Skin Lesions in Viral Hepatitis Histologic and lmmunofluorescent Findings
TERRY D. WEISS, M.D. CHENG C. TSAI, M.D. ANDREW R. BALDASSARE,
M.D.
JACK ZUCKNER. M.D. St. Louis, Missouri
A variety of skin rashes are known to occur as a part of the serum sickness-like prodrome of acute viral hepatitis which is thought to be due to immune complex deposition. We report the histologic and immunofluorescent findings in the skin and the serologic abnormalities in a patient with both erythematous maculopapular and purpuric rashes. We found circulating hepatltls 6 surface antigen (HBsAg), hypocomplementemia and cutaneous vasculitis associated with deposition of immunoglobulin and complement in the skin. We could not demonstrate intradermal deposition of HBsAg, but the findings are consistent with the immune complex hypothesis. Rashes occur in about 5 per cent of patients with viral hepatitis [l]. Such abnormalities were first noted by Graves[ 21 who, in 1843, described an urticarial rash; this has since been reemphasized by Horsfall and Tamm [3], Braverman [4] and Lockshin and Hurley [5]. Other dermatologic abnormalities which may occur include maculopapular erythematous lesions, blotchy etythema, purpura [6], a scarlatiniform rash [7], nodules [8] and petechiae [9, lo]. In only one previous report has the histopathology of the skin been described [8]. Immunofluorescent findings have not been published. We describe a patient with hepatitis B surface antigen (HBsAg)-positive hepatitis who had two different dermatologic abnormalities. The histologic and immunofluorescent findings in the skin are described.
MATERIALS AND METHODS
From the Division of Rheumatology, Department of Internal Medicine and the Department of Pathology, St. Louis University School of Medicine, St. Louis, Missouri. Requests for reprints should be addressed to Dr. Terry D. Weiss, Division of Rheumatology, St. Louis University Hospital, 1325 South Grand Boulevard, St. Louis, Missouri 63 104. Manuscript accepted June 9, 1977.
Skin biopsy specimens of both maculopapular erythematous lesions and purpuric lesions were snap-frozen in liquid nitrogen and stored at -70°C. Six to 7 p sections were cut in a cryostat and stained directly with fluorescein-conjugated antihuman albumin, immunoglobulins G (IgG), M (IgM), A (IgA), and E (IgE), complement (C3) and fibrin/fibrinogen.* The sections were examined with a Leitz Ortholux fluorescent microscope. The resulting immunofluorescence was quantitated on a scale of 0 to 4-t. The indirect immunofluorescent technic was applied for the detection of HBsAg in the skin. The section was first stained with specific horse anti-HBsAg antiserum,+ washed and then counterstained globulin antiserum.f
Specificity
with fluorescein-labelled of the antiserum
rabbit antihorse
was tested by immunodif-
* Meloy Laboratories, Springfield, Virginia and Behring Diagnostics, Sommerville, New Jersey. t Cordis Corporation, Miami, Florida. t Sylvana Company, Milburn, New Jersey.
February
1978 The American Journal of Medicine
Volume 64
269
SKIN LESIONS IN VIRAL HEPATITIS-WEISS
ET AL.
fusion to which known HBsAg serum was used. Skin biopsy tissues for routine light microscopy were fixed in 10 per cent formalin and embedded in paraffin. Sections were cut 5 to 6 ~1thick and stained with hematoxylin and eosin, periodic acid-Schiff, methenamine silver and Masson trichrome counterstain. CASE REPORT An 18 year old white girl was admitted to St. Louis University Hospital on July 5, 1975, with a chief complaint of malaise, anorexia, nausea and right upper quadrant abdominal discomfort of several days’ duration. Ten days prior to admission, a pruritic rash developed beginning on the dorsal and palmar surfaces of her hands and spreading to involve both upper and lower extremities, but sparing the face and trunk. Five days prior to admission she was first examined and found to have a skin eruption over the arms and legs. The rash over the upper extremities consisted of 1 by 1 cm pink maculopapular lesions which blanched with pressure. The lesions over the legs and feet were purpuric and did not blanch. She was taking no medications, denied recent infections and, aside from the pruritis associated with the rashes, felt well. A skin biopsy specimen of each type of lesion was obtained and tripelennamine 50 mg, four times a day was prescribed. Over the next few days she experienced malaise, nausea, anorexia and right upper quadrant discomfort. The maculopapular rash over the upper extremities became purpuric; it was slightly raised. Three days prior to admission her urine became brownish orange and then red in color. A stool one day prior to admission was light gray in color. Further history disclosed that two months previously the patient had received gamma globulin because she had had contact with a friend in whom hepatitis developed. The patient had been followed for the previous four years because of a polyarthritis. She had pain and swelling in distal and proximal interphalangeal finger joints, wrists, elbows, shoulders, ankles and feet, and a diagnosis of juvenile rheumatoid arthritis was made. She was treated with salicylates and gold salts until one year prior to the present illness. Neither joint pain nor swelling had occurred for the previous three years. She had never had a rash associated with arthritis. Physical examination upon admission disclosed a well developed, well nourished, white girl in no acute distress. Temperature was 100.6’F, pulse rate 96 beats/min, respirations 20/min and blood pressure 100/70 mm Hg. There was a maculopapular purpuric rash over the right forearm and a diffuse macular purpuric rash over the lower extremities. The scleras were slightly icteric. The liver was 15 cm in vertical span and tender, and the spleen tip was palpable on deep inspiration. The remainder of the physical examination was within normal limits. Laboratory data on admission included a hemoglobulin level of 14 g, a hematocrit value of 42.7 per cent, a white blood cell count of 7,100/mm3 with 46 per cent polymorphonuclears, 48 per cent lymphocytes, 4 per cent monocytes, 1 per cent eosinophils and 1 per cent basophils. Platelets were adequate. The urine was amber and turbid with
270
February
1978
The American Journal of Medicine
pH 6, specific gravity 1.022. There was trace proteinuria, large ketonuria and 2-F bacteriuria. There were 10 to 12 white blood cells and 5 to 7 red blood cells/hpf; bilirubin was present and the urobilinogen was 8 Erlich units. Urine culture grew lo4 colonies of enterococci/ml. The blood urea nitrogen was 10 mg/lOO ml and the serum creatinine 0.7 mg/lOO ml. The serologic test for syphilis (VDRL) was not reactive. A chest film disclosed no abnormalities. The electrocardiogram showed first degree atrioventricular (A-V) block. The serum glutamate pyruvate transaminase (SGPT) was 948 mu/ml (normal 5 to 24 mU/ml), and lactate dehydrogenase (LDH) 395 mu/ml (normal 100 to 225 mU/ml), alkaline phosphatase 235 mu/ml (normal 30 to 85 mU/ml), total bilirubin 2.7 mg/lOO ml, total protein 6.1 mg/lOO ml and albumin 3.9 mg/lOO ml. A serum protein electrophoresis was normal. The prothrombin time was 11.9 seconds or 100 per cent. A monospot test was negative; HBsAg was present by radioimmunoassay. The erythrocyte sedimentation rate was 25 mm/hour (Westergren). Antinuclear antibody (ANA), antimitochondrial and antismooth muscle antibodies were not found. Two lupus erythematosus cell preparations were negative. Anti-DNA antibody was less than 1 pg (normal). A latex fixation test for rheumatoid factor was negative. The serum IgG was 862 mg/lOO ml (normal 800 to 1,800 mg/lOO ml), IgA 41.2 mg/lOO ml (normal 90 to 450 mg/lOO ml), IgM 205 mg/lOO ml (normal 70 to 280 mg/lOO ml). Cryoglobulins were not detected. Serum complement studies included C3 of 26 mg/lOO ml (normal 55 to 120 mg/lOO ml) and C4 of 2.4 mg/lOO ml (normal 20 to 50 mg/lOO ml). A liver-spleen scan with technetium sulfur colloid showed a moderately enlarged liver measuring 22 cm by 17.5 cm in horizontal and vertical dimensions, respectively. The spleen was enlarged measuring 16 to 17 cm in longest diameter in the posterior view. The hospital course was characterized by steady clinical improvement. On the third hospital day, the temperature returned to normal and remained normal for the rest of her stay. By the sixth day, the microscopic hematuria had cleared spontaneously. The anorexia began to clear by the seventh hospital day. At that time the SGOT level rose to 3,860 mU/ ml, the SGPT level to 1,463 mU/ml, alkaline phosphatase 300 mU/ml and total bilirubin to 5.9 mg/iOO ml. The prothrombin time was 15.5 seconds (57 per cent). The patient continued to improve clinically with loss of malaise, abdominal discomfort and anorexia, and return of normal appetite. She complained of intermittent arthralgias, but no arthritis was detected. The rashes faded. The patient was discharged on the 16th hospital day; her bilirubin was 1.9 mg/iOO ml, SGCT 202 mU/ml, alkaline phosphatase 142 mu/ml and prothrombin time 100 per cent. She was seen again eight days later and was feeling well. The liver was not enlarged and the spleen tip was just barely palpable. Total bilirubin was then 1.3 mg/lOO ml, SGOT 60 Sigma Units (SU) (normal 8 to 26 SU), alkaline phosphatase 37 SU (normal 9 to 35 SU) and SGPT 90 SU (normal 5 to 35 SU). She was last seen on November 11, 1975, at which time she felt well. Laboratory data at that time, including the erythrocyte sedimentation rate, urinalysis, SGOT, SGPT, LDH, alkaline phosphatase, C3 and C4 were all within normal limits.
Volume 64
SKIN LESIONS IN VIRAL HEPATITIS-WEISS ET AL.
Hematoxylin and eosin stain of lesion in upper Figure 1. extremity showing mild perivascular infiltration with chronic inflammatory
cells.
deposition in vessel walls and 3-F in the interstitium. HBsAg was not detected by indirect immunofluorescent technic. The skin from a purpuric lesion of a lower extremity showed a marked perivascular infiltrate in the dermis, again consisting mainly of lymphocytes and histiocytes (Figure 2A). Several small and medium-sized blood vessels showed fibrinoid necrosis of vessel walls and extravasation of erythrocytes (Figure 2B). Polymorphonuclear leukocyte dust was also present. One muscular artery in the subcutis had focal healing vasculitic changes. lmmunofluorescent study revealed 2+ fine and coarsely granular staining of IgM and C3 in vessel walls in the middle and lower dermis (Figure 3). Staining for fibrin/fibrinogen was 2-F in vessel walls and 3+ in the interstitium. HBsAg could not be detected. COMMENTS
RESULTS
The skin from a maculopapular lesion of an upper extremity showed perivascular mononuclear cell infiltration around many small to medium-sized vessels in the upper and middle dermis. The infiltrate consisted primarily of lymphocytes, plasma cells and occasional histiocytes (Figure 1). lmmunofluorescent study of this specimen failed to demonstrate IgG, IgM, IgA, and IgE. Stain for complement (C3) showed l-i- fine granular
There are a variety of extrahepatic manifestations of viral hepatitis [ 111. These manifestations can be categorized into three groups: polyarteritis nodosa, glomerulonephritis and a serum sickness-like syndrome. Polyarteritis has an onset characterized by fever, polyarthralgia, myalgia, rash and urticaria. This progresses with the appearance of peripheral neuropathy, hypertension, eosinophilia, hematuria and azotemia. Biopsy of liver and muscle has shown fibrinoid necrosis
A, hematoxylin and eosin stain of lesion in lower extremity showing more dense chronic inflammatory cell infiltration than in the lesion in the upper extremity. 6, hematoxylin and eosin stain of lower dermis of specimen shown in A revealing vaculitis with chronic inflammatory cell infiltrate throughout the vessel wall. Polymorphonuclear leukocyte dust is also present. Figure 2.
February 1978
The American Journal of Medicine
Volume 84
271
SKIN LESIONS IN VIRAL HEPATITIS-WEISS
ET AL.
trimity showing granular deposition of IgM in the vessel wall _^^I ^^^U__^-I I^ ‘L-
and acute inflammation in the walls of small arteries and arterioles. Staining of muscle tissue with fluoresceinlabelled antibody to Australia antigen has demonstrated deposits in arterial walls along the elastic membrane. There is persistent hepatitis B surface antigenemia. Early in the acute phase, serum complement is depressed and there are circulating immune complexes which appear to be composed of HBsAg and the homologous antibody. Thirty to 40 per cent of patients with polyarteritis nodosa have hepatitis B surface antigenemia [12-141. Glomerulonephritis may be either acute or chronic. In the three cases described by Kneisir et al. [ 151, the histopathology ranged from membranous to focal segmental to mesangiopathic glomerulonephritis. In the patient with membranous type, staining with fluorescein-labelled antibodies was positive for IgG, IgA, C3 and hepatitis B antigen in peripheral capillary loops and, to a a lesser extent, in the mesangium. In the patient with focal disease, there was focal segmental deposition of IgM, C3 and HBsAg. Electron microscopy demonstrated electron dense particles within sclerotic areas consistent with the ultrastructure of the Dane particles seen in HBsAg-positive serum. In the last case, using trichrome and methenamine silver stains, glomerular disease was characterized by mesangial cell
272
February 1978
The American Journal of Medicine
hyperplasia and diffuse, irregular thickening of peripheral capillary loops with “double contour basement membranes.” IgM, IgG, C3 and HBsAg were present in capillary loops and in the mesangium. Electron microscopy again demonstrated electron dense particles located primarily in the mesangial matrix and cytoplasm of mesangial cells. The case in this report exemplifies the serum sickness syndrome. Symptoms typically occur in anicteric hepatitis or in the preicteric period. They include rash, urticaria, polyarthralgia and, sometimes, arthritis. Symptoms precede jaundice by a few days to six weeks and last up to seven days or more. When these symptoms are acute, there is a depression of serum total hemolytic complement (CH&, C3 and C4 [ 10,161. Cryoprecipitates from patients with and without arthritis have been found [ 171. These consist of HBsAg, antiHBsAg, immunoglobulins and complement components. However, only those patients with arthritis have IgA, C3, C4 and C5 in these complexes. Further, the IgG in those patients with arthritis is predominantly of the complement fixing IgGr and IgG3 subtypes. The complement system appears to be activated by the alternate (properdin) pathway. The CH50 in synovial fluid is also diminished, and HBsAg has been demonstrated in synovial fluid by microcomplement fixation tests [ 181. The synovial fluid is usually inflammatory. Synovial fluid white blood cell counts range from less than 1,000 [ 9,18,19] to as high as 90,000/mm3 [ 191 and may have either a polymorphonuclear [ 19,201 or mononuclear [9,18,19] predominance. Synovial biopsy specimens have shown some vascular congestion and plugging, occasional scattered lymphocytes and rare neutrophils. Electron microscopic studies of the synovial tissue have shown necrosis of vascular endothelium of several small vessels. The cytoplasm and nuclei of these endothelial cells contain electron dense particles 200 to 250 A with clear centers which may represent the Australia antigen [20]. A variety of rashes have been reported as part of this serum sickness-like syndrome of viral hepatitis. These include urticaria [2-6,9,10,21], macular rashes [9,18], maculopapular eruptions [ 6,8, lo], circinate and annular erythematous plaques, erythematous, blanching nontender nodules [8], purpura [6], petechiae [ 9, lo] and a scarlatiniform rash [7]. Our patient had both purpuric and maculopapular erythematous lesions. We are aware of only one other report of a patient with viral hepatitis in whom a skin biopsy was performed. Wenzel et al. [8] biopsied an erythematous, blanching, nontender nodule. Upper dermal capillaries showed a perivascular cuffing of lymphocytes and plasma cells. Findings were similar in the maculopapular erythematous lesion in our patient, but the purpuric lesion showed fibrinoid necrosis and vasculitis.
Volume 84
SKIN LESIONS IN VIRAL HEPATITIS-WEISS
In our patient, immunoglobulins were not found in the maculopapular eruption, but IgM, C3 and fibrimfibrinogen were found in the purpuric lesion. The fact that the maculopapular rash subsequently became purpuric suggests that these rashes were at various stages of development. This would explain the different immunofluorescent findings. HBsAg was not found in the skin, and this may be a temporal phenomenon as well, i.e., the biopsies may have been performed during antibody excess. In addition to the rashes, our patient had arthralgias, hypocomplementemia, hematuria and pyuria. These are symptoms consistent with the serum sickness-like prodome, and the urine abnormalities might represent a transient glomerulitis. The data suggest that HBsAg positivity may be associated with a spectrum of disease ranging from a
ET AL.
serum sickness-like illness to glomerulonephritis to polyarteritis nodosa. Further, it would seem that these are immune complex diseases with complexes of HBsAg and the homologous antibody. As noted, these complexes have been found in the circulation, kidney, vessel walls and possibly in synovial tissue. We did not find evidence of HBsAg in the skin, but the possibility of its presence cannot be excluded. The presence of vasculitic skin lesions, hypocomplementemia, and intradermal immunoglobulin and complement deposits support the notion that this syndrome is a part of the spectrum of disease produced by immune complexes associated with HBsAg-positive viral hepatitis. ACKNOWLEDGMENT We gratefully acknowledge the assistance of Ms. Janet Kister.
skilled
technical
REFERENCES 1.
2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12.
Artenstein MS, Demis DJ: Recent advances in the diagnosis and treatment of viral diseases of the skin. N Engl J Med 270: 1101, 1964. Graves RJ: Clinical Lectures on the Practice of Medicine, Dublin, Fannin & Co., 1843, p 937. Horsfall FL Jr, Tamm I: Viral and Rickettsial Infections of Man. Philadelphia, J.B. Lippincott Co., 1965, p 985. Braverman IM: Skin Signs of Systemic Disease, Philadelphia, W.B. Saunders Co., 1970, pp 245,339. Lockshin NA, Hurley f-t: Urticaria as a sign of viral hepatitis. Arch Dermatol 105: 570, 1972. Findlay GM, Martin NH, Michell JB: Hepatitis after yellow fever innoculation. Lancet 2: 301, 1944. Prestia AE, Lynfield YL: Scarlatiniform eruption in viral hepatitis. Arch Dermatol 101: 352, 1970. Wenzel RP, McCormick DP, Busch HJ, et al.: Arthritis and viral hepatitis. Arch Intern Med 130: 770, 1972. Fernandez R, McCarty DJ: The arthritis of viral hepatitis. Ann Intern Med 74: 207, 1971. Shumaker JB, Goldfinger SE, Alpert E, et al.: Arthritis and rash-clues to anicteric viral hepatitis. Arch Intern Med 133: 483, 1974. Rhoades ER, Copeland L: Extrahepatic complications of viral hepatitis. Oklahoma State Med Assoc J 68: 40. 1975. Gocke DJ, Hsu K, Morgan C, et al.: Association between polyarteritis and Australia antigen. Lancet 2: 1149,
February
13. 14.
15.
16.
17.
18.
19. 20.
21
1978
1970. Gocke DJ, Hsu K, Morgan C, et al.: Vasculitis in association with Australia antigen. J Exp Med 134: 330, 1971. Sergent JS, Lockshin MD, Gocke DJ, et al.: Polyarteritis nodosa with and without persistent HAA antigen. Long term course in 21 patients. Arthritis Rheum 16: 568, 1973. Knieser MR, Jenis EH, Lowenthal DT, et al.: Pathogenesis of renal disease associated with viral hepatitis. Arch Pathol 97: 193, 1974. Alpert E, lsselbacher KJ, Schur PH: The pathogenesis of arthritis associated with viral hepatitis. N Engl J f&d 285: 185, 1971. Wands JR, Mann E, Alpert E, et al.: The pathogensis of arthritis associated with acute hepatitis B surface antigen-positive hepatitis. J Clin Invest 55: 930. 1976. Onion DK, Crumpacker CS, Gilliland BC: Arthritis of hepatitis associated with Australia antigen. Ann Intern Med 75: 29, 1971. Duffy J, Lindsky MD, Sharp JT, et al.: Polyatthritis, polyarteritis and hepatitis B. Medicine (Baltimore) 55: 19, 1976. Schumacher HR, Gall EP: Arthritis in acute hepatitis and chronic active hepatitis-pathology of the synovial membrane with evidence for the presence of Australia antigen in synovial membranes. Am J Med 57: 655, 1974. Stevens DP. Walker J, Crum E, et al.: Anicteric hepatitis presenting as polyarthritis. JAMA 220: 687, 1972.
The American Journal of Medicine
Volume 64
273
TERRY D. WEISS, M.D. CHENG C. TSAI, M.D. ANDREW R. BALDASSARE,
M.D.
JACK ZUCKNER. M.D. St. Louis, Missouri
A variety of skin rashes are known to occur as a part of the serum sickness-like prodrome of acute viral hepatitis which is thought to be due to immune complex deposition. We report the histologic and immunofluorescent findings in the skin and the serologic abnormalities in a patient with both erythematous maculopapular and purpuric rashes. We found circulating hepatltls 6 surface antigen (HBsAg), hypocomplementemia and cutaneous vasculitis associated with deposition of immunoglobulin and complement in the skin. We could not demonstrate intradermal deposition of HBsAg, but the findings are consistent with the immune complex hypothesis. Rashes occur in about 5 per cent of patients with viral hepatitis [l]. Such abnormalities were first noted by Graves[ 21 who, in 1843, described an urticarial rash; this has since been reemphasized by Horsfall and Tamm [3], Braverman [4] and Lockshin and Hurley [5]. Other dermatologic abnormalities which may occur include maculopapular erythematous lesions, blotchy etythema, purpura [6], a scarlatiniform rash [7], nodules [8] and petechiae [9, lo]. In only one previous report has the histopathology of the skin been described [8]. Immunofluorescent findings have not been published. We describe a patient with hepatitis B surface antigen (HBsAg)-positive hepatitis who had two different dermatologic abnormalities. The histologic and immunofluorescent findings in the skin are described.
MATERIALS AND METHODS
From the Division of Rheumatology, Department of Internal Medicine and the Department of Pathology, St. Louis University School of Medicine, St. Louis, Missouri. Requests for reprints should be addressed to Dr. Terry D. Weiss, Division of Rheumatology, St. Louis University Hospital, 1325 South Grand Boulevard, St. Louis, Missouri 63 104. Manuscript accepted June 9, 1977.
Skin biopsy specimens of both maculopapular erythematous lesions and purpuric lesions were snap-frozen in liquid nitrogen and stored at -70°C. Six to 7 p sections were cut in a cryostat and stained directly with fluorescein-conjugated antihuman albumin, immunoglobulins G (IgG), M (IgM), A (IgA), and E (IgE), complement (C3) and fibrin/fibrinogen.* The sections were examined with a Leitz Ortholux fluorescent microscope. The resulting immunofluorescence was quantitated on a scale of 0 to 4-t. The indirect immunofluorescent technic was applied for the detection of HBsAg in the skin. The section was first stained with specific horse anti-HBsAg antiserum,+ washed and then counterstained globulin antiserum.f
Specificity
with fluorescein-labelled of the antiserum
rabbit antihorse
was tested by immunodif-
* Meloy Laboratories, Springfield, Virginia and Behring Diagnostics, Sommerville, New Jersey. t Cordis Corporation, Miami, Florida. t Sylvana Company, Milburn, New Jersey.
February
1978 The American Journal of Medicine
Volume 64
269
SKIN LESIONS IN VIRAL HEPATITIS-WEISS
ET AL.
fusion to which known HBsAg serum was used. Skin biopsy tissues for routine light microscopy were fixed in 10 per cent formalin and embedded in paraffin. Sections were cut 5 to 6 ~1thick and stained with hematoxylin and eosin, periodic acid-Schiff, methenamine silver and Masson trichrome counterstain. CASE REPORT An 18 year old white girl was admitted to St. Louis University Hospital on July 5, 1975, with a chief complaint of malaise, anorexia, nausea and right upper quadrant abdominal discomfort of several days’ duration. Ten days prior to admission, a pruritic rash developed beginning on the dorsal and palmar surfaces of her hands and spreading to involve both upper and lower extremities, but sparing the face and trunk. Five days prior to admission she was first examined and found to have a skin eruption over the arms and legs. The rash over the upper extremities consisted of 1 by 1 cm pink maculopapular lesions which blanched with pressure. The lesions over the legs and feet were purpuric and did not blanch. She was taking no medications, denied recent infections and, aside from the pruritis associated with the rashes, felt well. A skin biopsy specimen of each type of lesion was obtained and tripelennamine 50 mg, four times a day was prescribed. Over the next few days she experienced malaise, nausea, anorexia and right upper quadrant discomfort. The maculopapular rash over the upper extremities became purpuric; it was slightly raised. Three days prior to admission her urine became brownish orange and then red in color. A stool one day prior to admission was light gray in color. Further history disclosed that two months previously the patient had received gamma globulin because she had had contact with a friend in whom hepatitis developed. The patient had been followed for the previous four years because of a polyarthritis. She had pain and swelling in distal and proximal interphalangeal finger joints, wrists, elbows, shoulders, ankles and feet, and a diagnosis of juvenile rheumatoid arthritis was made. She was treated with salicylates and gold salts until one year prior to the present illness. Neither joint pain nor swelling had occurred for the previous three years. She had never had a rash associated with arthritis. Physical examination upon admission disclosed a well developed, well nourished, white girl in no acute distress. Temperature was 100.6’F, pulse rate 96 beats/min, respirations 20/min and blood pressure 100/70 mm Hg. There was a maculopapular purpuric rash over the right forearm and a diffuse macular purpuric rash over the lower extremities. The scleras were slightly icteric. The liver was 15 cm in vertical span and tender, and the spleen tip was palpable on deep inspiration. The remainder of the physical examination was within normal limits. Laboratory data on admission included a hemoglobulin level of 14 g, a hematocrit value of 42.7 per cent, a white blood cell count of 7,100/mm3 with 46 per cent polymorphonuclears, 48 per cent lymphocytes, 4 per cent monocytes, 1 per cent eosinophils and 1 per cent basophils. Platelets were adequate. The urine was amber and turbid with
270
February
1978
The American Journal of Medicine
pH 6, specific gravity 1.022. There was trace proteinuria, large ketonuria and 2-F bacteriuria. There were 10 to 12 white blood cells and 5 to 7 red blood cells/hpf; bilirubin was present and the urobilinogen was 8 Erlich units. Urine culture grew lo4 colonies of enterococci/ml. The blood urea nitrogen was 10 mg/lOO ml and the serum creatinine 0.7 mg/lOO ml. The serologic test for syphilis (VDRL) was not reactive. A chest film disclosed no abnormalities. The electrocardiogram showed first degree atrioventricular (A-V) block. The serum glutamate pyruvate transaminase (SGPT) was 948 mu/ml (normal 5 to 24 mU/ml), and lactate dehydrogenase (LDH) 395 mu/ml (normal 100 to 225 mU/ml), alkaline phosphatase 235 mu/ml (normal 30 to 85 mU/ml), total bilirubin 2.7 mg/lOO ml, total protein 6.1 mg/lOO ml and albumin 3.9 mg/lOO ml. A serum protein electrophoresis was normal. The prothrombin time was 11.9 seconds or 100 per cent. A monospot test was negative; HBsAg was present by radioimmunoassay. The erythrocyte sedimentation rate was 25 mm/hour (Westergren). Antinuclear antibody (ANA), antimitochondrial and antismooth muscle antibodies were not found. Two lupus erythematosus cell preparations were negative. Anti-DNA antibody was less than 1 pg (normal). A latex fixation test for rheumatoid factor was negative. The serum IgG was 862 mg/lOO ml (normal 800 to 1,800 mg/lOO ml), IgA 41.2 mg/lOO ml (normal 90 to 450 mg/lOO ml), IgM 205 mg/lOO ml (normal 70 to 280 mg/lOO ml). Cryoglobulins were not detected. Serum complement studies included C3 of 26 mg/lOO ml (normal 55 to 120 mg/lOO ml) and C4 of 2.4 mg/lOO ml (normal 20 to 50 mg/lOO ml). A liver-spleen scan with technetium sulfur colloid showed a moderately enlarged liver measuring 22 cm by 17.5 cm in horizontal and vertical dimensions, respectively. The spleen was enlarged measuring 16 to 17 cm in longest diameter in the posterior view. The hospital course was characterized by steady clinical improvement. On the third hospital day, the temperature returned to normal and remained normal for the rest of her stay. By the sixth day, the microscopic hematuria had cleared spontaneously. The anorexia began to clear by the seventh hospital day. At that time the SGOT level rose to 3,860 mU/ ml, the SGPT level to 1,463 mU/ml, alkaline phosphatase 300 mU/ml and total bilirubin to 5.9 mg/iOO ml. The prothrombin time was 15.5 seconds (57 per cent). The patient continued to improve clinically with loss of malaise, abdominal discomfort and anorexia, and return of normal appetite. She complained of intermittent arthralgias, but no arthritis was detected. The rashes faded. The patient was discharged on the 16th hospital day; her bilirubin was 1.9 mg/iOO ml, SGCT 202 mU/ml, alkaline phosphatase 142 mu/ml and prothrombin time 100 per cent. She was seen again eight days later and was feeling well. The liver was not enlarged and the spleen tip was just barely palpable. Total bilirubin was then 1.3 mg/lOO ml, SGOT 60 Sigma Units (SU) (normal 8 to 26 SU), alkaline phosphatase 37 SU (normal 9 to 35 SU) and SGPT 90 SU (normal 5 to 35 SU). She was last seen on November 11, 1975, at which time she felt well. Laboratory data at that time, including the erythrocyte sedimentation rate, urinalysis, SGOT, SGPT, LDH, alkaline phosphatase, C3 and C4 were all within normal limits.
Volume 64
SKIN LESIONS IN VIRAL HEPATITIS-WEISS ET AL.
Hematoxylin and eosin stain of lesion in upper Figure 1. extremity showing mild perivascular infiltration with chronic inflammatory
cells.
deposition in vessel walls and 3-F in the interstitium. HBsAg was not detected by indirect immunofluorescent technic. The skin from a purpuric lesion of a lower extremity showed a marked perivascular infiltrate in the dermis, again consisting mainly of lymphocytes and histiocytes (Figure 2A). Several small and medium-sized blood vessels showed fibrinoid necrosis of vessel walls and extravasation of erythrocytes (Figure 2B). Polymorphonuclear leukocyte dust was also present. One muscular artery in the subcutis had focal healing vasculitic changes. lmmunofluorescent study revealed 2+ fine and coarsely granular staining of IgM and C3 in vessel walls in the middle and lower dermis (Figure 3). Staining for fibrin/fibrinogen was 2-F in vessel walls and 3+ in the interstitium. HBsAg could not be detected. COMMENTS
RESULTS
The skin from a maculopapular lesion of an upper extremity showed perivascular mononuclear cell infiltration around many small to medium-sized vessels in the upper and middle dermis. The infiltrate consisted primarily of lymphocytes, plasma cells and occasional histiocytes (Figure 1). lmmunofluorescent study of this specimen failed to demonstrate IgG, IgM, IgA, and IgE. Stain for complement (C3) showed l-i- fine granular
There are a variety of extrahepatic manifestations of viral hepatitis [ 111. These manifestations can be categorized into three groups: polyarteritis nodosa, glomerulonephritis and a serum sickness-like syndrome. Polyarteritis has an onset characterized by fever, polyarthralgia, myalgia, rash and urticaria. This progresses with the appearance of peripheral neuropathy, hypertension, eosinophilia, hematuria and azotemia. Biopsy of liver and muscle has shown fibrinoid necrosis
A, hematoxylin and eosin stain of lesion in lower extremity showing more dense chronic inflammatory cell infiltration than in the lesion in the upper extremity. 6, hematoxylin and eosin stain of lower dermis of specimen shown in A revealing vaculitis with chronic inflammatory cell infiltrate throughout the vessel wall. Polymorphonuclear leukocyte dust is also present. Figure 2.
February 1978
The American Journal of Medicine
Volume 84
271
SKIN LESIONS IN VIRAL HEPATITIS-WEISS
ET AL.
trimity showing granular deposition of IgM in the vessel wall _^^I ^^^U__^-I I^ ‘L-
and acute inflammation in the walls of small arteries and arterioles. Staining of muscle tissue with fluoresceinlabelled antibody to Australia antigen has demonstrated deposits in arterial walls along the elastic membrane. There is persistent hepatitis B surface antigenemia. Early in the acute phase, serum complement is depressed and there are circulating immune complexes which appear to be composed of HBsAg and the homologous antibody. Thirty to 40 per cent of patients with polyarteritis nodosa have hepatitis B surface antigenemia [12-141. Glomerulonephritis may be either acute or chronic. In the three cases described by Kneisir et al. [ 151, the histopathology ranged from membranous to focal segmental to mesangiopathic glomerulonephritis. In the patient with membranous type, staining with fluorescein-labelled antibodies was positive for IgG, IgA, C3 and hepatitis B antigen in peripheral capillary loops and, to a a lesser extent, in the mesangium. In the patient with focal disease, there was focal segmental deposition of IgM, C3 and HBsAg. Electron microscopy demonstrated electron dense particles within sclerotic areas consistent with the ultrastructure of the Dane particles seen in HBsAg-positive serum. In the last case, using trichrome and methenamine silver stains, glomerular disease was characterized by mesangial cell
272
February 1978
The American Journal of Medicine
hyperplasia and diffuse, irregular thickening of peripheral capillary loops with “double contour basement membranes.” IgM, IgG, C3 and HBsAg were present in capillary loops and in the mesangium. Electron microscopy again demonstrated electron dense particles located primarily in the mesangial matrix and cytoplasm of mesangial cells. The case in this report exemplifies the serum sickness syndrome. Symptoms typically occur in anicteric hepatitis or in the preicteric period. They include rash, urticaria, polyarthralgia and, sometimes, arthritis. Symptoms precede jaundice by a few days to six weeks and last up to seven days or more. When these symptoms are acute, there is a depression of serum total hemolytic complement (CH&, C3 and C4 [ 10,161. Cryoprecipitates from patients with and without arthritis have been found [ 171. These consist of HBsAg, antiHBsAg, immunoglobulins and complement components. However, only those patients with arthritis have IgA, C3, C4 and C5 in these complexes. Further, the IgG in those patients with arthritis is predominantly of the complement fixing IgGr and IgG3 subtypes. The complement system appears to be activated by the alternate (properdin) pathway. The CH50 in synovial fluid is also diminished, and HBsAg has been demonstrated in synovial fluid by microcomplement fixation tests [ 181. The synovial fluid is usually inflammatory. Synovial fluid white blood cell counts range from less than 1,000 [ 9,18,19] to as high as 90,000/mm3 [ 191 and may have either a polymorphonuclear [ 19,201 or mononuclear [9,18,19] predominance. Synovial biopsy specimens have shown some vascular congestion and plugging, occasional scattered lymphocytes and rare neutrophils. Electron microscopic studies of the synovial tissue have shown necrosis of vascular endothelium of several small vessels. The cytoplasm and nuclei of these endothelial cells contain electron dense particles 200 to 250 A with clear centers which may represent the Australia antigen [20]. A variety of rashes have been reported as part of this serum sickness-like syndrome of viral hepatitis. These include urticaria [2-6,9,10,21], macular rashes [9,18], maculopapular eruptions [ 6,8, lo], circinate and annular erythematous plaques, erythematous, blanching nontender nodules [8], purpura [6], petechiae [ 9, lo] and a scarlatiniform rash [7]. Our patient had both purpuric and maculopapular erythematous lesions. We are aware of only one other report of a patient with viral hepatitis in whom a skin biopsy was performed. Wenzel et al. [8] biopsied an erythematous, blanching, nontender nodule. Upper dermal capillaries showed a perivascular cuffing of lymphocytes and plasma cells. Findings were similar in the maculopapular erythematous lesion in our patient, but the purpuric lesion showed fibrinoid necrosis and vasculitis.
Volume 84
SKIN LESIONS IN VIRAL HEPATITIS-WEISS
In our patient, immunoglobulins were not found in the maculopapular eruption, but IgM, C3 and fibrimfibrinogen were found in the purpuric lesion. The fact that the maculopapular rash subsequently became purpuric suggests that these rashes were at various stages of development. This would explain the different immunofluorescent findings. HBsAg was not found in the skin, and this may be a temporal phenomenon as well, i.e., the biopsies may have been performed during antibody excess. In addition to the rashes, our patient had arthralgias, hypocomplementemia, hematuria and pyuria. These are symptoms consistent with the serum sickness-like prodome, and the urine abnormalities might represent a transient glomerulitis. The data suggest that HBsAg positivity may be associated with a spectrum of disease ranging from a
ET AL.
serum sickness-like illness to glomerulonephritis to polyarteritis nodosa. Further, it would seem that these are immune complex diseases with complexes of HBsAg and the homologous antibody. As noted, these complexes have been found in the circulation, kidney, vessel walls and possibly in synovial tissue. We did not find evidence of HBsAg in the skin, but the possibility of its presence cannot be excluded. The presence of vasculitic skin lesions, hypocomplementemia, and intradermal immunoglobulin and complement deposits support the notion that this syndrome is a part of the spectrum of disease produced by immune complexes associated with HBsAg-positive viral hepatitis. ACKNOWLEDGMENT We gratefully acknowledge the assistance of Ms. Janet Kister.
skilled
technical
REFERENCES 1.
2. 3. 4. 5. 6. 7. 8. 9. 10.
11. 12.
Artenstein MS, Demis DJ: Recent advances in the diagnosis and treatment of viral diseases of the skin. N Engl J Med 270: 1101, 1964. Graves RJ: Clinical Lectures on the Practice of Medicine, Dublin, Fannin & Co., 1843, p 937. Horsfall FL Jr, Tamm I: Viral and Rickettsial Infections of Man. Philadelphia, J.B. Lippincott Co., 1965, p 985. Braverman IM: Skin Signs of Systemic Disease, Philadelphia, W.B. Saunders Co., 1970, pp 245,339. Lockshin NA, Hurley f-t: Urticaria as a sign of viral hepatitis. Arch Dermatol 105: 570, 1972. Findlay GM, Martin NH, Michell JB: Hepatitis after yellow fever innoculation. Lancet 2: 301, 1944. Prestia AE, Lynfield YL: Scarlatiniform eruption in viral hepatitis. Arch Dermatol 101: 352, 1970. Wenzel RP, McCormick DP, Busch HJ, et al.: Arthritis and viral hepatitis. Arch Intern Med 130: 770, 1972. Fernandez R, McCarty DJ: The arthritis of viral hepatitis. Ann Intern Med 74: 207, 1971. Shumaker JB, Goldfinger SE, Alpert E, et al.: Arthritis and rash-clues to anicteric viral hepatitis. Arch Intern Med 133: 483, 1974. Rhoades ER, Copeland L: Extrahepatic complications of viral hepatitis. Oklahoma State Med Assoc J 68: 40. 1975. Gocke DJ, Hsu K, Morgan C, et al.: Association between polyarteritis and Australia antigen. Lancet 2: 1149,
February
13. 14.
15.
16.
17.
18.
19. 20.
21
1978
1970. Gocke DJ, Hsu K, Morgan C, et al.: Vasculitis in association with Australia antigen. J Exp Med 134: 330, 1971. Sergent JS, Lockshin MD, Gocke DJ, et al.: Polyarteritis nodosa with and without persistent HAA antigen. Long term course in 21 patients. Arthritis Rheum 16: 568, 1973. Knieser MR, Jenis EH, Lowenthal DT, et al.: Pathogenesis of renal disease associated with viral hepatitis. Arch Pathol 97: 193, 1974. Alpert E, lsselbacher KJ, Schur PH: The pathogenesis of arthritis associated with viral hepatitis. N Engl J f&d 285: 185, 1971. Wands JR, Mann E, Alpert E, et al.: The pathogensis of arthritis associated with acute hepatitis B surface antigen-positive hepatitis. J Clin Invest 55: 930. 1976. Onion DK, Crumpacker CS, Gilliland BC: Arthritis of hepatitis associated with Australia antigen. Ann Intern Med 75: 29, 1971. Duffy J, Lindsky MD, Sharp JT, et al.: Polyatthritis, polyarteritis and hepatitis B. Medicine (Baltimore) 55: 19, 1976. Schumacher HR, Gall EP: Arthritis in acute hepatitis and chronic active hepatitis-pathology of the synovial membrane with evidence for the presence of Australia antigen in synovial membranes. Am J Med 57: 655, 1974. Stevens DP. Walker J, Crum E, et al.: Anicteric hepatitis presenting as polyarthritis. JAMA 220: 687, 1972.
The American Journal of Medicine
Volume 64
273
