FUDIES on Abnormal Liver Function Tests Associated with Rheumatic

Abnormal Liver Function Test in Patients with Rheumatic

Disease with Special Reference to Elevated

Alkaline Phosphatase

Masataka KATSU,* M.D., Junichi OGAWA, M.D.,

Rokuro OSAKO, M.D., and Tohru ABE, M.D.

It has become widely known that liver could be involved separately in few diseased conditions. Since Mackey had described •glupoid Hepatitis•h in systemic lupus erythematodes, many papers have been written regarding to hepatic status in patients with collagen diseases. Of late, not only collagen diseases but also other diseased conditions such as liver cirrhosis has been reviewed with the light of immunoserology resulting in the occurrences of non-organ specific antibody in these diseases. It is very interesting to study liver status in patients with rheumatic fever because rheumatic fever has been considered to be one of the mem- bers of collagen diseases. In other words, question that whether or not there is any specific hepatic lesion enough to be called •grheumatic hepatitis•h will be discussed.

FUDIES on abnormal liver function tests associated with rheumatic fever are scarcely reported in recent literatures.1),2) But in fact, we experience cases with abnormal liver function tests. In these instances, it usually is very difficult to interpret whether these abnormalities resulted from rheumatic process directed to liver on just coincidence.

Lately we had patient with acute rheumatic fever who showed definite abnormal liver status manifested with jaundice and enlarged liver. It is the purpose of this paper to disclose this point in detail and determine whether or not there is any specific hepatic involvement in acute rheumatic fever and rheumatic heart disease enough to be called •grheumatic hepatitis•h.

From now on, rheumatic fever and rheumatic heart disease will be referred to rheumatic diseases.

MATERIALS AND METHODS

Seventeen cases of acute rheumatic fever and 10 of rheumatic heart disease were selected from in- and out-patients. Diagnosis of acute rheumatic fever

From the Department of Internal Medicine, Kawasaki City Hospital, Kawasaki, Kanagawa-ken. Visiting professor, Department of Internal Medicine, Keio University. Director of Kawasaki City Hospital. 12 Vol.6 LIVER FUNCTION IN RHEUMATIC DISEASE 13 No.1 was entertained if patient's conditionsfulfilled modified Jone's criteria for rheumatic fever. As liver function tests, total protein, A/G ratio, albumin, alpha-, beta-, gamma-globulin,icterus index (Meulengracht), cephalin cholesterol flocculation, zink turbidity, serum glutamic oxaloacetic and pyruvic transaminase, alkaline phosphatase(Al-P), total cholesterolwere determined. Normal values and methods applied were tabulated.

RESULTS As convenience sake, liver function tests were divided into 4 groups. Group 1 was colloidal reaction which included CCF and ZTT, group 2 was Al-P, group 3 was enzymatic studies and group 4 was the rests. As was shown in Table I, it was of note that Al-P was elevated out of proportion in its percentage. Elevation of the other tests except total cholesterol did not exceed more than 30 per cent. Comparison was made between each tests in order to see whether or not there was any relationship among them. Number of patients with elevated Al-P wasplotted horizontally against vertical scale of patients' number grouped by ZTT and CCF (Fig. 1). Correlation between colloidal reaction and SGOT, SGPT was made with same fashion as well as correlation between Al-P and SGOT, SGPT. Results disclosed that various function tests of liver did not move parallel in rheumatic diseases.

Table I. Patient's Number with Abnormal Liver Function Jap. Heart J. J 14 KATSU, OGAWA, OSAKO, AND ABE anuary, 1965

Fig. 1. Fig. 2.

Follow-up studies of these tests indicated that they changed from either abnormal to normal or vice versa in rather short periods of time. Furthermore, they did not reflect clinical improvement or aggravation. It was supposed that functional abnormality of liver in rheumatic diseases developed to that direction in which Al-P tended to elevate. Such being the case, special attention was placed on Al-P as the index of liver function test in this circum- stance. By using Al-P, correlation between clinical features and other laboratory tests was entertained. Next figure indicated relationship between Al-P activity and ESR, ASL-O titer. Upper one was Al-P and ESR, lower Al-P and ASL-O titer (Fig. 2). Patients were divided into 2 groups owing to electrocardiographic (ECG) findings. Al-P activity and ECG changes were correlated. No such correlation was noted. And so was true with cardiac diameter on radiological silhouette (Fig. 3). Lastly, level of Al-P activity was plotted against cardiac murmur at various sites. As was clear in the first column, most of patients with murmur at aortic valve showed abnormally high titer of Al-P. On the contrary, patients with murmur at mitral valve or no murmur tended to have normal Al-P activity. With the idea that Al-P activity might be influenced with therapeutic agents such as aspyrin or mode of administration, search was made only to see negative data. Vol.6 LIVER FUNCTION IN RHEUMATIC DISEASE 15 No.1 It has been well known that one of the most prominent histological ex- pression of rheumatic fever was Aschoff body. But it has been not reported such kind of nodules in liver tissue. Next table illustrates histological findings of liver in various diseased conditions in which Al-P often elevates. These are (1) specimen from patients with rheumatic fever and mitral stenosis (2) from patient with arteriosclerotic heart disease who had been in congestive heart failure and (3) from patient with fatty liver. Fibrinoid degeneration was not noted in this specimen. Although there was round cell infiltration in Glisson's sheath but it was far behind the one to be called Aschoff body. It was also failed to find definite picture of angitis in specimen from rheumatic fever. The other findings such as congestion, atrophy of liver cells

Fig. 3. Fig. 4.

Table II. Histological Findings in Few Diseased Conditions Jap. Heart J. J 16 KATSU, OGAWA, OSAKO, AND ABE anuary, 1965 were noted in all specimens with different degree and these were supposed to be non-specific changes.

CASE REPORT

Recently we had a chance to see a case of acute rheumatic fever with definite hepatic involvement. Case: H. H. 20 year-old female, office worker.3) This 20 year-old Japanese female was admitted with chief complaints of fever, muscle pain and jaundice for 10 day's duration. She had been well until 2 weeks P. T. A. when she had •gcold•h. She took •gpills•h and her symptoms seemed to subside without any sequelae. About 10 days later, fever spiked up to 39•Ž associated with severe muscle pain over her lower extremities. Private physician was called. She was treated as common cold. In spite of various medication, her symptoms got worse. At this time, she developed jaundice on her sclerae. She was referred to our hospital for further evaluation and treatment. Past histories were non-contributory except thyroidectomy for hyperthyroidism in 1963. No histories of blood transfusion and drug injection which might elicit liver damage. Family histories were non-contributory. Physical examination on admission: Alert and acutely ill patient lying in bed with supine position complained severe muscle pain. Temperature 37.8•Ž, pulse 68 regular, resp. 20. Anemia and jaundice were noted on both conjunctivae. Tongue was coated and tonsils were enlarged. Teeth were well repaired. No lymphadenopathies. Lung was clear to P and A. Heart was enlarged to left and Gr. III blowing systolic murmur was audible at apex radiating to left axilla. Abdomen was soft and flat. On palpation, liver was felt about 3 F.B. below right costal margin. Surface was smooth and edge was sharp. No pedal edema noted. Almost all muscles over lower extremities were painful to touch but no joint swelling noted. Laboratory findings: Pertinent informations of laboratory findings were noted in the figure. Hospital course: On admission, rheumatic fever, Wail's disease and subacute bacterial endocarditis were considered as possible diagnosis. After necessary examinations were performed, streptomycin of 2 Gm. daily was instituted for possible infectious disease. Later all laboratory findings pointed to rheumatic fever and treated as such. Intra-venous administration of steriod hormone was given concomitantly with erythromysin P. O. Patient became free from fever and muscle pain shortly after this regimen. ECG on admission showed interference dissociation which became 1•‹ A-V block 2 weeks later, then converted to normal sinus rhythm at the end of hospita- lization. Along with ECG improvement, cardiac enlargement as well as jaundice improved. On discharge, cardiac murmur had disappeared.

DISCUSSION

Generally speaking, functional disorder of liver in infectious diseases were said to be (1) serum colloidal reaction becomes positive (2) in electropho- Vol.6 No.1 LIVER FUNCTION IN RHEUMATIC DISEASE 17

retic pattern, gamma-globulin increases with concomitant decrease albumin

resulting in reverse A/G ratio (3) BSP and Al-P may become abnormal.

Take rheumatic fever for instance, since it is infectious disease in some

sence, functional disorder of liver can be postulated to become so. ZTT and

CCF have been reported to elevate in some rheumatic diseases.4) In our

series, about 20-30% of patients showed abnormal results. Formally these

abnormal values had been thought to indicate true hepatic damage. How-

ever, since liver biopsy became available, it was thought that abnormality

did not necessarily indicate true hepatic damage.

It is true that abnormal function of liver manifested by elevated Al-P

might be induced by therapeutic agents.5) In rheumatic fever, aspyrin had

been mostly concerned with this respect. Some author considers abnormal

Al-P activity could be induced by ketoacidosis due to aspyrin. Haris6) et al.

pointed out hepatic damage not related to congestive heart failure in rheumatic fever about 2 weeks after corticosteroid treatment. It occurred about

one third of patients thus treated.

Recent studies about serum factor which might influence to colloidal

reaction resulted in the fact that•gfalse positive•h might be encountered in

patients with dysprotenemia. In these patients, abnormal CCF and ZTT were not indicative of hepatic damage.

As was already shown, elevated Al-P activity and SGOT, SGPT which

were more specifically indicative of hepatic damage did not proportionate with

colloidal reactions. This is another evidence that abnormal colloidal reactions in rheumatic diseases is not necessarily represent true hepatic damage.

Moreover, evidence that colloidal abnormalities were caused by therapeu-

tic agents especially by aspyrin was not obtained in our survey. This point

makes us raise some skepticism that former explanation. Elevated Al-P

activity in our cases was noted in about 50% and SGOT, SGPT in about 10%.

Besides, these changes were temporary and reversible. Conditions under

which Al-P elevated with normal SGOT, SGPT are said to be (1) congestive heart faifure (2) fatty liver (3) obstruction of bile duct in wider sence . In regards to item (1), 4 out of 18 patients with congestive heart failure showed elevated Al-P. All 4 patients who had elevated Al-P showed clinical signs of heart failure manifested by basal rales and pedal edema . On the contrary, none of rheumatic patients with elevated Al-P showed clinical signs of failure. Admittedly congestive heart failure can be subclinical, it still is not enough to explain elevated Al-P in rheumatic diseases on this item . Next pertaining to item (2)- fatty liver- in which liver function might reveal obstructive changes, can be ruled out by other abnormal function test.

Moderately advanced fatty liver usually shows multiple abnormalities of func- Jap. Heart J. J 18 KATSU, OGAWA, OSAKO, AND ABE anuary, 1965

Table III. Liver Function Status in Three Different Diseases in Which AL-P Tends to be Elevated

tion tests. And abnormalities in this condition can not be transitory. Lastly, obstruction of bile duct again can be elicited by therapeutic agents such as chlorpromazin and anabolic steroids. But looking back our cases from this point of view, no histories of such medication were obtained in even single case. Next figure summarizes those situations. Here again, liver status in rheumatic diseases is not exactly same with the other two. Congestive heart failure in rheumatic conditions even it were subclinical can be one reason for elevated Al-P activity. But it can not wholly explain such high percentage abnormality. Besides this, obstruction of cholangioles, sinusoid or Disse's chamber by edematous swelling due to rheumatic process should be considered for another possible explanation. And allergic conditions elucidated by rheumatic diseases might have something to do with Al-P elevation. It might be speculated that same rheumatic process directed to heart to such degree that cause ECG changes and valvular lesion induces hepatic involvement. Of late, in some cases of rheumatic fever, non-organ specific anti-liver antibody was detected. This again points to the influence of allergy in rheumatic fever to develop clinical and laboratory findings. But this antibody was not considered to be hepatotoxin in general.7),8) On the other hand, there are investigators who still think that antigen-antibody reaction in bile duct is capable of destruction of liver cells,9) although antigen and antibdoy are not toxic separately. With all speculation that rheumatic hepatitis could be present, we failed to depict any specific liver lesion for rheumatic origin histologically. Klinge10) described nodular or map-like hyaline fibrinoid degeneration in lobules and mononuclear or polynuclear white cell infiltration into sinusoid surrounded by capillaries in liver from rheumatic fever. This change was referred to focal necrosis of liver. Vol. 6 No. 1 LIVER FUNCTION IN RHEUMATIC DISEASE 19

In our cases, we failed to find this kind of changes. This does not mean

Klinge's description did not speak to the point. Because even histological changes seem to be temporary and reversible.

SUMMARY

(1) Twenty-seven cases of rheumatic fever and rheumatic heart disease were examined for liver status.

(2) In 50%, Al-P was elevated. Other liver function tests were abnormal with lesser degree.

(3) No correlation between elevated Al-P and ZTT, CCF, ESR, ASL-O titer, SGOT, SGPT, EGG findings and clinical course.

(4) Elevated Al-P activity tended to develop among patients with murmur at aortic valve.

(5) These abnormalities seemed to be temporary and reversible.

(6) No specific histological findings enough to be called •grheumatic hepatitis•h were noted in histological examinations.

(7) Possible causative factors for elevated Al-P in rheumatic diseases were discussed.

REFERENCE

1. Diechhoff.: Allergic u. Asthma. LPZ. 4: 230, 1958. 2. Wilson, M. G.: Advances in Rheumatic Fever. Harper & Row, Publishers, New York, 1962.

3. Katsu, M. et al.: Case report, read at the 7th Regional Meeting, J. R. A., 1963. 4. Kunkel, H. G.: Am. J. Med. 4: 201, 1948. 5. Lutembacher, P. R.: Sem. Hos. Paris, 2686, Nov. 1958.

6. Haris, et al.: cited from (5). 7. Gajdusek, D. C. et al.: Brit. Med. J. II: 1019, 1958. 8. Katsu, M. et al.: presented at the 8th J. R. A. 1964.

9. Paronetto, F. et al.: Gastroenterology. 43: 539, 1962. 10. Klinge, F.: Erg. Allg. Path. u. Path. Anatomie 27: 94, 1933.