From the medical university clinic Basel — chief: Professor H. Staub

Hepatitis Therapy With Ascorbic Acid Infusions¹

Comparison with other therapies

By H. Baur and H. Staub

Ascorbic acid works in virucidal concentrations, which with its low toxicity can be also be achieved in humans without danger. The virucidal effect is known against the virus of lyssa, variola, poliomyelitis, herpes simplex, influenza, hoof-and-mouth disease etc. (literature of Jungblut, 1939 [see *]; Baur, 1952). It was natural to examine the effect of large doses of ascorbic acid also with virus hepatitis, after similar attempts had led to encouraging results with poliomyelitis in adults  (Baur, 1952). Earlier therapeutic investigations with hepatitis by Staub (1950) had led to the postulate that the blood circulation rate of the liver increased by raised fluid supply via intravenous infusions in addition to physical rest and application of heat. This measure was — to be able to compare —  maintained for the high ascorbic acid dosage. It became possible thereby to be able to comfortably administer the large ascorbic acid quantity, distributed continuously over several hours (instead of with repeated IV injections).

As criteria for the therapeutic effects, the following served: the progression of bilirubin concentration in the serum (duration from the beginning of therapy to the decline in serum bilirubin and attainment of the normal value); duration of the elimination of bilirubin, urobilin and/or urobilinogen in the urine; duration of the dysproteinaemia (Takata reaction); progression of the diuresis (diuresis initiation); weight curve; and duration of illness. In particular, the daily determination of serum bilirubin concentration permits one to recognize whether a therapy leads to a prompt effect, namely a definite decrease of the serum bilirubin.

The results of the hepatitis therapy with ascorbic acid infusions were compared with a set of hepatitis groups(195 cases), which had been treated since 1947 in various ways.

Methods

All cases of virus hepatitis received the following uniform basic treatment: Perfect bed rest, hot compresses over liver and abdomen, Carlsbad salts, daily s.c. or IV vitamins of the B-complex (2 cm³ Becozym Roche) and a with low fat, carbohydrate- and protein-rich food (daily 50 g fat, 120 g protein, 400 g carbohydrate).

The additional treatment measures since 1947 can be divided into the following groups:

1947—1950

1. 2 times daily 5 units insulin s.c. and 50 g glucose orally (31 cases).
2. 3 times 20 g Levulose orally (10 cases) ².
3. Multivitamin preparation orally or IM; or 10 mg vitamin K (Synkavit Roche) IM; or 50 mg nicotinic acid amide IM; or 30—60 mg vitamin E (tocopherol acetate) IM; or 50 mg Cortin IM (Percorten) — a total of 83 cases.
4. Aureomycin daily 1 g; Cholagogue such as Chols�ure [Chol-acid]; Hexamethylene-tetramine; up to 1 g methionine and 1 g choline daily orally (12 cases).

1950—1953

5. Daily 1 l. Ringer or saline solution IV (15 cases).
6. Daily 1 l. Ringer or saline solution IV with 50—100 g Laevulose ² and the following Vitamin preparations: B-complex (2—4 cm³ Becozym Roche); or 0.2—0.5 g ascorbic acid; or 10—20 mg vitamin K (Synkavit Roche) (18 cases).
7. Daily infusion of 1 l. Ringer solution and B-complex combined with 2—3 days fasting (see Staub, 1950, p. 392) (26 cases).
8. Daily IV infusion with 1 l. of physiological saline solution with 10 g ascorbic acid (11 cases) ³.

The duration of the therapy of the groups 1—4 amounted to on average 1 month, the duration of the daily infusions of the groups of 5 and 6 2—3 weeks, and the duration of the ascorbic acid infusions 5 days (3—9). Infusions lasted on average 3 hours.

In order to be able to judge the effect of the infusion treatments with and without high-dose ascorbic acid, the serum bilirubin concentration was determined daily. If this fell spontaneously during the first 3 days, then the treatment remained unchanged. If it rose or remained constant, then the intravenous infusions were applied starting at the 3^rd or 4^th day.

Since ascorbic acid disturbs the diazotization and thus the bilirubin determination, it must be removed before from the serum. This succeeds so far only by enzymatic ascorbic acid oxidation with the ascorbic acid oxidase from the ovary of — when possible, unripe — cucumbers (Cucumis sativus L.) or pumpkin [or gourd] skins (Cucurbita Pepo L, Szent-Gy�rgyi, 1930/31; Diemair and Zerban, 1944). 1.8 cm³ serum with 0,2 cm³ freshly pressed juice from cucumbers or pumpkin skins was incubated 1 hour at 37� and diazotised afterwards. The bilirubin was determined partly after the old method of Jendrassik and Czike with deproteinization of the serum, since 1953 with the method according to Powell (1944) without deproteinization. Samples of bilirubin-containing serum with ascorbic acid additive in-vitro (after incubation with freshly-pressed juices) resulted in  the same values as without ascorbic acid. Attempts to compensate for the ascorbic acid with larger quantities of nitrite led to no satisfactory result.

In some of the cases treated with ascorbic acid the course of the serum bilirubin concentration was compared with the intensity of the serum color (extinction coefficient for blue). The vital phase of the evaluation of the effect of the therapy, i.e. the beginning of the serum bilirubin decrease, could be determined thereby — despite the high ascorbic acid concentration in serum — with assurance.

The Takata reaction was carried out at +3� C (Baur, 1948).

² The Levulose was kindly put at our disposal by the company Inopharm A.G. (Laevosan) .

³ Redoxon Hoffmann La Roche, Basel, which the firm kindly made available to us.

Results

In Fig 1. those cases of hepatitis of  are arranged from 1947—1953, with which progress could be judged from repeated laboratory determinations. Group 1 with insulin and glucose treatment exhibits on the average the longest duration of the disease. Group 8 with infusion of 10 g ascorbic acid is characterized by the shortest times and the fastest bilirubin decrease. The groups with the other therapeutic trials lie between these two extremes. The short duration of the disease and/or recovery period with treatment with ascorbic acid infusions is particularly obvious in the comparison with the other groups of infusions (group 5—7; in Fig. 1 hatched). The time difference from the beginning of therapy to the serum bilirubin decrease between group 8 on the one hand and 7 and 6 on the other hand is also statistically significant (so far as permissible with the small number of the cases). (p < 1%; after R. A. Fischer, 1948).

Fig. 2 features 5 examples of the treatment with ascorbic acid infusions. It becomes clear how quickly after the beginning of therapy the decrease of the serum bilirubin begins and how at the same time the diuresis promptly increases. With the infusion treatments (group of 5—8) over 2—3 weeks, this [diuresis] rose approximately proportional to the amount of the infused quantity. The body weight dropped over same time period with infusions without ascorbic acid (group of 5—7) close to approximately 14 kg and rose with convalescence. In contrast thereto the majority of the cases infused with ascorbic acid exhibited a continuous weight increase up to approximately 1 kg despite identical diuresis rise from the outset. In each case the ascorbic acid infusions were tolerated without reactions. No unwanted side effects were to be observed. The patients were already after the first ascorbic acid infusions subjectively better than before, coincident with the abatement of the icterus, and exhibited a clear improvement of the appetite.

Discussion

It is difficult to decide how much of the results in question is to be attributed to epidemiological and constitutional factors or to the therapy. The insulin-glucose therapy was performed over 1947/48, as the lethality of the hepatitis epidemica in Basel still ranged from 9 to 7%, after it had risen in 1946 to 19% (Staub, 1946/47). Possibly the unfavorable results of the insulin-glucose therapy thereby stand in connection. In the years after 1948 hepatitis lethality dropped in Basel to 0—1%. Since 1950 the different infusion treatments were performed. In these years until today epidemiological conditions were relatively constant. Therefore a participation of epidemiological factors in the favorable result of the ascorbic acid therapy appears improbable.

In order to be able to determine the instant of serum bilirubin decrease accurately, the experiment arrangement required, for consideration for the infusion treatment with or without ascorbic acid, only those cases in which the serum bilirubin concentration during the first 3 hospital days rose or remained constant. A selection of the more difficult cases is thereby put forward also for treatment with ascorbic acid infusions. In all 8 studied groups the portion of Takata-positive cases was approximately similarly large (¹/₃-¹/₂, see Baur, 1948).

With assumption of a virucidal active mechanism, no vitamin effect of the ascorbic acid is the basis. It would work by its redox potential like a chemotherapy (for the applicable theoretical introductions see Baur, 1952). Except for direct virucidal effects of ascorbic acid, the following therapeutic active mechanisms are still to be considered: Direct improvement of liver functions (protein and carbohydrate metabolism); the liver cell needs ascorbic acid for its activity (H�jer, 1924; Sato and Narubu, 1905; Spellberg and Keeton, 1939); lack of ascorbic acid exists with hepatitis and liver cirrhosis (Gaivan, 1940; Gounelle and Marche, 1943; Tomaszewski, 1936; Pennetti and De Ritis, 1939); Ascorbic acid is protective during experimental liver damage (Milhorat and coworkers., 1940; Beyer, 1943). Also the tonic effect observed here of the ascorbic acid infusions points to a metabolic effect. Furthermore is to be discussed as possible ascorbic acid effect: a favorable influence of inflammatory tissue reactions (in particular the connective tissue); detoxification due to reversible oxidizability of the ascorbic acid; vulnerability of the membrane permeability; improvement of adrenal function; increased diuresis; protection against sensitization (see Mancuso, 1951; Delaunoy and Bardeu, 1953 etc). The nearly constant weight gain in this connection is remarkable after approximately 5 ascorbic acid infusions. The primary weight loss during infusion treatment without ascorbic acid speaks against a solely diuretic effect of the ascorbic acid.

Quantitative determination of bilirubin in the urine showed that during the serum bilirubin decrease no additional bilirubinuria exists: abatement of the icterus is based thus on decrease of bilirubin formation. In conjunction therewith the rapid serum bilirubin decrease allows the additional following explanation of the active mechanism after ascorbic acid infusions: Ascorbic acid works possibly by “loading” the shift of the redox potential toward the negative side, inhibits splitting of the porphyrin ring of the bilirubin chain molecule, and thereby interrupts bilirubin formation (Bersin). Corresponding influences of the ascorbic acid on cyclic bonds generally and porphyrin in particular are known (Ekman, 1944; Vestling, 1941; Watt and Lehmann, 1952).

IV Application of the ascorbic acid was here restricted to the experimental arrangement so could be compared it with earlier infusion treatments. It remains to be clarified whether similar results could not be achieved also by substantial oral dosage.

Summary. The intravenous infusion of daily 10 g ascorbic acid (redox on Roche) in 1 litre of physiological NaCl solution during 5 days over 1951—1952 with 11 cases of hepatitis epidemica led to acceleration of serum bilirubin decrease and of weight gain, to shortening of the elimination period of bilirubin, urobilin and urobilinogen in the urine, the dysproteinemia and the duration of the disease. This favorable effect is compared with other therapeutic trials of 195 hepatitis cases of 1947—1953, with and without infusions, and made particularly clear thus. The ascorbic acid infusions did not cause unwanted side effects. It is discussed whether the ascorbic acid works here only virucidally or by the metabolism of the patient.

Summary.[original English] Investigations carried out between 1951 and 1952 on 11 cases of hepatitis epidemica showed that the intravenous infusion of 10 gm. ascorbic acid (Redoxon ‘Roche’) in 1 litre physiological NaCl solution daily for 5 days accelerated decrease of serum bilirubin and increase in weight, reduced the period of urinary excretion of bilirubin, urobilin and urobilinogen, shortened the duration of dysproteinemia and illness. This result compared favorably with other therapeutic trials in 195 cases of hepatitis epidemica from 1947—1953 with and without infusions. The ascorbic acid infusions caused no undesired side-effects. The question whether ascorbic acid exerts here only virucidal effects or acts upon the metabolism of the patient is discussed.

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¹presented in part before the PD. Association of the medical faculty Basel on 17 December 1952.

From Schweizerische Medizinische Wochenschrift, 1952, Number 21., pp. 595-597.

Editor’s notes:

1. The figures Abb. 1. and 2., which were nearly illegible in the reproduced source, have been redrawn for clarity.
2. [*]The Jungeblut reference in the text calls out 1939, whereas the reference in the bibliography calls out 1937.

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