in two weks. However, x-ray films showed clearing of the 1n1lltration. On April 24, 1954, he had high fever and a generalized rash appeared. All medication was stopped and his temperature returned to normal May 4, 1954, but jaundice appeared. Isoniazid was tried again and his temperature increased to 103 0 • He became irrational, highly jaundiced requiring sedation and restraint. Later he ceased to respond, was moaning loudly, became more Jaundiced on May 8, 1954 and expired in hepatic coma May 9, 1954. Autopsy showed deep icterus, deeply bUe stained free fluid in the abdomen. The lungs
"Missouri state Sanatorium.
107
108
JOSEPH ADRIANY
July. 1960
showed tuberculosis and hemorrhagic infarction. Extensive degeneration necrosis was found in the liver parenchyma, with cords of regenerating tissue and proliferation of bUe ducts. <>ccas1onally there were seen solitary multinucleated giant cell formations which appeared to be fused regenerating epithelial tissue. The histological features were of acute yellow atrophy. Dr. D. Gorelick, pathologist, reported: "Findings reveal an acute yellow atrophy of the liver which, in view of the patient's history, was probably a toxic manifestation secondary to a reaction to para-aminosalicylic acid or isonicotinic acid hydrazide."
The following case of a fatal liver necrosis after treatment with PAS and INH is of a patient who underwent pneumonectomy for pulmonary tuberculosis successfully. This 61 year-old white woman was admitted in January, 1956. Her sputum contained acid-fast bacUli and her x-ray films revealed evidence of extensive tuberculosis in the left lung. PAS and INH were begun in January and left pleuropneumonectomy was performed in March, 1956. She was discharged in July, 1956 to continue PAS and INH at home. Symptoms of indigestion, swel11ng of abdomen, bulky stools, fatigue and malaise developed and she was readmitted in January, 1957. No active tuberculosis was found and PAS was discontinued. Jaundice appeared in March, 1957, when liver function tests showed bromsufalein retention of 61 per cent. There was slight increase in serum alkaline phosphatase to 10 Bodansky units. The findings were typical of hepatocellular jaundice. The jaundice increased gradually and she died in hepatic coma in AprU, 1957. Autopsy by Dr. Fred Coller revealed acute yellow atrophy of the liver on macroscopic and microscopic examination. Since the incubation period exceeded 10 months, viral hepatitis due to homologous serum hepatitis was considered unlikely.
Comment Symptoms of severe toxic reactions to PAS and INH appear only in a minority of patients and therefore are thought to be due to sensitization, possibly to a protein drug combination acting as antigen, the toxin then possibly developing from a combination of the antibody with the antigen acting on the liver interfering with the metabolism of the liver cells probably by injury to the enzymes. Investigation using PAS or INH combinations with proteins as antigens to produce allergy might possibly shed some light on this mystery.