|Year : 2018 | Volume
| Issue : 1 | Page : 55-60
Exogenous ochronosis superimposed on chronic kidney disease: A case report and review of literature
Ishrat Hussain Dar1, Omar Farooq1, Samia Rashid Mir1, Ghulam Hassan Dar1, Arshi Beg2
1 Department of Medicine, Government Medical College, Srinagar, Jammu and Kashmir, India
2 Department of Pathology, Government Medical College, Srinagar, Jammu and Kashmir, India
|Date of Web Publication||21-May-2018|
Dr. Ishrat Hussain Dar
Associate Professor, Department of Medicine, Government Medical College, Srinagar - 190 010, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Ochronosis is a rare disease characterized by speckled and diffuse pigmentation symmetrically over the face, neck, and photo-exposed areas. It can present in exogenous or endogenous form. Endogenous ochronosis or alkaptonuria is an autosomal recessive disease caused by a deficiency of homogentisic acid (HGA) oxidase, which results in the accumulation of HGA, a hydroquinone (HQ) metabolite of tyrosine. Some evidence suggests that it is not HGA itself but a by-product of its oxidation, a benzoquinone acetic acid, that can polymerize to a melanin-like pigment by unknown mechanisms and accumulates both inter and intracellularly in connective tissue, most commonly the joints, cardiovascular system, kidney, skin, and glands, a pathological condition known as ochronosis (Development of an in vitro model to investigate joint ochronosis in alkaptonuria. Tinti L, Taylor AM et al. Rheumatology 2010; Oct 15: 1-7. doi: 10.1093/rheumatology/keq246). Exogenous ochronosis (EO) is a rare, cosmetically disfiguring condition, resulting from the long-term use of topical HQ in the treatment of melasma. It manifests as grey-brown or blue-black macules in HQ-exposed regions, characterized histologically by banana-shaped ocher-colored deposits in the dermis. HQ the topical bleaching agent of choice is widely prescribed by physicians and often used by patients without a prescription. The principal adverse effects of its chronic use are confetti-like depigmentation and rarely EO. EO is an avoidable dermatosis that needs to be recognized early with immediate discontinuation of HQ as treatment is difficult. Sun exposure facilitates the formation of EO and must be strictly avoided. We report case of a 65-year-old man who had chronic kidney disease but developed EO while using topical HQ.
Keywords: Chronic renal disease, exogenous, hemodialysis, hydroquinone, ochronosis
|How to cite this article:|
Dar IH, Farooq O, Mir SR, Dar GH, Beg A. Exogenous ochronosis superimposed on chronic kidney disease: A case report and review of literature. Sahel Med J 2018;21:55-60
|How to cite this URL:|
Dar IH, Farooq O, Mir SR, Dar GH, Beg A. Exogenous ochronosis superimposed on chronic kidney disease: A case report and review of literature. Sahel Med J [serial online] 2018 [cited 2022 Jul 5];21:55-60. Available from: https://www.smjonline.org/text.asp?2018/21/1/55/232782
| Introduction|| |
The term ochronosis is derived from the word “ochre” in Greek language, which refers to yellow discoloration. Ochronosis is a rare disease characterized by speckled and diffuse pigmentation symmetrically over the face, neck, and photo-exposed areas presenting in two forms (exogenous or endogenous). It is characterized histologically by banana-shaped ocher-colored deposits in the dermis. Exogenous ochronosis (EO) is a rare, cosmetically disfiguring condition, resulting from the long-term use of topical hydroquinone (HQ) in treatment of melasma. In this pathology, a microscopic deposition of ocher-colored pigment is found in the dermis as a result of prolonged use of this medication., It is a condition clinically and histopathologically similar to endogenous ochronosis, also known as alkaptonuria; the difference between them is that it does not present with systemic manifestations such as history of dark urine, gray-blue or gray-brown coloration of cartilages, conjunctivae, and arthropathy, while in EO, the affected area is limited to that treated with HQ. If used too frequently, HQ interferes in skin pigmentation through alteration of melanin formation, in interaction with copper at the site of tyrosinase activity, and in inhibition of DNA and RNA synthesis.
| Case Report|| |
A 65-year-old hypertensive man on erratic treatment reported to the medical emergency of our hospital with progressive swelling of the feet and face associated with shortness of breath, orthopnea, and paroxysmal nocturnal dyspnea of 2 weeks duration. Medical history revealed use of a topical skin brightener containing (2% HQ, 0.025% tretinoin, and 0.1% mometasone) for about 5 years prescribed by a quack (possibly for melasma). No history of intake of phenols, antituberculous, antimalarials, or drugs for hypo and hyperthyroidism was forthcoming. Examination revealed a moderately built, afebrile, pale, and conscious man with pitting pedal and scrotal edema. Vital signs revealed blood pressure (BP) of 230/120 mmHg at admission with a pulse rate of 84 beats/min, regular and normal volume, while respiratory rate was 18/min, jugular venous pressure was elevated (8 cm H2O), and hepatojugular reflux was present. Chest examination was normal except for bibasilar coarse crepitations; cardiovascular system examination revealed the apex to be shifted to the 6th intercostal space in the anterior axillary line on the left side with a tricuspid regurgitation murmur. Abdominal examination revealed a palpable tender liver 4 cm below the right costal margin with a tense shiny anterior abdominal wall without splenomegaly. The central nervous system was normal except for the bilateral absence of ankle jerks. Both arms and to some extent both legs showed flaky epithelial xerosis while the dorsa of both hands revealed a dark brown pigmentation over the knuckles and wrists. The forehead and temporomaxillary areas had multiple, ill-defined diffuse bluish-brown slaty-colored hyperpigmented plaques with velvety surface and hyperchromic, pinpoint, and caviar-like papules on the nose [Figure 1], [Figure 2], [Figure 3]. Complete blood count revealed anemia (macrocytic normocytic type) with a reticulocyte count of 1.81%. Biochemical investigations revealed mild hyperbilirubinemia, low serum albumin, moderately raised liver enzymes, high (urea, creatinine, uric acid, potassium, and phosphorus) with low sodium, calcium, and normal (sugar, ferritin, serum B12, folate, and magnesium) level. Urine color was normal and did not rapidly darken to brownish black on exposure to air. Routine urine examination showed active urinary sediment, broadcasts, and proteinuria. Twenty-four hours urinary protein was 850 mg. Urine for Bence–Jones protein, serum electrophoresis for M band, and skeletal survey were negative for multiple myeloma [Table 1] and [Table 2]. Arterial blood gas revealed metabolic acidosis. X-ray of the chest showed left ventricular hypertrophy, electrocardiogram showed intraventricular conduction defect, echocardiography was suggestive of hypertensive heart disease with tricuspid regurgitation, left ventricular type cardiomegaly with an ejection fraction of 55%, and ultrasonography of the abdomen showed a congested liver and small-sized kidneys with altered corticomedullary differentiation. Fundus examination showed Grade 3 arteriosclerotic changes without exudates or hemorrhage. Upper gastrointestinal endoscopy and colonoscopy done for workup of anemia were normal. A diagnosis of uncontrolled hypertension, hypertensive cardiovascular disease, hyperuricemia, and acute on chronic renal failure with biventricular failure was made. The patient was managed with supplemental oxygen, diuretics, antihypertensive drugs, and hemodialysis. A temporal area skin biopsy was performed which on histology revealed solar elastosis upper papillary dermis ocher-colored globular deposits without typical crescentic or banana shapes with a negative Pearl's iron stain and colloid milium foci with positive Masson-Fontana stain suggestive of EO [Figure 4]. A long-term plan for maintenance hemodialysis was instituted with strict adherence to modified dietary habits, and the patient was instructed not to use any exogenous topical medication or antimalarials. Topical glycolic acid and antioxidants in form of Vitamin A and E were prescribed for EO. Currently, on follow-up, the patient is doing well with good control of BP and improvement in the cardiac and kidney status. Written signed informed consent was obtained on 21st October 20110 for publication in Sahel Medical Journal.
|Figure 1: Depicting multiple, ill-defined diffuse bluish-brown slaty-colored hyperpigmented plaques with velvety surface on the forehead and temples|
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|Figure 2: Depicting a dark brown pigmentation over the knuckles and wrists of both hands and edema over the dorsa of both feet and legs|
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|Figure 4: Histopathological examination of temporal area skin biopsy depicting solar elastosis, upper papillary dermis ocher-colored globular deposits without typical crescentic or banana shapes with a negative Pearl's iron stain and positive Masson-Fontana, colloid milium foci suggestive of exogenous ochronosis|
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| Discussion|| |
The term ochronosis was first described by Virchow in 1866 referring to a brownish-yellow pigment (ocher) deposited in the connective tissues of various organs. EO was first described in 1906 by Pick. In 1912, Beddard and Plumtre described the disease when a patient used phenol for the treatment of an ulcer on the leg. In 1975, Findlay and de Beer described EO in patients who used topical lightening agents containing HQ. The exact incidence of EO is unknown with an assumption of low worldwide incidence. The earliest reports and largest series on EO described in 28%–35% of the black population came from South Africa. It was thought that the condition is exclusive to dark-skinned African individuals, but recent published reports show that it is seen in many fair-skinned individuals like in Europeans and Hispanics but with a low incidence in the USA. The incidence is said to be low in Asians, but cases are increasingly being reported from India, China, Thailand, and Singapore. The first case of EO was reported by Zawar and Mhaskar from Maharashtra, India (and possibly from South East Asia) in 2004 in a female farmer, who developed EO after unsupervised application of 4% HQ containing preparation for more than 3 months for melasma. Subsequently, a few more case reports from other parts of India have been described by other authors. In all these reports, unsupervised usage of the skin-lightening agents was a common highlighting feature.
Various factors necessary for the development of EO are unprotected prolonged sun exposure, prolonged use of skin-lightening agents mainly containing HQ, and the presence of a number of viable melanocytes. Outdoor occupation, application of HQ over a larger area or whole body, and/or applying HQ in large quantity may also predispose to this condition. EO has been reported following long-term application of the skin-lightening creams which contain HQ, phenol, or resorcinol. Of these, HQ has the strongest association, and the condition is due to continual use of HQ, generally, in higher concentrations more than 2%. An alcoholic solution containing HQ preparations is said to more readily predispose to EO than creams. Some of the recent reports mention the occurrence of EO even with as low concentrations of HQ as 2%. The lesions may develop gradually over 6 months to 3 years or longer. Recent case reports from India mention the occurrence of EO with use of 2% HQ preparations for 7–8 years.,,
Clinically, it presents as asymptomatic brown-grey or blue-black pigmentation in photo-exposed areas or on contact sites, mainly on the face, neck, back, and extensor surface of the extremities. It occurs over osseous surfaces often affecting the zygomatic regions in a symmetrical pattern. The lesions are grey-brown or blue-black macules usually with hyperchromic, pinpoint, and caviar-like papules.,
The exact pathogenesis of EO is not known. HQ interferes with skin pigmentation by inhibiting tyrosinase enzyme thereby blocking the synthesis of melanin. It also inhibits synthesis of DNA and RNA. Various theories put forth are speculative to explain the pathogenesis of EO. The most accepted theory till date for the pathogenesis of EO was put forth by Penneys stating that the hyperpigmentation is due to local competitive inhibition of the enzyme homogentisic oxidase by HQ, which leads to local accumulation of homogentisic acid (HGA) and its metabolic products that polymerize to form the so-called typical ochronotic pigment in the papillary dermis.
Histopathology, although invasive, remains the gold standard in the diagnosis of EO and confirms it beyond doubt. The pathognomonic histopathological feature is the presence of the ocher-colored, banana-shaped fibers in the dermis. Homogenization and swelling of collagen bundles in the papillary and reticular dermis may also be seen., Speckled macular lesions or early caviar-like papules are preferred lesions for a skin biopsy to yield more accuracy. For the EO diagnosis, the possibility of alkaptonuria should be excluded, at least from a clinical point of view. Histological features are common to both exogenous as well as endogenous ochronosis with deposition of HGA in collagen fibers assuming the shape of the fiber, i.e., sickle or banana shape. However, in our case, the deposits were globoid and were deposited on solar degenerated elastotic material with colloid milium foci lacking the typical crescentic or banana shapes indicating that the deposits have formed after the development of elastosis thus favoring an exogenous etiology.
Although a variety of dermatological manifestations such as hyperpigmentation, pallor, xerosis, ichthyosis, pruritus, prurigo nodularis, acquired perforating dermatosis (Kyrle disease), bacterial, fungal, and viral infections (e.g., with Streptococcus species, Staphylococcus aureus, tinea infections, and herpes zoster), purpura, porphyria cutanea tarda, pseudoporphyria, calcific uremic arteriolopathy (calciphylaxis), benign nodular calcification, half-and-half nails, koilonychia, transverse leukonychia, onychomycosis, onycholysis, splinter hemorrhages, subungual hyperkeratosis, brittle hair, sparse body and scalp hair, alopecia, red eyes (pingueculitis), angular cheilitis, uremic frost, and nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) have been described in patients with chronic kidney disease,,, particularly those on hemodialysis, we have not come across ochronosis as a manifestation despite a wide search of the available literature. Although our patient had xerosis as a manifestation of chronic kidney disease, ochronosis was unexpected thus strengthening our belief that it was of exogenous nature secondary to the use of topical HQ.
EO is a rare condition, cosmetically disfiguring and psychologically debilitating, that deserves early diagnosis and interruption of the causative drug at the earliest. The most important step is to stop the further use of the offending agent. A late or erroneous diagnosis may lead the patient to continuous drug application, at times in greater quantity on the affected areas, in an attempt to clear the “new spots,” resulting in worsening hyperpigmentation. HQ prescription to any patient should be accompanied by instructions about the possible side effects, including the information that the drug should be used for a limited period and always under medical advice. Despite several modalities of treatments available, the results are often inconsistent, unpredictable and are often far from gratifying. Avid sun protection is said to be helpful in the prevention of further progress of the condition to some extent. Wide brim hats, sun goggles, and appropriate sun protective clothing are equally important. Pharmacological treatments in form of physical sun blocks and chemical sunscreens widely help in clinical improvement of the skin lesions of EO, especially when combined with the other pharmacological agents such as topical retinoid acid, glycolic acid, and a topical corticosteroid (low-potency creams) used judiciously often leading to considerable improvement in pigmentation., A solitary case report suggested the efficacy of tetracycline in the clearance of popular sarcoid-like ochronosis. Antioxidants, high doses of Vitamin E and C, may assist dilution of the pigment. Both Vitamin C and Vitamin E act as depigmenting agents. Both act synergistically along with antioxidants to provide photoprotection.
Other modalities of treatment mentioned in literature are chemical peeling with glycolic acid or tricarboxylic acid, dermabrasion, and CO2 laser with improvement in pigmentation.,
| Conclusion|| |
Our patient had a phototype that corresponded to the most frequently affected by EO. The concentration of HQ used and the time of exposure to the drug were above the minimum values established for development of the disease. The clinical presentation and histopathological characteristics of the lesions had a classical presentation of EO, consistent with descriptions in the literature. The patient did not mention use of any other drug related with EO development and did not present signs or symptoms of endogenous ochronosis and thus excluded the possibility of alkaptonuria. EO is an underdiagnosed clinical entity, and its diagnosis is frequently missed in clinical practice. HQ containing topical depigmenting agents is the leading cause of EO, especially when used for longer duration. Despite wide variety of treatment options available, the treatment of EO is still unsatisfactory. The success of treatment is elusive even to the best therapeutic hands and is, therefore, remains a challenge to dermatologists. Hence, it is essential that the condition is suspected at an appropriate time, which might lead to the cessation of the progress of the condition.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2]