Pyoderma gangrenosum and autoimmune chronic active hepatitis in a 17-year-old female

A 17-year-old gi rl presented with fever, icterus and painful small nodules on her face and a larger nodular lesion on the left shin. The patient had fatigue, intermittent jaundice and abdominal pain over the preceding th ree months. ThL ,,odular lesions ulcerated and had the typical clinical and histopathological appearance of pyoderma gangrenosum. Although there was no hepatosplenomegaly, serum aminotransferases and immunoglobulin G were elevated; antismooth muscle antibodies were detectable. Inflam matory bowel disease was not presen r. Autoimmune chronic active hepatitis and pyoderma gangrenosum are a rare association and this is the youngest patient in whom the association has been reported. Ca n J Gastroenterol 1988;2( 4): 13 7-9

P YODERMA GANGRENOSUM IS AN Ul- cerative skin disease characterized by one or more painfu l nodules wh ich break down to fo rm progressively enlarging ulcers ( l ).The condition is rare in children (2).Pyoderma gangrenosum can occur alone or in association with systemic diseases such as in flam matory bowel disease and lymphoproliferative and rheumatic d isorders ( 1).The reported association of pyoderma gangrenosum with chronic active hepatitis is rare, described in only seven adults (3)(4)(5)(6)(7)(8).T he association of these two conditions in a 17-ycar-old girl is reported.

CASE PRESENTATION
A previously healthy 17-year-old caucasian female was admi tted to hospital with a three month h istory of fatigue, intermittent jaundice with righ t u pper quadrant pain and a one month history of painful mouth ulcers.Three days prior to ad mission the patient developed hard, mobile, tender ' pea-sized' lumps on he r face and back and a pain ful red nodule on the left shin.
On admission to the Hospital fo r Sick Children in Toronto the patient appeared un well.The patient was febrile (38.6°C) a nd had scleral icterus.Aph-Vol 2 No. 4, November 1988 thous ulcers were present on the buccal mucosa and tongue.Erythematous, painful, warm nodules l to 2 cm in d iameter were present on the back, face and legs and a similar 4 cm lesion was present on the left sh in (Figure 1).There was right upper q uadrant tenderness but no hepatosplenomegaly.
Laboratory investigatio ns revealed : hemoglobin 109 g/L ( 10.9 g/d L); white cell count 13.300 mm l; and e rythrocyte sedimentation rate 80 mm/h.The platelet count and coagulation studies were normal.Total serum bi lirubin was 39 µ.moVL (2.3 mg/d L) with direct bilirubin 15 µ.moVL(0 .9mg/d L); seru m aspartate aminotransferase 336 iu/L (normal equal to or less than 36); serum alanine aminotransferase 444 iu/L (normal equal to or less than 40).Anti-HAY, HBsAg and anti-HBs were negative.Antismooth muscle and an timicrosomal antibodies were positive.Antinuclear a nd anti-DNA anti bodies and rheumatoid factor were all negative.Serum imm u noglobulin G was 30.5 g/L (normal 8 to 15 g/L), lgA 2.89 g/L(normal 0.9 to 3.2g/L) and IgM 3.39 g/L (normal 0.45 to 1.5 g/L).Total serum protein measured 80 g/L (8.0 g/dL) and albumin was 29 g/l (2.9 g/dL).
Over the next three days the patien t developed pe rsistent fever (equal to or Figure 1) Pyoderma gangrenosum before ireatmenl.Necrotic ulcer on the paiieni's left shin.The lesion had a mucopurulent base with a violaceous undermined border and was surrounded by a peripheral zone of erychema Figur e 2) Resolving pyoderma gangrenosum.Afcet six months' chera/ry with oral prednisone ihe left shin ulcer has epithel1al1zed and is healing wiih skin f orrnauon greater than 40°C) and migratory polyarchralgias.The lesions on the face and left leg showed necrotic ulceration with a mucopurulent base and a violaceous undermined border surrounded by a peripheral zone of erythema, typical of pyoderma gangrenosum.The patient developed tachypnea and a left pleural effusion.Multiple cu ltures of blood, throat, urine, stool, skin and the pleural effusion {transudate) were sterile.An echocardiogram showed no evidence of valvu lar vegetations.Abdominal ultrasound and sinus x-rays were no rmal.A technetium methylene diphosphonate bone scan showed soft tissue uptake in the area of the leg ulcer but no evidence of osteomyelitis.
Skin and liver biopsies were obtained.A nonspecific acu te inflammatory infiltrate was seen in the deep dermis, with l38 negative immunofluorescence.This was consistent with pyoderma gangrenosum.The liver b iopsy showed portal fib rosis and periportal septum formation, with little portal inflammatory infiltrate.An air contrast barium enema, upper gastrointesti nal series and small bowel follow through were normal.Because an autoimmune etiology was suspected and no infectious agent found, the patient was treated with high dose corticosteroids.Methylprednisolo ne ( l g intravenously) was given daily for three days.
The patient defervesced on the second day of treatment a nd no new skin lesions appeared.The right upper quadrant pain and polyarthralgias resolved.After the three day course of methylprednisolone the patient was given 40 mg oral prednisone daily.The aminotransfcrases returned to normal.As the patient was weaned off the prednisone to 20 mg daily over the next month, the skin lesions flared.Subsequent improvement was achieved only after high dose prednisone (80 mg dai ly) was maintained.Ten months fol lowing presentation, steroid dose was slowly reduced.Initial skin lesions have healed with some scarring (Figure 2).Since th en other equally severe skin lesions have developed.Her liver d isease remains inactive.

DISCUSSION
In a review of pyoderma gangrenosum in childhood Powell and Perry (2) found only 4% of 180 paticn ts seen at th e Mayo Clinic between l930 and 1982 had onset of d isease before the age of 15 years and all had associated inflammatory bowel disease.Other disease entities commonly associated with pyoderma gangrenosum CAN J GA STROENTl:ROL have included arthritis, hypogammaglobulincmia, pulmonary tubcrculo~is, lt'ukemia and cardiovascular disease.with pauents ranging in age from one momh to 17 years.Although the association of pyoderma gangrcnosum and autonnmune chronic acrive hcpanus has hl'en reported previously, it is extremely uncommon.To the authors' knowledge.the patient described here is the younge,t ca:,c of pyoderma gangrcnosu m with aL • )Immune chronic active hepatitis ever reported.
Chronic active hepatitis is a syndrome 111th various etiologies.Patients typically complain ofhepatitic symptoms and have d, \'atcd scrum aminotransfcrascs.There 1, a variable histological picture of progre,s1,•e liver cell destruction.including chrome mflammatory cell infiltrates in th, portal areas, piecemeal necrosis and ht'patocyte drop-out.In autoimmune chronic active hepatitis (also known as lupo1d hepatitis).which was first described m young women, liver disease is a,si,c1ated with hypergammaglobulint'mia, formation of autoantibodics and polyo,crositis.The present pacicnt fulfills these criteri;i: th e absence of portal inflammatory cell infiltrate on liver b1op,y is likely attributable to ongoing steroid therapy at the time of biopsy Other etiologies for chronic active hcpatiti,(hepatitis B infection, Wilson's disease, drug toxicity, alpha-I-anti trypsin Jefic1ency) were excluded.
Corticosteroids are the treatment of choice for both pyoderma gangrenosum and autoimmune ch ronic active hepati-tL,11.9)In the present patient, high dose prednisone treatment stopped the pro-~rt',s1on of existing ulceration, prevented the formation of new lesions and suppressed the liver disease.Corncosteroids alone and in various combinations with azathioprine, mcrcaptopurinc.indomethacin and clofa:imine have been .i,dm the seven other patients with pyoderma gangrenosum and autoimmune ,hronic active hepatitis Two of these patients died, one of hepatic failure after nm, • vears and the other of opportunistic infection (3,4).In the rest of the pancnts, pyoderma gangrenosum wa:,.rclaavely well controlled although scv-~ral had a relapsing cou rse.
In the present patient.con trolling the \'ol 2 No. 4. November 1988 pyoderma gangrcnosum has been more difficult than managing the autoimmune chronic active hepantis.Potentially he-pacocox1c agents such as the sulfones, which have been useful in the management of pyodcrma gangrcnosum in association with orher conditions, arc contraindicated in this case.Az:uhioprinc might be a suitable additional drug in this patient because it has been used cffecnvcly in creating autoimmune chronic active hepatiti:; when combined wnh corticosteroids.
Although the inittal treatment has been influenced primarily by the difficulty controlling pyodcrma gangrenosum in the patient.the long term prognosis will be determined by the course of the liver disease.Progression to cirrhosis can occur despite resolution of symptoms and biochemical abnormalities.However, a recent retrospective analysis of 204 adult patients indicated that the presence of autoimmune markers and the absence of cirrhosis at diagnosis identifies patients who have a better prognosis ( 10).A lthough there has been no sign of inflammatory bowel disease.the possibility nf it developing m the future cannot be excluded.particularly h~•causc pyodcrma gangrcnosum has been more commonly associated with inflammatory bowel disease than wnh autoimmune c hronic active hepatitis in children.
The association of pyoderma gangrenosum and autoimmune chronic active hepatitis is rare in all age groups.H owever, when pyoderma gangrennsum 1s diagnosed, liver fun c tion should he assessed to determine whether auroimmunc chronic active hepatitis is also present.Minimum investigations include measurement of serum ammorransfcr-Pyoderma gangrenosum and autoimmune CAH ases, tetal and conjugated bilirubin, lgG concentration and autoantibodies.Disordered immune function may be common to both pyoderma gangrenosum and autoimmune chronic active hepatitis.but the etiological basis for th is association remains unclear.