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Case Report: Penicillamine-induced Pulmonary Elastosis Perforans Serpiginosa

A 59 year-old patient presented to a local ER with a 2-week history of cough, fever, and progressive dyspnea after returning from vacation in the southern Caribbean. Chest imaging revealed bilateral lower lobe consolidation with an associated left sided pleural effusion. The patient was admitted to hospital and evaluated by Respiratory and Infectious Disease sub-specialists. After 1 week in hospital no etiology for the consolidation was identified. After failing treatment with broad spectrum antibiotics (Ceftriaxone, Azithromycin), transfer to a tertiary care hospital for further evaluation was arranged.

Past medical history was significant for Cystinuria, diagnosed in the patient’s 20’s. This was complicated by recurrent renal stones and resulted in a right total nephrectomy. The Cystinura had been treated for over 20 years with high dose penicillamine (2g/d), complicated by the development of several skin dermopathies including pseudoxanthoma elasticum and elastosis perforans serpignosa.

Ten years prior the patient had suffered from chronic bilateral (R>>L) pleural effusions along with a pericardial effusion. This was ultimately evaluated by a Thoracic Surgeon who obtained pleural and pericardial biopsies via thoracoscopy. The biopsies were ultimately non-diagnostic and revealed evidence of chronic inflammation only. The presumptive diagnosis was Penicillamine induced pleuritis and pericarditis. The patient received chemical pleurodesis on the right side along with a pericardial window with good effect. The Penicillamine dose was subsequently reduced to 1g/d with no immediate recurrence of pleural or pericardial complications.

One year prior to presentation the patient began to develop dyspnea on exertion associated with clinical findings of right heart failure. An extensive evaluation was performed including echocardiogram, MRI, and angiogram which revealed findings consistent with pericardial constriction. At the time of writing, the patient was awaiting a cardiovascular surgery opinion for management.

The remainder of the history revealed that the patient had no other major medical comorbidities. The patient was a lifelong non-smoker and had no occupational history concerning for inorganic or organic dust exposure. There was no prior history of any infections including no previous pneumonias, tuberculosis, and no known TB exposure. The patient was originally born in the Carribean but had spent the majority of life in Canada. Medications included Penicillamine, Allopurinol, Hydrochlorothiazide. There was a family history of Cystinuria in the patients siblings.

Physical Exam

Physical findings taken from the original hospital admission notes included the following: patient looked generally well, no distress, with obvious dermatologic abnormalities consistent with pseudoxanthoma elasticum and elastosis perforans serpiginosa. Vitals: BP 130/80, HR 70, RR 20, SPO2 97% on 4L nasal prongs. No clubbing. No lymphadenopathy. Inspiratory crackles to right mid and lower lung zones. Normal cardiac and abdominal exam.

Radiology

Figure 1. CXR. Extensive ill-defined dense consolidation of right middle and lower lobes. Less severe consolidation of left lower lobe and lingua with small left pleural effusion.

Figure 2. CT Chest. Extensive consolidation of right middle and lower lobes with similar changes seen in the left lower lobe and lingula. Moderate left pleural effusion. Trace pericardial fluid with no effusion. No significant lymphadenopathy . No pulmonary emboli (not shown).

Laboratory

Blood work on admission to hospital initially demonstrated a WBC of 18.0 (Neutrophils 16.0), hemoglobin 121, platelets 731. Electrolytes showed a Na+ 139, K+ 3.5. LDH 149, Albumin 21. GGT 60. Arterial blood gas revealed a pH of 7.39, pCO2 47, pO2 152 (on 10L O2 by face mask), HCO3 28. Sputum, urine, blood C&S negative.

Surgery

At the tertiary care hospital, the patient was seen by Thoracic Surgery and underwent video assisted thoracoscopic surgery (VATS) with open lung biopy (lingular wedge resection) and pleural biopsy. Thoracoscopy revelead a small serous pleural effusion. The parietal pleura had a normal appearance. The visceral pleura appeared diffusely thickened and during intraoperative lung deflation/inflation, the left lung appeared trapped. The lung biopsy revealed abnormal elastic fibres with features consistent with elastosis perforans serpiginosa. The presumptive etiology was secondary to penicillamine use.

Histology/Pathology

“Throughout all sections, there is a unique and prominent pattern of pleural and secondary lobular septal thickening with florid reduplication of abnormal elastic fibres. On closer examination, these fibres exhibit irregular fragmentation and fuzzy “sawtooth” profiles. Such an elastosis is also noted within the adventitial sheath of pulmonary veins, arteries and, to a minor extent, in the walls of small airways. Areas of visceral pleura are crenated and redundant and bridged by fibrous bands. This, with irregular penetrating septae, impart an identical appearance to rounded atelectasis and this fits with the clinical observation of trapped lung.

The elastic changes seen in the lung are compatible with the generalized manifestations of “elastosis perforans serpiginosa (EPS)”. It is reasonable to speculate that the elastic changes within the lung and parietal pleura may be responsible for the chronic effusions (by interfering with lymphatic channels). The trapped lung may be directly caused by the elastic abnormalities but may also be secondary to the chronic effusion in a manner identical to one proposal for the pathogenesis of rounded atelectasis.

Discussion

Penicillamine is a heavy metal chelator used in the treatment of Wilson’s disease (an autosomal recessive disease of hepatic copper excretion) and Cysteinuria (an autosomal reccesive disease of cysteine excretion leading to kidney stone formation). It also used, less frequently, as adjunct therapy for certain connective tissue disorders such as systemic sclerosis and rheumatoid arthriris due to variety of immunomodulatory effects. Prolonged use at high doses (1–2 g daily) can lead to the development of several elastin fibre dermopathies including elastosis perforans serpiginosa and pseudoxanthoma elasticum (1,2). Characteristic elastin fibre changes have been seen in other organ systems including the eye (3), upper respiratory tract (4), and cardiovascular system (5).

Elastosis perforans serpiginosa (EPS) is a rare skin disease in which abnormal collections of elastic tissue fibers, connective tissue elements, and cellular debris are expelled from the papillary dermis through the epidermis. It occurs in 3 forms including idiopathic, drug-induced, and reactive. The reactive form is associated with several inherited connective tissue abnormalities such as Marfan syndrome, Ehlers Danlos syndrome, Down syndrome, scleroderma, and pseudoxanthoma elasticum. Using light and electron microscopy the elastin fibres are seen to have a thorny or barbed appearance that is unique to penicillamine-induced EPS (6).

Pseudoxanthoma elasticum (PXE) is a rare genetic disorder of elastic tissue with a characteristic histological appearance including fragmented elastin fibres and associated calcium deposition. PXE is caused by mutations in the ATP-binding cassette transporter C6 (ABCC6) gene, which has been mapped to 16p13.1 (7). The term pseudopseudoxanthoma elasticum (PPXE) distinguishes the acquired condition from the idiopathic, genetically controlled PXE. Acquired cases of PXE secondary to penicillamine use have been reported in the literature, most commonly affecting the skin, eyes, and cardiovascular system (8). Reports of pulmonary involvement are rare.

The mechanism(s) by which Penicillamine induces EPS and PPXE is only partly understood. Elastin normally organizes into fibrillar structures stabilized by collagen fibre cross-links. This process requires the oxidation of lysine and hydroxylysine by lysl oxidase, a copper dependant enzyme. Penicillamine interferes with this process in two ways; it acts as a chelator of copper leading to its depletion and ultimate interference with lysl oxidase function; and it reacts with the aldehyde byproducts of lysine and hydroxylysine oxidation forming stable thiozolidine compounds unable to form stable elastin cross links (9). Penicillamine only interferes with the formation of new elastin cross-links and does not affect mature elastin fibrils. As such the development of a dermopathy depends partly on the dose and duration of penicillamine use and the turnover rate of the tissue to involved.

Report of pulmonary PPXE or EPS are rare.

Coatesworth et al (5) described a case of PPXE in a patient who had been treated with Penicillamine (1.5g/d) for 27 years for Wilsons disease. This patient had a history of dysphonia, dysphagia, and progressive dyspnea. Pulmonary function testing revealed restrictive physiology (FEV1 81%, FVC 84%, TLC 77%) with eventual progression to a TLC 60%. Biopsy specimens from the skin, vocal cord, esophagus, and lung all revealed abnormal elastin fibres and the characteristic histological findings of PXE. The lung biopsy revealed abnormal elastin in the pleura and bronchial walls, but other wise normal lung parenchyma. Penicillamine was eventually discontinued and the patients started on Trientene, an alternative heavy metal chelator use in Wilsons disease. The patient eventually had regression of the skin changes and clinical improvement with regards to dysphagia and dyspnea. Pulmonary function testing improved (TLC 77%) and was sustained during followup over a year period.

A review of the PubMed database finds only 2 reports of EPS and penicillamine use (6,10).

In this report we describe the incidental finding of histopathological pleural and pulmonary changes consistent with elastosis perforans serpiginosa, presumed to be penicillamine induced. Penicillamine induced elastin fibre dermopathies are well described in the dermatology literature, but are less reported for other organ involvement. In particular there is a paucity of literature on the pulmonary effects of EPS or PPXE.

Pearls

1. Clinicians should be aware that penicillamine use may lead to dermopathies such as elastosis perforans serpiginosa or pseudoxanthoma elasticum and that these skin changes may be a clue to more serious involvement of elastic tissue in other internal organs such as the lungs.

2. Pulmonary function testing in these patients may be of value to screen for potential restrictive lung physiology and detect early lung involvement.

3. Lower doses of penicillamine may prevent, or at least delay, the onset or progression of elastin fibre disruption and subsequent organ damage.

References

1 Meyrick Thomas RH, Kirby JDT. Elastosis perforans serpiginosa and pseudoxanthoma elasticum-like skin change due to D-penicillamine. Clin Exp Dermatol 1985; 10:386–91.

2 Dalziel KL, Burge SM, Frith PA, et al. Elastic fibre damage induced by low-dose D-penicillamine. Br J Dermatol 1990; 123:305–12.

3 Narron GH, Zec N, Neves RI, et al. Penicillamine-induced pseudoxanthoma elasticum-like skin changes requiring rhytidectomy. Ann Plast Surg 1992; 29:367–70.

4 M. Babu Manohar, D.A.R. Boldy, R.L. Bryan, M.R.C. Path and K. Pearman, Penicillamine-induced changes in elastic tissue of the upper respiratory tract. J Laryngol Otol 1993; 107: 62–64.

5 Coatesworth AP, Darnton SJ, Green RM, Cayton RM, Antonakopoulos GN. A case of systemic pseudo-pseudoxanthoma elasticum with diverse symptomatology caused by long term penicillamine use. J Clin Pathol 1998; 51:169–171.

6 Bardach H, GebhartW, Niebauer G. “Lumpy-bumpy” elastic fibers in the skin and lungs of a patient with a penicillamine-induced elastosis perforans serpiginosa. J Cutan Pathol 1979; 6:243–52.

7 Chassaing N, Martin L, Calvas P, Le Bert M, Hovnanian A. Pseudoxanthoma elasticum: a clinical, pathophysiological and genetic update including 11 novel ABCC6 mutations. J Med Genet. Dec 2005; 42(12):881-92

8 Katsuaki Miki, Takashi Yuri, Nobuhiko Takeda Kazuya Takehana, Toshiji Iwasaka, Airo Tsubura. An autopsy case of pseudoxanthoma elasticum: histochemical characteristics. Med Mol Morphol. 2007; 40:172–177.

9 Rath N, Bhardwaj A, Kar HK, Sharma PK, Bharadwaj M, Bharija SC. Penicillamine induced pseudoxanthoma elasticum with elastosis perforans serpiginosa. Indian J Dermatol Venereol Leprol. 2005 May-Jun; 71(3):182-5.

10 Bardach H, Gebhart W, Niebauer G, Bardach G.Penicillamine-induced elastosis perforans serpiginosa and pulmonary cyst in Wilson's disease. Wien Klin Wochenschr. Feb 1981; 93(4):117-22.